Refine
Year of publication
Document Type
- Preprint (771)
- Article (725)
- Working Paper (6)
- Conference Proceeding (3)
- Doctoral Thesis (3)
- Report (2)
Has Fulltext
- yes (1510)
Is part of the Bibliography
- no (1510) (remove)
Keywords
- Heavy Ion Experiments (21)
- Hadron-Hadron scattering (experiments) (12)
- Hadron-Hadron Scattering (11)
- LHC (9)
- Heavy-ion collision (6)
- Heavy-ion collisions (5)
- ALICE experiment (4)
- Bone density (4)
- COVID-19 (4)
- Cancer (4)
Institute
- Physik (1127)
- Frankfurt Institute for Advanced Studies (FIAS) (1059)
- Informatik (928)
- Medizin (176)
- Geowissenschaften (39)
- Institut für Ökologie, Evolution und Diversität (14)
- Biowissenschaften (13)
- Biodiversität und Klima Forschungszentrum (BiK-F) (10)
- Senckenbergische Naturforschende Gesellschaft (8)
- ELEMENTS (7)
Intensive land use is a driving force for biodiversity decline in many ecosystems. In semi-natural grasslands, land-use activities such as mowing, grazing and fertilization affect the diversity of plants and arthropods, but the combined effects of different drivers and the chain of effects are largely unknown. In this study we used structural equation modelling to analyse how the arthropod communities in managed grasslands respond to land use and whether these responses are mediated through changes in resource diversity or resource quantity (biomass). Plants were considered resources for herbivores which themselves were considered resources for predators. Plant and arthropod (herbivores and predators) communities were sampled on 141 meadows, pastures and mown pastures within three regions in Germany in 2008 and 2009. Increasing land-use intensity generally increased plant biomass and decreased plant diversity, mainly through increasing fertilization. Herbivore diversity decreased together with plant diversity but showed no response to changes in plant biomass. Hence, land-use effects on herbivore diversity were mediated through resource diversity rather than quantity. Land-use effects on predator diversity were mediated by both herbivore diversity (resource diversity) and herbivore quantity (herbivore biomass), but indirect effects through resource quantity were stronger. Our findings highlight the importance of assessing both direct and indirect effects of land-use intensity and mode on different trophic levels. In addition to the overall effects, there were subtle differences between the different regions, pointing to the importance of regional land-use specificities. Our study underlines the commonly observed strong effect of grassland land use on biodiversity. It also highlights that mechanistic approaches help us to understand how different land-use modes affect biodiversity.
Cataract surgery is one of the oldest and the most frequent outpatient clinic operations in medicine performed worldwide. The clouded human crystalline lens is replaced by an artificial intraocular lens implanted into the capsular bag. During the last six decades, cataract surgery has undergone rapid development from a traumatic, manual surgical procedure with implantation of a simple lens to a minimally invasive intervention increasingly assisted by high technology and a broad variety of implants customized for each patient’s individual requirements. This review discusses the major advances in this field and focuses on the main challenge remaining – the treatment of presbyopia. The demand for correction of presbyopia is increasing, reflecting the global growth of the ageing population. Pearls and pitfalls of currently applied methods to correct presbyopia and different approaches under investigation, both in lens implant technology and in surgical technology, are discussed.
Background: With increasing numbers of lamellar keratoplasties, eye banks are challenged to deliver precut lamellar donor tissue. In Europe, the most common technique of corneal storage is organ culture which requires a deswelling process before surgical processing. The aim of this study was to investigate the influence of different deswelling times on the cutting plane quality after microkeratome-assisted lamellar dissection.
Methods: Eight paired donor corneas (16 specimens) not suitable for transplantation were organ cultured under standard conditions at the Eye Bank of the Ludwig-Maximilians Universität, Munich, Germany. Pairs of corneal buttons were analyzed during the deswelling process in dextrane-containing medium. While one cornea was cut at an early time point during the deswelling process and put back into deswelling medium thereafter, the partner cornea was completely deswollen and dissected after 72 hours. Specimens were then further processed for scanning electron microscopy. Surface quality was assessed both digitally using Scanning Probe Imaging Processing software, and manually by three blinded graders.
Results: The corneal buttons processed at the beginning of the deswelling process had a smoother surface when compared to the partner cornea that was cut at the end of the deswelling process. In our setting, no relevant difference was detectable between manual and automated microkeratome dissection.
Conclusion: For lamellar keratoplasty, organ-cultured corneas should be processed at an early stage during the deswelling process. We interpret the smoother dissection plane during early deswelling as a result of mechanical properties in a highly hydrated cornea.
Die Fundmeldungen in Band 33 von Botanik und Naturschutz in Hessen stammen von: Dirk Bönsel, Martin de Jong, Wolfgang Ehmke, Peter Emrich, Benjamin Feller, Brunhilde Göbel, Thomas Gregor, Arthur Händler, Sylvain Hodvina, Gerwin Kasperek, Egbert Korte, Ute Lange, Stefan Meyer, Hasko Friedrich Nesemann, Uwe Raabe, Bernd Sauerwein, Marco Schmidt, Christof Nikolaus Schröder, Antje Schwab, Rainer Stoodt und Michael Uebeler.
Body dysmorphic disorder (BDD), together with its subtype muscle dysmorphia (MD), has been relocated from the Somatoform Disorders category in the DSM-IV to the newly created Obsessive-Compulsive and Related Disorders category in the DSM-5. Both categorizations have been criticized, and an empirically derived classification of BDD is lacking. A community sample of N = 736 participants completed an online survey assessing different psychopathologies. Using a structural equation modeling approach, six theoretically derived models, which differed in their allocation of BDD symptoms to various factors (i.e. general psychopathology, somatoform, obsessive-compulsive and related disorders, affective, body image, and BDD model) were tested in the full sample and in a restricted sample (n = 465) which indicated primary concerns other than shape and weight. Furthermore, measurement invariance across gender was examined. Of the six models, only the body image model showed a good fit (CFI = 0.972, RMSEA = 0.049, SRMR = 0.027, TLI = 0.959), and yielded better AIC and BIC indices than the competing models. Analyses in the restricted sample replicated these findings. Analyses of measurement invariance of the body image model showed partial metric invariance across gender. The findings suggest that a body image model provides the best fit for the classification of BDD and MD. This is in line with previous studies showing strong similarities between eating disorders and BDD, including MD. Measurement invariance across gender indicates a comparable presentation and comorbid structure of BDD in males and females, which also corresponds to the equal prevalence rates of BDD across gender.
We apply seismic full waveform inversion to SH‐ and Love‐wave data for investigating the near‐surface lithology at an archaeological site. We evaluate the resolution of the applied full waveform inversion algorithm through ground truthing in the form of an excavation and sediment core studies. Thereby, we investigate the benefits of full waveform inversion in comparison with other established methods of near‐surface prospecting in terms of resolution capabilities and interpretation security. The study is performed in a presumed harbour area of the ancient Thracian city of Ainos. The exemplary target is the source of a linear magnetic anomaly oriented perpendicular to the coast, which was found in a previous magnetic gradiometry survey, suggesting a mole. The SH‐wave full waveform inversion recovered a subsurface SH‐wave velocity model with submeter resolution showing lateral and vertical velocity variation between 40 and 150 m/s. To tame the non‐linearity of the full waveform inversion, a sequential inversion of frequency bands has to be combined with time‐windowing in order to separate the Love wave from the reflected SH wavefield. We compare the full waveform inversion results with multichannel analysis of surface waves, standard seismic reflection imaging, electrical resistivity tomography and electromagnetic induction. It turns out that the respective depth sections are correlated to a certain degree with the full waveform inversion results. However, the structural resolution of the other geophysical methods is significantly lower than for the full waveform inversion. An exception is the reflection seismic imaging, which shows the same resolution as full waveform inversion but can only be interpreted together with the full waveform inversion–based velocity model. An archaeological excavation as well as coring data allows ground truthing and a direct understanding of the geophysical structures. The results show that the target was a sort of near‐surface trench of about 3–4 m width and 0.8 m to 1.0 m depth, filled with silty sediment, which differs from the layered surrounding in colour and composition. The ground truthing revealed that only SH‐wave full waveform inversion and seismic reflection imaging could image the trench and sediment structure with satisfying lateral and depth resolution. We emphasize that the velocity distribution from SH‐wave full waveform inversion agrees closely with the excavated subsurface structures, and that the discovered changes in seismic velocity correlate with changes in the sand content in the respective sediment facies sequences. The study demonstrated that SH‐wave full waveform inversion is capable to image structural and lithological changes in the near subsurface at scales as low as 0.5 m, thus providing the high resolution needed for archaeological and geoarchaeological prospection.
Synaptic dysfunction and synapse loss are key features of Alzheimer's pathogenesis. Previously, we showed an essential function of APP and APLP2 for synaptic plasticity, learning and memory. Here, we used organotypic hippocampal cultures to investigate the specific role(s) of APP family members and their fragments for dendritic complexity and spine formation of principal neurons within the hippocampus. Whereas CA1 neurons from APLP1-KO or APLP2-KO mice showed normal neuronal morphology and spine density, APP-KO mice revealed a highly reduced dendritic complexity in mid-apical dendrites. Despite unaltered morphology of APLP2-KO neurons, combined APP/APLP2-DKO mutants showed an additional branching defect in proximal apical dendrites, indicating redundancy and a combined function of APP and APLP2 for dendritic architecture. Remarkably, APP-KO neurons showed a pronounced decrease in spine density and reductions in the number of mushroom spines. No further decrease in spine density, however, was detectable in APP/APLP2-DKO mice. Mechanistically, using APPsalpha-KI mice lacking transmembrane APP and expressing solely the secreted APPsalpha fragment we demonstrate that APPsalpha expression alone is sufficient to prevent the defects in spine density observed in APP-KO mice. Collectively, these studies reveal a combined role of APP and APLP2 for dendritic architecture and a unique function of secreted APPs for spine density.
Throughout mankind’s history, the need to secure and protect the home settlement was an essential one. This holds especially true for the city of Ainos (modern Enez) in Turkish Thrace. Due to its continuous settlement history since the 7th/6th century BC, several different types of city walls were built—sometimes even on top of each other—several of which have been preserved over time. To decipher the construction style, the course and the age of a buried city wall segment in the southern part of the former city, a geoscientific multi-proxy approach including magnetic gradiometer (MG) and electrical resistivity tomography (ERT) measurements in combination with granulometrical, sedimentological and microfaunistical investigations on sediment cores was applied. We were able to (1) present reasonable arguments for its Hellenistic age; (2) reveal the course of this wall segment and extrapolate it further north into a less studied area; and (3) demonstrate that in this near-coastal area, the former swampy terrain had been consolidated for constructing the wall. Our multi-proxy approach serves as a valuable example for investigating buried structures in archaeological contexts, avoiding a less-economical, time-consuming, or even forbidden excavation.
Gene families evolve by the processes of speciation (creating orthologs), gene duplication (paralogs), and horizontal gene transfer (xenologs), in addition to sequence divergence and gene loss. Orthologs in particular play an essential role in comparative genomics and phylogenomic analyses. With the continued sequencing of organisms across the tree of life, the data are available to reconstruct the unique evolutionary histories of tens of thousands of gene families. Accurate reconstruction of these histories, however, is a challenging computational problem, and the focus of the Quest for Orthologs Consortium. We review the recent advances and outstanding challenges in this field, as revealed at a symposium and meeting held at the University of Southern California in 2017. Key advances have been made both at the level of orthology algorithm development and with respect to coordination across the community of algorithm developers and orthology end-users. Applications spanned a broad range, including gene function prediction, phylostratigraphy, genome evolution, and phylogenomics. The meetings highlighted the increasing use of meta-analyses integrating results from multiple different algorithms, and discussed ongoing challenges in orthology inference as well as the next steps toward improvement and integration of orthology resources.
Fragestellung Intoleranzreaktionen auf nicht-steroidale Antiphlogistika sind häufig und basieren auf der Hemmung des Enzyms Cyclooxygenase-1 (COX-1), wohingegen deren therapeutische Effekte auf einer COX-2 Hemmung beruhen. In dieser Studie wurde die Verträglichkeit des selektiven COX-2 Inhibitors Celecoxib bei Patienten mit Intoleranzreaktionen auf nicht-steroidale Antiphlogistika untersucht. Methodik Bei 77 Patienten (24 Männer, 53 Frauen) mit Intoleranzreaktionen auf nicht-steroidale Antiphlogistika wurden standardisierte Hauttestungen (Prick, Scratch, Epikutantestung) sowie anschließend orale fraktionierte Placebo-kontrollierte einfach blinde Expositionstestungen unter Einschluß von Celecoxib (maximale Einzeldosis 200mg, kumukative Tagesdosis 350mg) durchgeführt. Ergebnisse 21 Patienten wiesen anamnestisch lediglich Hautsymptome (Urtikaria) auf, 25 Patienten nur eine Atemwegssymptomatik (Asthma), bei 18 Patienten traten Haut- und Atemwegssymptome auf, und bei 13 Patienten war es zu einem anaphylaktischen Schock gekommen. Azetylsalizylsäure war in 38 Fällen ein Auslöser der Beschwerden. In 46 Fällen verursachten mehrere nicht-steroidale Antiphlogistika chemisch unterschiedlicher Gruppen die Symptomatik. Die orale Expositionstestung mit Celecoxib verlief bei allen 77 Patienten unauffällig. Schlußfolgerung Vor dem Hintergrund der hohen Inzidenz von Intoleranzreaktionen gegen nicht-steroidale Antiphlogistika stellt der Einsatz selektiver COX-2 Inhibitoren eine therapeutische Alternative sowie eine geeignete Maßnahme zur Prävention entsprechender Reaktionen dar.
Background: Computed tomography (CT) low-dose (LD) imaging is used to lower radiation exposure, especially in vascular imaging; in current literature, this is mostly on latest generation high-end CT systems.
Purpose: To evaluate the effects of reduced tube current on objective and subjective image quality of a 15-year-old 16-slice CT system for pulmonary angiography (CTPA).
Material and Methods: CTPA scans from 60 prospectively randomized patients (28 men, 32 women) were examined in this study on a 15-year-old 16-slice CT scanner system. Standard CT (SD) settings were 100 kV and 150 mAs, LD settings were 100 kV and 50 mAs. Attenuation of the pulmonary trunk, various anatomic landmarks, and image noise were quantitatively measured; contrast-to-noise ratios (CNR) and signal-to-noise ratios (SNR) were calculated. Three independent blinded radiologists subjectively rated each image series using a 5-point grading scale.
Results: CT dose index (CTDI) in the LD series was 66.46% lower compared to the SD settings (2.49 ± 0.55 mGy versus 7.42 ± 1.17 mGy). Attenuation of the pulmonary trunk showed similar results for both series (SD 409.55 ± 91.04 HU; LD 380.43 HU ± 93.11 HU; P = 0.768). Subjective image analysis showed no significant differences between SD and LD settings regarding the suitability for detection of central and peripheral PE (central SD/LD, 4.88; intra-class correlation coefficients [ICC], 0.894/4.83; ICC, 0.745; peripheral SD/LD, 4.70; ICC, 0.943/4.57; ICC, 0.919; all P > 0.4).
Conclusion: The LD protocol, on a 15-year-old CT scanner system without current high-end hardware or post-processing tools, led to a dose reduction of approximately 67% with similar subjective image quality and delineation of central and peripheral pulmonary arteries.
Simple Summary: Early and accurate diagnosis of breast cancer that has spread to other organs and tissues is crucial, as therapeutic decisions and outcome expectations might change. Computed tomography (CT) is often used to detect breast cancer’s spread, but this method has its weaknesses. The computer-assisted technique “radiomics” extracts grey-level patterns, so-called radiomic features, from medical images, which may reflect underlying biological processes. Our retrospective study therefore evaluated whether breast cancer spread can be predicted by radiomic features derived from iodine maps, an application on a new generation of CT scanners visualizing tissue blood flow. Based on 77 patients with newly diagnosed breast cancer, we found that this approach might indeed predict cancer spread to other organs/tissues. In the future, radiomics may serve as an additional tool for cancer detection and risk assessment.
Abstract: Dual-energy CT (DECT) iodine maps enable quantification of iodine concentrations as a marker for tissue vascularization. We investigated whether iodine map radiomic features derived from staging DECT enable prediction of breast cancer metastatic status, and whether textural differ- ences exist between primary breast cancers and metastases. Seventy-seven treatment-naïve patients with biopsy-proven breast cancers were included retrospectively (41 non-metastatic, 36 metastatic). Radiomic features including first-, second-, and higher-order metrics as well as shape descriptors were extracted from volumes of interest on iodine maps. Following principal component analysis, a multilayer perceptron artificial neural network (MLP-NN) was used for classification (70% of cases for training, 30% validation). Histopathology served as reference standard. MLP-NN predicted metastatic status with AUCs of up to 0.94, and accuracies of up to 92.6 in the training and 82.6 in the validation datasets. The separation of primary tumor and metastatic tissue yielded AUCs of up to 0.87, with accuracies of up to 82.8 in the training, and 85.7 in the validation dataset. DECT iodine map-based radiomic signatures may therefore predict metastatic status in breast cancer patients. In addition, microstructural differences between primary and metastatic breast cancer tissue may be reflected by differences in DECT radiomic features.
Background: Bone age (BA) assessment performed by artificial intelligence (AI) is of growing interest due to improved accuracy, precision and time efficiency in daily routine. The aim of this study was to investigate the accuracy and efficiency of a novel AI software version for automated BA assessment in comparison to the Greulich-Pyle method.
Methods: Radiographs of 514 patients were analysed in this retrospective study. Total BA was assessed independently by three blinded radiologists applying the GP method and by the AI software. Overall and gender-specific BA assessment results, as well as reading times of both approaches, were compared, while the reference BA was defined by two blinded experienced paediatric radiologists in consensus by application of the Greulich-Pyle method.
Results: Mean absolute deviation (MAD) and root mean square deviation (RSMD) were significantly lower between AI-derived BA and reference BA (MAD 0.34 years, RSMD 0.38 years) than between reader-calculated BA and reference BA (MAD 0.79 years, RSMD 0.89 years; p < 0.001). The correlation between AI-derived BA and reference BA (r = 0.99) was significantly higher than between reader-calculated BA and reference BA (r = 0.90; p < 0.001). No statistical difference was found in reader agreement and correlation analyses regarding gender (p = 0.241). Mean reading times were reduced by 87% using the AI system.
Conclusions: A novel AI software enabled highly accurate automated BA assessment. It may improve efficiency in clinical routine by reducing reading times without compromising the accuracy compared with the Greulich-Pyle method.
Background: To evaluate survival data and local tumor control after transarterial chemoembolization in two groups with different embolization protocols for the treatment of HCC patients.
Methods: Ninty-nine patients (mean age: 63.6 years), 78 male (78.8%) with HCC were repeatedly treated with chemoembolization in 4-week-intervals. Eighty-eight patients had BCLC-Stage-B and in 11 patients, chemoembolization was performed for bridging (BCLC-Stage-A). In total, 667 chemoembolization treatments were performed (mean 6.7 treatments/patient). The administered chemotherapeutic agent included mitomycin. For embolization, lipiodol only (n = 51;51.5%; mean age 63.8 years; 38 male), or lipiodol plus degradable starch microspheres (DSM) (n = 48; 48.5%; mean age 63.4 years; 40 male) were used. The local tumor response was assessed by MRI using Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). Patient survival times were evaluated using Kaplan-Meier curves and log-rank tests.
Results: The local tumor control in the lipiodol-group was: PR (partial response) in 11 (21.6%), SD (stable disease) in 32 (62.7%) and PD (progressive disease) in 8 cases (15.7%). In the lipiodol-DSM-group, PR was seen in 14 (29.2%), SD in 22 (45.8%), and PD in 12 (25.0%) individuals (p = 0.211). The median survival of patients after chemoembolization with lipiodol was 25 months and in the lipiodol-DSM-group 28 months (p = 0.845).
Conclusion: Our data suggest a slight benefit of the use of lipiodol and DSM in comparison of using lipiodol only for chemoembolization of HCC in terms of local tumor control and survival data, this trend did not reach the level of significance.
BACKGROUND: Evaluation of latest generation automated attenuation-based tube potential selection (ATPS) impact on image quality and radiation dose in contrast-enhanced chest-abdomen-pelvis computed tomography examinations for gynaecologic cancer staging.
METHODS: This IRB approved single-centre, observer-blinded retrospective study with a waiver for informed consent included a total of 100 patients with contrast-enhanced chest-abdomen-pelvis CT for gynaecologic cancer staging. All patients were examined with activated ATPS for adaption of tube voltage to body habitus. 50 patients were scanned on a third-generation dual-source CT (DSCT), and another 50 patients on a second-generation DSCT. Predefined image quality setting remained stable between both groups at 120 kV and a current of 210 Reference mAs. Subjective image quality assessment was performed by two blinded readers independently. Attenuation and image noise were measured in several anatomic structures. Signal-to-noise ratio (SNR) was calculated. For the evaluation of radiation exposure, CT dose index (CTDIvol) values were compared.
RESULTS: Diagnostic image quality was obtained in all patients. The median CTDIvol (6.1 mGy, range 3.9-22 mGy) was 40 % lower when using the algorithm compared with the previous ATCM protocol (median 10.2 mGy · cm, range 5.8-22.8 mGy). A reduction in potential to 90 kV occurred in 19 cases, a reduction to 100 kV in 23 patients and a reduction to 110 kV in 3 patients of our experimental cohort. These patients received significantly lower radiation exposure compared to the former used protocol.
CONCLUSION: Latest generation automated ATPS on third-generation DSCT provides good diagnostic image quality in chest-abdomen-pelvis CT while average radiation dose is reduced by 40 % compared to former ATPS protocol on second-generation DSCT.
We sought to determine the effects of the use of a Bioengineered Combo Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Coronary Stent (Combo® DTS) in patients with chronic total occlusion (CTO) by evaluating clinical outcomes and by performing an optical coherence tomography (OCT) analysis. We retrospectively analyzed data from 39 patients who had successfully undergone OCT-guided revascularization of a CTO being treated with a Combo® DTS. Clinical assessment, angiography (with quantitative coronary angiography analysis) and OCT examination were performed at baseline and at follow-up. The median follow-up period was 189 days, ranging from 157 to 615 days. At follow-up, revascularization was required due to angiographic restenosis in 40% (14 of 35) of patients. OCT analysis detected neointima proliferation in 23 (76.6%) patients. Neointima formation was often associated with microvessels in 18 patients (60%). Neoatheroslcerosis was observed in 2 (6.6%) patients. Malapposition was found in 4 patients (13.3%), and stent fractures were found in 11 patients (36.6%). Rate of strut coverage was 96.3% at follow-up. In conclusion, the implantation of a Combo® DTS after successful CTO recanalization was associated with a restenosis rate of 40% despite good stent implantation at baseline, proven by OCT. Neointima formation was found as a main contributor to restenosis. Nevertheless, we observed a low rate of major cardiovascular events in our follow-up.
Survival following relapse in children with Acute Myeloid leukemia: a report from AML-BFM and COG
(2021)
Simple Summary: Acute myeloid leukemia in children remains a difficult disease to cure despite intensive therapies that push the limits of tolerability. Though the intent of initial therapy should be the prevention of relapse, about 30% of all patients experience a relapse. Hence, relapse therapy remains critically important for survival. This retrospective analysis of two large international study groups (COG and BFM) was undertaken to describe the current survival, response rates and clinical features that predict outcomes. We demonstrate that children with relapsed AML may be cured with cytotoxic therapy followed by HSCT. High-risk features at initial diagnosis and early relapse remain prognostic for post-relapse survival. Current response criteria are not aligned with the standards of care for children, nor are the count recovery thresholds meaningful for prognosis in children with relapsed AML. Our data provide a new baseline for future treatment planning and will allow an updated stratification in upcoming studies.
Abstract: Post-relapse therapy remains critical for survival in children with acute myeloid leukemia (AML). We evaluated survival, response and prognostic variables following relapse in independent cooperative group studies conducted by COG and the population-based AML-BFM study group. BFM included 197 patients who relapsed after closure of the last I-BFM relapse trial until 2017, while COG included 852 patients who relapsed on the last Phase 3 trials (AAML0531, AAML1031). Overall survival at 5 years (OS) was 42 ± 4% (BFM) and 35 ± 2% (COG). Initial high-risk features (BFM 32 ± 6%, COG 26 ± 4%) and short time to relapse (BFM 29 ± 4%, COG 25 ± 2%) predicted diminished survival. In the BFM dataset, there was no difference in OS for patients who had a complete remission with full hematopoietic recovery (CR) following post-relapse re-induction compared to those with partial neutrophil and platelet recovery (CRp and CRi) only (52 ± 7% vs. 63 ± 10%, p = 0.39). Among 90 patients alive at last follow-up, 87 had received a post-relapse hematopoietic stem cell transplant (HSCT). OS for patients with post-relapse HSCT was 54 ± 4%. In conclusion, initial high-risk features and early relapse remain prognostic. Response assessment with full hematopoietic recovery following initial relapse therapy does not predict survival. These data indicate the need for post-relapse risk stratification in future studies of relapse therapies.
Simple Summary: Children with acute myeloid leukemia (AML) experience high relapse rates of about 30%; still, survival rates following the first relapse are encouraging. Hence, it is critically important to examine the consequences of a second relapse; however, little is known about this subgroup of patients. This retrospective population-based analysis intends to describe response, survival and prognostic factors relevant for the survival of children with second relapse of AML. Treatment approaches include many different therapeutic regimens, including palliation and intensive treatment with curative intent (63% of the patients). Survival is poor; however, patients who respond to reinduction attempts can be rescued with subsequent hematopoietic stem cell transplantation. We deciphered risk factors, such as short time interval from first to second relapse below one year as being associated with a poor outcome. This analysis will help to improve future international treatment planning and patient care of children with advanced AML.
Abstract: Successful management of relapse is critical to improve outcomes of children with acute myeloid leukemia (AML). We evaluated response, survival and prognostic factors after a second relapse of AML. Among 1222 pediatric patients of the population-based AML-Berlin–Frankfurt–Munster (BFM) study group (2004 until 2017), 73 patients met the quality parameters for inclusion in this study. Central review of source documentation warranted the accuracy of reported data. Treatment approaches included palliation in 17 patients (23%), intensive therapy with curative intent (n = 46, 63%) and other regimens (n = 10). Twenty-five patients (35%) received hematopoietic stem cell transplantation (HSCT), 21 of whom (88%) had a prior HSCT. Survival was poor, with a five-year probability of overall survival (pOS) of 15 ± 4% and 31 ± 9% following HSCT (n = 25). Early second relapse (within one year after first relapse) was associated with dismal outcome (pOS 2 ± 2%, n = 44 vs. 33 ± 9%, n = 29; p < 0.0001). A third complete remission (CR) is required for survival: 31% (n = 14) of patients with intensive treatment achieved a third CR with a pOS of 36 ± 13%, while 28 patients (62%) were non-responders (pOS 7 ± 5%). In conclusion, survival is poor but possible, particularly after a late second relapse and an intensive chemotherapy followed by HSCT. This analysis provides a baseline for future treatment planning.
Background: Evaluation of automated attenuation-based tube potential selection and its impact on image quality and radiation dose in CT (computed tomography) examinations for cancer staging.
Methods: A total of 110 (59 men, 51 women) patients underwent chest-abdomen-pelvis CT examinations; 55 using a fixed tube potential of 120 kV/current of 210 Reference mAs (using CareDose4D), and 55 using automated attenuation-based tube potential selection (CAREkV) also using a current of 210 Reference mAs. This evaluation was performed as a single-centre, observer-blinded retrospective analysis. Image quality was assessed by two readers in consensus. Attenuation, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured or calculated for objective image evaluation. For the evaluation of radiation exposure, dose-length-product (DLP) values were compared and Size-specific dose estimates (SSDE) values were calculated.
Results: Diagnostic image quality was obtained from all patients. The median DLP (703.5 mGy · cm, range 390–2203 mGy · cm) was 7.9% lower when using the algorithm compared with the standard 120 kV protocol (median 756 mGy · cm, range 345–2267 mGy · cm). A reduction in potential to 100 kV occurred in 32 cases; therefore, these patients received significantly lower radiation exposure compared with the 120 kV protocol.
Conclusion: Automated attenuation-based tube potential selection produces good diagnostic image quality in chest-abdomen-pelvis CT and reduces the patient’s overall radiation dose by 7.9% compared to the standard 120 kV protocol.
Objectives: The aim of our study was to find out how much energy is applicable in second-generation dual source high-pitch computed tomography (CT) in imaging of the abdomen.
Materials and methods: We examined an upper abdominal phantom using a Somatom Definition Flash CT-Scanner (Siemens, Forchheim, Germany). The study protocol consisted of a scan-series at 100 kV and 120 kV. In each scan series we started with a pitch of 3.2 and reduced it in steps of 0.2, until a pitch of 1.6 was reached. The current was adjusted to the maximum the scanner could achieve. Energy values, image noise, image quality, and radiation exposure were evaluated.
Results: For a pitch of 3.2 the maximum applicable current was 142 mAs at 120 kV and in 100 kV the maximum applicable current was 114 mAs. For conventional abdominal imaging, current levels of 200 to 260 mAs are generally used. To achieve similar current levels, we had to decrease the pitch to 1.8 at 100 kV - at this pitch we could perform our imaging at 204 mAs. At a pitch of 2.2 in 120 kV we could apply a current of 206 mAs.
Conclusion: We conclude our study by stating that if there is a need for a higher current, we have to reduce the pitch. In a high-pitch dual source CT, we always have to remember where our main focus is, so we can adjust the pitch to the energy we need in the area of the body that has to be imaged, to find answers to the clinical question being raised.
Purpose: To determine the value of the 2D multiple-echo data image combination (MEDIC) sequence relative to the short-tau inversion recovery (STIR) sequence regarding the depiction of chondral lesions in the patellofemoral joint.
Materials and methods: During a period of 6 month patients with acute pain at the anterior aspect of the knee, joint effusion and suspected chondral lesion defect in the patellofemoral joint underwent MRI including axial MEDIC and STIR imaging. Patients with chondral lesions in the patellofemoral joint on at least one sequence were included. The MEDIC and STIR sequence were quantitatively compared regarding the patella cartilage-to-effusion contrast-to-noise ratio (CNR) and qualitatively regarding the depiction of chondral lesions independently scored by two radiologists on a 3-point scale (1 = not depicted; 2 = blurred depicted; 3 = clearly depicted) using the Wilcoxon-Mann-Whitney-Test. For the analysis of inter-observer agreement the Cohen's Weighted Kappa test was used.
Results: 30 of 58 patients (male: female, 21:9; age: 44 ± 12 yrs) revealed cartilage lesions (fissures, n = 5 including fibrillation; gaps, n = 15; delamination, n = 7; osteoarthritis, n = 3) and were included in this study. The STIR-sequence was significantly (p < 0.001) superior to the MEDIC-sequence regarding both, the patella cartilage-to-effusion CNR (mean CNR: 232 ± 61 vs. 40 ± 16) as well as the depiction of chondral lesion (mean score: 2.83 ± 0.4 vs. 1.75 ± 0.7) with substantial inter-observer agreement in the rating of both sequences (κ = 0.76–0.89).
Conclusion: For the depiction of chondral lesions in the patellofemoral joint, the axial STIR-sequence should be chosen in preference to the axial MEDIC-sequence.
Die Fundmeldungen in Band 34 von Botanik und Naturschutz in Hessen stammen von: Dirk Bönsel, Martin De Jong, Klaus Dühr, Uta Engel, Benjamin Feller, Christian Feuring, Thomas Gregor, Arthur Händler, Karsten Horn, Diemut Klärner, Julia Kruse, Eric Martiné, Hasko Friedrich Nesemann, Kai Uwe Nierbauer, Uwe Raabe, Susanne Raehse, Felix Reischmann, Bernd Sauerwein, Petra Schmidt, Fabian Schrauth, Christof Nikolaus Schröder, Helmut Siebert, Michael Thieme, Otto Wacker und Rüdiger Wittig.
Background: Patients with chronic kidney disease (CKD) are at increased risk for inappropriate or potentially harmful prescribing. The aim of this study was to examine whether a multifaceted intervention including the use of a software programme for the estimation of creatinine clearance and recommendation of individual dosage requirements may improve correct dosage adjustment of relevant medications for patients with CKD in primary care.
Methods: A cluster-randomized controlled trial was conducted between January and December 2007 in small primary care practices in Germany. Practices were randomly allocated to intervention or control groups. In each practice, we included patients with known CKD and elderly patients (>=70 years) suffering from hypertension. The practices in the intervention group received interactive training and were provided a software programme to assist with individual dose adjustment. The control group performed usual care. Data were collected at baseline and at 6 months. The outcome measures, analyzed across individual patients, included prescriptions exceeding recommended maximum daily doses, with the primary outcome being prescriptions exceeding recommended standard daily doses by 30% or more.
Results: Data from 44 general practitioners and 404 patients are included. The intervention was effective in reducing prescriptions exceeding the maximum daily dose per patients, with a trend in reducing prescriptions exceeding the standard daily dose by more than 30%.
Conclusions: A multifaceted intervention including the use of a software program effectively reduced inappropriately high doses of renally excreted medications in patients with CKD in the setting of small primary care practices.
Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury
(2018)
Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury (AKI). Non-coding RNAs are crucially involved in its pathophysiology. We identified hypoxia-induced long non-coding RNA Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) to be upregulated in renal I/R injury. We here elucidated the functional role of Malat1 in vitro and its potential contribution to kidney injury in vivo. Malat1 was upregulated in kidney biopsies and plasma of patients with AKI, in murine hypoxic kidney tissue as well as in cultured and ex vivo sorted hypoxic endothelial cells and tubular epithelial cells. Malat1 was transcriptionally activated by hypoxia-inducible factor 1-α. In vitro, Malat1 inhibition reduced proliferation and the number of endothelial cells in the S-phase of the cell cycle. In vivo, Malat1 knockout and wildtype mice showed similar degrees of outer medullary tubular epithelial injury, proliferation, capillary rarefaction, inflammation and fibrosis, survival and kidney function. Small-RNA sequencing and whole genome expression analysis revealed only minor changes between ischemic Malat1 knockout and wildtype mice. Contrary to previous studies, which suggested a prominent role of Malat1 in the induction of disease, we did not confirm an in vivo role of Malat1 concerning renal I/R-injury.
The Behavioral Inhibition System (BIS) as defined within the Reinforcement Sensitivity Theory (RST) modulates reactions to stimuli indicating aversive events. Gray’s trait Anxiety determines the extent to which stimuli activate the BIS. While studies have identified the amygdala-septo-hippocampal circuit as the key-neural substrate of this system in recent years and measures of resting-state dynamics such as randomness and local synchronization of spontaneous BOLD fluctuations have recently been linked to personality traits, the relation between resting-state dynamics and the BIS remains unexplored. In the present study, we thus examined the local synchronization of spontaneous fMRI BOLD fluctuations as measured by Regional Homogeneity (ReHo) in the hippocampus and the amygdala in twenty-seven healthy subjects. Correlation analyses showed that Gray’s trait Anxiety was significantly associated with mean ReHo in both the amygdala and the hippocampus. Specifically, Gray’s trait Anxiety explained 23% and 17% of resting-state ReHo variance in the left amygdala and the left hippocampus, respectively. In summary, we found individual differences in Gray’s trait Anxiety to be associated with ReHo in areas previously associated with BIS functioning. Specifically, higher ReHo in resting-state neural dynamics corresponded to lower sensitivity to punishment scores both in the amygdala and the hippocampus. These findings corroborate and extend recent findings relating resting-state dynamics and personality while providing first evidence linking properties of resting-state fluctuations to Gray’s BIS.
Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
The formation of oligomers of the amyloid-β peptide plays a key role in the onset of Alzheimer's disease. We describe herein the investigation of disease-relevant small amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing functionally relevant structural attributes. In particular, we can show that amyloid-β oligomers develop in two distinct arrangements leading to either neurotoxic oligomers and fibrils or non-toxic amorphous aggregates. Comprehending the key-attributes responsible for those pathways on a molecular level is a pre-requisite to specifically target the peptide's tertiary structure with the aim to promote the emergence of non-toxic aggregates. Here, we show for two fibril inhibiting ligands, an ionic molecular tweezer and a hydrophobic peptide that despite their different interaction mechanisms, the suppression of the fibril pathway can be deduced from the disappearance of the corresponding structure of the first amyloid-β oligomers.
Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV diseas.
Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interferes with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses and synergistically increase the effects of ganciclovir, eltrombopag is also a drug repurposing candidate for the treatment of therapy-refractory HCMV disease.
Background: H5N1 influenza vaccines, including live intranasal, appear to be relatively less immunogenic compared to seasonal analogs. The main influenza virus surface glycoprotein hemagglutinin (HA) of highly pathogenic avian influenza viruses (HPAIV) was shown to be more susceptible to acidic pH treatment than that of human or low pathogenic avian influenza viruses. The acidification machinery of the human nasal passageway in response to different irritation factors starts to release protons acidifying the mucosal surface (down to pH of 5.2). We hypothesized that the sensitivity of H5 HA to the acidic environment might be the reason for the low infectivity and immunogenicity of intranasal H5N1 vaccines for mammals. Methodology/Principal Findings: We demonstrate that original human influenza viruses infect primary human nasal epithelial cells at acidic pH (down to 5.4), whereas H5N1 HPAIVs lose infectivity at pH <= 5.6. The HA of A/Vietnam/1203/04 was modified by introducing the single substitution HA2 58K -> I, decreasing the pH of the HA conformational change. The H5N1 reassortants containing the indicated mutation displayed an increased resistance to acidic pH and high temperature treatment compared to those lacking modification. The mutation ensured a higher viral uptake as shown by immunohistochemistry in the respiratory tract of mice and 25 times lower mouse infectious dose50. Moreover, the reassortants keeping 58K -> I mutation designed as a live attenuated vaccine candidate lacking an NS1 gene induced superior systemic and local antibody response after the intranasal immunization of mice. Conclusion/Significance: Our finding suggests that an efficient intranasal vaccination with a live attenuated H5N1 virus may require a certain level of pH and temperature stability of HA in order to achieve an optimal virus uptake by the nasal epithelial cells and induce a sufficient immune response. The pH of the activation of the H5 HA protein may play a substantial role in the infectivity of HPAIVs for mammals.
Background: Various kinase inhibitors are known to be ATP-binding cassette (ABC) transporter substrates and resistance acquisition to kinase inhibitors has been associated to increased ABC transporter expression. Here, we investigated the role of the ABC transporters ABCB1, ABCC1, and ABCG2 during melanoma cell resistance acquisition to the V600-mutant BRAF inhibitors PLX4032 (vemurafenib) and PLX4720. PLX4032 had previously been shown to interfere with ABCB1 and ABCG2. PLX4720 had been demonstrated to interact with ABCB1 but to a lower extent than PLX4032.
Findings: PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion. In a panel of 16 V600E BRAF-mutated melanoma cell lines consisting of four parental cell lines and their sub-lines with acquired resistance to PLX4032, PLX4720, vincristine (cytotoxic ABCB1 and ABCC1 substrate), or mitoxantrone (cytotoxic ABCG2 substrate), we detected enhanced ABC transporter expression in 4/4 cytotoxic ABC transporter substrate-resistant, 3/4 PLX4720-resistant, and 1/4 PLX4032-resistant melanoma cell lines.
Conclusion: PLX4032 has the potential to induce ABC transporter expression but this potential is lower than that of PLX4720 or cytotoxic ABC transporter substrates. Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies.
Oncolytic effects of a novel Influenza A virus expressing Interleukin-15 from the NS reading frame
(2012)
Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.
Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa.
The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient’s risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.
Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.
The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), is effective against T-cell acute lymphoblastic leukaemia (T-ALL) but not against B-cell ALL (B-ALL). The underlying mechanisms have remained elusive. Here, data from pharmacogenomics studies and a panel of ALL cell lines reveal an inverse correlation between nelarabine sensitivity and the expression of SAMHD1, which can hydrolyse and inactivate triphosphorylated nucleoside analogues. Lower SAMHD1 abundance is detected in T-ALL than in B-ALL in cell lines and patient-derived leukaemic blasts. Mechanistically, T-ALL cells display increased SAMHD1 promoter methylation without increased global DNA methylation. SAMHD1 depletion sensitises B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induces AraG resistance. SAMHD1 has a larger impact on nelarabine/AraG than on cytarabine in ALL cells. Opposite effects are observed in acute myeloid leukaemia cells, indicating entity-specific differences. In conclusion, SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine.
Background: Acute bleeding requires fast and targeted therapy. Therefore, knowledge of the patient's potential to form a clot is crucial. Point-of-care testing (POCT) provides fast and reliable information on coagulation. Structural circumstances, such as person-bound sample transport, can prolong the reporting of the results. The aim of the present study was to investigate the diagnostic quality and accuracy between POCT INR diagnostics and standard laboratory analysis (SLA) as well as the time advantage between a pneumatic tube and a personal-based transport system. Methods: Two groups of haemorrhagic patients (EG: emergency department; OG: delivery room; each n = 12) were examined in the context of bleeding emergencies using POCT and SLA. Samples were transported via a pneumatic tube system or by a personal transport service. Results: INR results between POCT and SLA showed a high and significant correlation (EG: p < 0.001; OG: p < 0.001). POCT results were reported significantly more quickly (EG: 1.1 vs. 39.6 min; OG: 2.0 vs. 75.0 min; p < 0.001) and required less time for analysis (EG: 0.3 vs. 24.0 min; OG: 0.5 vs. 45.0 min; p < 0.001) compared to SLA. The time for transportation with the pneumatic tube was significantly shorter (8.0 vs. 18.5 min; p < 0.001) than with the personal-based transport system. Conclusion: The results of the present study suggest that POCT may be a suitable method for the emergency diagnosis and may be used as prognostic diagnostic elements in haemotherapy algorithms to initiate targeted haemotherapy at an early point in time.
We combined biostratigraphical analyses, archaeological surveys, and Glacial Isostatic Adjustment (GIA) models to provide new insights into the relative sea-level evolution in the northeastern Aegean Sea (eastern Mediterranean). In this area, characterized by a very complex tectonic pattern, we produced a new typology of sea-level index point, based on the foraminiferal associations found in transgressive marine facies. Our results agree with the sea-level history previously produced in this region, therefore confirming the validity of this new type of index point. The expanded dataset presented in this paper further demonstrates a continuous Holocene RSL rise in this portion of the Aegean Sea. Comparing the new RSL record with the available geophysical predictions of sea-level evolution indicates that the crustal subsidence of the Samothraki Plateau and the North Aegean Trough played a major role in controlling millennial-scale sea-level evolution in the area. This major subsidence rate needs to be taken into account in the preparation of local future scenarios of sea-level rise in the coming decades.
Objectives: To compare radiation dose and image quality of single-energy (SECT) and dual-energy (DECT) head and neck CT examinations performed with second- and third-generation dual-source CT (DSCT) in matched patient cohorts. Methods: 200 patients (mean age 55.1 ± 16.9 years) who underwent venous phase head and neck CT with a vendor-preset protocol were retrospectively divided into four equal groups (n = 50) matched by gender and BMI: second (Group A, SECT, 100-kV; Group B, DECT, 80/Sn140-kV), and third-generation DSCT (Group C, SECT, 100-kV; Group D, DECT, 90/Sn150-kV). Assess- ment of radiation dose was performed for an average scan length of 27 cm. Contrast-to-noise ratio measure- ments and dose-independent figure-of-merit calcu- lations of the submandibular gland, thyroid, internal jugular vein, and common carotid artery were analyzed quantitatively. Qualitative image parameters were evalu- ated regarding overall image quality, artifacts and reader confidence using 5-point Likert scales. Results: Effective radiation dose (ED) was not signifi- cantly different between SECT and DECT acquisition for each scanner generation (p = 0.10). Significantly lower effective radiation dose (p < 0.01) values were observed for third-generation DSCT groups C (1.1 ± 0.2 mSv) and D (1.0 ± 0.3 mSv) compared to second-generation DSCT groups A (1.8 ± 0.1 mSv) and B (1.6 ± 0.2 mSv). Figure-of- merit/contrast-to-noise ratio analysis revealed superior results for third-generation DECT Group D compared to all other groups. Qualitative image parameters showed non-significant differences between all groups (p > 0.06). Conclusion: Contrast-enhanced head and neck DECT can be performed with second- and third-generation DSCT systems without radiation penalty or impaired image quality compared with SECT, while third-generation DSCT is the most dose efficient acquisition method. Advances in knowledge: Differences in radiation dose between SECT and DECT of the dose-vulnerable head and neck region using DSCT systems have not been evaluated so far. Therefore, this study directly compares radiation dose and image quality of standard SECT and DECT protocols of second- and third-generation DSCT platforms.
The objective of this pilot clinical study was to assess the safety, technical feasibility, pharmacokinetic (PK) profile and tumour response of DC Bead™ with irinotecan (DEBIRI™) delivered by intra-arterial embolisation for the treatment of metastatic colorectal cancer. Eleven patients with unresectable liver metastases from CRC, tumour burden <30% of liver volume, adequate haematological, liver and renal function, performance status of <2 were included in this study. Patients received up to 4 sessions of TACE with DEBIRI at 3-week intervals. Feasibility of the procedure, safety and tumour response were assessed after each cycle. PK was measured after the first cycle. Patients were followed up to 24 weeks. Only mild to moderate adverse events were observed. DEBIRI is a technically feasibile procedure; no technical complications were observed. Average Cmax for irinotecan and SN-38 was 194 ng/ml and 16.7 ng/ml, respectively, with average t½ of 4.6 h and 12.4 h following administration of DEBIRI. Best overall response during the study showed disease control in 9 patients (2 patients with partial response and 7 with stable disease, overall response rate of 18%). Our study shows that transarterial chemoembolisation with irinotecan-loaded DC beads (DEBIRI) is safe, technically feasible and effective with a good PK profile.
Patients after orthopic liver transplantation (OLT) are at risk of developing graft dysfunction. Sphingolipids (SL’s) have been identified to play a pivotal role in the regulation of hepatocellular apoptosis, inflammation and immunity. We aimed to investigate the serum SL profile in a prospective real-world cohort of post-OLT patients. From October 2015 until July 2016, 149 well-characterized post-OLT patients were analyzed. SL’s were assessed in serum probes via Liquid Chromatography/Tandem Mass Spectrometry. Twenty-nine (20%) patients had a biopsy proven graft rejection with decreased C20-ceramide (Cer) (p = 0.042), C18-dihydroceramide (DHC) (p = 0.022) and C24DHC (p = 0.060) levels. Furthermore, C18DHC (p = 0.044) and C24DHC (p = 0.011) were significantly down-regulated in patients with ischemic type biliary lesions (ITBL; n = 15; 10%). One-hundred and thirty-three patients (89%) have so far received tacrolimus as the main immunosuppressive agent with observed elevations of C14Cer (p = 0.052), C18Cer (p = 0.049) and C18:1Cer (p = 0.024). Hepatocellular carcinoma (HCC) pre-OLT was associated with increases in C24:1Cer (p = 0.024) and C24:1DHC (p = 0.024). In this large prospective cross-sectional study of patients, post-OLT serum levels of (very-)long chain (dihydro-)ceramides associate with graft rejection, ITBL, tacrolimus intake and HCC pre-OLT. Hence, serum SL’s may be indicative of graft complications. Further research is necessary to identify their diverse mechanistic role in regulating immunity and inflammation in patients post-OLT.
We present an empirical study focusing on the estimation of a fundamental multi-factor model for a universe of European stocks. Following the approach of the BARRA model, we have adopted a cross-sectional methodology. The proportion of explained variance ranges from 7.3% to 66.3% in the weekly regressions with a mean of 32.9%. For the individual factors we give the percentage of the weeks when they yielded statistically significant influence on stock returns. The best explanatory power – apart from the dominant country factors – was found among the statistical constructs „success“ and „variability in markets“.
Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.
In the upcoming years, the internet of things (IoT)will enrich daily life. The combination of artificial intelligence(AI) and highly interoperable systems will bring context-sensitive multi-domain services to reality. This paper describesa concept for an AI-based smart living platform with open-HAB, a smart home middleware, and Web of Things (WoT) askey components of our approach. The platform concept con-siders different stakeholders, i.e. the housing industry, serviceproviders, and tenants. These activities are part of the Fore-Sight project, an AI-driven, context-sensitive smart living plat-form.
Purpose: To investigate the diagnostic performance of noise-optimized virtual monoenergetic images (VMI+) in dual-energy CT (DECT) of portal vein thrombosis (PVT) compared to standard reconstructions. Method: This retrospective, single-center study included 107 patients (68 men; mean age, 60.1 ± 10.7 years) with malignant or cirrhotic liver disease and suspected PVT who had undergone contrast-enhanced portal-phase DECT of the abdomen. Linearly blended (M_0.6) and virtual monoenergetic images were calculated using both standard VMI and noise-optimized VMI+ algorithms in 20 keV increments from 40 to 100 keV. Quantitative measurements were performed in the portal vein for objective contrast-to-noise ratio (CNR) calculation. The image series showing the greatest CNR were further assessed for subjective image quality and diagnostic accuracy of PVT detection by two blinded radiologists. Results: PVT was present in 38 subjects. VMI+ reconstructions at 40 keV revealed the best objective image quality (CNR, 9.6 ± 4.3) compared to all other image reconstructions (p < 0.01). In the standard VMI series, CNR peaked at 60 keV (CNR, 4.7 ± 2.1). Qualitative image parameters showed the highest image quality rating scores for the 60 keV VMI+ series (median, 4) (p ≤ 0.03). The greatest diagnostic accuracy for the diagnosis of PVT was found for the 40 keV VMI+ series (sensitivity, 96%; specificity, 96%) compared to M_0.6 images (sensitivity, 87%; specificity, 92%), 60 keV VMI (sensitivity, 87%; specificity, 97%), and 60 keV VMI+ reconstructions (sensitivity, 92%; specificity, 97%) (p ≤ 0.01). Conclusions: Low-keV VMI+ reconstructions resulted in significantly improved diagnostic performance for the detection of PVT compared to other DECT reconstruction algorithms.
Objective: The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF).
Materials and Methods: We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period.
Results: A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF.
Conclusions: No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases.
Background; Salivary gland carcinomas (SGC) cover a heterogeneous group of malignancies with a lack of data of high-level evidence.
Methods; Clinical data of 127 patients treated for SGC at a university cancer center between 2002 and 2017 were analyzed retrospectively. The association of clinicopathological characteristics, treatment modalities, adverse events, and outcome was assessed.
Results: Patients received surgery (n = 65), surgery followed by (chemo-)radiotherapy (n = 56), or primary (chemo-)radiotherapy (n = 6). Injury to the cranial nerves or their branches was the most frequent surgical complication affecting 40 patients (33.1%). Ten year overall and progression-free survival rates were 73.2% and 65.4%, respectively. Parotid tumor site, advanced tumor, and positive nodal stage remained independent negative prognostic factors for overall survival, loco-regional and distant tumor control in multivariate analysis.
Conclusions: Optimizing treatment strategies for SGC, depending on distinct clinicopathological factors, remains challenging due to the low incidence rates of the disease.
Pattern recognition approaches to the analysis of neuroimaging data have brought new applications such as the classification of patients and healthy controls within reach. In our view, the reliance on expensive neuroimaging techniques which are not well tolerated by many patient groups and the inability of most current biomarker algorithms to accommodate information about prior class frequencies (such as a disorder's prevalence in the general population) are key factors limiting practical application. To overcome both limitations, we propose a probabilistic pattern recognition approach based on cheap and easy-to-use multi-channel near-infrared spectroscopy (fNIRS) measurements. We show the validity of our method by applying it to data from healthy controls (n = 14) enabling differentiation between the conditions of a visual checkerboard task. Second, we show that high-accuracy single subject classification of patients with schizophrenia (n = 40) and healthy controls (n = 40) is possible based on temporal patterns of fNIRS data measured during a working memory task. For classification, we integrate spatial and temporal information at each channel to estimate overall classification accuracy. This yields an overall accuracy of 76% which is comparable to the highest ever achieved in biomarker-based classification of patients with schizophrenia. In summary, the proposed algorithm in combination with fNIRS measurements enables the analysis of sub-second, multivariate temporal patterns of BOLD responses and high-accuracy predictions based on low-cost, easy-to-use fNIRS patterns. In addition, our approach can easily compensate for variable class priors, which is highly advantageous in making predictions in a wide range of clinical neuroimaging applications. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially,thedevelopmentoffibrosisandportalhypertensioninNAFLDpatientsrequirestreatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. Asexpected,WDinducedobesityandliverfibrosisasconfirmedbySiriusRedandOilRed O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increasedduringfeedingofWD,indicatinginfiltrationofmacrophagesintotheliver,eventhoughthis increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
Eukaryotic ribosome biogenesis requires the concerted action of numerous ribosome assembly factors, for most of which structural and functional information is currently lacking. Nob1, which can be identified in eukaryotes and archaea, is required for the final maturation of the small subunit ribosomal RNA in yeast by catalyzing cleavage at site D after export of the preribosomal subunit into the cytoplasm. Here, we show that this also holds true for Nob1 from the archaeon Pyrococcus horikoshii, which efficiently cleaves RNA-substrates containing the D-site of the preribosomal RNA in a manganese-dependent manner. The structure of PhNob1 solved by nuclear magnetic resonance spectroscopy revealed a PIN domain common with many nucleases and a zinc ribbon domain, which are structurally connected by a flexible linker. We show that amino acid residues required for substrate binding reside in the PIN domain whereas the zinc ribbon domain alone is sufficient to bind helix 40 of the small subunit rRNA. This suggests that the zinc ribbon domain acts as an anchor point for the protein on the nascent subunit positioning it in the proximity of the cleavage site.
Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology
(2017)
Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.
Activation of Mitochondrial complex II-dependent respiration is beneficial for α-Synucleinopathies
(2015)
Parkinson’s disease and dementia with Lewy bodies are major challenges in research and clinical medicine world-wide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APP-transgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synuclein-transgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNAArg genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.
hintergrund: Männer in Deutschland sterben früher als Frauen und nehmen weniger häufig Krebsvorsorgeuntersuchungen wahr.
Fragestellung: Ziel war die prospektive Evaluation einer „Movember-Gesundheitsinitiative“ am Universitätsklinikum Frankfurt (UKF) im November 2019.
Methoden: Im Rahmen der „Movember-Gesundheitsinitiative“ wurde allen männlichen Mitarbeitern des UKF ab dem 45. Lebensjahr und bei erstgradiger familiärer Vorbelastung eines Prostatakarzinoms ab dem 40. Lebensjahr im November 2019 gemäß S3-Leitlinien der Deutschen Gesellschaft für Urologie (DGU) eine Prostatakarzinom-Vorsorgeuntersuchung angeboten.
Ergebnisse: Insgesamt nahmen 14,4 % der Mitarbeiter teil. Eine familiäre Vorbelastung gaben insgesamt 14,0 % Teilnehmer an. Das mediane Alter betrug 54 Jahre. Der mediane PSA(prostataspezifisches Antigen)-Wert lag bei 0,9 ng/ml, der mediane PSA-Quotient bei 30 %. Bei 5 % (n = 6) zeigte sich ein suspekter Tastbefund in der DRU (digital-rektale Untersuchung). Nach Altersstratifizierung (≤ 50 vs. > 50 Lebensjahre) zeigten sich signifikante Unterschiede im medianen PSA-Wert (0,7 ng/ml vs. 1,0 ng/ml, p < 0,01) und der bereits zuvor durchgeführten urologischen Vorsorge (12,1 vs. 42,0 %, p < 0,01). Vier Teilnehmer (3,3 %) zeigten erhöhte Gesamt-PSA-Werte. Bei 32,2 % der Teilnehmer zeigte sich mindestens ein kontrollbedürftiger Befund. Insgesamt wurden 6 Prostatabiopsien durchgeführt. Hierbei zeigte sich in einem Fall ein intermediate-risk Prostatakarzinom (Gleason 3 + 4, pT3a, pPn1, pNx, R0).
Schlussfolgerungung: Im Rahmen der UKF-Movember-Gesundheitsinitiative 2019 konnten durch ein Vorsorgeangebot 121 Männer für eine Prostatakrebs-Vorsorge inklusive PSA-Testung gewonnen werden. Auffällige/kontrollbedürftige Befunde zeigten sich bei 32,2 %. Bei einem Mitarbeiter wurde ein therapiebedürftiges Prostatakarzinom entdeckt und therapiert.
An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), has been known for decades to be effective against acute lymphoblastic leukaemias of T-cell (T-ALL), but not of B-cell (B-ALL) origin. The mechanisms underlying this lineage-specific drug sensitivity have remained elusive. Data from pharmacogenomics studies and from a panel of ALL cell lines revealed an inverse correlation of SAMHD1 expression and nelarabine sensitivity. SAMHD1 can hydrolyse and thus inactivate triphosphorylated nucleoside analogues. Transcriptomic and protein expression profiling of cell lines and patient-derived leukaemic blasts revealed lower SAMHD1 abundance in T-ALL than in B-ALL. Mechanistically, SAMHD1 promoter methylation strongly correlated with suppressed SAMHD1 expression, while T-ALL cells did not display increased global DNA methylation. Targeted SAMHD1 degradation using virus-like particles containing Vpx sensitised B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induced AraG resistance. SAMHD1 had a larger impact on cytarabine activity than on nelarabine/ AraG activity in acute myeloid leukaemia (AML) cells, but more strongly affected nelarabine/ AraG activity in ALL cells. This indicates a critical role of the cancer entity. In conclusion, lineage-specific differences in SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. SAMHD1 is a potential biomarker for the identification of ALL patients likely to benefit from nelarabine therapy and a therapeutic target to overcome nelarabine resistance.
Ecological networks are more sensitive to plant than to animal extinction under climate change
(2016)
Impacts of climate change on individual species are increasingly well documented, but we lack understanding of how these effects propagate through ecological communities. Here we combine species distribution models with ecological network analyses to test potential impacts of climate change on >700 plant and animal species in pollination and seed-dispersal networks from central Europe. We discover that animal species that interact with a low diversity of plant species have narrow climatic niches and are most vulnerable to climate change. In contrast, biotic specialization of plants is not related to climatic niche breadth and vulnerability. A simulation model incorporating different scenarios of species coextinction and capacities for partner switches shows that projected plant extinctions under climate change are more likely to trigger animal coextinctions than vice versa. This result demonstrates that impacts of climate change on biodiversity can be amplified via extinction cascades from plants to animals in ecological networks.
Purpose: The aim of this study was to prospectively compare the therapy response and safety of microwave (MWA) and radiofrequency ablation (RFA) for the treatment of liver metastases using a dual ablation system.
Methods: Fifty patients with liver metastases (23 men, mean age: 62.8 ± 11.8 years) were randomly assigned to MWA or RFA for thermal ablation using a one generator dual ablation system. Magnetic resonance imaging (MRI) was acquired before treatment and 24 h post ablation. The morphologic responses to treatment regarding size, volume, necrotic areas, and diffusion characteristics were evaluated by MRI. Imaging follow-up was obtained for one year in three months intervals, whereas clinical follow-up was obtained for two years in all patients.
Results: Twenty-six patients received MWA and 24 patients received RFA (mean diameter: 1.6 cm, MWA: 1.7 cm, RFA: 1.5 cm). The mean volume 24 h after ablation was 37.0 cm3 (MWA: 50.5 cm3, RFA: 22.9 cm3, P < 0.01). The local recurrence rate was 0% (0/26) in the MWA-group and 8.3% (2/24) in the RFA-group (P = 0.09). The rate of newly developed malignant formations was 38.0% (19/50) for both groups (MWA: 38.4%, RFA: 37.5%, P = 0.07). The overall survival rate was 70.0% (35/50) after two years (MWA: 76.9%, RFA: 62.5%, P = 0.60). No major complications were reported.
Conclusion: In conclusion, MWA and RFA are both safe and effective methods for the treatment of liver metastases with MWA generating greater volumes of ablation. No significant differences were found for overall survival, rate of neoplasm, or major complications between both groups.
The three-dimensional quantification of small scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe and TACTS/ESMVal aircraft campaigns. The focus of this work is on the so-called dynamics mode data characterized by a medium spectral and a very high spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3 and CFC-12) and their spatial resolution are discussed. During ESSenCe, high resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in-situ data indicate a good agreement between the data sets. During TACTS/ESMVal a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere has been performed. This filament could be reconstructed with an unprecedented spatial resolution of better than 500 m vertically and 20 km × 20 km horizontally.
The three-dimensional quantification of small-scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents the first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe (ESa Sounder Campaign) and TACTS/ESMVal (TACTS: Transport and composition in the upper troposphere/lowermost stratosphere, ESMVal: Earth System Model Validation) aircraft campaigns. The focus of this work is on the so-called dynamics-mode data characterized by a medium-spectral and a very-high-spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3, and CFC-12) and their spatial resolution are discussed. During ESSenCe, high-resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in situ data indicate a good agreement between the data sets. During TACTS/ESMVal, a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere was performed. It was possible to reconstruct this filament at an unprecedented spatial resolution of better than 500 m vertically and 20 × 20 km horizontally.
The first concerted multi-model intercomparison of halogenated very short-lived substances (VSLS) has been performed, within the framework of the ongoing Atmospheric Tracer Transport Model Intercomparison Project (TransCom). Eleven global models or model variants participated (nine chemical transport models and two chemistry–climate models) by simulating the major natural bromine VSLS, bromoform (CHBr3) and dibromomethane (CH2Br2), over a 20-year period (1993–2012). Except for three model simulations, all others were driven offline by (or nudged to) reanalysed meteorology. The overarching goal of TransCom-VSLS was to provide a reconciled model estimate of the stratospheric source gas injection (SGI) of bromine from these gases, to constrain the current measurement-derived range, and to investigate inter-model differences due to emissions and transport processes. Models ran with standardised idealised chemistry, to isolate differences due to transport, and we investigated the sensitivity of results to a range of VSLS emission inventories. Models were tested in their ability to reproduce the observed seasonal and spatial distribution of VSLS at the surface, using measurements from NOAA's long-term global monitoring network, and in the tropical troposphere, using recent aircraft measurements – including high-altitude observations from the NASA Global Hawk platform.
The models generally capture the observed seasonal cycle of surface CHBr3 and CH2Br2 well, with a strong model–measurement correlation (r ≥ 0.7) at most sites. In a given model, the absolute model–measurement agreement at the surface is highly sensitive to the choice of emissions. Large inter-model differences are apparent when using the same emission inventory, highlighting the challenges faced in evaluating such inventories at the global scale. Across the ensemble, most consistency is found within the tropics where most of the models (8 out of 11) achieve best agreement to surface CHBr3 observations using the lowest of the three CHBr3 emission inventories tested (similarly, 8 out of 11 models for CH2Br2). In general, the models reproduce observations of CHBr3 and CH2Br2 obtained in the tropical tropopause layer (TTL) at various locations throughout the Pacific well. Zonal variability in VSLS loading in the TTL is generally consistent among models, with CHBr3 (and to a lesser extent CH2Br2) most elevated over the tropical western Pacific during boreal winter. The models also indicate the Asian monsoon during boreal summer to be an important pathway for VSLS reaching the stratosphere, though the strength of this signal varies considerably among models.
We derive an ensemble climatological mean estimate of the stratospheric bromine SGI from CHBr3 and CH2Br2 of 2.0 (1.2–2.5) ppt, ∼ 57 % larger than the best estimate from the most recent World Meteorological Organization (WMO) Ozone Assessment Report. We find no evidence for a long-term, transport-driven trend in the stratospheric SGI of bromine over the simulation period. The transport-driven interannual variability in the annual mean bromine SGI is of the order of ±5 %, with SGI exhibiting a strong positive correlation with the El Niño–Southern Oscillation (ENSO) in the eastern Pacific. Overall, our results do not show systematic differences between models specific to the choice of reanalysis meteorology, rather clear differences are seen related to differences in the implementation of transport processes in the models.
The first concerted multi-model intercomparison of halogenated very short-lived substances (VSLS) has been performed, within the framework of the ongoing Atmospheric Tracer Transport Model Intercomparison Project (TransCom). Eleven global models or model variants participated, simulating the major natural bromine VSLS, bromoform (CHBr3) and dibromomethane (CH2Br2), over a 20-year period (1993-2012). The overarching goal of TransCom-VSLS was to provide a reconciled model estimate of the stratospheric source gas injection (SGI) of bromine from these gases, to constrain the current measurement-derived range, and to investigate inter-model differences
due to emissions and transport processes. Models ran with standardised idealised chemistry, to isolate differences due to transport, and we investigated the sensitivity of results to a range of VSLS emission inventories. Models were tested in their ability to reproduce the observed seasonal and spatial distribution of VSLS at the surface, using measurements from NOAA’s long-term global monitoring network, and in the tropical troposphere, using recent aircraft measurements - including high altitude observations from the NASA Global Hawk platform.
The models generally capture the seasonal cycle of surface CHBr3 and CH2Br2 well, with a strong model measurement correlation (r ≥0.7) and a low sensitivity to the choice of emission inventory, at most sites. In a given model, the absolute model-measurement agreement is highly sensitive to the choice of emissions and inter-model differences are also apparent, even when using the same inventory, highlighting the challenges faced in evaluating such inventories at the global scale. Across the ensemble, most consistency is found within the tropics where most of the models (8 out of 11) achieve optimal agreement to surface CHBr3 observations using the lowest of the three CHBr3 emission inventories tested (similarly, 8 out of 11 models for CH2Br2). In general, the models are able to reproduce well observations of CHBr3 and CH2Br2 obtained in the tropical tropopause layer (TTL) at various locations throughout the Pacific. Zonal variability in VSLS loading in the TTL is generally consistent among models, with CHBr3 (and to a lesser extent CH2Br2) most elevated over the tropical West Pacific during boreal winter. The models also indicate the Asian Monsoon during boreal summer to be an important pathway for VSLS reaching the stratosphere, though the strength of this signal varies considerably among models.
We derive an ensemble climatological mean estimate of the stratospheric bromine SGI from CHBr3 and CH2Br2 of 2.0 (1.2-2.5) ppt, ∼57% larger than the best estimate from the most re- cent World Meteorological Organization (WMO) Ozone Assessment Report. We find no evidence for a long-term, transport-driven trend in the stratospheric SGI of bromine over the simulation period. However, transport-driven inter-annual variability in the annual mean bromine SGI is of the order of a ±5%, with SGI exhibiting a strong positive correlation with ENSO in the East Pacific
We report on HCFC-22 data acquired by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) in the reduced spectral resolution nominal observation mode. The data cover the period from January 2005 to April 2012 and the altitude range from the upper troposphere (above cloud top altitude) to about 50 km. The profile retrieval was performed by constrained nonlinear least squares fitting of modelled spectra to the measured limb spectral radiances. The spectral ν4-band at 816.5 ± 13 cm−1 was used for the retrieval. A Tikhonov-type smoothing constraint was applied to stabilise the retrieval. In the lower stratosphere, we find a global volume mixing ratio of HCFC-22 of about 185 pptv in January 2005. The rate of linear growth in the lower latitudes lower stratosphere was about 6 to 7 pptv year−1 in the period 2005–2012. The profiles obtained were compared with ACE-FTS satellite data v3.5, as well as with MkIV balloon profiles and cryosampler balloon measurements. Between 13 and 22 km, average agreement within −3 to +5 pptv (MIPAS – ACE) with ACE-FTS v3.5 profiles is demonstrated. Agreement with MkIV solar occultation balloon-borne measurements is within 10–20 pptv below 30 km and worse above, while in situ cryosampler balloon measurements are systematically lower over their full altitude range by 15–50 pptv below 24 km and less than 10 pptv above 28 km. MIPAS HCFC-22 time series below 10 km altitude are shown to agree mostly well to corresponding time series of near-surface abundances from the NOAA/ESRL and AGAGE networks, although a more pronounced seasonal cycle is obvious in the satellite data. This is attributed to tropopause altitude fluctuations and subsidence of polar winter stratospheric air into the troposphere. A parametric model consisting of constant, linear, quasi-biennial oscillation (QBO) and several sine and cosine terms with different periods has been fitted to the temporal variation of stratospheric HCFC-22 for all 10°-latitude/1-to-2-km-altitude bins. The relative linear variation was always positive, with relative increases of 40–70 % decade−1 in the tropics and global lower stratosphere, and up to 120 % decade−1 in the upper stratosphere of the northern polar region and the southern extratropical hemisphere. Asian HCFC-22 emissions have become the major source of global upper tropospheric HCFC-22. In the upper troposphere, monsoon air, rich in HCFC-22, is instantaneously mixed into the tropics. In the middle stratosphere, between 20 and 30 km, the observed trend is inconsistent with the trend at the surface (corrected for the age of stratospheric air), hinting at circulation changes. There exists a stronger positive trend in HCFC-22 in the Southern Hemisphere and a more muted positive trend in the Northern Hemisphere, implying a potential change in the stratospheric circulation over the observation period.
We report on HCFC-22 data acquired by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) in reduced spectral resolution nominal mode in the period from January 2005 to April 2012 from version 5.02 level-1b spectral data and covering an altitude range from the upper troposphere (above cloud top altitude) to about 50 km. The profile retrieval was performed by constrained nonlinear least squares fitting of measured limb spectral radiances to modelled spectra. The spectral v4-band at 816.5 ± 13 cm-1 was used for the retrieval. A Tikhonov-type smoothing constraint was applied to stabilise the retrieval. In the lower stratosphere, we find a global volume mixing ratio of HCFC-22 of about 185 pptv in January 2005. The linear growth rate in the lower latitudes lower stratosphere was about 6 to 7 pptv yr-1 in the period 2005–2012. The obtained profiles were compared with ACE-FTS satellite data v3.5, as well as with MkIV balloon profiles and in situ cryosampler balloon measurements. Between 13 and 22 km, average agreement within -3 to +5 pptv (MIPAS–ACE) with ACE-FTS v3.5 pro files is demonstrated. Agreement with MkIV solar occultation balloon-borne measurements is within 10–20 pptv below 30 km and worse above, while in situ cryosampler balloon measurements are systematically lower over their full altitude range by 15– 50 pptv below 24 km and less than 10 pptv above 28 km. Obtained MIPAS HCFC-22 time series below 10 km altitude are shown to agree mostly well to corresponding time series of near-surface abundances from NOAA/ESRL and AGAGE networks, although a more pronounced seasonal cycle is obvious in the satellite data, probably due to tropopause altitude fluctuations and subsidence of polar winter stratospheric air into the troposphere. A parametric model consisting of constant, linear, quasi-biennial oscillation (QBO) and several sine and cosine terms with different periods has been fitted to the temporal variation of stratospheric HCFC-22 for all 10° latitude/1 to 2 km altitude bins. The relative linear variation was always positive, with relative increases of 40–70%decade-1 in the tropics and global lower stratosphere, and up to 120%decade-1 in the upper stratosphere of the northern polar region and the southern extratropical hemisphere. In the middle stratosphere between 20 and 30 km, the observed trend is not consistent with the age of stratospheric air-corrected trend at ground, but stronger positive at the Southern Hemisphere and less strong increasing in the Northern Hemisphere, hinting towards changes in the stratospheric circulation over the observation period.
An accelerating Brewer-Dobson circulation (BDC) is a robust signal of climate change in model predictions but has been questioned by trace gas observations. We analyze stratospheric mean age of air and the full age spectrum as measures for the BDC and its trend. Age of air is calculated with the Chemical Lagrangian Model of the Stratosphere (CLaMS) driven by ERA-Interim, JRA-55 and MERRA-2 reanalysis data to assess the robustness of the representation of the BDC in current generation meteorological reanalyses. We find that climatological mean age significantly depends on the reanalysis, with JRA-55 showing the youngest and MERRA-2 the oldest mean age. Consideration of the age spectrum indicates that the older age for MERRA-2 is related to a stronger spectrum tail, likely related to weaker tropical upwelling and stronger recirculation. Seasonality of stratospheric transport is robustly represented in reanalyses, with similar mean age variations and age spectrum peaks. Long-term changes over 1989–2015 turn out to be similar for the reanalyses with mainly decreasing mean age accompanied by a shift of the age spectrum peak towards shorter transit times, resembling the forced response in climate model simulations to increasing greenhouse gas concentrations. For the shorter periods 1989–2001 and 2002–2015 age of air changes are less robust. Only ERA-Interim shows the hemispheric dipole pattern in age changes during 2002–2015 as viewed by recent satellite observations. Consequently, the representation of decadal variability of the BDC in current generation reanalyses appears less robust and a major uncertainty of modelling the BDC.
SARS-CoV-2 and stroke characteristics: a report from the Multinational COVID-19 Stroke Study Group
(2020)
Background: Stroke is reported as a consequence of SARS-CoV-2 infection. However, there is a lack of regarding comprehensive stroke phenotype and characteristics
Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) among SARS-CoV-2 infected patients. We further investigated the association of demographics, clinical data, geographical regions, and countries’ health expenditure among AIS patients with the risk of large vessel occlusion (LVO), stroke severity as measured by National Institute of Health stroke scale (NIHSS), and stroke subtype as measured by the TOAST criteria. Additionally, we applied unsupervised machine learning algorithms to uncover possible similarities among stroke patients.
Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least one eligible stroke patient. Out of 432 patients included, 323(74.8%) had AIS, 91(21.1%) ICH, and 18(4.2%) CVST. Among 23 patients with subarachnoid hemorrhage, 16(69.5%) had no evidence of aneurysm. A total of 183(42.4%) patients were women, 104(24.1%) patients were younger than 55 years, and 105(24.4%) patients had no identifiable vascular risk factors. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 infection. Among AIS patients 44.5% had LVO; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median NIHSS (8[3-17], versus 11 [5-17]; p=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; p<0.001) in countries with middle to high-health expenditure when compared to countries with lower health expenditure. The unsupervised machine learning identified 4 subgroups, with a relatively large group with no or limited comorbidities.
Conclusions: We observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. Among hospitalized patients, the stroke severity was lower and rate of mechanical thrombectomy was higher among countries with middle to high-health expenditure.
Dendritic spines are crucial for excitatory synaptic transmission as the size of a spine head correlates with the strength of its synapse. The distribution of spine head sizes follows a lognormal-like distribution with more small spines than large ones. We analysed the impact of synaptic activity and plasticity on the spine size distribution in adult-born hippocampal granule cells from rats with induced homo- and heterosynaptic long-term plasticity in vivo and CA1 pyramidal cells from Munc-13-1-Munc13-2 knockout mice with completely blocked synaptic transmission. Neither induction of extrinsic synaptic plasticity nor the blockage of presynaptic activity degrades the lognormal-like distribution but changes its mean, variance and skewness. The skewed distribution develops early in the life of the neuron. Our findings and their computational modelling support the idea that intrinsic synaptic plasticity is sufficient for the generation, while a combination of intrinsic and extrinsic synaptic plasticity maintains lognormal like distribution of spines.
The TOM complex is the main entry point for precursor proteins into mitochondria. Precursor proteins containing targeting sequences are recognized by the TOM complex and imported into the mitochondria. We have determined the structure of the TOM core complex from Neurospora crassa by single-particle cryoEM at 3.3 Å resolution, showing its interaction with a bound presequence at 4 Å resolution, and of the TOM holo complex including the Tom20 receptor at 6-7 Å resolution. TOM is a transmembrane complex consisting of two β-barrels, three receptor subunits and three short transmembrane subunits. Tom20 has a transmembrane helix and a receptor domain on the cytoplasmic side. We propose that Tom20 acts as a dynamic gatekeeper, guiding precursor proteins into the pores of the TOM complex. We analyze the interactions of Tom20 with other TOM subunits, present insights into the structure of the TOM holo complex, and suggest a translocation mechanism.
Objectives: To evaluate the predictive value of volumetric bone mineral density (BMD) assessment of the lumbar spine derived from phantomless dual-energy CT (DECT)-based volumetric material decomposition as an indicator for the 2-year occurrence risk of osteoporosis-associated fractures. Methods: L1 of 92 patients (46 men, 46 women; mean age, 64 years, range, 19–103 years) who had undergone third-generation dual-source DECT between 01/2016 and 12/2018 was retrospectively analyzed. For phantomless BMD assessment, dedicated DECT postprocessing software using material decomposition was applied. Digital files of all patients were sighted for 2 years following DECT to obtain the incidence of osteoporotic fractures. Receiver operating characteristic (ROC) analysis was used to calculate cut-off values and logistic regression models were used to determine associations of BMD, sex, and age with the occurrence of osteoporotic fractures. Results: A DECT-derived BMD cut-off of 93.70 mg/cm3 yielded 85.45% sensitivity and 89.19% specificity for the prediction to sustain one or more osteoporosis-associated fractures within 2 years after BMD measurement. DECT-derived BMD was significantly associated with the occurrence of new fractures (odds ratio of 0.8710, 95% CI, 0.091–0.9375, p < .001), indicating a protective effect of increased DECT-derived BMD values. Overall AUC was 0.9373 (CI, 0.867–0.977, p < .001) for the differentiation of patients who sustained osteoporosis-associated fractures within 2 years of BMD assessment. Conclusions: Retrospective DECT-based volumetric BMD assessment can accurately predict the 2-year risk to sustain an osteoporosis-associated fracture in at-risk patients without requiring a calibration phantom. Lower DECT-based BMD values are strongly associated with an increased risk to sustain fragility fractures.
Key Points: Dual-energy CT–derived assessment of bone mineral density can identify patients at risk to sustain osteoporosis-associated fractures with a sensitivity of 85.45% and a specificity of 89.19%. The DECT-derived BMD threshold for identification of at-risk patients lies above the American College of Radiology (ACR) QCT guidelines for the identification of osteoporosis (93.70 mg/cm 3 vs 80 mg/cm 3 ).
System size dependence of multiplicity fluctuations of charged particles produced in nuclear collisions at 158 A GeV was studied in the NA49 CERN experiment. Results indicate a non-monotonic dependence of the scaled variance of the multiplicity distribution with a maximum for semi-peripheral Pb+Pb interactions with number of projectile participants of about 35. This effect is not observed in a string-hadronic model of nuclear collision HIJING.
Highlights
• 153 chemicals of emerging concern detected in complex multi-component mixtures.
• 108 possible mixture risk assessment scenarios were investigated.
• Non-detects, QSARs, and experimental ecotoxicological data were integrated for risk assessment.
• 8 chemicals were the main risk drivers in at least one site across the River Aconcagua basin.
Abstract
Environmental risk assessments strategies that account for the complexity of exposures are needed in order to evaluate the toxic pressure of emerging chemicals, which also provide suggestions for risk mitigation and management, if necessary. Currently, most studies on the co-occurrence and environmental impacts of chemicals of emerging concern (CECs) are conducted in countries of the Global North, leaving massive knowledge gaps in countries of the Global South.
In this study, we implement a multi-scenario risk assessment strategy to improve the assessment of both the exposure and hazard components in the chemical risk assessment process. Our strategy incorporates a systematic consideration and weighting of CECs that were not detected, as well as an evaluation of the uncertainties associated with Quantitative Structure-Activity Relationships (QSARs) predictions for chronic ecotoxicity. Furthermore, we present a novel approach to identifying mixture risk drivers. To expand our knowledge beyond well-studied aquatic ecosystems, we applied this multi-scenario strategy to the River Aconcagua basin of Central Chile. The analysis revealed that the concentrations of CECs exceeded acceptable risk thresholds for selected organism groups and the most vulnerable taxonomic groups. Streams flowing through agricultural areas and sites near the river mouth exhibited the highest risks. Notably, the eight risk drivers among the 153 co-occurring chemicals accounted for 66–92 % of the observed risks in the river basin. Six of them are pesticides and pharmaceuticals, chemical classes known for their high biological activity in specific target organisms.
Purpose: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).
Methods: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.
Results: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.
Conclusions: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI–TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced.
(2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored.
(3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%.
(4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
Vaccination represents one of the fundamentals in the fight against SARS-CoV-2. Myocarditis has been reported as a rare but possible adverse consequence of different vaccines, and its clinical presentation can range from mild symptoms to acute heart failure. We report a case of a 29-year-old man who presented with fever and retrosternal pain after receiving SARS-CoV-2 vaccine. Cardiac magnetic resonance imaging and laboratory data revealed typical findings of acute myocarditis.
Angiotensin II (ANG II), das physiologisch aktivste Produkt des Renin-Angiotensin-Systems (RAS), ist als ein Vasokonstriktor maßgeblich an der Modulation des Blutdrucks beteiligt. Darüber hinaus spielt das Octapeptid eine wichtige Rolle in der Freisetzung von Vasopressin und Hypophysenhormonen und reguliert den Flüssigkeits- und Salzhaushalt. Die Modulation des Blutdrucks sowie die Stimulation der Vasopressinfreisetzung werden über seine AT1-Rezeptoren vermittelt. Viele dieser physiologischen Funktionen zeigen eine klare Tag/Nacht-Variation. Der Nucleus suprachiasmaticus des Hypothalamus (SCN) repräsentiert den zentralen Schrittmacher der circadianen Uhr der Säugertiere und reguliert mitunter den Schlaf/Wach-Zyklus und den circadianen Rhythmus des Blutdrucks. Mit der Entwicklung eines transgen-hypertensiven Rattenstammes [TGR(mREN2)27], der über eine der Herzfrequenz und Aktivität entgegengesetzt phasenverschobene circadiane Rhythmik des Blutdrucks verfügt, konnte eine enge physiologische Beziehung zwischen ANG II und dem SCN aufgezeigt werden. Diese Hypertonie wird durch das zusätzliche und zudem noch übermäßig exprimierte Mäuse-Renin2-Gen im Zirkulations-RAS dieser Ratten verursacht. Die hieraus folgende übermäßige Bereitstellung von Renin im Blutkreislauf führt zu einer erhöhten Konzentration von ANG II im systemischen Kreislauf. Die Funktionswege, die zur phasenverschobenen circadianen Rhythmik des Blutdrucks bei TGR führen sowie die Rolle, die das Octapeptid ANG II generell in der Blutdruckmodulation bei normotensiven und transgen-hypertensiven Tieren spielt, sind noch weitgehend unbekannt. Es wird angenommen, dass das Gehirn-RAS über eine autonome ANG II-Synthese Einfluss auf die Modulation des Blutdrucks ausübt. Ob dieser Einfluss des Gehirn-RAS direkt am zentralen Schrittmacher der circadianen Rhythmik ansetzt und ob und wie sich dieser Einfluss durch das Transgen der TGR verändert, ist ebenfalls nicht bekannt. Um die Wirkung des im Blutkreislauf übermäßig vorhandenen ANG II auf Komponenten des Gehirn-RAS in Hirnarealen vor und hinter der funktionellen Blut/Hirn-Schranke auf zuzeigen, wurden im Verlauf dieser Arbeit der SCN sowie zwei Zirkumventrikularorgane von normotensiven Sprague-Dawley (SDR) und transgen-hypertensiven TGR(mREN2)27 (TGR) Ratten auf die Dichte und Verteilung ihrer AT1-Rezeptoren hin überprüft. Da die physiologische Rolle von ANG II im SCN selbst auch ungeklärt ist und ultrastrukturelle Befunde zur Lokalisation des Octapeptids und seiner AT1-Rezeptoren im SCN bisher nicht verfügbar sind, wurde in dieser Dissertationsarbeit eine immunhistologische Technik entwickelt, mit deren Hilfe sich Immunreaktionen gegen das Octapeptid ANG II und seine AT1-Rezeptoren auf licht- und elektronenmikroskopischer Ebene darstellen lassen. Die hier beschriebenen Befunde machen den Einfluss des Transgens - vermittelt durch die erhöhte ANG II-Konzentration im Blutkreislauf von TGR - auf Veränderungen in Dichte und Verteilung der AT1-Rezeptoren in Hirnarealen vor und hinter der funktionellen Blut/Hirn-Schranke deutlich. AT1-Rezeptoren erscheinen in Hirnarealen mit offenem Kapillarsystem reduziert, im SCN dagegen unverändert und in anderen Regionen mit funktioneller Blut/Hirn-Schranke teilweise erhöht. Lokal begrenzte Veränderungen in der Bereitstellung der AT1-Rezeptoren innerhalb einzelner Kerngebiete hängen maßgeblich von deren topographischer Organisation ab, die bei bisherigen autoradiographischen- und Ligand-Bindungs-Studien jedoch keine Berücksichtigung fand. Die hier vorliegende Arbeit demonstriert erstmalig, dass ANG II im SCN als ein Neurotransmitter und -Modulator fungiert, dessen Effekte über seinen AT1-Rezeptor vermittelt werden. Der Rezeptor vermittelt des Weiteren auch den aktiven - vermutlich bidirektionalen - Transport von ANG II durch die Kapillarendothelien des SCN und ist an der Aufnahme von ANG II (Endozytose) und dessen intrazellulären Transport in einem Hormon/Rezeptor-Komplex in Neuronen, Glia- und Endothelzellen im SCN beteiligt. Die Befunde machen darüber hinaus eine Synthese von ANG II in distinkten Neuronen des SCN wahrscheinlich und deuten an, dass autonom produziertes ANG II im SCN an der Regulation des Blutdrucks und der Freisetzung von Vasopressin beteiligt ist.
Objectives: To investigate the diagnostic accuracy of color-coded contrast-enhanced dual-energy CT virtual noncalcium (VNCa) reconstructions for the assessment of lumbar disk herniation compared to unenhanced VNCa imaging.
Methods: A total of 91 patients were retrospectively evaluated (65 years ± 16; 43 women) who had undergone third-generation dual-source dual-energy CT and 3.0-T MRI within an examination interval up to 3 weeks between November 2019 and December 2020. Eight weeks after assessing unenhanced color-coded VNCa reconstructions for the presence and degree of lumbar disk herniation, corresponding contrast-enhanced portal venous phase color-coded VNCa reconstructions were independently analyzed by the same five radiologists. MRI series were additionally analyzed by one highly experienced musculoskeletal radiologist and served as reference standard.
Results: MRI depicted 210 herniated lumbar disks in 91 patients. VNCa reconstructions derived from contrast-enhanced CT scans showed similar high overall sensitivity (93% vs 95%), specificity (94% vs 95%), and accuracy (94% vs 95%) for the assessment of lumbar disk herniation compared to unenhanced VNCa images (all p > .05). Interrater agreement in VNCa imaging was excellent for both, unenhanced and contrast-enhanced CT (κ = 0.84 vs κ = 0.86; p > .05). Moreover, ratings for diagnostic confidence, image quality, and noise differed not significantly between unenhanced and contrast-enhanced VNCa series (all p > .05).
Conclusions: Color-coded VNCa reconstructions derived from contrast-enhanced dual-energy CT yield similar diagnostic accuracy for the depiction of lumbar disk herniation compared to unenhanced VNCa imaging and therefore may improve opportunistic retrospective lumbar disk herniation assessment, particularly in case of staging CT examinations.
Key Points
• Color-coded dual-source dual-energy CT virtual noncalcium (VNCa) reconstructions derived from portal venous phase yield similar high diagnostic accuracy for the assessment of lumbar disk herniation compared to unenhanced VNCa CT series (94% vs 95%) with MRI serving as a standard of reference.
• Diagnostic confidence, image quality, and noise levels differ not significantly between unenhanced and contrast-enhanced portal venous phase VNCa dual-energy CT series.
• Dual-source dual-energy CT might have the potential to improve opportunistic retrospective lumbar disk herniation assessment in CT examinations performed for other indications through reconstruction of VNCa images.
Streams and rivers are characterised by the presence of various chemicals of emerging concern (CECs), including pesticides, pharmaceuticals, personal care products, and industrial chemicals. While these chemicals are found usually only in low (ng/L) concentrations, they might still harm aquatic life and disrupt the ecological balance of aquatic ecosystems due to their high ecotoxicological potency. Environmental risk assessments that account for the complexity of exposures are needed in order to evaluate the toxic pressure of these chemicals, which also provide suggestions for risk mitigation and management, if necessary. Currently, most studies on the co-occurrence and environmental impacts of CECs are conducted in countries of the Global North, leaving massive knowledge gaps in countries of the Global South.
In this study, we implement a multi-scenario risk assessment strategy to improve the assessment of both the exposure and hazard components in the chemical risk assessment process. Our strategy incorporates a systematic consideration and weighting of CECs that were not detected, as well as an evaluation of the uncertainties associated with Quantitative Structure-Activity Relationships (QSARs) predictions for chronic ecotoxicity. Furthermore, we present a novel approach to identifying mixture risk drivers. To expand our knowledge beyond well-studied aquatic ecosystems, we applied this multi-scenario strategy to the River Aconcagua basin of Central Chile. The analysis revealed that the concentrations of CECs exceeded acceptable risk thresholds for selected organism groups and the most vulnerable taxonomic groups. Streams flowing through agricultural areas and sites near the river mouth exhibited the highest risks. Notably, the eight risk drivers among the 153 co-occurring chemicals accounted for 66-92% of the observed risks in the river basin. Six of them are pesticides and pharmaceuticals, chemical classes known for their high biological activity in specific target organisms.
Despite recent advances in the treatment of metastatic prostate cancer (PCa), resistance development after taxane treatments is inevitable, necessitating effective options to combat drug resistance. Previous studies indicated antitumoral properties of the natural compound amygdalin. However, whether amygdalin acts on drug-resistant tumor cells remains questionable. An in vitro study was performed to investigate the influence of amygdalin (10 mg/mL) on the growth of a panel of therapy-naïve and docetaxel- or cabazitaxel-resistant PCa cell lines (PC3, DU145, and LNCaP cells). Tumor growth, proliferation, clonal growth, and cell cycle progression were investigated. The cell cycle regulating proteins (phospho)cdk1, (phospho)cdk2, cyclin A, cyclin B, p21, and p27 and the mammalian target of rapamycin (mTOR) pathway proteins (phospho)Akt, (phospho)Raptor, and (phospho)Rictor as well as integrin β1 and the cytoskeletal proteins vimentin, ezrin, talin, and cytokeratin 8/18 were assessed. Furthermore, chemotactic activity and adhesion to extracellular matrix components were analyzed. Amygdalin dose-dependently inhibited tumor growth and reduced tumor clones in all (parental and resistant) PCa cell lines, accompanied by a G0/G1 phase accumulation. Cell cycle regulating proteins were significantly altered by amygdalin. A moderate influence of amygdalin on tumor cell adhesion and chemotaxis was observed as well, paralleled by modifications of cytoskeletal proteins and the integrin β1 expression level. Amygdalin may, therefore, block tumor growth and disseminative characteristics of taxane-resistant PCa cells. Further studies are warranted to determine amygdalin’s value as an antitumor drug.
We study how species richness of arthropods relates to theories concerning net primary productivity, ambient energy, water-energy dynamics and spatial environmental heterogeneity. We use two datasets of arthropod richness with similar spatial extents (Scandinavia to Mediterranean), but contrasting spatial grain (local habitat and country). Samples of ground-dwelling spiders, beetles, bugs and ants were collected from 32 paired habitats at 16 locations across Europe. Species richness of these taxonomic groups was also determined for 25 European countries based on the Fauna Europaea database. We tested effects of net primary productivity (NPP), annual mean temperature (T), annual rainfall (R) and potential evapotranspiration of the coldest month (PETmin) on species richness and turnover. Spatial environmental heterogeneity within countries was considered by including the ranges of NPP, T, R and PETmin. At the local habitat grain, relationships between species richness and environmental variables differed strongly between taxa and trophic groups. However, species turnover across locations was strongly correlated with differences in T. At the country grain, species richness was significantly correlated with environmental variables from all four theories. In particular, species richness within countries increased strongly with spatial heterogeneity in T. The importance of spatial heterogeneity in T for both species turnover across locations and for species richness within countries suggests that the temperature niche is an important determinant of arthropod diversity. We suggest that, unless climatic heterogeneity is constant across sampling units, coarse-grained studies should always account for environmental heterogeneity as a predictor of arthropod species richness, just as studies with variable area of sampling units routinely consider area.
Hintergrund: Im Rahmen der Erforschung von Mechanismen der Presbyopie-Entstehung hat das Interesse an Methoden zur Linsendensitometrie wieder zugenommen. Für spezielle Fragestellungen sind flexible Untersuchungsmethoden notwendig.
Methoden: Basierend auf Aufnahmen mit der Scheimpflug-Kamera Pentacam HR (Oculus, Wetzlar) wurde ein MATLAB-Programm (V7.0, The MathWorks) erstellt, um größere Datenmengen automatisiert auszuwerten. Die Erkennung der Pupillenmitte als Referenzpunkt erfolgt mittels eines Randerkennungsalgorithmus. Als Kennzahlen dienen klassische Parameter der beschreibenden Statistik (Mittel, Minimum, Maximum, Standardabweichung und Variationskoeffizient) für einen definierten rechteckigen Bereich und für die zentrale vertikale Achse.
Ergebnisse: In einer Präliminarserie von 18 Augen war eine automatisierte Messung mit korrekter Pupillenerkennung in 80% der Fälle möglich. Verglichen mit der hersteller-eigenen Software (Pentacam 6.03r11) besitzt das eigene Programm eine erweiterte Spannweite der Messwerte. Die Messwerte können automatisch nach Excel (Microsoft) exportiert werden. Ein modularer Aufbau ermöglicht eine flexible Erweiterung für weitere Fragestellungen (z.B. Quantifizierung von Kern- und Rindentrübungen).
Schlussfolgerungen: Mittels eines selbst programmierten MATLAB-basierten Programmes kann eine automatisierte Messung und Analyse von linsndensitometrischen Parametern durchgeführt werden.
Background: According to current taxonomy only three out of 27 Sinohimalayan leaf warbler species (Phylloscopidae) are considered genetically uniform across their entire breeding range along the Southeastern margin of the Qinghai-Tibetan Plateau, the Buff-barred Warbler (Phylloscopus pulcher) being one of them. Because marked differentiation among Himalayan and Chinese populations has been recently demonstrated for a number of Phylloscopus species (or sister species) we investigated the intraspecific variation of a mitochondrial gene, songs and morphology of P. pulcher in a phylogeographic approach.
Methods: We sequenced a fragment of the mitochondrial cytochrome b, reconstructed haplotype networks and analyzed DNA polymorphism among Himalayan and Chinese populations. We measured time and frequency parameters of two distinct song types and analyzed among population-differentiation in a principal component analysis and a discriminant analysis. We also compared measurements of body size dimensions taken from museum specimens.
Results: The mitochondrial haplotype network (cytb) was divided into two distinct clusters corresponding to geographic origin of samples. Pairwise genetic distances among Himalayan and Chinese mtDNA lineages account for 1.3% which coincides with Pleistocene lineage separation at roughly 650,000 years ago. Genetic diversity is slightly higher in the Chinese part of the species’ range with respect to haplotype and nucleotide diversity while the less diversified Himalayan population lineage shows signs of recent range expansion. The vocal repertoire of P. pulcher comprises two distinct verse types that are combined with short interspersed click notes to long continuous song displays. Trill verse types showed significant differences among regions in almost all measured frequency and time parameters: Chinese males displayed more rapid and more broad-banded trills at a lower pitch. In contrast, warbling verse types showed a distinctively different structure among regions: Himalayan songs consisted of repeated syllables while Chinese songs comprised repetitions of single, long and strongly modulated elements. Subtle morphological differences among specimens from the two study regions could only be confirmed for plumage coloration but not for metric characters.
Conclusions: Based on the genetic and bioacoustic distinctiveness of Chinese Buff-barred Warbler populations, we recommend that the name Phylloscopus pulcher vegetus Bangs, 1913 should be re-validated for this taxon.
Songs in passerine birds are important for territory defense and mating. Speciation rates in oscine passerines are so high, due to cultural evolution, that this bird lineage makes up half of the extant bird species. Leaf warblers are a speciose Old-World passerine family of limited morphological differentiation, so that songs are even more important for species delimitation. We took 16 sonographic traits from song recordings of 80 leaf warbler taxa and correlated them with 15 potentially explanatory variables, pairwise, and in linear models. Based on a well-resolved molecular phylogeny of the same taxa, all pairwise correlations were corrected for relatedness with phylogenetically independent contrasts and phylogenetic generalized linear models were used. We found a phylogenetic signal for most song traits, but a strong one only for the duration of the longest and of the shortest element, which are presumably inherited instead of learned. Body size of a leaf warbler species is a constraint on song frequencies independent of phylogeny. At least in this study, habitat density had only marginal impact on song features, which even disappeared through phylogenetic correction. Maybe most leaf warblers avoid the deterioration through sound propagation in dense vegetation by singing from exposed perches. Latitudinal (and longitudinal) extension of the breeding ranges was correlated with most song features, especially verse duration (longer polewards and westwards) and complexity (lower polewards). Climate niche or expansion history might explain these correlations. The number of different element types per verse decreases with elevation, possibly due to fewer resources and congeneric species at higher elevations.
Our study is the first to objectively assess sleep and sleep-related respiration in orchestra musicians. We hypothesized low sleep quality due to high work demands and irregular work-sleep schedules, and a better respiration for wind instrument (WI) players than string instrument (SI) players due to habitual upper airway muscles training. We recorded overnight polysomnography with 29 professional orchestra musicians (21 men, 14 WI/ 15 SI). The musicians presented a sleep efficiency of 88% (IQR 82–92%) with WI having a significant higher sleep efficiency than SI (89%, 85–93% vs. 85%, 74–89%; p = 0.029). The group had a total sleep time around 6 hours (377min, 340-421min) with signs of increased NREM 1 (light sleep) and decreased REM (dream sleep). The musicians displayed an apnea-hypopnea-index of 2.1events/hour (0.7–5.5) and an oxygen saturation of 98% (97–100%). While SI player exhibited declining sleep-related respiration with age (breathing events: r = 0.774, p = 0.001, oxygen: r = -0.647, p = 0.009), WI player showed improved respiration with age (breathing events: r = -0.548, p = 0.043; oxygen: r = 0.610, p = 0.020). Our study is the first objective investigation of sleep pattern and respiration during sleep with overnight polysomnography in professional orchestra musicians. While sleep and respiration were unexpectedly good, our results revealed possible signs of sleep deprivation and an interesting age-related pattern on respiration depending on instrument. While sample size was small and results modest, these findings present first objective evidence towards the assumption that habitual playing of a WI–and training of the upper airway muscles–may have a protective effect on respiration.
Die dynamische Entwicklung im Bereich neuer Mobilitätsdienstleistungen hat dazu geführt, dass der städtische Mobilitätsmarkt von einer hohen Dynamik und einer Vielzahl neuer Akteure gekennzeichnet ist. Smartphones und mobiles Internet unterstützen die neuen Angebote wie flexibles, stationäres oder Peer-to-Peer-Carsharing sowie Mitnahme- und Fahrradverleihsysteme. Die neuen Angebote reagieren auf eine veränderte Nachfrage, generieren aber wiederum auch neue Nutzungsmuster. Kommunale und regionale Akteure stehen vor der Aufgabe, auf die neuen Herausforderungen, die sich in räumlichen und politischen Konflikten niederschlagen können, zu reagieren. Die vorliegende Studie zeigt auf Basis einer Bestandsaufnahme von Sharing-Systemen in der Region FrankfurtRheinMain Handlungsoptionen für Vertreter aus Politik und Verwaltung auf, um die neuen Angebote im Sinne einer nachhaltigen Verkehrs- und Stadtentwicklung zu integrieren. Dabei zeigt sie zunächst die Chancen und Herausforderungen auf, die sich aus den jüngsten Entwicklungen ergeben. Anschließend folgt eine ausführliche Bestandsaufnahme, die sich in sechs Handlungsfelder gliedert: Fahrradverleihsysteme, Carsharing, Mitnahmeangebote und Mitfahrparkplätze, Verknüpfung des öffentlichen Verkehrs mit multimodalen Angeboten, multimodale Mobilitätsapps und -plattformen sowie Parken. Dabei werden Aussagen zu Angebotsformen, verkehrlichen und ökologischen Wirkungen sowie zu regionalen Entwicklungen getroffen. Anschließend werden auf Basis vorhandener Untersuchungen und im Rahmen des Projekts durchgeführter Fokusgruppen Nutzungsmuster, Bekanntheit und Attraktivität von Sharing-Systemen dargestellt. Die Handlungsempfehlungen wurden in mehreren Workshops mit regionalen Praxisakteuren aus den Bereichen Stadtverwaltung, Carsharing, Verkehrsverbund, Fahrradverleihsysteme, Mitfahrangebote etc. und vertiefenden Expertengesprächen entwickelt.
Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α‐mediated stress signaling
(2016)
Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine–threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species‐generating NADPH oxidase‐4 (Nox4) is induced downstream of ATF4, binds to a PP1‐targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4‐regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia–reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4–GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2α phosphorylation to protect tissues under stress.
Freshwater ecosystems are increasingly impacted by alien invasive species which have the potential to alter various ecological interactions like predator-prey and host-parasite relationships. Here, we simultaneously examined predator-prey interactions and parasitization patterns of the highly invasive round goby (Neogobius melanostomus) in the rivers Rhine and Main in Germany. A total of 350 N. melanostomus were sampled between June and October 2011. Gut content analysis revealed a broad prey spectrum, partly reflecting temporal and local differences in prey availability. For the major food type (amphipods), species compositions were determined. Amphipod fauna consisted entirely of non-native species and was dominated by Dikerogammarus villosus in the Main and Echinogammarus trichiatus in the Rhine. However, the availability of amphipod species in the field did not reflect their relative abundance in gut contents of N. melanostomus. Only two metazoan parasites, the nematode Raphidascaris acus and the acanthocephalan Pomphorhynchus sp., were isolated from N. melanostomus in all months, whereas unionid glochidia were only detected in June and October in fish from the Main. To analyse infection pathways, we examined 17,356 amphipods and found Pomphorhynchus sp. larvae only in D. villosus in the river Rhine at a prevalence of 0.15%. Dikerogammarus villosus represented the most important amphipod prey for N. melanostomus in both rivers but parasite intensities differed between rivers, suggesting that final hosts (large predatory fishes) may influence host-parasite dynamics of N. melanostomus in its introduced range.
Die Lincoln-Siedlung, eine ehemalige Housing Area der US-Army im Süden von Darmstadt, wird seit dem amerikanischen Truppenabzug im Jahr 2008 als autoreduziertes Wohnquartier entwickelt. Der Autobesitz der Bewohner*innen wird über eine zentrale Stellplatzvergabe mit einem Stellplatzschlüssel von 0,65 Parkplätzen pro Wohneinheit reglementiert. Gleichzeitig stehen zahlreiche Alternativen, wie eine verbesserte Fuß- und Radverkehrsinfrastruktur, eine eng getaktete ÖPNV-Verbindung in die Innenstadt, mehrere (teils vergünstigte) Carsharing- und Fahrradverleihangebote sowie eine Mobilitätsberatung zur Verfügung. Die vorliegende Studie stützt sich auf eine quantitative Haushaltsbefragung (N = 166), evaluiert die genannten Elemente alternativer Mobilität aus Bewohner*innensicht und untersucht die umzugsbedingten Veränderungen im Mobilitätsverhalten der Bewohner*innen. Diese befürworten die Maßnahmen grundsätzlich, bezweifeln jedoch teilweise deren Wirksamkeit, etwa hinsichtlich der Minderung von Verkehrsaufkommen und Schadstoffbelastung. Im Hinblick auf das Mobilitätsverhalten zeigen die Daten eine signifikante Verringerung von Besitz und Nutzung privater Pkw im Vergleich zum Zeitraum vor dem Umzug in die Lincoln-Siedlung. Die Nutzung von Carsharing-Angeboten sowie Bus und Bahn ist hingegen signifikant angewachsen. Diese Veränderungen sind hinsichtlich der überwiegend kurzen Wohndauer der befragten Personen sowie der andauernden Quartiersentwicklung bemerkenswert. Als künftige Maßnahmen konnten bessere Informationen über das Gesamtkonzept und die einzelnen Mobilitätsangebote sowie die Kommunikation von Visionen der fertiggestellten Siedlung identifiziert werden.
The introduction of robotically assisted surgery was a milestone for minimally invasive surgery in the 21st century. Currently, there are two CE-approved robotically assisted surgery systems for use and development in pediatrics. Specifically, tremor filtration and optimal visualization are approaches which can have enormous benefits for procedures in small bodies. Robotically assisted surgery in children might have advantages compared to laparoscopic or open approaches. This review focuses on the research literature regarding robotically assisted surgery that has been published within the past decade. A literature search was conducted to identify studies comparing robotically assisted surgery with laparoscopic and open approaches. While reported applications in urology were the most cited, three other fields (gynecology, general surgery, and “others”) were also identified. In total, 36 of the publications reviewed suggested that robotically assisted surgery was a good alternative for pediatric procedures. After several years of experience of this surgery, a strong learning curve was evident in the literature. However, some authors have highlighted limitations, such as high cost and a limited spectrum of small-sized instruments. The recent introduction of reusable 3 mm instruments to the market might help to overcome these limitations. In the future, it can be anticipated that there will be a broader range of applications for robotically assisted surgery in selected pediatric surgeries, especially as surgical skills continue to improve and further system innovations emerge.
Five new species of freshwater gastropods of the tateid genus Sulawesidrobia are described from the ancient Lake Matano on Sulawesi, Indonesia: S. wilsoni sp. nov., S. carsonae sp. nov., S. ehrlichi sp. nov., S. crutzeni sp. nov., and S. dinersteini sp. nov. The descriptions were based on shell morphology, anatomy as well as phylogenetic analysis using DNA sequence data of a fragment of the mitochondrial cytochrome oxidase I. All three suits of characters were included into the diagnoses. The new species formed a clade with two species from Lake Towuti, but separate from already known species from Lake Matano. The species were discovered between 2003 and 2005. However, not a single specimen of Sulawesidrobia was found when several sites were revisited in 2018 and 2019. This may be a consequence of the release of South American flowerhorn cichlid fish into the lake, in combination with heavy eutrophication of the once ultra-oligotrophic lake. It seems likely that several populations or even entire species of Sulawesidrobia in Lake Matano may be extinct. The species names given reflect this by acknowledging important conservationists.
Dieser Bericht stellt die wesentlichen Ergebnisse der sozialwissenschaftlichen und ökologischen Begleitforschung in der Modellregion Elektromobilität Rhein-Main (SÖB) dar. Dabei wird zunächst das Projektumfeld vorgestellt, indem auf die Rahmenbedingungen des Förderprogramms sowie weitere Programme und Projekte im Bereich Elektromobilität eingegangen wird. Im zweiten Kapitel wird das Projektkonsortium und dessen Einbettung in die Modellregion Rhein-Main erläutert, sowie die Verknüpfung mit der überregionalen Begleitforschung der Nationalen Organisation Wasser- und Brennstoffzellentechnologie (NOW). Im Kapitel 3 wird das Forschungsdesign der SÖB skizziert. Dazu werden einige Erkenntnisse aus der ersten Förderperiode beleuchtet, die für die Forschungsziele der aktuellen Förderperiode ausschlaggebend waren. Des Weiteren erfolgt eine Ausführung der methodischen Vorgehensweisen der Projektpartner. Das darauf folgende Kapitel 4 stellt die wesentlichen Ergebnisse des Projekts dar. Dabei wurde bewusst versucht, die verschie¬denen Erkenntnisse der einzelnen Partner thematisch miteinander zu verknüpfen. Aus den Ergeb¬nissen wurden Handlungsempfehlungen für verschiedene Bereiche und Akteure generiert, die in Kapitel 5 einfließen. Abschließend rundet ein Fazit mit zusammenfassenden Erkenntnissen den Bericht ab.
Endocrine disrupting chemicals (EDCs) are man-made compounds interfering with hormone signaling and thereby adversely affecting human health. Recent reports provide evidence for the presence of EDCs in commercially available bottled water, including steroid receptor agonists and antagonists. However, since these findings are based on biological data the causative chemicals remain unidentified and, therefore, inaccessible for toxicological evaluation. Thus, the aim of this study is to assess the antiestrogenic and antiandrogenic activity of bottled water and to identify the causative steroid receptor antagonists. We evaluated the antiestrogenic and antiandrogenic activity of 18 bottled water products in reporter gene assays for human estrogen receptor alpha and androgen receptor. Using nontarget high-resolution mass spectrometry (LTQ-Orbitrap Velos), we acquired corresponding analytical data. We combined the biological and chemical information to determine the exact mass of the tentative steroid receptor antagonist. Further MS(n) experiments elucidated the molecule's structure and enabled its identification. We detected significant antiestrogenicity in 13 of 18 products. 16 samples were antiandrogenic inhibiting the androgen receptor by up to 90%. Nontarget chemical analysis revealed that out of 24520 candidates present in bottled water one was consistently correlated with the antagonistic activity. By combining experimental and in silico MS(n) data we identified this compound as di(2-ethylhexyl) fumarate (DEHF). We confirmed the identity and biological activity of DEHF and additional isomers of dioctyl fumarate and maleate using authentic standards. Since DEHF is antiestrogenic but not antiandrogenic we conclude that additional, yet unidentified EDCs must contribute to the antagonistic effect of bottled water. Applying a novel approach to combine biological and chemical analysis this is the first study to identify so far unknown EDCs in bottled water. Notably, dioctyl fumarates and maleates have been overlooked by science and regulation to date. This illustrates the need to identify novel toxicologically relevant compounds to establish a more holistic picture of the human exposome.
In der vorliegenden Studie werden Heuschreckengemeinschaften durch quantitative Erfassungen in feinstrukturell untersuchten Habitaten detailliert beschrieben. Wichtige Merkmale sind dabei Stetigkeit und Dominanz einzelner Heuschreckenarten bzw. Deckung, Höhe und Dichte der Vegetation in den Lebensräumen.
Für sechs Strukturtypen aus Silikatmagerrasen und Grünland trockener Standorte erfolgt die Abgrenzung von Heuschreckengemeinschaften nach dem Leitartenprinzip. Die „Gemeinschaft der Schiefergrusfluren“ (Typ 1) besiedelt sehr lückige Magerrasen und ist artenarm mit Myrmeleotettix maculatus als eudominanter Leitart. Weitere fünf Zönosen unterscheiden sich durch das Vorkommen der phytophilen Differentialarten Chorthippus parallelus und Omocestus viridulus von den Schiefergrusfluren: Die „Gemeinschaft der offenen, niedrigen Horstgrasrasen“ (Typ 2) wird charakterisiert durch die hochstete, eudominante Leitart Stenobothrus stigmaticus. Zwei Zönosen, in denen Stenobothrus lineatus als gemeinsame Leitart hochstet vorkommt, lassen sich für „dichte, niedrige Horstgrasrasen“ (Typ 3) abgrenzen. Auf extensiv beweideten Flächen (Typ 3.1) kommen Stenobothrus nigromaculatus, S. stigmaticus und Decticus verrucivorus als weitere Leitarten vor; diese Arten fehlen auf Brachen (Typ 3.2). Mit Chorthippus parallelus und C. biguttulus sind zwei eurytope Heuschrecken in „dichten, hohen Horstgrasbeständen“ (Typ 4) hochstet; Leitarten hat dieser Strukturtyp nicht. Metrioptera roeselii kennzeichnet als Differentialart „dichte Obergrasbestände“ (Typ 5).
Die Besiedlungsschwerpunkte einzelner Arten in verschiedenen Strukturtypen sind auf die Habitatpräferenzen der Heuschrecken zurückzuführen. Auch die Bewirtschaftung ist entscheidend. Sie beeinflusst die Raumstruktur und damit das Mikroklima und wirkt sich auf die Populationsdynamik der Heuschrecken aus. Mit steigender Nutzungsintensität kommt es zu einer starken Abnahme der Individuendichten.
Schriftenschau
(2011)
Background: In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision.
Methods: Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP.
Results: The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs’ decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48–0.59; ORs per country 0.11–1.78).
Conclusions: Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making.
Background: Pediatric community acquired pneumonia (pedCAP) is one of the leading causes for childhood morbidity accounting for up to 20% of pediatric hospital admissions in high income countries. In spite of its high morbidity, updated epidemiological and pathogen data after introduction of preventive vaccination and novel pathogen screening strategies are limited. Moreover, there is a need for validated recommendations on diagnostic and treatment regimens in pedCAP. Through collection of patient data and analysis of pathogen and host factors in a large sample of unselected pedCAP patients in Germany, we aim to address and substantially improve this situation.
Methods: pedCAPNETZ is an observational, multi-center study on pedCAP. Thus far, nine study centers in hospitals, outpatient clinics and practices have been initiated and more than 400 patients with radiologically confirmed pneumonia have been enrolled, aiming at a total of 1000 study participants. Employing an online data base, information on disease course, treatment as well as demographical and socioeconomical data is recorded. Patients are followed up until day 90 after enrollment; Comprehensive biosample collection and a central pedCAPNETZ biobank allow for in-depth analyses of pathogen and host factors. Standardized workflows to assure sample logistics and data management in more than fifteen future study centers have been established.
Discussion: Through comprehensive epidemiological, clinical and biological analyses, pedCAPNETZ fills an important gap in pediatric and infection research. To secure dissemination of the registry, we will raise clinical and scientific awareness at all levels. We aim at participating in decision making processes for guidelines and prevention strategies. Ultimately, we hope the results of the pedCAPNETZ registry will help to improve care and quality of life in pedCAP patients in the future.
Feeding exclusively on blood, vampire bats represent the only obligate sanguivorous lineage among mammals. To uncover genomic changes associated with adaptations to this unique dietary specialization, we generated a new haplotype-resolved reference-quality genome of the common vampire bat (Desmodus rotundus) and screened 26 bat species for genes that were specifically lost in the vampire bat lineage. We discovered previously-unknown gene losses that relate to metabolic and physiological changes, such as reduced insulin secretion (FFAR1, SLC30A8), limited glycogen stores (PPP1R3E), and a distinct gastric physiology (CTSE). Other gene losses likely reflect the biased nutrient composition (ERN2, CTRL) and distinct pathogen diversity of blood (RNASE7). Interestingly, the loss of REP15 likely helped vampire bats to adapt to high dietary iron levels by enhancing iron excretion and the loss of the 24S-hydroxycholesterol metabolizing enzyme CYP39A1 could contribute to their exceptional cognitive abilities. Finally, losses of key cone phototransduction genes (PDE6H, PDE6C) suggest that these strictly-nocturnal bats completely lack cone-based vision. These findings enhance our understanding of vampire bat biology and the genomic underpinnings of adaptations to sanguivory.
Treatment with inhibitors of the receptor tyrosine kinase FLT3 are currently studied as promising therapies in acute myeloid leukemia (AML). However, only a subset of patients benefit from these treatments and the presence of activating mutations within FLT3 can predict response to a certain extent only. ...