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BH3 mimetics are novel anticancer therapeutics that induce apoptosis by targeting anti‐apoptotic BCL‐2 proteins. Highly specific inhibitors of the main anti-apoptotic proteins BCL-2, BCL‐XL and MCL‐1 promise new opportunities for the treatment of AML. However, it is currently unclear which of these anti-apoptotic BCL-2 proteins represents the most promising target in AML. Therefore, we investigated the effect of BH3 mimetics targeting either BCL-2 (ABT-199, S55746), BCL-XL (A-1331852) or MCL-1 (S63845) on eleven AML cell lines. Drug sensitivity screening revealed heterogeneous sensitivity towards the different BH3 mimetics, with the best responses observed upon targeting of MCL-1. Selected cell lines that displayed sensitivity towards the specific BH3 mimetics underwent intrinsic apoptosis, which was characterized by loss of mitochondrial membrane potential, exposure of phosphatidylserine and activation of caspases. Furthermore, S63845 turned out to displace BIMS and NOXA from MCL-1 to induce apoptotic cell death. Importantly, the translational relevance of this study was demonstrated by experiments in primary AML blasts, which displayed similar sensitivity towards BH3 mimetics as the cell lines did. Additionally, experiments with nonmalignant cells could confirm the clinical relevance of the MCL-1 inhibitor. There we could show, that S63845 does not cause cytotoxicity on HPCs at efficacious doses.
In conclusion, our findings reveal that the inhibition of BCL-2 proteins, especially MCL-1, by BH3 mimetics can be a promising strategy in AML treatment.
Two salts of the 6,6-difluoro-6H-dibenzo[c,e][1,2]oxaborinin-6-ide anion with different cations
(2020)
The crystal structures are reported of the 6,6-difluoro-6H-dibenzo[c,e][1,2]oxaborinin-6-ide (or 9,9-difluoro-10-oxa-9-boraphenanthren-9-ide) anion with two different cations, namely, potassium 6,6-difluoro-6H-dibenzo[c,e][1,2]oxaborinin-6-ide, K+·C12H8BF2O−, (II), featuring a polymeric structure, and bis(tetraphenylphosphonium) bis(6,6-difluoro-6H-dibenzo[c,e][1,2]oxaborinin-6-ide) acetonitrile trisolvate, 2C24H20P+·2C12H8BF2O−·3CH3CN, (III), which is composed of discrete cations, anions and acetonitrile solvent molecules linked by C—H...O, C—H...N and C—H...F hydrogen bonds. There are only minor differences in the geometrical parameters of the anions in these structures.
Study design: Systematic review. Background and objectives: Preoperative neuromuscular function is predictive for knee function and return to sports (RTS) after reconstruction of the anterior cruciate ligament (ACL). The aim of this review was to examine the potential benefits of prehabilitation on pre-/postoperative objective, self-reported and RTS-specific outcomes. Methods: A systematic search was conducted within three databases. From the 1.071 studies screened, two randomized control trials (RCTs), two control trials (CTs) and two cohort studies (CS) met the inclusion criteria. Methodological quality rating adopted the PEDro- (RCT, CT) or Newcastle-Ottawa-Scale (CS). Results and conclusions: Methodological quality of the included studies was moderate (PEDro score: 6.5 ± 1.7; range 4 to 9). Two studies reported higher increases of the maximal quadriceps torque from baseline to pre-reconstruction: one study in the limb symmetry index (LSI), and one in both legs of the prehabilitation group compared to the controls. At 12-weeks post-reconstruction, one study (from two) indicated that the prehabilitation group had a lesser post-operative decline in the single-leg-hop for distance LSI (clinically meaningful). Similar findings were found in terms of quadriceps strength LSI (one study). At both pre-reconstruction (three studies) and two-year post-surgery (two studies), the prehabilitation groups reached significantly higher self-reported knee function (clinically meaningful) than the controls. RTS tended to be faster (one study). At two years post-surgery, RTS rates (one study) were higher in the prehabilitation groups. The results provide evidence for the relevance of prehabilitation prior to ACL-reconstruction to improve neuromuscular and self-reported knee function as well as RTS. More high quality confirmatory RCTs are warranted.
Die angespannte Lage am Wohnungsmarkt hat in vielen Städten eine neue Welle von Verdrängungsprozessen induziert und insbesondere die Situation einkommensschwacher Haushalte häufig prekär werden lassen. Angesichts dieser Entwicklungen haben sich vielerorts mietenpolitische Bewegungen konstituiert, die sich für eine Abkehr von einer neoliberalisierten und zunehmend finanzialisierten Wohnungsversorgung einsetzen. Lisa Vollmer nimmt in ihrer Forschungsarbeit zwei solcher Bewegungen in den Blick und fragt danach, wie sich politische Kollektivität in den alltäglichen Praktiken von Mieter*innen in Berlin bzw. New York formiert.
Weiß, Ulrike ; Möller, Moritz ; Husseini, Sayed Adham ; Manderscheid, Christine ; Häusler, Julia ; Geisslinger, Gerd ; Niederberger, Ellen
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.
Objectives: The ongoing coronavirus pandemic is challenging, especially in severely affected patients who require intubation and sedation. Although the potential benefits of sedation with volatile anesthetics in coronavirus disease 2019 patients are currently being discussed, the use of isoflurane in patients with coronavirus disease 2019–induced acute respiratory distress syndrome has not yet been reported. Design: We performed a retrospective analysis of critically ill patients with hypoxemic respiratory failure requiring mechanical ventilation. Setting: The study was conducted with patients admitted between April 4 and May 15, 2020 to our ICU. Patients: We included five patients who were previously diagnosed with severe acute respiratory syndrome coronavirus 2 infection. Intervention: Even with high doses of several IV sedatives, the targeted level of sedation could not be achieved. Therefore, the sedation regimen was switched to inhalational isoflurane. Clinical data were recorded using a patient data management system. We recorded demographical data, laboratory results, ventilation variables, sedative dosages, sedation level, prone positioning, duration of volatile sedation and outcomes. Measurements & Main Results: Mean age (four men, one women) was 53.0 (± 12.7) years. The mean duration of isoflurane sedation was 103.2 (± 66.2) hours. Our data demonstrate a substantial improvement in the oxygenation ratio when using isoflurane sedation. Deep sedation as assessed by the Richmond Agitation and Sedation Scale was rapidly and closely controlled in all patients, and the subsequent discontinuation of IV sedation was possible within the first 30 minutes. No adverse events were detected. Conclusions: Our findings demonstrate the feasibility of isoflurane sedation in five patients suffering from severe coronavirus disease 2019 infection. Volatile isoflurane was able to achieve the required deep sedation and reduced the need for IV sedation.
We explore the tilted-pulse-front excitation technique to control the superradiant emission of terahertz (THz) pulses from large-area photonconductive semiconductor switches. Two cases are studied. First, a photoconductive antenna emitting into free space, where the propagation direction of the optically generated THz beam is controlled by the choice of the tilt angle of the pump pulse front. Second, a THz waveguide structure with an integrated photoconductive window for the generation of THz radiation, where the injection of the THz radiation into a waveguide mode is optimized by the pulse front tilt. By providing long interaction lengths, such a waveguide-based optical-pump/THz-probe set-up may provide a new platform for the study of diverse short-lived optically induced excitations.
Motivated by the question of whether and how wave–wave interactions should be implemented into atmospheric gravity-wave parametrizations, the modulation of triadic gravity-wave interactions by a slowly varying and vertically sheared mean flow is considered for a non-rotating Boussinesq fluid with constant stratification. An analysis using a multiple-scale WKBJ (Wentzel–Kramers–Brillouin–Jeffreys) expansion identifies two distinct scaling regimes, a linear off-resonance regime, and a nonlinear near-resonance regime. Simplifying the near-resonance interaction equations allows for the construction of a parametrization for the triadic energy exchange which has been implemented into a one-dimensional WKBJ ray-tracing code. Theory and numerical implementation are validated for test cases where two wave trains generate a third wave train while spectrally passing through resonance. In various settings, of interacting vertical wavenumbers, mean-flow shear, and initial wave amplitudes, the WKBJ simulations are generally in good agreement with wave-resolving simulations. Both stronger mean-flow shear and smaller wave amplitudes suppress the energy exchange among a resonantly interacting triad. Experiments with mean-flow shear as strong as in the vicinity of atmospheric jets suggest that internal gravity-wave dynamics are dominated in such regions by wave modulation. However, triadic gravity-wave interactions are likely to be relevant in weakly sheared regions of the atmosphere.
Aim: The aim of this study is to utilize the niche measurement guidelines outlined by Jordans et al. in order to establish normal values and accurate description of caesarean section scars in a normal population. After defining the normal distribution, abnormal pregestational scar characteristics will be identified for predicting adverse pregnancy outcomes. Methods: This is a prospective observational multicenter clinical study where women with a history of only one caesarean section and yet open family planning are enrolled. The uterine length, cervical length, niche length, niche depth, niche width, residual myometrial thickness, endometrial thickness, scar to internal os distance, anterior myometrial thickness superior and inferior to the scar and the posterior myometrial thickness opposite the scar, superior and inferior to it are measured in a pregestational uterus. The lower uterine segment is measured over a length of 3 cm during subsequent pregnancy and followed up until delivery. Results: Data from 500 patients will yield normal distribution curves for all predefined measurements. Establishing a correlation between deviations from the normal measures and adverse events would be instrumental for counseling women regarding subsequent pregnancy and mode of delivery.
Conclusion: This study will demonstrate the changes of the post-caesarean scar from a non-pregnant uterus until delivery and can confirm the importance of the scar characteristics in predicting pregnancy outcome.
Pinter, Andreas ; Hoffmann, Matthias ; Reich, Kristian ; Augustin, Matthias ; Kaplan, Kadriye ; Gudjónsdóttir, Sigrún Dögg ; Delvin, Thomas ; Mrowietz, Ulrich
Background: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis. Objectives: To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes and safety in subjects with moderate-to-severe plaque psoriasis who were naïve to systemic treatment. Methods: Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24-week, open-label, assessor-blinded, multi-centre, head-to-head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non-responders. Results: A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab. Conclusions: Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate-to-severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic-naïve subjects over 24 weeks.
Die Sonografie wird als primäre Untersuchungsmethode zur Abklärung vielfältiger Krankheitsbilder eingesetzt und hat sich auch in Leitlinien etabliert. Die Rolle der Sonografie in der Geriatrie ist weniger bekannt und nicht systematisch untersucht.
Ziel der Studie war die Evaluierung der Sonografie als routinemäßig eingesetztes Verfahren und erweiterte körperliche Untersuchung bei geriatrischen Patienten in der medizinischen Akutversorgung. Alle sogenannten geriatrischen Assessments und auch die Sonografie als Screening-Untersuchung erfolgten unabhängig von der Symptomatik des geriatrischen Patienten. Die Befunde wurden mit einem hand-held ultrasound device (HHUSD) und einem high-end ultrasound (HEUS) erhoben und dann verglichen. Die HEUS-Ergebnisse wurden als Goldstandard angesehen. Die Untersuchungen mit HEUS erfolgten meist zu einem späteren Zeitpunkt als mit HHUSD; in der Regel in einem Zeitraum von bis zu sieben Tagen.
Es handelt sich um eine prospektive Studie, die 86 Patienten in einem Zeitraum von 10 Monaten eingeschlossen hat. Die Untersucherin und Doktorandin stellte Folgendes dar: Das Abdomen und die basalen Abschnitte des Thorax sowie die Schilddrüse. Zusätzlich erfolgte eine elastografische Untersuchung der Leber mittels FibroScan.
Die Ultraschalluntersuchung war bei 22/86 (25,6 %) Patienten aufgrund der Symptomatik indiziert und erfolgte bei 64/86 (74,4 %) Patienten als Screening, also ohne klinische Fragestellung. Die Indikationen der Untersuchungen waren: Tumorsuche (8/86 (9,3 %)), Anämie (5/86 (5,8 %)), Leberwert-Erhöhung (5/86 (5,8 %)), Dyspnoe (5/86 (5,8 %)), Frage nach Milzpathologien (2/86 (2,3 %)), Gewichtsverlust (1/86 (1,2 %)), Infektfokussuche (1/86 (1,2 %)), Durchfall (1/86 (1,2 %)), Frage nach intraabdominalem Hämatom (1/86 (1,2 %)) und Kontrolle bei bekanntem Bauchaortenaneurysma (1/86 (1,2 %)). Bei einigen Patienten kamen mehrere Fragestellungen vor.
Die Befunde, die am häufigsten gefunden wurden, waren: Cholezystolithiasis (28/86 (32,6 %); mit HHUSD 5 falsch negative Ergebnisse), rechtsseitiger Pleuraerguss (27/86 (31,4 %); 5 falsch positive Ergebnisse mit HHUSD), Schilddrüsenknoten (26/86 (30,2 %); 2 falsch negative und 1 falsch positiver Befunde mit HHUSD), Nierenzysten (24/86 (27,9 %); 6 falsch negative Ergebnisse mit HHUSD) und Fettleber (23/86 (26,7 %); 3 falsch negative Befunde mit HHUSD). Von 64/86 (74,4 %) untersuchten Patienten ergab sich bei 8/86 (9,3 %) eine therapeutische Konsequenz. Die wichtigsten Befunde, die mit HHUSD übersehen wurden waren: 2 zystische Formationen im Pankreas (2/86 (2,3 %); mit HEUS insgesamt (6/86 (7,0 %)), eine Lebezirrhose (mit HEUS 2/86 (2,3 %)), eine Choledocholithiasis (1/86 (1,2 %); mit HEUS 2/86 (2,3 %)) und ein Lungeninfiltrat (1/86 (1,2 %); mit HEUS 2/86 (2,3 %)). Alle übersehenen Befunde hatten keine dringende therapeutische Konsequenz, so dass die point of care Sonografie (POCUS) hier ausreichend war, um die „ja/nein“-Fragen zu klären.
Bei 65/86 (75,6 %) Patienten war eine Messung der Lebersteifigkeit mittels FibroScan erfolgreich.
Es gab keine Interobserver-Variabilität. Die Untersucherin war eine Fachärztin für Innere Medizin aber keine DEGUM-ausgebildete Ultraschallerin.
Insgesamt zeigte sich eine ausreichende bis gute Übereinstimmung der erhobenen Befunde zwischen HHUSD und HEUS. Die POCUS-Untersuchung lieferte in den meisten Fällen eine Antwort auf die häufigsten Fragestellungen in der Geriatrie (wie Hydratationsstatus, Harnverhalt). Weiterhin konnte die Behandlung bei zufällig gescreenten Patienten optimiert werden. Zur Bestimmung der Organgröße konnte ebenfalls eine gute Korrelation der beiden Geräte festgestellt werden, so dass sich die alleinige Untersuchung mit HHUSD in diesen Fällen ausreichend gezeigt hätte. Ein routinemäßiger Einsatz der Sonografie in der Geriatrie muss in weiteren Studien untersucht werden. Da es sich bei geriatrischen Patienten um multimorbide Patienten mit entsprechend angepassten therapeutischen Zielen handelt, hatten mehrere der erhobenen Befunde in dieser Studie zum Zeitpunkt der geriatrischen Behandlung keine therapeutische Konsequenz.
GLC Newsletter 1/2020
(2020)
At the beginning of the 1980s, an increased frequency of immune deficiency was discovered in a population of homosexual men, which is nowadays known as the Acquired Immune Deficiency Syndrome (AIDS). A few years later, the retro virus Human Immunodeficiency Virus 1(HIV-1) has been discovered as the cause of AIDS. Since the beginning of the pandemic, more that 74 million people have become infected and more than 32 million people died. In 2018, it was estimated that 38 million people where living with HIV-1 of which 24.5 million had access to Highly Active Antiretroviral Therapy (HAART), which blocks viral replication and prevents the progression towards AIDS. In the most cases an HIV-1 infection leads to the patient’s death within a few years Without HAART.
Taken together, this thesis shows that hematopoietic stem and progenitor cells harbor the prerequisites and characteristics to form an HIV-1 reservoir in vivo. The subsets of HSCs, MPPs and CD34+CD38+ progenitors harbor CD4 & CXCR4 double-positive cells as well as a lower amount of CD4 & CCR5 doublepositive cells. In addition, the susceptibility to X4-tropic HIV-1 is shown in vitro. Susceptibility to R5-tropic HIV-1 is only seen to a very low amount for CD34+CD38+ progenitors. The results also show that transduced HSPCs are capable to pass on integrated viral genomes via proliferation and differentiation during in vitro colony formation. More over the experiments provide evidence that this can take place for long time span as the outcome of the replating assays shows. Ex vivo analysis of HSPCs isolated from PLHIV also suggests that these cells are susceptible to HIV-1. Proviral DNA detection using a nested PCR showed infection of Lin- cells of a single donor with an R5-tropic subtype B HIV-1 clone. However, the assay could not detect infection of CD34+ cells. The
received results of this thesis are in agreement with previously published results. Albeit the obvious susceptibility to HIV-1 and existing reports of viral survival within HSPCs for several years, the low frequency of detected in vivo infected HSPCs could be related to the cytopathic effects of HIV-1 during replication resulting in cell death of potentially infected CD34+ cells. Other reasons could be associated with assay sensitivity or the small number of available patient samples. This makes hematopoietic stem and progenitor cells a target, which can be infected by HIV-1. The role and the clinical relevance of hematopoietic stem and progenitor cells in contribution to the latent viral HIV-1 reservoir within an HIV-1 infected patient needs to be further analyzed.
Climate controls the broad-scale distribution of vegetation and change in climate will alter the vegetation distribution, biome boundaries, biodiversity, phenology and supply of ecosystem services. A better understanding of the consequences of climate change is required, particularly in under-investigated regions such as tropical Asia, i.e., South and South-east Asia, which is a host to 7 of the 36 global biodiversity hotspots. Conservation strategies would also require an in-depth understanding of the response of vegetation to climate change. Therefore, the main objective of this thesis was to investigate the impact of climate change and rising CO2 vegetation in tropical Asia. Dynamic global vegetation model (DGVMs) are the well-known tools to investigate vegetation-climate interactions and climate change impacts on ecosystems. In this thesis, I used a complex trait-based DGVM called adaptive dynamic vegetation model version 2 (aDGVM2).
In Chapter 1, I presented a brief background of the phytogeography and discussed the exiting knowledge gap on vegetation-climate interactions in the region. One major disadvantage for available DGVMs studies for the tropical Asia is that most of them have used fixed plant functional types (PFTs) and do not explicitly represent the distinct varieties of vegetation type of the region such as Asian savannas. In Chapter 2, I discussed at great length to improve DGVMs for South Asia and discussed ways to include them in the model for better representation of region vegetation-climate interaction.
I upgraded the current version of aDGVM2 and added a new vegetation type i.e., C3 grasses, and modified the sub-module to simulate photosynthesis for each individual plants to aDGVM2. In chapter 3, I used this updated version of aDGVM2 to simulate the current and future vegetation distribution in South Asia under RCP4.5 and RCP8.5 (RCP: representative concentration pathway). The model predicted an increase in biomass, canopy cover, and tree height under the presence of CO2 fertilization, which triggered transitions towards tree-dominated biomes by the end of the 21st century under both RCPs. I found that vegetation along the Western Ghats and the Himalayas are more susceptible to change due to climate change and open biomes such as grassland and savanna are prone to woody encroachment.
In Chapter 4, the study domain was extended to include South-east Asia to verify if the model configuration used in Chapter 3 can also simulate vegetation patterns in tropical Asia. The aDGVM2 simulations showed a robust trend of increasing vegetation biomass and transitions from small deciduous vegetation to taller evergreen vegetation across most of tropical Asia. Shifts in plant phenology also affect ecosystem carbon cycles and ecosystem feedback to climate, yet the quantification of such impacts remains challenging. The study showed increased biomass due to CO2 fertilization, indicates that the region can remain a carbon sink given there is no other resource limitation. However, nutrient limitations on CO2 fertilization effects were not included in the study, and carbon sink potential has to be seen with caution.
In Chapter 5, I focused on Asian savannas, which have been mismanaged since the colonial era due to misinterpretation as a degraded forest. I proposed a biome classification scheme to distinguish between degraded forest or woodland and savanna based on the abundance of grass biomass and canopy cover. I found that considering vegetation systems as woodland or degraded forest could easily be mistaken as a potential for forest restoration within a tree-centric perspective. This would put approximately 35% to 40% of a unique savanna biome at risk. Although projected woody encroachments may imply a transition toward the forest that benefits climate mitigation. This raises potential conflicts of interest between biodiversity conservation in open ecosystems, i.e., savanna and active afforestation, to enhance carbon sequestration. Proper management strategies should be taken into account to maintain a balance for both objective
In conclusion, the model predicted that vegetation in South and South-East Asia would significantly shift towards tree-dominated biomes due to CO2-induced fertilization of C3-photosynthesis. The simulation under fixed CO2 and rising CO2 scenarios clearly showed that rising level of atmospheric CO2 is responsible for most of the predicted change in biome properties. This study is an important step towards understanding ecosystems of South and Southeast Asia, specifically savannas. The aDGVM2 can serve as tools to inform decision making for climate adaptation and mitigation for savanna. The thesis, thus contributes to our ability to improve conservation strategies to mitigate the consequences of climate change.
Das Vorkommen von Kunststoffmaterialien <5 mm, sogenanntem Mikroplastik
(MP), in marinen Ökosystemen wurde bereits eingehend untersucht. Im Gegensatz dazu existieren erhebliche Wissenslücken hinsichtlich der Abundanz und der Auswirkung von MP in limnischen Ökosystemen. Vor diesem Hintergrund steht das Umweltvorkommen, mögliche Eintragspfade und die Auswirkungen von MP auf aquatische Invertebraten im Fokus dieser Arbeit. Zur Bestimmung der MP-Abundanz in Fließgewässern sind Sedimente der Elbe untersucht worden. Hierfür wurde zunächst eine Methode zur Extraktion und Identifizierung von MP aus Umweltproben entwickelt, optimiert und validiert. In der anschließenden Analyse konnten in elf Probenahmestellen 55–17400 MP kg-1 in den Sedimenten nachgewiesen werden. Der Einfluss der Gezeitenströmung wurde anhand der abnehmenden MP-Abundanz in der Tideelbe deutlich. Insgesamt weisen die Ergebnisse darauf hin, dass Sedimente von Fließgewässern eine Senke für MP darstellen. Für die Evaluation von Eintragspfaden von MP in Oberflächengewässer wurden die
Einleiter von fünf Kläranlagen beprobt und 240–897 MP m-3 in den Einleitern detektiert. Die Detailuntersuchung einer Kläranlage zeigte, dass >99% der MP-Fracht im Verlauf der Abwasseraufbereitung entfernt wird. Hierbei erfolgte die Hauptentfernung
bereits in der Vorklärung. Somit stellen Kläranlagen effektive Barrieren für den Eintrag von MP dar.
Insgesamt wird ersichtlich, dass die getesteten Arten C. riparius und G. pulex relativ insensitiv gegenüber einer MP-Exposition sind. So konnten bei G. pulex keine und bei C. riparius erst bei sehr hohen MP-Konzentrationen adverse Effekte detektiert werden. Hierbei ist die Autökologie der Spezies eine mögliche Erklärung für die Toleranz gegenüber partikulären Stressoren. Auf Basis dieser Daten sowie der ermittelten MPAbundanz kann das Umweltrisiko von MP in limnischen Ökosystemen vorläufig als
gering eingeschätzt werden. Hierbei gilt es jedoch zu beachten, dass eine abschließende
Bewertung aufgrund der nach wie vor existierenden Unsicherheiten nicht möglich ist. Diese Unsicherheiten betreffen die Umweltkonzentration von MP <80 μm, das Verhaltensowie das Wirkpotential dieser heterogenen und dynamischen Stressorenklasse
in umweltrelevanten Szenarien.
Zielstellung: Es sollte im Rahmen dieser Arbeit geprüft werden ob (1) ein Zusammenhang zwischen einer radiologischen Beinlängendifferenz und einer veränderten Hüft- bzw. Kniegelenksbelastung bei Coxarthrosepatienten besteht. Des Weiteren galt es zu prüfen (2) ob die radiologisch-anatomische Beinachse bei Coxarthrosepatienten einen Einfluss auf die Gelenksbelastung von Hüfte und Knie habe und (3) ob sich in diesem Zusammenhang Unterschiede zwischen unilateral und bilateral betroffenem Patientenkollektiv darstellen ließe.
Hintergründe: Es konnte bereits gezeigt werden, dass Coxarthrosepatienten ein verändertes Gangbild aufweisen. Diese Veränderungen sind mitverantwortlich für eine veränderete Gelenkbelastung sowohl in Knie als auch Hüfte, sowohl im Vergleich zwischen betroffener und nicht betroffener Seite als auch im Vergleich zu hüftgesunden Normprobanden. Insbesondere bezüglich der Kniegelenksbelastung konnte bei den Betroffenen ein reduziertes Knieadduktionsmoment (KAM) während der Standphase nachgewiesen werden. Dies steht im Einklang mit der Beobachtung, dass Coxarthrosepatienten vermehrt eine laterale Kniearthrose auf der ipsilateralen Seite entwickeln. Coxarthrosepatienten zeigten darüber hinaus eine veränderte Beinachse, mit einer Tendenz hin zu einer Valgusfehlstellung. In wieweit insbesondere die proximale Beinachse einen Einfluss auf die alterierten Gelenkmomente hat, bleibt bislang jedoch offen. Zu bilateralen Patienten sind darüber hinaus nur wenige Daten vorliegend.
Methoden: Um die oben genannten Hypothesen zu prüfen wurden bei insgesamt 29 Patienten, bei welchen die Indikation für eine Hüfttotalendoprothese aufgrund einer fortgeschrittenen Coxarthrose gestellt wurde, eine instrumentelle Bewegungsanalyse sowie eine biplanare EOSRöntgenaufnahme, welche in diesem Zusammenhang die konventionelle präoperative Planungsaufnahme ersetzte, durchgeführt. Anschließend wurden die Daten, die aus der 3D EOS Rekonstruktion über die Beinachse gewonnen wurden, sowie die Ergebnisse der Bewegungsanalyse mit bereits zuvor erhobenen Normdaten sowie untereinander verglichen und statistisch analysiert.
Ergebnisse: Es zeigte sich, dass die Patienten eine bis auf MFA nicht von der Norm abweichende Beinachse hatten. Die bilateralen zeigten eine signifikant größere Beinlängendifferenz als die Norm, die unilateralen Patienten jedoch diesbezüglich keine Abweichung. Insgesamt zeigten die Patienten ein verändertes Gangbild, welches weitgehend den bereits in der Literatur beschriebenen Veränderungen entsprach.
Bezüglich der Gelenkmomente zeigte sich ein im Vergleich zur Norm erniedrigtes KAM 2, die übrigen Gelenkmomente zeigten keine Abweichungen von der Norm.
Es zeigten sich weder für die Beinachse noch für die Gelenkmomente signifikante Unterschiede zwischen unilateralem und bilateralem Patientenkollektiv.
Die unilateralen Patienten als gesamtes zeigten keine Korrelationen mit der absoluten Beinlängendifferenz. In einer unilateralen Subgruppe, in der die betroffene Seite länger war, konnte eine inverse Korrelation mit HAM 1 und HAM 2 gefunden werden.
KAM 1 und KAM 2 korrelierten signifikant mit allen Beinachsenparametern. In einer schrittweisen Regressionsanalyse mit HKA, FO und MFA konnten damit 68% der KAM 1 Alterationen und 57,5 % der Veränderungen von KAM 2 erklärt werden. HAM 1 und HAM 2 zeigten jeweils eine signifikante Korrelation mit MFA.
Schlussfolgerung: Die vorliegenden Ergebnisse zeigen, dass die Beinachse, insbesondere das Offset, einen Teil der Veränderungen der Kniegelenksbelastung erklären. Eine intraoperative Vergrößerung des Offsets und damit eine Varisierung der Beinachse könnte möglicherweise so zu einer Normalisierung der Kniegelenksbelastung führen.
Bergmann, Lothar ; Grünwald, Viktor ; Maute, Luise ; Grimm, Marc-Oliver ; Weikert, Steffen ; Schleicher, Jan ; Klotz, Theodor ; Greiner, Jochen ; Flörcken, Anne ; Hartmann, Arndt ; Gauler, Thomas
Background: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. Methods: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. Results: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65–4.18) in favor of SUN. There was no trend for overall survival. Conclusions: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.