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ABSTRACT
The Upper Pleistocene geoarchives in the south‐eastern Carpathian Basin are represented predominantly by loess–palaeosol records. In 2015, a 10 m sediment core composed of clay‐rich lacustrine sediments was recovered by vibracoring a dry lake basin located between the Vršac Mountains (Serbia) and the Banat Sands in the south‐eastern Carpathian Basin; a location relevant for placing regional archaeological results in a palaeoenvironmental context. Here, we present results from geoelectrical prospection and a lithostratigraphic interpretation of this sequence supported by a detailed granulometric study supplemented by ostracod analysis. An age model based on luminescence dating is discussed against sedimentological proxy data and its implication for palaeoenvironmental change. The cores show a stratigraphy of lighter ochre‐coloured and darker greyish sediment, related to the deposition of clay and silt trapped in an aquatic environment. Geophysical measurements show ~20 m thick lacustrine sediments. The grain‐size distributions including the variability in fine clay are indicative of a lacustrine environment. Fine particles were brought into the depositional environments by aquatic input and settled from suspension; also, direct dust input is constrained by grain‐size results. Riverine input and aeolian dust input interplayed at the locality.
Baltic coastal lagoons are severely threatened by eutrophication. To evaluate the impact of eutrophication on macrophytobenthos, we compared the seasonal development in macrophytobenthic composition, biomass and production, water column parameters (light, nutrients), phytoplankton biomass and production in one mesotrophic and one eutrophic German coastal lagoon. We hypothesized that light availability is the main driver for primary production, and that net primary production is lower at a higher eutrophication level. In the mesotrophic lagoon, macrophytobenthic biomass was much higher with distinct seasonal succession in species composition. Filamentous algae dominated in spring and late summer and probably caused reduced macrophytobenthic biomass and growth during early summer, thus decreasing vegetation stability. Light attenuation was far higher in the eutrophic lagoon, due to high phytoplankton densities, explaining the low macrophytobenthic biomass and species diversity in every season. Areal net primary production was far lower in the eutrophic lagoon. The “paradox of enrichment” hypothesis predicts lower production at higher trophic levels with increased nutrient concentrations. Our results prove for the first time that this hypothesis may be valid already at the primary producer level in coastal lagoons.
Background: To reduce the burden of disease attributable to alcohol, screening for at-risk alcohol use in the general population is recommended. Screening is usually carried out at only one point in time although individual alcohol use may change over time and self-reported consumption may be biased by underreporting. However, there are gaps in research on temporal variability of alcohol use. Therefore, this cumulative dissertation investigated (1) changes in drinking patterns within 4 weeks; (2) changes in screening results within 12 months and factors predicting a transition from low-risk to at-risk alcohol use; (3) whether underreporting can be reduced by prompting respondents to recall their alcohol use in the past week prior to screening.
Methods: Participants were adults from the general population recruited in a municipal registry office. For the first paper, 288 alcohol users were assessed four times using Timeline Follow-Back, each one week apart. Changes in drinking patterns were analyzed using latent transition modeling. For the second paper, 831 control group participants of a randomized controlled trial were screened for at-risk alcohol use at baseline, 3, 6, and 12 months later using the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C). The transition from low-risk to at-risk alcohol use was predicted using logistic regression. For the third paper, 2,379 alcohol users were screened for at-risk alcohol use using the AUDIT-C, either before or after receiving the prompt to recall their past week alcohol use. Data were analyzed using logistic regression.
Results: Within 4 weeks, 35 percent of alcohol users changed their drinking pattern. Changes were more likely for individuals with moderate or heavy compared to light drinking. Within 12 months, 30 percent of alcohol users changed their screening result. Changes were more likely for at-risk compared to low-risk alcohol users. Transitioning from low-risk to at-risk alcohol use was more likely for women (vs. men; Odds Ratio, OR = 1.66), 18- to 29-year-old adults (vs. 30- to 45-year-old adults; OR = 2.30), and individuals reporting two or more drinking days in the past week (vs. less than two; OR = 3.11). When respondents were prompted to recall their alcohol use in the past week prior to screening, they were less likely to report at-risk alcohol use compared to when the screening was conducted without prior prompt (OR = 0.83).
Conclusions: One in three alcohol users changed their consumption, some of them even within a period as short as 4 weeks. These changes might compromise the validity of screening that is commonly based on a single assessment of typical alcohol use. Furthermore, underreporting cannot be reduced by prompting individuals to recall their alcohol use in the past week prior to the screening for at-risk alcohol use. Rather, consecutive questionnaires addressing different aspects of alcohol use within a single survey might be a potential source of bias.
Schilddrüsenhormone haben einen vielfältigen Einfluss auf den Stoffwechselmetabolismus. Die genauen molekularen Mechanismen, die mit Veränderungen der Schilddrüsenhormon-spiegel einhergehen, sind jedoch in vielen Bereichen noch unbekannt. Das Ziel der Arbeit bestand deshalb darin, auf Basis von Daten einer repräsentativen Stichprobe der Allgemein-bevölkerung die Zusammenhänge zwischen den Schilddrüsenhormonen und einem umfang-reichen Metabolitenpanel zu untersuchen, um so weitere Einblicke in die zugrunde-liegenden Ätiologien und Signal-wege zu erhalten.
Von 952 Teilnehmenden der SHIP-Trend-Studie wurden aus Plasma- und Urinproben in einem kombinierten Messverfahren (LC-MS sowie 1H-NMR) sowohl mit ungerichtetem als auch mit gerichtetem Ansatz das Metabolom quantifiziert. Um den Zusammenhang zwischen Thyroxin (fT4), Triiodthyronin (fT3) und Thyreotropin (TSH) mit den identifizierten Metaboliten zu untersuchen, wurden lineare Regressionsmodelle herangezogen. Bei Vorliegen eines signi-fikanten Interaktionseffekts zwischen fT4, fT3 bzw. TSH und dem Geschlecht wurden diese Analysen für Männer und Frauen getrennt durchgeführt. Eine Random-Forest-Analyse wurde angewendet, um die Relevanz phänotypischer Charakteristiken für die individuelle fT4-Konzentration vorherzusagen und die beobachteten Geschlechterunterschiede in den Asso-ziationen zu erklären.
Zwischen TSH und den Metaboliten im Plasma und Urin ließen sich keine signifikanten Assoziationen identifizieren. 106 von 613 Plasmametaboliten waren signifikant mit fT4 assoziiert. Assoziationen zwischen fT4 und den Urinmetaboliten ließen sich hingegen deutlich seltener beobachten (12 von 587). Die Mehrheit der mit fT4 assoziierten Plasmametabolite (n = 84) konnte den Klassen der Lipide und Lipidabkömmlingen zugeordnet werden. Die Analyse unterschiedlicher, mittels 1H-NMR-Spektroskopie quantifizierter Lipoproteinsub-fraktionen zeigte zudem in-verse Assoziationen zwischen der fT4-Konzentration und einer Reihe von großen sowie kleinen LDL- und HDL-Unterklassen auf. Dabei ließen sich auch einige geschlechtsspezifische Assoziationen beobachten. So konnten beispielsweise die Assoziationen zwischen fT4 und den HDL3-Subfraktionen nur bei Männern beobachtet werden. Assoziationen zwischen fT4 und verschiedenen mehrfach ungesättigten sowie gesättigten Fettsäuren waren hingegen nur bei Frauen sichtbar. Die identifizierten Geschlechterunterschiede in den Assoziationen lassen sich vermutlich bei Männern auf einen höheren Alkoholkonsum und bei Frauen auf Vorerkrankungen der Schilddrüse sowie den menopausalen Status zurückführen, denn die genannten phänotypischen Charakteristiken zeigten sich in den Random-Forest-Analysen als wichtige geschlechtsspezifische Faktoren für den individuellen fT4-Spiegel. Assoziationen zwischen fT3 und den Metaboliten im Plasma ließen sich im Vergleich zu fT4 deutlich seltener beobachten (55 von 613). Zudem waren 13 Urinmetabolite signifikant mit fT3 assoziiert. Die mittels 1H-NMR-Spektroskopie durch-geführte Analyse der Lipoproteinsubfraktionen zeigte positive Assoziationen zwischen fT3 und kleinen LDL-Unterklassen auf.
Die vorliegende Studie zeigte eine umfangreiche Signatur von Metaboliten auf, deren Konzentrationen im Plasma mit Serumspiegeln von fT4 und fT3, aber nicht mit TSH assoziiert waren. Somit deutet sie auf die besondere Relevanz von fT4 Spiegeln in der Therapie von Schilddrüsenerkrankungen hin, um eine ausreichende Versorgung peripherer Gewebe mit Schilddrüsen-hormonen zu gewährleisten.
AbstractWe propose a new scattering mechanism of Rydberg excitons, i.e., those with high principal quantum numbers, namely scattering by coupled LO phonon-plasmon modes, which becomes possible due to small differences in energies of the states due to different quantum defects. Already in very low-density electron–hole plasmas these provide a substantial contribution to the excitonic linewidth. This effect should allow determining plasma densities by a simple line shape analysis. Whenever one expects that low-density electron–hole plasma is present the plasmon induced broadening is of high significance and must be taken into account in the interpretation.
Modern space missions depend more and more on electric propulsion devices for in-space
flights. The superior efficiency by ionizing the feedgas and propelling them using electric
fields with regard to conventional chemical thrusters makes them a great alternative. To
find optimized thruster designs is of high importance for industrial applications. Building
new prototypes is very expensive and takes a lot of time. A cheaper alternative is to rely
on computer simulations to get a deeper understanding of the underlying physics. In order
to gain a realistic simulation the whole system has to be taken into account including the
channel and the plume region. Because numerical models have to resolve the smallest time
and spatial scales, simulations take up an unfeasible amount of time. Usually a self-similarity
scaling scheme is used to greatly speed up these simulations. Until now the limits of this
method have not been thoroughly discussed. Therefore, this thesis investigates the limits
and the influence of the self-similarity scheme on simulations of ion thrusters. The aim
is to validate the self-similarity scaling and to look for application oriented tools to use
for thruster design optimization. As a test system the High-Efficiency-Multistage-Plasma
thruster (HEMP-T) is considered.
To simulate the HEMP-T a fully kinetic method is necessary. For low-temperature plasmas,
as found in the HEMP-T, the Particle-in-Cell (PIC) method has proven to be the best
choice. Unfortunately, PIC requires high spatial and temporal resolution and is hence
computationally costly. This limits the size of the devices PIC is able to simulate as well
as limiting the exploration of a wider design space of different thrusters. The whole system
is physically described using the Boltzmann and Maxwell equations. Using these system
of equations invariants can be derived. In the past, these invariants were used to derive a
self-similarity scaling law, maintaining the exact solution for the plasma volume, which is
applicable to ion thrusters and other plasmas. With the aid of the self-similarity scaling
scheme the computation cost can be reduced drastically. The drawback of the geometrical
scaling of the system is, that the plasma density and therefore the Debye length does not
scale. This expands the length at which charge separation occurs in respect to the system
size. In this thesis the limits of this scaling are investigated and the influence of the scaling
at higher scaling factors is studied. The specific HEMP-T design chosen for these studies is
the DP1.
Because the application of scaling laws is limited by the increasing influence of charge separation with increased scaling, PIC simulations still are computationally costly. Another approach to explore a wider design space is given using Multi-Objective-Design-Optimization
(MDO). MDO uses different tools to generate optimized thruster designs in a comparatively
short amount of time. This new approach is validated using the PIC method. During this
validation the drawback of the MDO surfaces. The MDO calculations are not self-consistent
and are based on empirical values of old thruster designs as input parameters, which not
necessarily match the new optimized thruster design. By simulating the optimized thruster
design with PIC and recalculate the former input parameters, a more realistic thruster design is achieved. This process can be repeated iteratively. The combination of self-consistent
PIC simulations with the performance of MDO is a great way to generate optimized thruster
designs in a comparatively short amount of time. The proof of concept of such a combination
is the pinnacle of this thesis.
AbstractJean Paul’s collection Grönländische Prozesse, oder Satirische Skizzen (1783–4/1821) has been scrutinized regarding its exuberant similes and its satirical wit, but ranked low compared to his novels. From the beginning, however, it exposes a groundbreaking strategy resonating in his more famous literary and theoretical works alike. The first sketch “On literary writing. An opusculum posthumum” converts a rhetoric of the known material world – with its diversity of life forms – into a materialistic-physiological writing (and vice versa). The text interchanges processes of transformation (e. g. ‘metabolic,’ ‘biotic,’ ‘chemical’) with techniques that are capable of changing things rhetorically. Pertaining to Jean Paul’s later analysis of antithetical wit, I suggest grasping the structure of this interchanging as a rhetorical process in itself, which can be pinpointed by the figure of antimetabole (or commutatio). Consequently, this complex dynamics is connected to transitions between ‘alive’ and ‘dead’. The status of “On literary writing” as a posthumously published draft and pseudo-poetological treatise, introduced by a fictive editor, thus exactly fits the rhetorico-physiological processes it stages and complements a genuinely anticipatory writing.
Contaminated surfaces have been discussed as a possible source of severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2). Under experimental conditions, SARS-CoV-2 can remain
infectious on surfaces for several days. However, the frequency of SARS-CoV-2 detection on surfaces
in healthcare settings and the public is currently not known. A systematic literature review was
performed. On surfaces around COVID-19 cases in healthcare settings (42 studies), the SARS-CoV2 RNA detection rates mostly were between 0% and 27% (Ct values mostly > 30). Detection of
infectious SARS-CoV-2 was only successful in one of seven studies in 9.2% of 76 samples. Most of the
positive samples were obtained next to a patient with frequent sputum spitting during sampling.
Eight studies were found with data from public surfaces and RNA detection rates between 0% and
22.1% (Ct values mostly > 30). Detection of infectious virus was not attempted. Similar results
were found in samples from surfaces around confirmed COVID-19 cases in non-healthcare settings
(7 studies) and from personal protective equipment (10 studies). Therefore, it seems plausible to
assume that inanimate surfaces are not a relevant source for transmission of SARS-CoV-2. In public
settings, the associated risks of regular surface disinfection probably outweigh the expectable health
benefit
Pancreatic ductal adenocarcinoma (PDAC), due to its genomic heterogeneity and lack of development of effective therapies, will become the second leading cause of cancer-related death within 10 years. Therefore, identifying novel targets that can predict response to specific treatments is a key goal to personalize pancreatic cancer therapy and improve survival. Given that the occurrence of oncogenic KRAS mutations is a characteristic event in PDAC leading to genome instability, a better understanding of the role of DNA repair mechanisms in this process is desirable. The aim of our study was to investigate the role of the error-prone DNA double strand breaks (DSBs) repair pathway, alt-EJ in the presence of KRAS G12D mutation in pancreatic cancer formation. Our findings showed that oncogenic KRAS contributes to the activation of the alt-EJ mechanism by increasing the expression of Polθ, Lig3 and Mre11, key components of alt-EJ in both mouse and human PDAC models. In addition, we demonstrated that alt-EJ has increased activity in DNA DSBs repair pathway in a mouse and human model of PDAC bearing KRAS G12D mutation. We further focused on estimating the impact of alt-EJ inactivation by polymerase theta (Polθ) deletion on pancreatic cancer development and survival in genetically engineered mouse models (GEMMs). Here, we described that although deficiency of Polθ resulted in delayed cancer progression and prolonged survival of experimental mice, it can lead to full-blown PDAC. Our study showed that disabling one component of the alt-EJ may be insufficient to fully suppress pancreatic cancer progression and a complete understanding of all alt-EJ factors and their involvement in DSB repair and oncogenesis is required.
More than half of the infectious diseases in humans are caused by zoonotic pathogens or pathogens of animal origin that were transmitted to humans a long time ago. Two important rodent-associated zoonotic pathogens are hantaviruses and human-pathogenic Leptospira spp. Both pathogens induce lifelong infection in the rodent hosts that shed the pathogen. Infection with these zoonotic pathogens in humans can cause clinical symptoms. Since some rodents, like the common vole (Microtus arvalis) and the bank vole (Clethrionomys glareolus syn. Myodes glareolus), have cyclic mass reproduction, this can result in years of population outbreaks in an increased number of disease cases in humans. This was found to be the case with the leptospirosis outbreaks in Germany and tularemia outbreaks in Spain, which were traced back to increased common vole density, as well as with the hantavirus disease outbreaks in several European countries, which were associated with bank vole population outbreaks.
The aim of this work was to define the distribution and prevalence of different hantaviruses and leptospires as well as their coinfection in different European rodents, with a focus on voles from the genus Microtus and the identification of factors that affect the pathogen prevalence in rodent hosts. Therefore, common voles, bank voles, striped field mice (Apodemus agrarius) and other rodents were screened by molecular methods for the presence and prevalence of Leptospira spp. and different hantaviruses. Additionally, in selected studies, the presence of anti-hantavirus antibodies was screened by enzyme-linked immunosorbent assay (ELISA) using recombinant hantavirus-nucleocapsid proteins. The prevalence of hantavirus, Leptospira spp. and double-infections with both pathogens was analyzed using individual and population-based factors. Small mammals from four different European countries, Spain in the West, Germany and Austria in Central and Lithuania in Northeastern Europe, were included in the studies.
With the molecular screenings, two new hantavirus strains were detected in continental Europe and were named Traemmersee hantavirus (TRAV) and Rusne hantavirus (RUSV) after the trapping locations in Germany and Lithuania, respectively. TRAV was detected in a field vole (Microtus agrestis) from the federal state of Brandenburg, Germany, while RUSV was detected in root voles (Microtus oeconomus) from Lithuania. Phylogenetic analysis of both hantaviruses indicates their close relation to Tatenale hantavirus and Kielder hantavirus, which were discovered in field voles in Great Britain. A pairwise evolutionary distance (PED) analysis showed that all four hantaviruses belong to the same hantavirus species, for which the putative name “Tatenale orthohantavirus” was proposed. Additionally, a recombinant RUSV antigen was generated and used successfully in ELISA for the detection of RUSV-specific antibodies and for the analysis of the cross-reactivity of monoclonal and polyclonal antibodies.
In Germany, Tula orthohantavirus (TULV) was foremost detected in common voles in Thuringia and Brandenburg but was also detected in field voles in Brandenburg. Puumala orthohantavirus (PUUV) was detected in Thuringia at the virus distribution border, but sequences differed strongly from known sequences from another neighboring trapping location. While in Austria Dobrava-Belgrade orthohantavirus (DOBV), genotype Kurkino, was detected for the first time in striped field mice, no hantavirus RNA was detected in common voles from Spain. The cause of this absence in the Iberian common vole population might be its long-term isolation from the common vole populations more to the east. The TULV prevalence in Germany in this study was dependent on the season and on the prior growth of the reservoir population. An individual factor that affected the hantavirus prevalence, was the increasing age of the common vole.
Leptospira spp.-DNA was detected in common voles from Spain and Germany, as well as in one striped field mouse from Austria. Except for the two detections of L. borgpetersenii in Spain, which were probably the result of spillover infections, only the genomospecies L. kirschneri was detected in common voles from Spain and Germany. The high prevalence of Leptospira spp., as well as the detection of only one genomospecies, confirm that L. kirschneri is the genomospecies for which the common vole is the main reservoir. Important factors for the Leptospira spp. prevalence were found to be, in addition to temperature and rainfall, the season and the preceding common vole density. Like the case with hantavirus, the age of the vole was found to be an influencing factor.
In Germany, coinfections of TULV and Leptospira spp. were detected. These were associated with high common vole density and increased with the age of the common vole. Furthermore, the incidence of coinfections seems to be impacted more by the Leptospira spp. than by the hantavirus prevalence.
As part of this thesis, TULV and PUUV were detected in previously untested regions in Germany, DOBV was detected for the first time in Austria and the distribution range of the putative species “Tatenale orthohantavirus” was extended to continental Europe for the first time with detection in two countries. Screenings in Spain indicate that certain common vole populations can be free from TULV infection. Furthermore, leptospires were detected in rodents from Spain, Germany and Austria. It was verified that certain Leptospira genomospecies are host-specific. Factors that influence the prevalence of infection or coinfection by hantaviruses and leptospires were determined.
The origin and hosts associated with the Tatenale orthohantavirus should be clarified in further studies including the field vole and the root vole as well as other members of the genus Microtus in Europe and Asia. The development of a RUSV-antigen-based ELISA will enable future screening in humans and therefore might provide information about the human pathogenicity of this pathogen. For final confirmation of the zoonotic potential, isolation of the virus and development of a focus reduction neutralization test are necessary. The expansion of the striped field mouse to Austria and the detectable carryover of DOBV associated with this implies that further screening studies to more precisely characterize the distribution of DOBV (and other pathogens) are needed. The studies of DOBV spread in Austria as well as PUUV spread in Germany could help to better understand the emergence of zoonotic pathogens in new regions. The here described hantavirus-Leptospira spp. and Neoehrlichia mikurensis-Bartonella spp. coinfections should be further analyzed to characterize the interactions of the pathogens in the context of a microbiome and their influence on epidemiological aspects of the involved pathogens. The here identified individual and population-based impact factors for the TULV and Leptospira spp. prevalence should support the development and optimization of prediction models.
Die Akute Myeloische Leukämie (AML) ist eine klonale Neoplasie der hämatopoetischen Stammzellen, die das Knochenmark, das Blut und andere Organe infiltriert (Döhner and Bloomfield, 2015; Herold, 2015). Patienten mit malignen hämatologischen Erkrankungen haben ein erhöhtes Risiko an einer invasiven Pilzinfektion zu erkranken, dies gilt insbesondere für Patienten mit prolongierter und starker Neutropenie, die bei Patienten nach intensiver Chemotherapie regelhaft auftritt (Rodríguez-Veiga et al., 2019). Von einer schweren Neutropenie spricht man, wenn der Wert der Neutrophilen Granulozyten im Blut 500 Zellen/ μL unterschreitet (Herold, 2015, p.66). Aus diesem Grund gibt es eine starke Empfehlung zur Anwendung einer antimykotischen Prophylaxe bei diesen Patienten (Mellinghoff et al., 2018). Hierfür kommen verschiedene Azol- Antimykotika zum Einsatz. Nach Umstellen des Standards der antimykotischen Prophylaxe bei AML- Patienten nach intensiver Chemotherapie auf Posaconazol, welches auf Grund mehrerer Studien zur Erstlinienanwendung empfohlen wurde, schien die Rate an prolongierter Neutropenie und Thrombozytopenie zuzunehmen (Mellinghoff et al., 2018). Ziel dieser retrospektiven Studie war es Hinweise zu ermitteln, ob dieser Zusammenhang zufällig ist oder ob die Gabe von Posaconazol tatsächlich durch Arzneimittelwechselwirkungen mit den eingesetzten Zytostatika zu einer verlängerten Aplasiedauer führen könnte. Hier untersuchten wir den Einfluss der antimykotischen Medikation und anderer Faktoren auf die Dauer der Aplasie an Patienten mit AML in der Klinik für Hämatologie und Onkologie der Universitätsmedizin Greifswald. Es konnten 83 erwachsene Patienten mit einem medianen Alter von 54 Jahren in die Studie eingeschlossen und 218 Therapiezyklen ausgewertet werden. Es zeigten sich signifikante Assoziationen zwischen der Dauer der Aplasie der Neutrophilen und der Medikation mit Voriconazol oder Posaconazol im Vergleich zu Fluconazol oder keiner antimykotischen Prophylaxe. Insbesondere in den zweiten und dritten Chemotherapie- Zyklen zeigte sich ein erhöhtes Risiko einer prolongierten Aplasie für Neutrophile bei der Anwendung mit Posaconazol oder Voriconazol. Für die Thrombozyten- Regeneration zeigten sich Assoziationen, die zwar nicht signifikant waren, allerdings den gleichen Trend anzeigen. Es erscheint uns möglich, dass hier auf Grund des Interaktionspotenzials von Posaconazol und Voriconazol ein erhöhtes Risiko einer prolongierten Aplasie besteht.
: Background: High-impact trauma frequently leads to injuries of the orbit, but literature
focusing on the viscerocranium rather than the neurocranium is underrepresented. Methods: Retrospective cohort study (2006–2014) at an urban level 1 trauma center assessing the frequency and
typical patterns of orbital injuries on whole-body computed tomography (WBCT) with maxillofacial
multi-slice CT (MSCT) after severe trauma. (1) Screening of consecutive WBCT cases for dedicated
maxillofacial MSCT. (2) Examination by two independent experts’ radiologists for (peri-/)orbital
injuries. (3) Case review for trauma mechanisms. Results: 1061 WBCT were included revealing 250
(23.6%) patients with orbital injuries. Less than one-quarter (23.3%) of patients showed osseous
and 9.5% showed soft tissue injuries. Combined osseous and soft tissue lesions were present in
39.2% of orbital injuries, isolated soft tissue injuries were rare. Single- or two-wall fractures of the
orbit were prevalent, and the orbital floor was affected in 67% of fractures. Dislocated extraocular
muscles (44.6%), deformation of the ocular globe (23.8%), and elongation of the optic nerve (12.9%)
were the most frequently soft tissue findings. Vascular trauma was suspected in 15.8% of patients.
Conclusions: Orbital trauma was confirmed in 23.6% of cases with suspected facial injuries after severe
trauma. Concomitant soft tissue injuries should be excluded explicitly in cases with orbital fractures
to prevent loss of vision or ocular motility.
To induce an appropriate immune response, pathogen- or damage-associated molecular
patterns (PAMPs and DAMPs) are sensed by innate immune cells. One of the first
mechanisms after recognition is the assembly of an inflammasome leading to the cleavage of
pro-IL-1β and pro-IL-18 into the active cytokines IL-1β and IL-18, respectively. Hyperinflammatory
conditions and excessive activation of the inflammasome, however, are drivers
of inflammatory and autoimmune diseases. The NLR family pyrin domain-containing 3
(NLRP3) inflammasome is suggested to be involved in the development of gout,
artherosclerosis, type II diabetes, cryopyrin-associated periodic syndrome (CAPS), various
types of cancer, and inflammatory bowel disease (IBD). To tackle these diseases, drugs
interfering with IL-1 signaling are of great value. Anakinra, an IL-1 receptor antagonist,
inhibits binding of both IL-1α and IL-1β. Rilonacept consists of the Fc portion of human IgG1
with two IL-1 receptors grafted onto it. This allows neutralization of IL-1α and IL-1β. The
monoclonal IgG1 antibody Canakinumab specifically blocks IL-1β. Although well tolerated,
patients undergoing a therapy with these drugs are at a higher risk of developing bacterial
respiratory tract infections.
The human upper respiratory tract (URT) is commonly colonized asymptomatically by
bacteria like Staphylococcus aureus and Streptococcus pneumoniae. Only a limited number of
studies have so far addressed the role of the NLRP3 inflammasome during pneumococcal
infections. Imbalances in the immune system enhance the dissemination of these bacteria into
the lungs thereby causing life-threatening infections. Asides from immune-compromising
therapies such as IL-1 inhibition, viral infections are common factors leading to the
development of a secondary, bacterial infection. Influenza A virus infection of C57BL/6J
mice was characterized by a bi-phasic disease progression with a complete remission around
day 16 irrespectively of a previous Streptococcus pneumoniae 19F colonization. At this time
point, low amounts of bacteria were recovered from the lungs of 50% of co-infected mice.
This co-infection model was used for in-depth analyses of the innate immune responses.
Bioactive lipids, such as eicosanoids, are host-derived metabolites, which can heavily impact
the cellular immune response and skew it towards a pro- or anti-inflammatory phenotype.
Eicosanoid analyses revealed increased levels of different hydroxydocosahexaenoic acids
(HDHAs) and hydroxyeicosatetraenoic acids (HETEs) in the lung after single viral infection.
Staphylococcal pneumonia mainly resulted in high expression of 20-HETE. During a coinfection
with S. pneumoniae and influenza A virus (IAV), reduction of HETEs and HDHAs
was measured. Furthermore, ceramide-1-phosphate (C1P) was elevated in the lung, whereas
sphingosine-1-phosphate (S1P) was reduced. The tight control of an inflammatory response
by bioactive lipid mediators might be protective during later stages of an infection.
Cytokine analyses revealed high expression of inflammatory cytokines in lungs and plasma of
single bacteria- and virus infected as well as co-infected mice at early stages of an infection.
In all three infections monocyte chemoattractant protein-1 (MCP-1) dependent monocyte
recruitment was noted. The elevated expression of CC chemokine receptor 2 (CCR2) and
major histocompatibility complex II (MHCII) in the majority of analysed myeloid cells
indicated an activation of these cells. In single virus and co-infections, we further observed a
mainly neutrophil-independent immune response. During pneumococcal pneumonia, an influx
of neutrophils was observed.
Neutrophils, as first recruited responders during an inflammation, can release their granule
contents after activation in order to eliminate extracellular pathogens. However, excessive
neutrophil activation correlates with tissue damage and detrimental outcome of an infection.
As a result of excessive cell death, large amounts of ATP are released into the extracellular
space. Pneumolysin (Ply), a pore-forming toxin and major virulence factor of S. pneumoniae,
is a potent activator of human neutrophils. Stimulation of neutrophils with sublytic
concentrations of Ply readily resulted in the release of resistin and other granule proteins into
the supernatant. Microscale Thermophoresis (MST) analyses revealed that ATP neutralizes
Ply by binding it in the extracellular space. Co-stimulation of neutrophils with both lytic and
sublytic amounts of Ply and physiologically relevant concentrations of ATP resulted in
diminished neutrophil activation. We speculate that during hyper-inflammation (caused by
excessive neutrophil recruitment and activation), tissue injury results in the release of large
amounts of extracellular ATP which, in turn, will bind to Ply. Ultimately, binding of ATP to
Ply inhibits further neutrophil activation and might mitigate immunopathology.
To understand the resilience of African savannas to global change, quantitative information on the long-term dynamics of vegetation is required. Past dynamics can be reconstructed with the REVEALS model, which requires pollen productivity estimates (PPE) that are calibrated using surface pollen and vegetation data. Here we calculated PPE values for five savanna taxa using the extended R-value (ERV) model and two pollen dispersal options: the Gaussian plume model (GPM) and the Lagrangian stochastic model (LSM). The ERV calculations failed to produce a reliable PPE for Poaceae. We therefore used Combretaceae as the reference taxon – although values obtained with Poaceae as the reference taxon are presented in the supplement. Our results indicate that Combretaceae is the taxon with the highest pollen productivity and Grewia the taxon with the lowest productivity. Acacia and Dichrostachys are intermediate pollen producers. We find no clear indication of whether the GPM PPEs or the LSM PPEs are more realistic, but the differences between these values confirmed that the pollen fall speed has a greater effect in the modelling of GPM than in the LSM. We also applied REVEALS to the pollen record of Lake Otjikoto (northern Namibia) and obtained the first quantitative reconstruction of the last 130 years of vegetation history in the region. Cover estimates for Poaceae indicate the predominance of a semi-open landscape throughout the 20th century, while cover values below 50% since the 21st century correspond to a thick savanna. This change in grass cover is associated with the spread of Vachellia, Senegalia and Grewia reflecting an encroached state.
Introduction
Stroke is the leading neurological cause of adult long-term disability in Europe. Even though functional consequences directly related to neurological impairment are well studied, post-stroke trajectories of functional health according to the International Classification of Functioning, Disability and Health are poorly understood. Particularly, no study investigated the relationship between post-stroke trajectories of activities of daily living (ADL) and self-rated health (SRH). However, such knowledge is of major importance to identify patients at risk of unfavourable courses. This prospective observational study aims to investigate trajectories of ADL and SRH, and their modifying factors in the course of the first year after stroke.
Methods and analysis
The study will consecutively enrol 300 patients admitted to a tertiary care hospital with acute ischaemic stroke or transient ischaemic attack (TIA; Age, Blood Pressure, Clinical Features, Duration of symptoms, Diabetes score ≥3). Patient inclusion is planned from May 2021 to September 2022. All participants will complete an interview assessing ADL, SRH, mental health, views on ageing and resilience-related concepts. Participants will be interviewed face-to-face 1–5 days post-stroke/TIA in the hospital; and will be followed up after 6 weeks, 3 months, 6 months and 12 months via telephone. The 12-month follow-up will also include a neurological assessment. Primary endpoints are ADL operationalised by modified Rankin Scale scores and SRH. Secondary outcomes are further measures of ADL, functional health, physical activity, falls and fatigue. Views on ageing, social support, resilience-related concepts, affect, frailty, illness perceptions and loneliness will be examined as modifying factors. Analyses will investigate the bidirectional relationship between SRH and ADL using bivariate latent change score models.
Ethics and dissemination
The study has been approved by the institutional review board of the University Medicine Greifswald (Ref. BB 237/20). The results will be disseminated through scientific publications, conferences and media. Moreover, study results and potential implications will be discussed with patient representatives.
Trial registration number NCT04704635.
Innerhalb der Proteinfamilien der Antistasine und der Hirudine konnte ein breites Spektrum von Faktoren identifiziert werden. Obwohl die Funktionen dieser Hirudin-ähnlichen Faktoren (HLF) aus Hirudo sp. und Hirudinaria manillensis, sowie des Antistasin-ähnlichen Faktors (ALF) aus Hirudo verbana, bis zu diesem Zeitpunkt unbekannt waren, könnte der hohe Grad an Übereinstimmung zu den Antistasinen bzw. Hirudinen bezüglich ihrer Genstruktur und Aminosäuresequenzen auf eine Anpassung der Blutegel auf ihr Wirtsspektrum hindeuten. So ist es mit der funktionellen Charakterisierung von rekombinanten Formen dieser Speicheldrüsenproteine möglich, die Frage zu beantworten, weshalb der Blutegel nicht nur einen potenten Inhibitor für die jeweiligen Faktoren der Blutgerinnung in seinen Speicheldrüsen sekretiert, sondern wohl möglich eine Vielzahl variierender Faktoren vorliegen.
Dieser Beitrag führt in den Stand und den regulatorischen Rahmen der Sektorenkopplung im Status quo ein. Ein Fokus wird dabei auf die Erreichung der Klimaschutzziele gelegt. Zur Systematisierung wurde ein Systembild, welches die wesentlichen Anknüpfungspunkte darstellt, entwickelt und dargestellt. Anhand dessen wird der technisch-systemische Rahmen der Sektorenkopplung erläutert und zentrale ökonomische Aspekte aufzeigt. Daran anknüpfend wird zudem die Begrifflichkeit der "Sektorenkopplung" untersucht. Anschließend wird der regulatorische Rahmen der Sektorenkopplung für die Sektoren Energiewirtschaft, Industrie, Verkehr, Gebäude und Landwirtschaft sowie der Abfallwirtschaft untersucht und dargestellt. Die Betrachtung dieser Sektoren geht davon aus, dass diese zukünftig auf Basis von erneuerbar erzeugtem Strom direkt oder indirekt elektrifiziert und verknüpft werden. Die Darstellung der institutionellen Regelungen im Status quo gibt einen strukturierten Überblick über das bestehende System und zeigt rechtliche Ansatzpunkte bzw. eventuelle Regelungslücken hinsichtlich bestehender und zukünftiger Herausforderungen für das Ziel einer nachhaltigen Sektorenkopplung auf.
Abstract
Aim
Species ranges are highly dynamic, shifting in space and time as a result of complex ecological and evolutionary processes. Disentangling the relative contribution of both processes is challenging but of primary importance for forecasting species distributions under climate change. Here, we use the spectacular range expansion (ca. 1000 km poleward shift within 10 years) of the butterfly Pieris mannii to unravel the factors underlying range dynamics, specifically the role of (i) niche evolution (changes in host‐plant preference and acceptance) and (ii) ecological processes (climate change).
Location
Provence‐Alpes‐Côte d’Azur, France; North Rhine‐Westphalia, Rhineland‐Palatinate and Hesse, Germany.
Taxon
Insect and angiosperms.
Methods
We employed a combination of (i) common garden experiments, based on replicated populations from the species’ historical and newly established range and host‐plant species representative for each distribution range, co‐occurrence analyses and (ii) grid‐based correlative species distribution modelling (SDM) using Maxent.
Results
We observed changes in oviposition preference, with females from the newly established populations showing reduced host‐plant specialization and also an overall increased fecundity. These changes in behaviour and life history may have enabled using a broader range of habitats and thus facilitated the recent range expansion. In contrast, our results indicate that the range expansion is unlikely to be directly caused by anthropogenic climate change, as the range was not constrained by climate in the first place.
Main conclusions
We conclude that evolution of a broader dietary niche rather than climate change is associated with the rapid range expansion, and discuss potential indirect consequences of climate change as trigger for the genetic differences found. Our study thus illustrates the importance of species interactions in shaping species distributions and range shifts, and draws attention to indirect effects of climate change. Embracing this complexity is likely the key to a better understanding of range dynamics.
Survival, development, and function of cells depend on numerous signaling pathways or-
chestrating the response to external and internal stimuli. Besides the well-established signaling through reversible phosphorylation, the concept of specific, spatio-temporal redox modifi-
cations of protein cysteinyl and methionyl side chains that regulate the biological function of these proteins is supported by an overwhelming amount of data. Although the specific reduction of protein redox modifications has been studied intensively, the oxidation of protein side chains was thought to be a result of so-called ‘oxidative stress’. However, this term has been increasingly challenged, since signaling pathways depend on specific, spatio-temporal oxidation of target proteins, most likely catalyzed by specific enzymes. The discovery of MICAL (molecule interacting with CasL) proteins evinced
the first examples of specific oxidases in signal transduction in the redox regulation of cellular functions.As part of the semaphorin signaling pathway, MICAL proteins were characterized to stereospecifically oxidize methionyl residues in actin, thereby regulating actin deolymerization, a process important in neurogenesis and cell migration. This oxidation can be reversed by the specific methionine-R-sulfoxide eductase B1. Besides the regulation of actin dynamics, MICALs are involved in the regulation of cell proliferation and
apoptosis, and the production of hydrogen peroxide may qualify them as specific oxidases also for cysteinyl residues.
Summary
Outer membrane extensions are common in many marine bacteria. However, the function of these surface enlargements or extracellular compartments is poorly understood. Using a combined approach of microscopy and subproteome analyses, we therefore examined Pseudoalteromonas distincta ANT/505, an Antarctic polysaccharide degrading gamma‐proteobacterium. P. distincta produced outer membrane vesicles (MV) and vesicle chains (VC) on polysaccharide and non‐polysaccharide carbon sources during the exponential and stationary growth phase. Surface structures of carbohydrate‐grown cells were equipped with increased levels of highly substrate‐specific proteins. At the same time, proteins encoded in all other polysaccharide degradation‐related genomic regions were also detected in MV and VC samples under all growth conditions, indicating a basal expression. In addition, two alkaline phosphatases were highly abundant under non‐limiting phosphate conditions. Surface structures may thus allow rapid sensing and fast responses in nutritionally deprived environments. It may also facilitate efficient carbohydrate processing and reduce loss of substrates and enzymes by diffusion as important adaptions to the aquatic ecosystem.
Re-Establishment Techniques and Transplantations of Charophytes to Support Threatened Species
(2021)
Re-establishment of submerged macrophytes and especially charophyte vegetation is a common aim in lake management. If revegetation does not happen spontaneously, transplantations may be a suitable option. Only rarely have transplantations been used as a tool to support threatened submerged macrophytes and, to a much lesser extent, charophytes. Such actions have to consider species-specific life strategies. K-strategists mainly inhabit permanent habitats, are perennial, have low fertility and poor dispersal ability, but are strong competitors and often form dense vegetation. R-strategists are annual species, inhabit shallow water and/or temporary habitats, and are richly fertile. They disperse easily but are weak competitors. While K-strategists easily can be planted as green biomass taken from another site, rare R-strategists often must be reproduced in cultures before they can be planted on-site. In Sweden, several charophyte species are extremely rare and fail to (re)establish, though apparently suitable habitats are available. Limited dispersal and/or lack of diaspore reservoirs are probable explanations. Transplantations are planned to secure the occurrences of these species in the country. This contribution reviews the knowledge on life forms, dispersal, establishment, and transplantations of submerged macrophytes with focus on charophytes and gives recommendations for the Swedish project.
Objective: To compare the effectiveness and complications of intraligamentary anesthesia
(ILA) with conventional inferior alveolar nerve block (IANB) during injection and dental
treatment of mandibular posterior teeth.
Materials and Methods: In this randomized, prospective clinical trial, 72 patients (39 males, 33
females) patients scheduled for dental treatment of mandibular posterior teeth, were randomly
allocated to ILA group (n=35) received ILA injection or IANB group (n=37) received the
conventional IANB. Our primary outcome was to assess pain and stress (discomfort) during the
injection and dental treatment, using the Numeric Rating Scale (NRS) from 0 to 10 (0 = no
pain, 10= the worst pain imaginable). Whereas; recording 24 hours postoperative complications
were our Secondary outcomes.
Results: Patients in ILA group reported significantly less pain during injection when compared
with IANB group (p=0.03). While pain during dental treatment was similar in both groups
(p=0.2). Patients in both groups also reported similar low values of discomfort during treatment
(p= 0.7). Although no signs of nerve contact or any other postoperative complications were
observed, five patients in IANB group (none in ILA group) reported temporary irritations
Conclusion: This study showed equivalent effectiveness of both intraligamentary anesthesia
and conventional inferior alveolar nerve block, for pain control during routine dental treatment
of mandibular posterior teeth. Nevertheless, ILA showed significantly less pain during
injection. No major postoperative complications in both groups were observed.
Clinical Relevance: ILA could be considered as an effective alternative for routine dental
treatment.
Cold physical plasmas, especially noble gas driven plasma jets, emit considerable amounts of ultraviolet radiation (UV). Given that a noble gas channel is present, even the energetic vacuum UV can reach the treated target. The relevance of UV radiation for antimicrobial effects is generally accepted. It remains to be clarified if this radiation is relevant for other biomedical application of plasmas, e.g., in wound care or cancer remediation. In this work, the role of (vacuum) ultraviolet radiation generated by the argon plasma jet kINPen for cysteine modifications was investigated in aqueous solutions and porcine skin. To differentiate the effects of photons of different wavelength and complete plasma discharge, a micro chamber equipped with a MgF2, Suprasil, or Borosilicate glass window was used. In liquid phase, plasma-derived VUV radiation was effective and led to the formation of cysteine oxidation products and molecule breakdown products, yielding sulfite, sulfate, and hydrogen sulfide. At the boundary layer, the impact of VUV photons led to water molecule photolysis and formation of hydroxyl radicals and hydrogen peroxide. In addition, photolytic cleavage of the weak carbon-sulfur bond initiated the formation of sulfur oxy ions. In the intact skin model, protein thiol modification was rare even if a VUV transparent MgF2 window was used. Presumably, the plasma-derived VUV radiation played a limited role since reactions at the boundary layer are less frequent and the dense biomolecules layers block it effectively, inhibiting significant penetration. This result further emphasizes the safety of physical plasmas in biomedical applications.
Ziel:
Teleradiologische Befundung hat in den letzten Jahren an Bedeutung gewonnen. Ziel der vorliegenden Arbeit ist es, die Befundqualität bei teleradiologischer Befundung und deren Abhängigkeit von der Berufserfahrung der befundenden Ärzt*innen zu evaluieren.
Material und Methoden:
Als Indikator für Befundqualität wurde die Anzahl von Befundunterschieden definiert. Über einen Zeitraum von 21 Monaten wurden prospektiv alle Befundunterschiede ermittelt, die nachts, an Wochenenden und Feiertagen in der teleradiologischen Befundung und in der Befundung vor Ort auftraten. Unterschiede wurden nach Schweregrad klassifiziert. Die Berufserfahrung des Befundenden wurde erhoben. Zur Berechnung der Stärke des Zusammenhangs zwischen Berufserfahrung und Befundunterschied, Anforderungsart und Befundunterschied sowie bei Kombination der Faktoren wurde das relative Risiko für einen Unterschied bei Befundung durch Ärzt*innengruppen mit unterschiedlicher Berufserfahrung berechnet. Für die Kombination der Einflussfaktoren wurde die absolute und relative Risikoreduktion bezogen auf das Risiko für das Auftreten eines Befundunterschiedes berechnet.
Ergebnisse:
Im Studienzeitraum wurden 7.761 Untersuchungen registriert. 7.209 Untersuchungen konnten in die Analyse einbezogen werden. 17 % (1.215) der Befunde enthielten Befundunterschiede. Teleradiologische Befundung hatte keinen signifikanten Einfluss auf das Risiko für Befundunterschiede. Bei Befundung durch Weiterbildungsassistent*innen mit weniger als vier Jahren Berufserfahrung bestand in der Gesamtstichprobe ein signifikant höheres Risiko für Befundunterschiede. Bei Teleradiologischer Befundung lag gegenüber der In-House-Befundung bei Befundung durch Weiterbildungsassistent*innen mit mindestens 4-jähriger Erfahrung ein signifikant geringeres Risiko für Minor-, nicht aber für Major- Befundunterschiede vor.
Schlussfolgerungen:
Unterschiedsraten bei teleradiologischer Befundung sind vergleichbar mit den Raten bei regulärer Notfallversorgung. Das Risiko für Befundunterschiede bei assistenzärztlicher Versorgung sinkt bei beiden Anforderungsarten mit steigender Berufserfahrung. Teleradiologische Befundung kann auch bei Ärzt*innen in Weiterbildung einen hohen Grad an Befundsicherheit in der Befundung außerhalb der regulären Dienstzeiten liefern.
Quality of Life in Young Adults With Cerebral Palsy: A Longitudinal Analysis of the SPARCLE Study
(2021)
Introduction: While most people with cerebral palsy (CP) will have a life expectancy similar to that of the general population, international research has primarily focused on childhood and adolescence; and knowledge about the quality of life (QoL) of young adults with CP, its trajectories, and associated factors remains scarce.
Methods: This longitudinal study included young adults with CP living in five European regions and who had previously participated in the SPARCLE cohort as children and/or adolescents. Their QoL in the psychological well-being and social relationships domains was estimated using age-appropriate validated instruments (KIDSCREEN-52 in childhood/adolescence and WHOQOL-Bref in young adulthood). We used generalized linear mixed-effect models with random intercept to estimate long-term trajectories of QoL in both domains and to investigate whether severity of impairment, pain, and seizure influenced these trajectories. We sought to identify potentially different trajectories of QoL from childhood to adulthood using a shape-based clustering method.
Results: In total, 164 young adults with CP aged 22–27 years participated in the study. Psychological well-being linearly decreased by 0.78 points (scale 0–100) per year (95% confidence interval (CI) −0.99 to −0.56) from childhood to young adulthood, whereas QoL in the social relationships domain increased (β coefficient 1.24, 95% CI 0.92–1.55). Severity of impairment was associated with reduced QoL in all life periods of the study (childhood, adolescence, and young adulthood): motor impairment with social relationships, and more nuancedly intellectual disability with psychological well-being and social relationships. At all periods, frequent pain significantly reduced psychological well-being, and seizures were associated with lower QoL in the social relationships domain. In both domains, we identified a group of individuals with CP who presented a reverse trajectory compared with the general QoL trajectory.
Conclusion: Identification of QoL trajectories and their associated factors yields improved knowledge about the experience of individuals with CP until young adulthood. Further studies are needed to better understand the determinants that have the greatest influence on the different shapes of long-term trajectories of QoL.
Hintergrund
Die stetig steigende Anzahl von akademischen Veröffentlichungen macht es zunehmend schwierig, Publikationen zu identifizieren, welche die neuesten wissenschaftlichen Erkenntnisse repräsentieren und es ermöglichen, auf dem neuesten Stand der Forschung und evidenzbasierter Behandlungsempfehlungen zu bleiben.
Ziel
Ziel dieser Studie war es, die Suchstrategien und Auswahlpräferenzen zu untersuchen, die verschiedene akademisch tätigen Zahnärzte bei der Auswahl der fünf bedeutendsten Publikationen aus dem Jahres 2016 im Fachgebiet der Kinderzahnheilkunde verwendeten.
Design
Die fünf an der Studie teilnehmenden Zahnärzte wurden gebeten, ohne untereinander darüber zu kommunizieren, die Datenbanken PubMed, Google Scholar und Livivo zu durchsuchen. Zudem sollten sie dabei ihre individuelle Suchstrategie dokumentieren. Die Aus-wahlkriterien wurden anschließend gemäß einer 10-Punkte-Checkliste evaluiert. Der Evidenzlevel der identifizierten Publikationen wurde anschließend gemäß ihrer Publikationsart bewertet.
Ergebnisse
Alle Studienteilnehmer wählten unterschiedliche Publikationen ohne Überschneidungen aus. Alle von ihnen ausgewählten Publikationen waren Zeitschriftenartikel. Neunzehn Artikel wurden in der Datenbank PubMed identifiziert, jeweils drei Artikel wurden in Google Scholar und Livivo gefunden. Die Relevanz des Artikels für die klinische Entscheidungsfindung war das wichtigste Kriterium bei der Auswahl durch die Teilnehmer.
Fazit
Die persönlichen Interessen und Fachgebiete der Kliniker beeinflussten die Auswahl der Zeitschriftenartikel in erheblichem Maße. Dies könnte die interindividuelle Variabilität der diagnostischen und therapeutischen Ansätze erklären, die bei Zahnärzten beobachtet wer-den kann, und trägt wahrscheinlich zu einer Verbreiterung des Wissenspools bei. Dies wird jedoch richtigerweise durch evidenzbasierte Behandlungsempfehlungen komplementiert, was die Qualität der Behandlung überregional sicherstellt.
In der DDR wurde im Leistungssport staatlicherseits ein System entwickelt, welches sich unter anderem durch den Einsatz von leistungssteigernden Substanzen auszeichnete. Diese Substanzen zogen häufig schwere somatische Schäden nach sich. Die Sportler*innen wussten in den meisten Fällen nicht, dass sie diese Mittel erhielten und waren häufig minderjährig. Der Alltag der Sportler*innen war meist durch prekäre physische sowie psychische Trainingsbedingungen geprägt. Auf Grund von Schilderungen der Betroffenen, Berichten von Sporthistoriker*innen und Unterlagen des Ministeriums für Staatssicherheit lässt sich vermuten, dass ein erheblicher Teil der Sportler*innen unter psychischen Erkrankungen leidet. Daher sollte die psychische Verfassung überblickshaft dargestellt werden.
Vor diesem Hintergrund wurden Fragebogenpakete an 1200 Proband*innen verschickt, die sich bis zum Erhebungszeitpunkt ratsuchend an die Doping-Opfer-Hilfe e.V. gewendet hatten. Diese Pakete enthielten jeweils 13 Selbstbeurteilungsskalen zur psychischen Symptomatik bzw. Persönlichkeitsmerkmalen. Die Ergebnisse wurden mit einer nach Alter und Geschlecht parallelisierten Stichprobe (N=255) aus der Allgemeinbevölkerung verglichen.
Auf allen untersuchten Skalen konnten signifikante Unterschiede festgestellt werden. Der Großteil der betroffenen Sportlerinnen und Sportler wies eine klinisch-relevante psychische Belastung auf. Exemplarisch hierfür sind eine hohe Punktprävalenz für Posttraumatische Belastungsstörungen (21,1%) und eine klinisch relevante depressive Symptomatik (65,19%).
Vermutlich konnten die negativen Erlebnisse im Kindes- und Jugendalter auf zwei Arten pathogen wirken. Zum einen konnten sie direkt psychische Erkrankungen auslösen und zum anderen fand eine negative Beeinflussung der Entwicklung statt, welche bei den Betroffenen zu einer erhöhten Vulnerabilität gegenüber späteren Stressereignissen führen konnte. Aufgrund des Querschnittsdesigns der Studie müssen potenziell kausale Zusammenhänge jedoch mit Zurückhaltung diskutiert werden. Eine Berücksichtigung der Sportarten bei weiteren Untersuchungen könnte besondere Risikogruppen darstellen.
Phytopathogenic Verticillia cause Verticillium wilt on numerous economically important crops. Plant infection begins at the roots, where the fungus is confronted with rhizosphere inhabiting bacteria. The effects of different fluorescent pseudomonads, including some known biocontrol agents of other plant pathogens, on fungal growth of the haploid Verticillium dahliae and/or the amphidiploid Verticillium longisporum were compared on pectin-rich medium, in microfluidic interaction channels, allowing visualization of single hyphae, or on Arabidopsis thaliana roots. We found that the potential for formation of bacterial lipopeptide syringomycin resulted in stronger growth reduction effects on saprophytic Aspergillus nidulans compared to Verticillium spp. A more detailed analyses on bacterial-fungal co-cultivation in narrow interaction channels of microfluidic devices revealed that the strongest inhibitory potential was found for Pseudomonas protegens CHA0, with its inhibitory potential depending on the presence of the GacS/GacA system controlling several bacterial metabolites. Hyphal tip polarity was altered when V. longisporum was confronted with pseudomonads in narrow interaction channels, resulting in a curly morphology instead of straight hyphal tip growth. These results support the hypothesis that the fungus attempts to evade the bacterial confrontation. Alterations due to co-cultivation with bacteria could not only be observed in fungal morphology but also in fungal transcriptome. P. protegens CHA0 alters transcriptional profiles of V. longisporum during 2 h liquid media co-cultivation in pectin-rich medium. Genes required for degradation of and growth on the carbon source pectin were down-regulated, whereas transcripts involved in redox processes were up-regulated. Thus, the secondary metabolite mediated effect of Pseudomonas isolates on Verticillium species results in a complex transcriptional response, leading to decreased growth with precautions for self-protection combined with the initiation of a change in fungal growth direction. This interplay of bacterial effects on the pathogen can be beneficial to protect plants from infection, as shown with A. thaliana root experiments. Treatment of the roots with bacteria prior to infection with V. dahliae resulted in a significant reduction of fungal root colonization. Taken together we demonstrate how pseudomonads interfere with the growth of Verticillium spp. and show that these bacteria could serve in plant protection.
Zu viele Unfälle, oft im Zusammenhang mit Sach- und/oder Personenschaden, geschehen in Deutschland im öffentlichen Straßenverkehr aufgrund von alkoholisierten Kraftfahrzeugführern. [5] Um diese zumindest etwas zu minimieren, wurde 2007 der §24c StVG eingeführt, welcher den Fahranfängern das alkoholisierte Führen eines Kraftfahrzeuges im öffentlichen Straßenverkehr verbietet. Gerade in dieser Gruppe von Fahrzeugführern kommt es laut Statistischem Bundesamt häufiger zu Verkehrsunfällen, da Fahranfänger meist noch nicht routiniert im Führen eines Kraftfahrzeuges sind [13]. Unter Alkoholeinfluss wird die Fahrweise noch zusätzlich negativ beeinträchtigt.
Aufgabe dieser Arbeit war es zu prüfen, ob die Einführung des §24c StVG zu einer Änderung im Trinkverhalten der Fahranfänger im Untersuchungsmaterial des Instituts für Rechtsmedizin der Universitätsmedizin Greifswald geführt hat.
Dazu wurden insgesamt 24.814 Protokolle zur Feststellung der Alkoholkonzentration im Blut (von denen 12.706 mit in die Statistik eingingen) in einem Untersuchungszeitraum von zehn Jahren (2004 bis 2013) bearbeitet und mit Hilfe eines Access-Programmes ausgewertet.
Mittels Chi-Quadrat-Homogenitätstestes konnte als Ergebnis eine signifikante Minimierung der alkoholisierten Fahranfänger, die ein Kraftfahrzeug im öffentlichen Straßenverkehr führten, nachgewiesen werden, so dass sich einschätzen lässt, dass § 24c StVG, zumindest in der untersuchten Region, einen positiven Einfluss auf die Fahranfänger gehabt haben durfte. Es wurden, verglichen mit den Nicht-Fahranfängern, weniger Fahranfänger nach der Einführung des neuen Gesetzes durch Alkohol am Steuer auffällig. Während 2004 noch 13,2% der protokollierten Delinquenten Fahranfänger waren, wurden es nach 2007 stetig weniger und 2013 waren es nur noch 3,9%.
Sowohl bei den Fahranfängern als auch bei den Nicht-Fahranfängern gibt es wesentlich mehr männliche als weibliche Delinquenten. Unfälle mit Sach- und/oder Personenschäden werden anteilsmäßig häufiger durch alkoholisierte Fahranfänger verursacht. Die BAK-Werte liegen bei den Nicht-Fahranfängern im Durchschnitt ca. 0,3 bis 0,4‰ höher als bei den Fahranfängern.
Da sich das neue Fahranfängergesetz offensichtlich bewährt hat, liegt es nahe über ein generelles Alkoholverbot am Steuer für alle Fahrzeugführer nachzudenken. Allerdings ist die Einführung eines solchen Gesetzes rechtlich schwierig, aufwendig und teilweise umstritten.
Prozess- und Kostenanalyse der Verpackungsoptionen von Sterilgütern in deutschen Krankenhäusern
(2021)
Die Sterilgutversorgung durch die Wiederaufbereitung von Medizinprodukten liegt als ein patientenferner Prozess häufig außerhalb des Fokus von Krankenhausmanagern, obwohl dieser Bereich sowohl medizinisch als auch ökonomisch von wesentlicher Bedeutung für die Qualität des Behandlungsprozesses ist. Der Einsatz verschiedener Erhebungstechniken, wie die Dokumentenanalyse und Zeitmessung, kann zu einem umfassenden Gesamtüberblick beitragen und damit eine Entscheidung unterstützen.
Die vorliegende Arbeit untersucht die unterschiedlichen Verpackungsoptionen von Sterilgütern in sechs Krankenhäusern in Deutschland. Mit Hilfe einer umfangreichen Zeitmessstudie werden zunächst die zeitlichen Unterschiede sowohl bei den verpackungsbezogenen Prozessen als auch bei den infrastrukturellen Prozessen verdeutlicht. Weiterhin werden alle relevanten Kostenpositionen ermittelt, sodass im Ergebnis Kosten für jede Verpackungsoptionen resultieren. Sowohl für die erhobenen Zeiten als auch für die Kosten wird eine Verteilungsanpassung und anschließend auf dieser Grundlage eine Monte-Carlo-Simulation durchgeführt. Um die gewonnen Ergebnisse auf ihre Stabilität zu prüfen, erfolgt eine ausführliche Szenarioanalyse, in der verschiedenste Inputparameter, wie die Personal- und Materialkosten, aber auch die Umschlagshäufigkeiten verändert werden und somit aufzeigen, unter welchen Umständen die Vorteilhaftigkeit einer einzelnen Verpackungsoption gegeben ist. Ergeben sich beispielsweise durch einen Wechsel der Verpackungsoptionen freie personelle Kapazitäten, können diese für eine Ausweitung des Leistungsspektrums sowohl im eigenen Haus als auch für Dritte genutzt werden.
Die Arbeit zeigt, dass nicht allein die Wahl der Verpackungsoption entscheidend ist, sondern ebenso ein optimaler Prozessablauf maßgeblichen Einfluss auf den Zeitaufwand und die Kosten haben kann. Darüber hinaus liefert die Arbeit Handlungs- und Optimierungsansätze und kann damit bei Entscheidungsprozessen unterstützen.
: Platelets are components of the blood that are highly reactive, and they quickly respond
to multiple physiological and pathophysiological processes. In the last decade, it became clear that
platelets are the key components of circulation, linking hemostasis, innate, and acquired immunity.
Protein composition, localization, and activity are crucial for platelet function and regulation. The
current state of mass spectrometry-based proteomics has tremendous potential to identify and quantify thousands of proteins from a minimal amount of material, unravel multiple post-translational
modifications, and monitor platelet activity during drug treatments. This review focuses on the role
of proteomics in understanding the molecular basics of the classical and newly emerging functions
of platelets. including the recently described role of platelets in immunology and the development
of COVID-19.The state-of-the-art proteomic technologies and their application in studying platelet
biogenesis, signaling, and storage are described, and the potential of newly appeared trapped ion
mobility spectrometry (TIMS) is highlighted. Additionally, implementing proteomic methods in
platelet transfusion medicine, and as a diagnostic and prognostic tool, is discussed.
Streptococcus pneumoniae is a commensal of the human upper respiratory tract and moreover, the
causative agent of several life-threatening diseases including pneumonia, sepsis, otitis media, and
meningitis. Due to the worldwide rise of resistance to antibiotics in pneumococci the understanding
of its physiology is of increasing importance. In this context, the analysis of the pneumococcal
proteome is helpful as comprehensive data on protein abundances in S. pneumoniae may provide
an extensive source of information to facilitate the development of new vaccines and drug
treatments.
It is known that protein phosphorylation on serine, threonine and tyrosine residues is a major
regulatory post-translational modification in pathogenic bacteria. This reversible post-translational
modification enables the translation of extracellular signals into cellular responses and therewith
adaptation to a steadily changing environment. Consequently, it is of particular interest to gather
precise information about the phosphoproteome of pneumococci. S. pneumoniae encodes a single
Serine/Threonine kinase-phosphatase couple known as StkP-PhpP.
To address the global impact and physiological importance of StkP and PhpP which are closely
linked to the regulation of cell morphology, growth and cell division in S. pneumoniae, proteomics
with an emphasis on phosphorylation and dephosphorylation events on Ser and Thr residues was
applied. Thus, the non-encapsulated pneumococcal D39Δcps strain (WT), a kinase (ΔstkP) and
phosphatase mutant (ΔphpP) were analyzed in in a mass spectrometry based label-free
quantification experiment. The global proteome analysis of the mutants deficient for stkP or phpP
already proved the essential role of StkP-PhpP in the protein regulation of the pneumococcus.
Proteins with significantly altered abundances were detected in diverse functional groups in both
mutants. Noticeable changes in the proteome of the stkP deletion mutant were observed in
metabolic processes such as “Amino acid metabolism” and also in pathways regulating genetic
and environmental information processing like “Transcription” and “Signal transduction”.
Prominent changes in the metabolism of DNA, nucleotides, carbohydrates, cofactors and vitamins
as well as in the categories “Transport and binding proteins” and “Glycan biosynthesis and
metabolism” have been additionally detected in the proteome of the phosphatase mutant. Still, the
quantitative comparison of WT and mutants revealed more significantly altered proteins in ΔphpP
than in ΔstkP. Moreover, the results indicated that the loss of function of PhpP causes an increased
abundance of proteins in the pneumococcal phosphate uptake system Pst. Furthermore, the
obtained quantitative proteomic data revealed an influence of StkP and PhpP on the twocomponent
systems ComDE, LiaRS, CiaRH, and VicRK.
Recent studies of the pneumococcal StkP/PhpP couple demonstrated that both proteins play an
essential role in cell growth, cell division and separation. Growth analyses and the phenotypic
characterization of the mutants by electron-microscopy performed within this work pointed out
that ΔphpP and ΔstkP had different growth characteristics and abnormal cell division and cell
separation. Nevertheless, the morphological effects could not be explained by changes in protein
abundances on a global scale. So, the in-depth analysis of the phosphoproteome was mandatory
to deliver further information of PhpP and StkP and their influence in cell division and
peptidoglycan synthesis by modulating proteins involved in this mechanisms.
For more detailed insights into the activity, targets and target sites of PhpP and StkP the advantages
of phosphopeptide enrichment using titanium dioxide and spectral library based data evaluation
were combined. Indeed, the application of an adapted workflow for phosphoproteome analyses
and the use of a recently constructed broad spectral library, including a large number of
phosphopeptides (504) highly enhanced the reliable and reproducible identification of
phosphorylated proteins in this work.
Finally, already known targets and target sites of StkP and PhpP, detected and described in other
studies using different experimental procedures, have been identified as a proof of principle
applying the mass spectrometry based phosphoproteome approach presented in this work.
Referring to the role of StkP in cell division and cell separation a number of proteins participating
in cell wall synthesis and cell division that are apparently phosphorylated by StkP was identified.
In comparison to StkP, the physiological function and role of the co-expressed phosphatase PhpP
is poorly understood. But, especially the list of previously unknown putative target substrates of
PhpP has been extended remarkably in this work. Among others, five proteins with direct
involvement in cell division (DivIVA, GpsB) and peptidoglycan biosynthesis (MltG, MreC, MacP)
can be found under the new putative targets of PhpP.
All in all, this work provides a complex and comprehensive protein repository of high proteome
coverage of S. pneumoniae D39 including identification of yet unknown serine/threonine/tyrosine
phosphorylation, which might contribute to support various research interests within the scientific
community and will facilitate further investigations of this important human pathogen.
Proteomic Adaptation of Clostridioides difficile to Treatment with the Antimicrobial Peptide Nisin
(2021)
Infections with bacterial pathogens are a major cause of morbidity and mortality
worldwide. Furthermore, the extensive use of antibiotics increased the frequency of infections with drug-resistant pathogens. Streptococcus pneumoniae, a major cause of
bacterial pneumonia, is among the pathogens that often show resistances. As an
additional side effect, the use of antibiotics can disrupt the patient’s intestinal microbiome, allowing Clostridioides difficile to cause severe, recurring and hard-to-treat
colitis. Hence, new antimicrobials are needed to combat infections caused by these
pathogens. A promising approach is the usage of antimicrobial peptides (AMPs), defense
molecules produced by organisms from all domains of life. AMPs can specifically perforate
bacterial membranes and stimulate the overall immune response of the host.
In this work, the proteomic adaptations of S. pneumoniae to the human antimicrobial
peptides LL-37 and hBD3 were assessed by high-resolution mass spectrometry and
compared to general membrane stress, in order to evaluate the specificity of the bacterial
reactions. Furthermore, C. difficile was challenged with the Lactococcus lactis-derived
AMP nisin, and the proteomic alterations were examined. In essence, application of LL-37
and hBD3 changed the abundance of pneumococcal proteins involved in membrane
transport, including a putative AMP transporter, a protease, virulence proteins and
genetic regulators. Moreover, a challenge with LL-37 caused an increase of proteins
involved in cell surface modifications that alter the bacterial membrane charge and repel cationic molecules such as LL-37. In support of this, mutants unable to express these
proteins were more sensitive to LL-37. In contrast, general membrane stress, induced by
the application of cationic detergents, produced a diverse proteomic adjustment, though the same two-component regulatory system was activated. In C. difficile, levels of flagella proteins were significantly increased shortly after treatment with nisin, being in
accordance with subsequent electron microscopy data and pointing at a role of these
proteins in adaptation to nisin. Interestingly, a flagella-overexpressing mutant showed an
enhanced resistance towards nisin, independent of bacterial motility.
Taken together, the bacterial pathogens under investigation seem to possess
mechanisms to reduce the effect of AMPs on their physiology, a finding that should be
considered developing drugs based on AMPs. Although AMPs exhibit membrane
perturbations as a common mechanism of action, bacterial adaptation to AMPs appear
multifactorial and dependent on the exact pathogen observed and AMP used.
Das Prostatakarzinom ist die häufigste Krebserkrankung des Mannes und die Inzidenz nimmt seit fast drei Jahrzehnten stetig zu. Moderne Therapieverfahren führen zu einem längeren Überleben der Patienten, durchaus auch mit kompletter Remission. Dennoch können im Rahmen der Therapie, insbesondere unter der Hormonentzugstherapie, weitere Veränderungen des Tumors zu einer Progression der Erkrankung führen. Durch den Verlust der Androgenabhängigkeit des Tumors bezeichnet man dies als kastrationsresistentes Prostatakarzinom. Dieser Progress ist häufig mit einer Zunahme von neuroendokrinen Zellen assoziiert, die im Rahmen einer sog. Neuroendokrinen Transdifferenzierung (NETD) aus den Drüsenzellen des Adenokarzinoms entstehen.
Im Rahmen der vorliegenden Arbeit wurde eine solche Differenzierung durch die Kultivierung der Prostatakarzinomzelllinie LNCaP in Gegenwart von IL-6 simuliert. Diese experimentell erzeugte NETD konnte sowohl durch die Überexpression typischer Markerproteine, als auch durch die charakteristische Veränderung der Zellmorphologie nachgewiesen werden.
Um die molekularbiologischen Mechanismen im Rahmen der NETD besser zu verstehen, wurde das Proteom der differenzierten Zellen mit dem von Kontrollzellen verglichen. Differentiell exprimierte Proteine wurden mittels Massenspektrometrie identifiziert.
Die Proteine Gelsolin, Septin 7 und PC1 wurden in weiterführenden Experimenten validiert. Im Kontext der NETD erwies sich Gelsolin aufgrund seiner bekannten Funktionen als besonders interessant. Daher wurde dessen Expression mittels RNA- Interferenz moduliert und die Auswirkungen auf Zellfunktion und Morphologie untersucht. Gelsolin ist ein multifunktionelles Protein, welches sowohl Zytoskelett- modulierend wirkt, als auch in die Regulation der Apoptose involviert ist. Die vorliegende Arbeit zeigt, dass ein Gelsolin knockdown eine deutliche Expressionserhöhung der aktivierten Caspase 3 bewirkt, was mit einer erhöhten Apoptoserate korreliert. Naheliegend war es auch der Frage nachzugehen, ob Gelsolin an der Ausprägung der charakteristischen morphologischen Veränderungen im Zuge der NETD beteiligt ist. Der begleitend zur IL-6-Behandlung durchgeführte knockdown ergab jedoch keinen relevanten Einfluss auf die Ausbildung von Zellausläufern.
Eine auf immunzytochemischer Färbetechnik basierende Analyse zeigte eine Kolokalisation von Gelsolin mit den Proteinen VDAC1 und PC1. Beide sind als Stabilisatoren des mitochondrialen Membranpotenzials bekannt. Somit könnte Gelsolin als Adapterprotein im Rahmen der Apoptoseregulation fungieren.
Die vorliegende Arbeit hat differentiell exprimierte Proteine identifiziert, die im Kontext einer NETD erstmals beschrieben wurden und somit den Weg bereitet, den Erkenntnisgewinn zu molekularbiologischen Abläufen bei der Entwicklung eines kastrationsresistenten Prostatakarzinoms auszuweiten.
Haloalkanes are serious environmental pollutants commonly employed as pesticides, herbicides, and chemical warfare agents. Although haloalkane production is performed mostly in the chemical industry, it also occurs naturally, mostly enzymatically (halide methyltransferases and haloperoxidases). Elimination of toxic haloalkanes is very important and using haloalkane dehalogenases is a promising and environmentally friendly way to achieve this.[53] Therefore, assays are needed for detecting dehalogenase activity either to find new enzymes or to generate laboratory-evolved variants. In this thesis, a new assay for dehalogenase activity was developed based on halide detection. In this assay halides, as dehalogenase products, are oxidized under mild conditions using the vanadium-dependent chloroperoxidase from Curvularia inaequalis, forming hypohalous acids that are detected using aminophenyl fluorescein.[53] This new halide oxidation assay is much more sensitive than previously known assays, with detection limits of 20 nM for bromide and 1 μM for chloride and iodide. Validation of the assay was done by comparison to a well-established GC-MS method in terms of determining the specific activities of two dehalogenases towards five common substrates (Figure 5).
The HOX assay was modified for iodide-specific detection by using two other dyes, o-phenylenediamine (OPD) and 3,3′,5,5′-tetramethylbenzidine (TBM), instead of APF. Also, selective bromide detection in the presence of the common contaminant chloride was achieved by using a bromoperoxidase. Since the assay relies on halide detection, it is possible to use it for other halide-producing enzymes (Section 8.1). For example, the TMB-modified version was used for screening of halide methyltransferase libraries towards various alkyl iodides.[166] Furthermore, the HOX assay was used to identify promiscuous dehalogenase activity of the epoxide hydrolase CorEH from Corynebacterium sp. C12.[105]
Moreover, studies showed that the HOX assay could be used with in-vitro synthesized protein. Selected dehalogenases, DhlA, DhaA, and DmmA, were synthesized in vitro and used in the assay; the product formation was also validated using GC-MS. In conclusion, the HOX assay can be used with purified protein, whole cells, or in vitro synthesized proteins.
The HOX assay application in microfluidic droplets was investigated since an ultra-high-throughput assay for haloalkane dehalogenases is needed. This investigation showed no leakage of reaction components and products in the short term (~24 h), based on tests done on water-in-oil droplets generated by microfluidic chips. Even though 20 μM droplets were not working, 70 μM droplets were successful for assay implementation. Since the Damborsky group in Brno (CZ) and the deMello group in Zürich (CH), have large dehalogenase libraries and more experience in microfluidics, respectively, we collaborated with these groups to finalize implementation of the assay in an ultrahigh-throughput format. Since the studies are ongoing, final results could not yet be shown in this thesis. However, it can be noted that the issue with 20 μm droplets has been sorted out since our collaborators in Brno noticed that the low fluorescence of the droplets is actually caused by excessive accumulation of fluorescein, which is self-quenching, resulting in low fluorescence once the concentration exceeds 1 μM. By lowering the APF concentration they could optimize the maximum amount of fluorescein formed, and a mutant library has now been successfully screened by our collaborators at the ETH. The last topic of the thesis was an investigation of converting an epoxide hydrolase into a haloalkane dehalogenase. These studies focused on increasing the minor dehalogenase activity of two previously identified epoxide hydrolase (Cif) variants. These Cif variants hardly led to soluble proteins, the PROSS algorithm was used to increase soluble expression. New variants of Cif were generated using a 3DM analysis and the PROSS[164] design. The activities of these variants were determined with the newly developed HOX assay in a whole-cell format. Cif23 E153N-H269D and the PROSS D7 E153N-H269D variant, were found being active against 1,2-dibromoethane. Since the determination of enzyme concentration was hard to measure due to the expression/purification problem, specific activities could not be determined. To solve this problem, a HiBiT-tag was added to the selected variants for determining soluble expression. However, the planned studies could not be completed because of a lack of time and will form the basis for a future study.
Einleitung
Die postoperative Serombildung ist eine der häufigsten Komplikationen (3 - 85 %) nach mammachirurgischen Eingriffen und kann durch sekundär auftretende Komplikationen, wie beispielsweise Infektionen, Schmerzen, oder die Notwendigkeit rezidivierender Punktionen zu einer Prolongation der Hospitalisierungsdauer und Wundkonsolidierung führen. Neben dem Standardverfahren der Totraumreduktion mittels Drainageanlage existieren zahlreiche Alternativen, wie die Anwendung von Fibrinkleber oder der Wundverschluss mittels sogenannter „Quilting sutures“. Eine weitere Möglichkeit der Totraumreduktion stellt ein auf Polyurethanbasis produzierter Gewebekleber (TissuGlu®), dessen Einfluss auf die postoperative Komplikationsrate sowie konsekutiv notwendige Interventionen im Rahmen dieser prospektiven, randomisiert-kontrollierten Nicht-Unterlegenheitsstudie vergleichend zur Drainageanlage untersucht wurde, dar.
Material und Methoden
In einem Gesamtstudienzeitraum von drei Jahren umfasste die finale Studienpopulation insgesamt 70 Patienten, von welchen 35 in die Gewebekleber- und 35 in die Drainagegruppe randomisiert wurden. Alle Patienten erhielten eine Mastektomie (ME), indikationsgerecht erweitert um eine Sentinel-Lymphonodektomie (SLNE). Im Rahmen eines sich postoperativ anschließenden 90-tägigen Follow-Ups erfolgte die Datenerhebung, welche der vergleichenden Betrachtung postoperativer Komplikationen und daraus konsekutiv resultierender Interventionen diente. Eine Nicht-Unterlegenheitsanalyse aller Interventionen sollte hierbei zeigen, ob die Anwendung des Gewebeklebers eine sichere und effiziente Alternative zur Drainageanlage in der Mammachirurgie darstellt.
Ergebnisse
Im Rahmen dieser Studie konnte hinsichtlich postoperativer Interventionen Nicht-Unterlegenheit für die Anwendung des Gewebeklebers nachgewiesen werden. Dennoch ließen sich für die Drainagegruppe weniger postoperative Komplikationen (0,9 ± 0,6 vs. 1,1 ± 0,7 Komplikationen; p = 0.091) sowie konsekutiv indizierte Interventionen (2,7 ± 1,2 vs. 3,0 ± 3,1 Interventionen; p = 0.408) ermitteln. Bezogen auf die isolierte Betrachtung der postoperativen Serombildung und deren Behandlung zeigte sich, dass trotz einer geringfügig geringeren Rate primärer Serome in der Gewebeklebergruppe (80,0 % vs. 86,1 %; p = 0.688), sowohl die durchschnittliche Punktionshäufigkeit pro behandelter Brust (2,8 ± 2,6 vs. 1,6 ± 1,2; p = 0.013) als auch das punktierte Volumen (394,1ml ± 423ml vs. 198,6 ml ± 291 ml; p = 0.021) nach Kleberanwendung signifikant höher lag als in der Drainagegruppe. In der Gewebeklebergruppe konnte dagegen, vergleichend zur Drainagegruppe, eine postoperative Schmerzreduktion mit statistischer Signifikanz ab Tag vier (p < 0.001) sowie die Verkürzung der Hospitalisierungsdauer (3,0 ± 1,4 vs. 5,8 ± 2,4 Tage; p < 0.001) gezeigt werden. Im Hinblick auf seromassoziierte Risikofaktoren beeinflussen der BMI, das Vorliegen eines Diabetes mellitus, der Gesundheitszustand des Patienten, validiert anhand des ASA-Scores, und die Operationsdauer die Inzidenz postoperativer Serome mit statistischer Signifikanz. Ein Einfluss des Patientenalters konnte nicht signifikant belegt werden, ist unter Berücksichtigung der Pathogenese von Seromentstehung und Wundheilung jedoch nicht sicher auszuschließen.
Schlussfolgerung
Die Anwendung des polyurethanbasierten Gewebeklebers TissuGlu® nach Mastektomie mit oder ohne SLNE ist primär durch eine gegenüber der Drainageeinlage geringere Invasivität gekennzeichnet und zeigt, bei grundlegend nachgewiesener Nichtunterlegenheit, signifikante Vorteile hinsichtlich des postoperativen Schmerzzustandes und der Dauer des stationären Krankenhausaufenthaltes. Dennoch nehmen die nach Gewebekleberanwendung durch rezidivierende Serome hervorgerufenen hohen Interventionsraten und erhöhte Punktionsvolumina negativen Einfluss auf die patientenspezifische Rekonvaleszenz und können somit das postoperative Infektionsrisiko erhöhen. Bezüglich der Inzidenz postoperativer Serome zeigte sich ein signifikanter Einfluss des BMI, eines vorbestehenden Diabetes mellitus, des Gesundheitszustandes gemessen anhand des ASA-Scores sowie der OP-Dauer. In Hinblick auf postoperative Komplikationen und Interventionen kann sowohl die Anwendung des Gewebeklebers als auch der Drainage jeweils vergleichend mit dem chirurgischen Wundverschluss ohne zusätzliche totraumreduzierende Maßnahmen einen interessanten Untersuchungsschwerpunkt weiterführender Studien darstellen. Zudem sollte eine Validierung der hier gewonnen Daten, insbesondere hinsichtlich Langzeitkomplikationen nach Anwendung des TissuGlu®-Gewebeklebers, im Rahmen weiterer prospektiver mono- und multizentrischer Studien erfolgen.
Promiscuous Dehalogenase Activity of the Epoxide Hydrolase CorEH from Corynebacterium sp. C12
(2021)
Haloalkane dehalogenases and epoxide hydrolases are phylogenetically related and structurally homologous enzymes that use nucleophilic aspartate residues for an SN2 attack on their substrates. Despite their mechanistic similarities, no enzymes are known that exhibit both epoxide hydrolase and dehalogenase activity. We screened a subset of epoxide hydrolases, closely related to dehalogenases, for dehalogenase activity and found that the epoxide hydrolase CorEH from Corynebacterium sp. C12 exhibits promiscuous dehalogenase activity. Compared to the hydrolysis of epoxides like cyclohexene oxide (1.41 μmol min–1 mg–1), the dehalogenation of haloalkanes like 1-bromobutane (0.25 nmol min–1 mg–1) is about 5000-fold lower. In addition to the activity with 1-bromobutane, dehalogenase activity was detected with other substrates like 1-bromohexane, 1,2-dibromoethane, 1-iodobutane, and 1-iodohexane. This study shows that dual epoxide hydrolase and dehalogenase activity can be present in one naturally occurring protein scaffold.
EGFR is overexpressed in the majority of clear cell renal cell carcinomas (CCRCCs). Although EGFR deregulation was found to be of great significance in CCRCC biology, the EGFR
overexpression is not associated with EGFR-targeted therapy responsiveness. Moreover, the prognostic role of EGFR expression remains controversial. In the present study, we evaluated the role
played by EGFR overexpression in CCRCC and its prognostic significance associated with different
immunohistochemical localization patterns. In our study, the Total Score (TS) related to membranouscytoplasmic EGFR expression showed a significant correlation with grade, pathologic stage (pT),
and Stage, Size, Grade, and Necrosis (SSIGN) score, and a negative correlation with nuclear EGFR
expression. No significant correlations were shown between nuclear EGFR and clinic-pathological
features. Additionally, a correlation between SGLT1 expression levels and pT was described. Multivariate analysis identifies pT and SSIGN score as independent prognostic factors for CCRCC. A
significantly increased survival rate was found in the case of positive expression of nuclear EGFR
and SGLT1. Based on our findings, SGLT1 and nuclear EGFR overexpression defines a subgroup of
CCRCC patients with good prognosis. Membranous-cytoplasmic EGFR expression was shown to be
a poor prognostic factor and could define a CCRCC subgroup with poor prognosis that should be
responsive to anti-EGFR therapies
Background: Cognitive Training (CT) may contribute to the maintenance and even enhancement of cognitive functions in healthy older adults. However, the question who benefits most from multi-domain CTs is still highly under-investigated.
Objective: The goal is to investigate prognostic factors and models for changes in cognitive test performance in healthy older adults after a multi-domain CT.
Methods: The data bases MEDLINE, Web of Science Core Collection, CENTRAL, and PsycInfo were searched up to July 2019. Studies investigating prognostic factors and/or models on cognitive outcomes (global cognition, memory, attention, executive functions, language, visuo-spatial abilities) after conducting a multi-domain CT in healthy older adults were included. Risk of Bias was assessed using the QUIPS and the PROBAST tool.
Results: 23 prognostic factor and model studies were included. Results indicate a high heterogeneity regarding the conducted multi-domain CTs, the investigated prognostic factors, the investigated outcomes, and the used statistical approaches. Age and neuropsychological performance at study entry were the most investigated predictors, yet they show inconsistent results.
Conclusion: Data on prognostic factors and models of changes after multi-domain CT are still too rare and inconsistent to draw clear conclusions due to statistical shortcomings and low reporting quality. Approaches for future research are outlined.
Registration: https://www.crd.york.ac.uk/prospero/, ID: CRD42020147531
Hintergrund: Trotz der geringen Versorgungsrate mit Cochlea-Implantaten (CIs) bei gleichzeitig steigender Indikation liegen die CI-Implantationszahlen bei Erwachsenen in Deutschland noch immer auf einem relativ niedrigen Niveau.
Methoden: Da in der Literatur kaum fundierte Prognosen vorliegen, wird ein System Dynamics-Modell entwickelt, das die Anzahl und Kosten von CI-Implantationen der erwachsenen Bevölkerung über 40 Jahre aus Sicht der Gesetzlichen Krankenversicherung (GKV) prognostiziert.
Ergebnisse: Die demografische Alterung wird zu einer geringfügigen Steigerung der CI-Nachfrage führen, die durchschnittliche jährliche Kosten von ca. 538 Mio. € verursacht. Der medizinisch-technische Fortschritt mit nachfolgender Ausweitung der CI-Indikationskriterien und die zunehmende Bereitschaft von CI-Kandidaten zur Implantation werden die Implantationszahlen deutlich erhöhen, sodass mit durchschnittlichen jährlichen Kosten von 2,3 Mrd. € zu rechnen ist.
Schlussfolgerung: Die CI-Nachfrage durch Erwachsene wird künftig steigen und damit auch die Kosten für die CI-Versorgung. Kontinuierliche Forschung und Entwicklung in CI-Technologie und -Versorgung sind von entscheidender Bedeutung, um die Finanzierung der wachsenden CI-Nachfrage durch kostensenkende Innovationen langfristig sicherzustellen.