Funktion und Regulation des Chemokinrezeptors CXCR7

Der Chemokinrezeptor CXCR7 spielt eine essentielle Rolle bei der normalen Entwicklung und fördert die Initiation und Progression verschiedener pathologischer Prozesse wie Krebs und Autoimmunerkrankungen. Er ist ein atypischer Rezeptor, der nicht an G-Proteine koppelt und als effektiver Scavenger für SDF-1 agiert. Der zweite SDF-1-bindende Chemokinrezeptor CXCR4 aktiviert intrazelluläre Signalkaskaden über G-Proteine und vermittelt so physiologisch und pathologisch relevante Zellmigrationsprozesse. Indem er als Scavenger für SDF-1 agiert, moduliert CXCR7 den CXCR4-SDF-1-Signalweg. Um die Funktionen von CXCR7 besser zu verstehen und die strukturellen Domänen zu definieren, welche die entgegengesetzten Effekte der beiden SDF-1-Rezeptoren regulieren, wurden Tail swap-Mutanten und weitere Rezeptorchimären erzeugt. Diese Rezeptoren wurden in HEK293 oder CHO-K1 Zellen exprimiert und es wurde das Rezeptortrafficking, die Bindung, Internalisierung und Degradation von SDF-1, die G-Protein Kopplung und die Aktivierung von MAP-Kinasen untersucht. Die Ergebnisse bestätigen, dass CXCR7 ein effektiver Scavenger für SDF-1 ist und weisen darauf hin, dass diese Funktion aufgrund von starker Rezeptordegradation strengen Regulationsmechanismen wie de novo Synthese und Rezeptorrecycling unterliegt. Des Weiteren konnte gezeigt werden, dass die C-terminale Domäne von CXCR7 eine entscheidende Rolle bei der Regulation der Rezeptorfunktion spielt und dass diese regulatorische Funktion durch umfangreiche C-terminale Phosphorylierungen von Serin- und Threonin-Resten vermittelt wird

Myasthenia gravis - a retrospective analysis of e-mail inquiries made to a patient organisation and specialized center to uncover unmet needs from patients and caregivers

Background and aims: Myasthenia Gravis requires expert treatment from specialized neurologists. In Germany, this treatment is mainly provided by 18 Integrated Myasthenia Centers (iMZ) accredited by the German Myasthenia Gravis Association (DMG). The DMG is a large and well-organized patient organisation that is regarded as a trusted source for disease-specific information. The aim of this study was to analyse the type of requests that each of these institutions receives in order to identify any potential unmet needs regarding the availability of advice for patients and caregivers. This data can then be used in further research to tailor modern digital communication tools to the specific needs of MG patients. Methods: Counselling requests sent via e-mail to both institutions were extracted for defined examination periods and divided into a period 'before COVID-19 pandemic' (01.07.2019-31.12.2019) and 'during COVID-19 pandemic' (01.07.2020-31.12.2020). Requests were then analysed using four main categories: medical requests, organisational issues, COVID-19 and social legislation inquiries. Results: One thousand seven hundred eleven requests for advice were addressed to DMG and iMZ Charite. Most inquiries directed to the DMG (47%; n = 750) were related to medical issues, most frequently to side effects of medications (n = 325; 20%) and questions about treatment (n = 263; 16%), followed by inquiries regarding organisational issues (26%; n = 412). About half of the inquiries (n = 69; 58%) to the iMZ Charite were related to medical issues and almost one in three inquiries concerned organisational issues (n = 37; 30%). About one in ten inquiries concerned socio-legal matters (iMZ: n = 7; 6% and DMG: n = 177; 11%). During the pandemic, COVID-19 related issues accounted for 8% (n = 6) of inquiries at iMZ, and 16% (n = 253) at DMG. Conclusions: MG sufferers have a high demand for timely advice. In the current setting, they address their requests to both iMZs and the DMG via e-mail. Our findings confirm that the DMG is highly trusted by patients and caregivers and is used to obtain second opinions. A relevant proportion of requests to the iMZ could be answered more effectively through standardized responses or improved process management. The implementation of modern digital solutions, including telemedicine, for communication between patient and specialist should be evaluated in further research

Analysis of rotorcraft wind turbine wake encounters using piloted simulation

The use of offshore wind farms in Europe to provide a sustainable alternative energy source is now considered normal. Particularly in the North Sea, a large number of wind farms exist with a significant distance from the coast. This is becoming standard practice as larger areas are required to support operations. Efficient transport and monitoring of these wind farms can only be conducted using helicopters. As wind turbines continue to grow in size, there is a need to continuously update operational requirements for these helicopters, to ensure safe operations. This study assesses German regulations for flight corridors within offshore wind farms. A semi-empirical wind turbine wake model is used to generate velocity data for the research flight simulator AVES. The reference offshore wind turbine NREL 5 MW has been used and scaled to represent wind turbine of different sizes. This paper reports result from a simulation study concerning vortex wake encounter during offshore operations. The results have been obtained through piloted simulation for a transport case through a wind farm. Both subjective and objective measures are used to assess the severity of vortex wake encounters

Burden of disease in myasthenia gravis: taking the patient’s perspective

Background: Myasthenia gravis (MG) leads to exertion-dependent muscle weakness, but also psychological and social well-being are limited. We aim to describe the burden of disease in MG including sociodemographic, economical, psychosocial as well as clinical aspects, to compare health-related quality of life (HRQoL) of patients with MG to the general population (genP) and to explore risk factors for a lower HRQoL. Methods: This case-control study was conducted with MG patients of the German Myasthenia Association. A questionnaire-based survey included sociodemographic and clinical data as well as standardized questionnaires, e.g. the Short Form Health (SF-36). HRQoL was compared to genP in a matched-pairs analysis. Participants of the German Health Interview and Examination Survey for Adults (DEGS1) served as control group. Results: In our study, 1660 MG patients participated and were compared to 2556 controls from the genP. Patients with MG showed lower levels of physical functioning (SF-36 mean 56.0, SD 30.3) compared to the genP (mean 81.8, SD 22.1, adjusted difference: 25, 95% CI 22-29) and lower mental health sub-score (SF-36 mean 67.3, SD 19.8, vs. 74.1, SD 16.7, adjusted difference: 5, 95% CI 2-8). Female gender, higher age, low income, partnership status, lower activities of daily life, symptoms of depression, anxiety and fatigue and self-perceived low social support were associated with a lower HRQoL in MG patients. Discussion: HRQoL is lower in patients with MG compared to genP. The burden of MG on patients includes economic and social aspects as well as their emotional well-being. New therapies must achieve improvements for patients in these areas

Piloted Simulation of the Rotorcraft Wind Turbine Wake Interaction during Hover and Transit Flights

Helicopters are used for offshore wind farms for maintenance and support flights. The number of helicopter operations is increasing with the expansion of offshore wind energy, which stresses the point that the current German regulations have not yet been validated through scientific analysis. A collaborative research project between DLR, the Technical University of Munich, the University of Stuttgart and the University of Tübingen has been conducted to examine the sizes of the flight corridors on offshore wind farms and the lateral safety clearance for helicopter hoist operations at offshore wind turbines. This paper details the results of piloted helicopter simulations in a realistic offshore wind farm scenario. The far-wake of rotating wind turbines and the near-wake of non-rotating wind turbines have been simulated with high-fidelity computational fluid dynamics under realistic turbulent inflow conditions. The resulting flow fields have been processed by superposition during piloted simulations in the research flight simulator AVES to examine the flight corridors in transit flights and the lateral safety clearance in hovering flights. The results suggest a sufficient size for the flight corridor and sufficient lateral safety clearance at the offshore wind turbines in the considered scenarios

Pregnancy in myasthenia gravis: a retrospective analysis of maternal and neonatal outcome from a large tertiary care centre in Germany

Purpose: Myasthenia gravis (MG) is a rare, potentially life-threatening autoimmune disease with fluctuating muscle weakness frequently affecting women of childbearing age. MG can affect maternal as well as neonatal outcome with risk of worsening of myasthenic symptoms in the mothers and risk of transient neonatal myasthenia gravis (TNMG) and arthrogryposis multiplex congenita (AMC) or foetal acetylcholine receptor antibody-associated disorders (FARAD) in the neonates. Methods: Retrospective analysis of maternal and neonatal outcome in a cohort of pregnant MG patients treated at a tertiary care centre in Germany. Results: Overall, 66 pregnancies were analysed. During 40 (63%) pregnancies, women experienced a worsening of myasthenic symptoms, of whom 10 patients (15.7%) needed acute therapy with IVIg or plasma exchange. There was no case of myasthenic crisis. Rate of caesarean section was comparable to the overall C-section rate at our centre (38% vs. 40%). However, there was a slightly higher rate for operative vaginal delivery (15% vs. 10%) as potential indicator for fatiguing striated musculature in MG patients during the expulsion stage. Rate of TNMG as well as AMC was 3% (two cases each). Conclusions: Maternal and neonatal outcome in our cohort was favourable with a low rate of myasthenic exacerbations requiring acute therapies and a low rate of TNMG and AMC/FARAD. Our data might help neurologists and obstetricians to advice MG patients with desire to have children

Identifying patients at risk for myasthenic crisis with hemogram and inflammation-related laboratory parameters – a pilot study

Background: Myasthenia gravis (MG) is a rare autoimmune disease characterized by fatigable weakness of the voluntary muscles and can exacerbate to life-threatening myasthenic crisis (MC), requiring intensive care treatment. Routine laboratory parameters are a cost-effective and widely available method for estimating the clinical outcomes of several diseases, but so far, such parameters have not been established to detect disease progression in MG. Methods: We conducted a retrospective analysis of selected laboratory parameters related to inflammation and hemogram for MG patients with MC compared to MG patients without MC. To identify potential risk factors for MC, we applied time-varying Cox regression for time to MC and, as a sensitivity analysis, generalized estimating equations logistic regression for the occurrence of MC at the next patient visit. Results: 15 of the 58 examined MG patients suffered at least one MC. There was no notable difference in the occurrence of MC by antibody status or sex. Both regression models showed that higher counts of basophils (per 0.01 unit increase: HR = 1.32, 95% CI = 1.02–1.70), neutrophils (per 1 unit increase: HR = 1.40, 95% CI = 1.14–1.72), potentially leukocytes (per 1 unit increase: HR = 1.15, 95% CI = 0.99–1.34), and platelets (per 100 units increase: HR = 1.54, 95% CI = 0.99–2.38) may indicate increased risk for a myasthenic crisis. Conclusion: This pilot study provides proof of the concept that increased counts of basophils, neutrophils, leukocytes, and platelets may be associated with a higher risk of developing MC in patients with MG

Long-term air pollution and traffic noise exposures and mild cognitive impairment in older adults : a cross-sectional analysis of the Heinz Nixdorf recall study

Background: Mild cognitive impairment (MCI) describes the intermediate state between normal cognitive aging and dementia. Adverse effects of air pollution (AP) on cognitive functions have been proposed, but investigations of simultaneous exposure to noise are scarce. Objectives: We analyzed the cross-sectional associations of long-term exposure to AP and traffic noise with overall MCI and amnestic (aMCI) and nonamnestic (naMCI) MCI. Methods: At the second examination of the population-based Heinz Nixdorf Recall study, cognitive assessment was completed in 4,086 participants who were 50–80 years old. Of these, 592 participants were diagnosed as having MCI (aMCI, n = 309; naMCI, n = 283) according to previously published criteria using five neuropsychological subtests. We assessed long-term residential concentrations for size-fractioned particulate matter (PM) and nitrogen oxides with land use regression, and for traffic noise [weighted 24-hr (LDEN) and night-time (LNIGHT) means]. Logistic regression models adjusted for individual risk factors were calculated to estimate the association of environmental exposures with MCI in single- and two-exposure models. Results: Most air pollutants and traffic noise were associated with overall MCI and aMCI. For example, an interquartile range increase in PM2.5 and a 10 A-weighted decibel [dB(A)] increase in LDEN were associated with overall MCI as follows [odds ratio (95% confidence interval)]: 1.16 (1.05, 1.27) and 1.40 (1.03, 1.91), respectively, and with aMCI as follows: 1.22 (1.08, 1.38) and 1.53 (1.05, 2.24), respectively. In two-exposure models, AP and noise associations were attenuated [e.g., for aMCI, PM2.5 1.13 (0.98, 1.30) and LDEN 1.46 (1.11, 1.92)]. Conclusions: Long-term exposures to air pollution and traffic noise were positively associated with MCI, mainly with the amnestic subtype