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Background: The hospital reform initiated through an expert opinion of the German research institute IGES places great emphasis on the aspect of outpatient care. In this context, the current IGES guidelines extend further than has previously been the case. There are only very isolated instances where this theoretical potential has been translated into practical application in urology. This study aims to reflect the theoretical potential calculated using real data from urology with a view to practical application., Material and Methods: Using the algorithm of the "Hospital Structure Navigator" of DKTIG (Deutsche Krankenhaus TrustCenter und Informationsverarbeitung GmbH), focused on the extension of the AOP (Ambulatory Operations and Procedures) catalogue, section-21 data of the year 2022 from the Clinic for Urology at the University Hospital Schleswig-Holstein was analysed. The inclusion and exclusion criteria provided by IGES were applied, along with a limitation of the length of stay to two days and a minimum case number of 30 cases per year. Since this resulted in a very low potential for target DRGs (Diagnosis-Related Groups), the criteria were further modified. With this approach, a plausibility check for the outpatient treatment capability of identified cases was conducted., Results: After applying the inclusion and exclusion criteria, only one applicable DRG (L18B) emerged, but with the expanded criteria, eight DRGs were identified. From the case flat rates determined, three appropriate OPS codes were identified:1.) Ureterorenoscopic removal of stones from the kidney with lithotripsy (5-550.31)2.) Transurethral resection of a bladder tumour, not fluorescence-supported (5-573.40)3.) Bougienage of a ureter, transurethral (5-560.2) CONCLUSION: With the current set of criteria defined by IGES for urology, no significant outpatient potential can be achieved. However, the expansion of criteria has uncovered areas that could be well implemented with a broader set of criteria and are currently seen more systematically in the realm of measures replacing inpatient procedures or hybrid DRGs. In addition to the need to clarify the fundamental outpatient feasibility of the methods on an individual case basis, there are limitations here, especially for multimorbid populations. Therefore, in expanding the catalogue, the legislator must take into account the higher risk and monitoring effort required for these patients., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Molybdenum alkylidynes endowed with tripodal silanolate ligands belong to the most active and selective catalysts for alkyne metathesis known to date. This paper describes a new generation that is distinguished by an unprecedented level of stability and practicality without sacrificing the chemical virtues of their predecessors. Specifically, pyridine adducts of type 16 are easy to make on gram scale, can be routinely weighed and handled in air, and stay intact for many months outside the glovebox. When dissolved in toluene, however, spontaneous dissociation of the stabilizing pyridine ligand releases an active species of excellent performance and functional group tolerance. Specifically, a host of polar and apolar groups, various protic sites, and numerous basic functionalities proved compatible. The catalysts are characterized by crystallographic and spectroscopic means, including 95 Mo NMR; their activity and stability are benchmarked in detail, and the enabling properties are illustrated by advanced applications to natural product synthesis. For the favorable overall application profile and ease of handling, complexes of this new series are expected to replace earlier catalyst generations and help encourage a more regular use of alkyne metathesis in general.

Simulating the carbon-water fluxes at more widely distributed meteorological stations based on the sparsely and unevenly distributed eddy covariance flux stations is needed to accurately understand the carbon-water cycle of terrestrial ecosystems. We established a new framework consisting of machine learning, determination coefficient (R 2 ), Euclidean distance, and remote sensing (RS), to simulate the daily net ecosystem carbon dioxide exchange (NEE) and water flux (WF) of the Eurasian meteorological stations using a random forest model or/and RS. The daily NEE and WF datasets with RS-based information (NEE-RS and WF-RS) for 3774 and 4427 meteorological stations during 2002-2020 were produced, respectively. And the daily NEE and WF datasets without RS-based information (NEE-WRS and WF-WRS) for 4667 and 6763 meteorological stations during 1983-2018 were generated, respectively. For each meteorological station, the carbon-water fluxes meet accuracy requirements and have quasi-observational properties. These four carbon-water flux datasets have great potential to improve the assessments of the ecosystem carbon-water dynamics., (© 2023. Springer Nature Limited.)

Background and Study Aims:  The traditional percutaneous placement of dorsal root ganglion (DRG) electrodes may not be eligible for every patient. In this tertiary spine surgery and interventional pain therapy center, alternative neurostimulation implantation techniques were developed and applied where standard percutaneous approaches failed or were contraindicated., Case Presentation:  Three alternative implantation techniques can be used: (1) open surgical placement of DRG leads, (2) two-lead insertion via a lateral to medial transforaminal approach (level L3), and (3) percutaneous approach with two leads close to the spinal nerves L4 (peripheral nerve stimulation)., Results:  The placement of the leads occurred without complications and resulted in similar expected outcomes as with the common percutaneous technique with long-term stable pain suppression at 7 months and 1 year., Conclusions:  In patients in whom the DRG cannot be approached by the standard percutaneous approach, at least three alternatives may be used in experienced hands resulting in stable pain suppression of similar magnitude., Competing Interests: None declared., (Thieme. All rights reserved.)

Rewetting previously drained peatlands restores the critical function of peatlands as long-term carbon storages and sinks currently threatened by climate change and additional human-induced disturbances. Understanding and projecting the restoration process by rewetting, however, currently face a pressing challenge, the lack of consistent and gap-free records of important carbon cycling indicators of peatlands such as the gross primary production (GPP) over long term. In this study, we reconstructed the GPP in a rewetted peatland called Zarnekow (Fluxnet-ID: DE-Zrk) in Germany from 2000 to 2020 by combining long-term satellite observations and limited-term tower-based eddy covariance (EC) measurements based on Random Forest regression models. The R 2 between the reconstructed data and EC data was 0.6. The reasonable reconstruction of long-term GPP enabled trend analysis that identified two distinct periods of decreasing/increasing in GPP due to rewetting and droughts. Rewetting in the winter of 2004 and 2005 stabilized GPP after a decreasing period. A drought in 2018 significantly increased GPP, and GPP remained high over the following two years. Furthermore, the month-specific trends show significant seasonality at this site, specifically, an increasing trend over the 21 years in the growing-season months of June to August and a decreasing trend in the other months. The most important variables for satellite-based estimates of GPP at this site include total evapotranspiration, land surface temperature, enhanced vegetation index and near-infrared reflectance vegetation index. Long-term analyses of carbon fluxes through the combination of satellite observations and EC measurements provide crucial insights into the restoration of carbon sequestration functions in rewetted peatlands., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Junfeng Xu reports financial support was provided by Natural Science Foundation of Zhejiang Province. Torsten Sachs reports financial support was provided by Helmholtz Young Investigators Grant. Zhan Li reports financial support was provided by Helmholtz Association's Initiative and Networking Fund. Aram Kalhori reports financial support was provided by Helmholtz Association's Initiative and Networking Fund., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Long-term atmospheric CO 2 concentration records have suggested a reduction in the positive effect of warming on high-latitude carbon uptake since the 1990s. A variety of mechanisms have been proposed to explain the reduced net carbon sink of northern ecosystems with increased air temperature, including water stress on vegetation and increased respiration over recent decades. However, the lack of consistent long-term carbon flux and in situ soil moisture data has severely limited our ability to identify the mechanisms responsible for the recent reduced carbon sink strength. In this study, we used a record of nearly 100 site-years of eddy covariance data from 11 continuous permafrost tundra sites distributed across the circumpolar Arctic to test the temperature (expressed as growing degree days, GDD) responses of gross primary production (GPP), net ecosystem exchange (NEE), and ecosystem respiration (ER) at different periods of the summer (early, peak, and late summer) including dominant tundra vegetation classes (graminoids and mosses, and shrubs). We further tested GPP, NEE, and ER relationships with soil moisture and vapor pressure deficit to identify potential moisture limitations on plant productivity and net carbon exchange. Our results show a decrease in GPP with rising GDD during the peak summer (July) for both vegetation classes, and a significant relationship between the peak summer GPP and soil moisture after statistically controlling for GDD in a partial correlation analysis. These results suggest that tundra ecosystems might not benefit from increased temperature as much as suggested by several terrestrial biosphere models, if decreased soil moisture limits the peak summer plant productivity, reducing the ability of these ecosystems to sequester carbon during the summer., (© 2022 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Background: Attacks on health care represent an area of growing international concern. Publicly available data are important in documenting attacks, and are often the only easily accessible data source. Data collection processes about attacks on health and their implications have received little attention, despite the fact that datasets and their collection processes may result in differing numbers. Comparing two separate datasets compiled using publicly-available data revealed minimal overlap. This article aims to explain the reasons for the lack of overlap, to better understand the gaps and their implications., Methods: We compared the data collection processes for datasets comprised of publicly-reported attacks on health care from the World Health Organization (WHO) and Insecurity Insight's Security in Numbers Database (SiND). We compared each individual event to compile a comparable dataset and identify unique and matched events in order to determine the overlap between them. We report descriptive statistics for this comparison., Results: We identified a common dataset of 287 events from 2017, of which only 33 appeared in both datasets, resulting in a mere 12.9% (n = 254) overlap. Events affecting personnel and facilities appeared most often in both, and 22 of 31 countries lacked any overlap between datasets., Conclusions: We conclude that the minimal overlap suggests significant underreporting of attacks on health care, and furthermore, that dataset definitions and parameters affect data collection. Source variation appears to best explain the discrepancies and closer comparison of the collection processes reveal weaknesses of both automated and manual data collection that rely on hidden curation processes. To generate more accurate datasets compiled from public sources requires systematic work to translate definitions into effective online search mechanisms to better capture the full range of events, and to increase the diversity of languages and local sources to better capture events across geographies., (© 2023. The Author(s).)

Despite the importance of high-latitude surface energy budgets (SEBs) for land-climate interactions in the rapidly changing Arctic, uncertainties in their prediction persist. Here, we harmonize SEB observations across a network of vegetated and glaciated sites at circumpolar scale (1994-2021). Our variance-partitioning analysis identifies vegetation type as an important predictor for SEB-components during Arctic summer (June-August), compared to other SEB-drivers including climate, latitude and permafrost characteristics. Differences among vegetation types can be of similar magnitude as between vegetation and glacier surfaces and are especially high for summer sensible and latent heat fluxes. The timing of SEB-flux summer-regimes (when daily mean values exceed 0 Wm -2 ) relative to snow-free and -onset dates varies substantially depending on vegetation type, implying vegetation controls on snow-cover and SEB-flux seasonality. Our results indicate complex shifts in surface energy fluxes with land-cover transitions and a lengthening summer season, and highlight the potential for improving future Earth system models via a refined representation of Arctic vegetation types., (© 2022. The Author(s).)

Introduction: Meaningful activities (MA) have a positive impact on identity, well-being, participation and inclusion. Although people with intellectual disabilities (PID) depend on their direct support professionals (DSPs) to engage in MA, the DSPs need support which could enable them to offer more qualitative care and support., Methods and Analysis: To identify DSPs' needs, and to develop a tool/service, an innovative and iterative approach is developed, based on the human-centred design (HCD) process, combined with traditional qualitative and quantitative research methods. In the inspiration phase (needs analysis), in-depth interviews will be conducted in two day care centres in Flanders using an interpretative phenomenological analyses, one with a supply-driven approach and the other with a demand-driven approach, followed by a survey sent to all Flemish day care centres. In the ideation phase, the insights of phase 1 will guide a cocreation process (comprising a World Cafe, brainstorm and prototype sessions) with the DSPs, PID and other stakeholders. In the implementation phase, the solution will be tested in the two day care centres from phase 1 by means of living labs and a realist evaluation. By adopting this protocol, the functionality, quality, usability and acceptance are expected to increase. This protocol adopts all phases of the HCD process and shows the complementarity of HCD with traditional research methods. PID and the DSPs will benefit as the end result is truly grounded in their specific needs and wishes., Ethics and Dissemination: Ethical approval by the Ethics Committee of the University Hospital Ghent, Belgium (reference numbers: B670202042983 and PA2021-091). All participants will sign informed consent forms. Results of this study will be submitted for publication in relevant peer-reviewed journals and will be presented at relevant conferences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Arctic warming is affecting snow cover and soil hydrology, with consequences for carbon sequestration in tundra ecosystems. The scarcity of observations in the Arctic has limited our understanding of the impact of covarying environmental drivers on the carbon balance of tundra ecosystems. In this study, we address some of these uncertainties through a novel record of 119 site-years of summer data from eddy covariance towers representing dominant tundra vegetation types located on continuous permafrost in the Arctic. Here we found that earlier snowmelt was associated with more tundra net CO 2 sequestration and higher gross primary productivity (GPP) only in June and July, but with lower net carbon sequestration and lower GPP in August. Although higher evapotranspiration (ET) can result in soil drying with the progression of the summer, we did not find significantly lower soil moisture with earlier snowmelt, nor evidence that water stress affected GPP in the late growing season. Our results suggest that the expected increased CO 2 sequestration arising from Arctic warming and the associated increase in growing season length may not materialize if tundra ecosystems are not able to continue sequestering CO 2 later in the season., (© 2022. The Author(s).)

Trauma is the leading cause of death in individuals under 44 years of age. Thorax trauma (TxT) is strongly associated with trauma-related death, an unbalanced innate immune response, sepsis, acute respiratory distress syndrome, and multiple organ dysfunction. It is shown that different in vivo traumata, such as TxT or an in vitro polytrauma cytokine cocktail trigger secretion of small extracellular nanovesicles (sEVs) from endothelial cells with pro-inflammatory cargo. These sEVs transfer transcripts for ICAM-1, VCAM-1, E-selectin, and cytokines to systemically activate the endothelium, facilitate neutrophil-endothelium interactions, and destabilize barrier integrity. Inhibition of sEV-release after TxT in mice ameliorates local as well as systemic inflammation, neutrophil infiltration, and distant organ damage in kidneys (acute kidney injury, AKI). Vice versa, injection of TxT-plasma-sEVs into healthy animals is sufficient to trigger pulmonary and systemic inflammation as well as AKI. Accordingly, increased sEV concentrations and transfer of similar cargos are observed in polytrauma patients, suggesting a fundamental pathophysiological mechanism., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Upon resettlement, refugees face many challenges, including limited knowledge of available food and food insecurity, that increase their risks of diet-related diseases. Nutrition education may help them better navigate the challenges of their new food environments and help them live healthier lives. This review assesses the evidence on nutrition education delivery strategies and outcomes among refugees in the United States and other high-income countries using Levac review guidelines. Multiple electronic databases were searched using combinations of the following terms: nutrition, food, cooking, or gardening; education, workshop, curriculum, class, literacy, or program; and refugee. The quality of the peer-reviewed papers was assessed using the Medical Education Research Study Quality Instrument (MERSQI) scoring method. A total of 1930 studies were identified, and 17 met the inclusion criteria. The mean MERSQI score of the peer-reviewed studies was 9.02 (SD, 3.3; range, 1-14). The key nutrition education delivery strategies included conducting a needs assessment and providing client-centered education, a collaborative approach in program design, and hands-on activities such as cooking and store visits. A refugee's literacy level, cultural, and language barriers are common challenges to nutrition education delivery. Because there is limited evidence regarding the efficacy of programs regarding changes in refugees' nutrition knowledge and diet-related behaviors, future research should include rigorously designed studies and the development and implementation of standardized assessment and training tools. The adoption of a context-specific and flexible model is important for effective nutrition education delivery among the refugee population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Attacks on health care in armed conflict, including those on health workers, facilities, patients and transports, represent serious violations of human rights and international humanitarian law. Information about these incidents and their characteristics are available in myriad forms: as published research or commentary, investigative reports, and within online data collection initiatives. We review the research on attacks on health to understand what data they rely on, what subjects they cover and what gaps exist in order to develop a research agenda going forward., Methods and Findings: This study utilizes a systematic review of peer-reviewed to identify and understand relevant data about attacks on health in situations of conflict. We identified 1479 papers published before January 1, 2020 using systematic and hand-searching and chose 45 articles for review that matched our inclusion criteria. We extracted data on geographical and conflict foci, methodology, objectives and major themes. Among the included articles, 26 focused on assessment of evidence of attacks, 15 on analyzing their impacts, three on the legal and human rights principles and one on the methods of documentation. We analyzed article data to answer questions about where and when attacks occur and are investigated, what types of attacks occur, who is perpetrating them, and how and why they are studied. We synthesized cross-cutting themes on the impacts of these attacks, mitigation efforts, and gaps in existing data., Conclusion: Recognizing limitations in the review, we find there have been comparatively few studies over the past four decades but the literature is growing. To deepen the discussions of the scope of attacks and to enable cross-context comparisons, documentation of attacks on health must be enhanced to make the data more consistent, more thorough, more accessible, include diverse perspectives, and clarify taxonomy. As the research on attacks on health expands, practical questions on how the data is utilized for advocacy, protection and accountability must be prioritized.

Background: The recommended amount of sunscreen by hand application (2 mg/cm 2 ) is in reality not achieved, which decreases the homogeneity and thereby the effective sun protection factor (SPF)., Materials and Methods: The homogeneity of sunscreen applied by a newly developed spray applicator using an electrostatically charged aerosol, for which a hand rubbing of the formulation is not necessary, is evaluated. In vivo experiments were performed on the volar forearms of human volunteers using the spray applicator compared to the standardized hand application according to ISO 24444., Results: The distribution homogeneity was assessed qualitatively using in vivo laser scanning microscopy and quantitatively by absorption spectroscopy after tape stripping and by the standard deviation of multiple spatially displaced reflectance measurements for non-invasive SPF determination below the minimal erythemal dose, which showed a significantly higher homogeneity by 20.9% after spray application compared to hand application., Conclusion: Non-invasive SPF determination of multiple spatially displaced reflectance measurements was proven to be a suitable method for the non-invasive determination of the sunscreen distribution homogeneity. Electrostatically charged spray application increased the sunscreen distribution homogeneity on the skin and can reduce the amount of overspray., (© 2020 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Context: A narrow base of gait (BOG), the mediolateral distance between the foot and the body's line of gravity at midstance, during running is a suggested cause of injuries such as iliotibial band syndrome and tibial stress injury. However, an understanding of modifiable and nonmodifiable factors that influence BOG is lacking, which limits the development of corrective strategies., Objective: To determine if BOG varies by sex and running speed and the influence of running kinematics and anthropometrics on BOG., Design: Cross-sectional study., Setting: Record review of routinely collected performance data from a National Collegiate Athletic Association Division I intercollegiate athletic program., Patients or Other Participants: A total of 166 Division I collegiate athletes (basketball, cross-country, football, soccer)., Main Outcome Measure(s): Running biomechanics (N = 166) and dual-energy x-ray absorptiometry-derived anthropometric data (n = 68) were extracted. Running variables were BOG, step rate, stride length, foot-inclination angle, center-of-mass vertical displacement, heel-to-center of mass anteroposterior distance, and peak stance-phase angles: hip flexion, hip adduction, pelvic drop, knee flexion, and ankle dorsiflexion. Extracted anthropometric variables were height; leg, femur, and tibia length; and anterior-superior iliac spine, hip-joint, and greater trochanter width. We calculated linear mixed-effects models to assess the influence of sex and running speed on BOG and identify the kinematic and anthropometric variables most associated with BOG., Results: A significant interaction between sex and running speed on BOG was observed, with males demonstrating a smaller BOG than females at faster speeds and BOG decreasing overall with speed. The kinematic measures most associated with BOG at preferred running speed were foot-inclination angle at initial contact and peak stance-phase hip adduction and ankle dorsiflexion. Anterior-superior iliac spine width was the anthropometric variable most associated with BOG at preferred running speed., Conclusions: Sex and running speed must be considered when determining the appropriateness of an individual's BOG. Additionally, BOG was associated with several potentially modifiable kinematic parameters., (© by the National Athletic Trainers' Association, Inc.)

Peatland rewetting aims at stopping the emissions of carbon dioxide (CO 2 ) and establishing net carbon sinks. However, in times of global warming, restoration projects must increasingly deal with extreme events such as drought periods. Here, we evaluate the effect of the European summer drought 2018 on vegetation development and the exchange of methane (CH 4 ) and CO 2 in two rewetted minerotrophic fens (Hütelmoor-Hte and Zarnekow-Zrk) including potential carry-over effects in the post-drought year. Drought was a major stress factor for the established vegetation but also promoted the rapid spread of new vegetation, which will likely gain a lasting foothold in Zrk. Accordingly, drought increased not only respiratory CO 2 losses but also photosynthetic CO 2 uptake. Altogether, the drought reduced the net CO 2 sink in Hte, while it stopped the persistent net CO 2 emissions of Zrk. In addition, the drought reduced CH 4 emissions in both fens, though this became most apparent in the post-drought year and suggests a lasting shift towards non-methanogenic organic matter decomposition. Occasional droughts can be beneficial for the restoration of the peatland carbon sink function if the newly grown vegetation increases CO 2 sequestration in the long term. Nonetheless, care must be taken to prevent extensive peat decay. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.

Drought and heat events, such as the 2018 European drought, interact with the exchange of energy between the land surface and the atmosphere, potentially affecting albedo, sensible and latent heat fluxes, as well as CO 2 exchange. Each of these quantities may aggravate or mitigate the drought, heat, their side effects on productivity, water scarcity and global warming. We used measurements of 56 eddy covariance sites across Europe to examine the response of fluxes to extreme drought prevailing most of the year 2018 and how the response differed across various ecosystem types (forests, grasslands, croplands and peatlands). Each component of the surface radiation and energy balance observed in 2018 was compared to available data per site during a reference period 2004-2017. Based on anomalies in precipitation and reference evapotranspiration, we classified 46 sites as drought affected. These received on average 9% more solar radiation and released 32% more sensible heat to the atmosphere compared to the mean of the reference period. In general, drought decreased net CO 2 uptake by 17.8%, but did not significantly change net evapotranspiration. The response of these fluxes differed characteristically between ecosystems; in particular, the general increase in the evaporative index was strongest in peatlands and weakest in croplands. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.

The FLUXNET2015 dataset provides ecosystem-scale data on CO 2 , water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.

A new family of structurally well-defined molybdenum alkylidyne catalysts for alkyne metathesis, which is distinguished by a tripodal trisilanolate ligand architecture, is presented. Complexes of type 1 combine the virtues of previous generations of silanolate-based catalysts with a significantly improved functional group tolerance. They are easy to prepare on scale; the modularity of the ligand synthesis allows the steric and electronic properties to be fine-tuned and hence the application profile of the catalysts to be optimized. This opportunity is manifested in the development of catalyst 1f , which is as reactive as the best ancestors but exhibits an unrivaled scope. The new catalysts work well in the presence of unprotected alcohols and various other protic groups. The chelate effect entails even a certain stability toward water, which marks a big leap forward in metal alkylidyne chemistry in general. At the same time, they tolerate many donor sites, including basic nitrogen and numerous heterocycles. This aspect is substantiated by applications to polyfunctional (natural) products. A combined spectroscopic, crystallographic, and computational study provides insights into structure and electronic character of complexes of type 1 . Particularly informative are a density functional theory (DFT)-based chemical shift tensor analysis of the alkylidyne carbon atom and 95 Mo NMR spectroscopy; this analytical tool had been rarely used in organometallic chemistry before but turns out to be a sensitive probe that deserves more attention. The data show that the podand ligands render a Mo-alkylidyne a priori more electrophilic than analogous monodentate triarylsilanols; proper ligand tuning, however, allows the Lewis acidity as well as the steric demand about the central atom to be adjusted to the point that excellent performance of the catalyst is ensured.

We propose a continuous weak measurement protocol testing the nonlocality of Majorana bound states through current shot noise correlations. The experimental setup contains a topological superconductor island with three normal-conducting leads weakly coupled to different Majorana states. Putting one lead at finite voltage and measuring the shot noise correlations between the other two (grounded) leads, devices with true Majorana states are distinguished from those without by strong current correlations. The presence of true Majorana states manifests itself in unusually high noise levels or the near absence of noise, depending on the chosen device configuration. Monitoring the noise statistics amounts to a weak continuous measurement of the Majorana qubit and yields information similar to that of a full braiding protocol, but at much lower experimental effort. Our theory can be adapted to different platforms and should allow for the clear identification of Majorana states.

Recent warming in the Arctic, which has been amplified during the winter 1-3 , greatly enhances microbial decomposition of soil organic matter and subsequent release of carbon dioxide (CO 2 ) 4 . However, the amount of CO 2 released in winter is highly uncertain and has not been well represented by ecosystem models or by empirically-based estimates 5,6 . Here we synthesize regional in situ observations of CO 2 flux from arctic and boreal soils to assess current and future winter carbon losses from the northern permafrost domain. We estimate a contemporary loss of 1662 Tg C yr -1 from the permafrost region during the winter season (October through April). This loss is greater than the average growing season carbon uptake for this region estimated from process models (-1032 Tg C yr -1 ). Extending model predictions to warmer conditions in 2100 indicates that winter CO 2 emissions will increase 17% under a moderate mitigation scenario-Representative Concentration Pathway (RCP) 4.5-and 41% under business-as-usual emissions scenario-RCP 8.5. Our results provide a new baseline for winter CO 2 emissions from northern terrestrial regions and indicate that enhanced soil CO 2 loss due to winter warming may offset growing season carbon uptake under future climatic conditions.

Objectives: Severe psychiatric disorders may be accompanied by life-threatening conditions, lack of insight, and treatment refusal. Involuntary treatment may be indicated in patients who lack capacity to consent and refuse treatment. In this context, there is a lack of systematic data regarding the use of electroconvulsive therapy (ECT) in Germany., Methods: A questionnaire with 25 items comprising quantitative and qualitative data was sent to all psychiatric hospitals in Germany that perform ECT. Cases of ECT treatment in incapable patients refusing therapy were identified retrospectively in a 12-month period., Results: Fifty-three hospitals completed the questionnaire, and 15 cases of ECT in incapable and refusing patients were reported. A marked clinical response was observed in 14 patients. Capacity to consent was restored in 11 patients. In contrast to this particularly good effectiveness, psychiatrists' attitudes revealed a widespread lack of experience as well as reservations and uncertainties regarding the use of ECT against the patient's wishes., Conclusions: In line with other recent publications, our data suggest a very good benefit-to-risk ratio for ECT in incapable patients refusing the treatment, while at the same time the provision of ECT in such patients is rare in Germany. In light of the scarcity of treatment alternatives and the possible consequences of a refusal to perform ECT in life-threatening conditions, a general rejection of involuntary ECT does not seem ethically appropriate.

The new approach to the anticancer agent rhizoxin D described herein does not cohere with the conventional logic of metathesis, according to which macrocycles are best closed at a disubstituted olefinic site; rather, the trisubstituted C11-C12 alkene flanked by an allylic -OH group served as the pivot point for synthesis. This motif was attained in good yield and excellent selectivity by a sequence of alkyne metathesis, trans-hydrostannation and cross coupling. Because the exact same substructure is prominently featured in numerous other natural products, the underpinning strategy, though unusual, might bear more general relevance., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Neutrophils are important mediators of the innate immune defense and of the host response to a physical trauma. Because aberrant infiltration of injured sites by neutrophils was shown to cause adverse effects after trauma, we investigated how neutrophil infiltration could be modulated at the cellular level. Our data indicate that protein kinase D (PKD) is a vital regulator of neutrophil transmigration. PKD phosphorylates the Cofilin-phosphatase Slingshot-2L (SSH-2L). SSH-2L in turn dynamically regulates Cofilin activity and actin polymerization in response to a chemotactic stimulus for neutrophils, for example, fMLP. Here, we show that inhibition of PKD by two specific small molecule inhibitors results in broad, unrestricted activation of Cofilin and strongly increases the F-actin content of neutrophils even under basal conditions. This phenotype correlates with a significantly impaired neutrophil deformability as determined by optical stretcher analysis. Consequently, inhibition of PKD impaired chemotaxis as shown by reduced extravasation of neutrophils. Consequently, we demonstrate that transendothelial passage of both, neutrophil-like NB4 cells and primary PMNs recovered from a hemorrhagic shock trauma model was significantly reduced. Thus, inhibition of PKD may represent a promising modulator of the neutrophil response to trauma., (©2018 Society for Leukocyte Biology.)

Epstein-Barr Virus (EBV) BamHI-A rightward frame 1 (BARF1) protein is considered a viral oncogene in epithelial cells and has immune-modulating properties. During viral lytic replication BARF1 is expressed as an early gene, regulated by the immediate early EBV protein R. However, in viral latency BARF1 is exclusively expressed in epithelial tumors such as nasopharyngeal (NPC) and gastric carcinoma (GC) but not in lymphomas, indicating that activation of the BARF1 promoter is cell type specific. Undifferentiated NPC is characterized by high expression of ΔNp63 isoforms of the epithelial differentiation marker p63, a member of the p53 family of transcription factors. Transcription factor binding site analysis indicated potential p53 family binding sites within the BARF1 promoter region. This study investigated ability of various p53 family members to transactivate the BARF1 promoter. Using BARF1 promoter luciferase reporter constructs we demonstrate that only p63 isoform ΔNp63α is capable of transactivating the BARF1 promoter, but not the TAp63 isoforms, p53 or p73. Direct promoter binding of ΔNp63α was confirmed by Chromatin Immune Precipitation (ChIP) analysis. Deletion mutants of the BARF1 promoter revealed multiple ΔNp63 response elements to be responsible for BARF1 promoter transactivation. However, ΔNp63α alone was not sufficient to induce BARF1 in tumor cells harboring full EBV genomes, indicating that additional cofactors might be required for full BARF1 regulation. In conclusion, in EBV positive NPC and GC, BARF1 expression might be induced by the epithelial differentiation marker ΔNp63α, explaining BARF1 expression in the absence of lytic reactivation., Competing Interests: The authors declare no conflict of interest.

TALE-homeodomain proteins function as components of heteromeric complexes that contain one member each of the PBC and MEIS/PREP subclasses. We recently showed that MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC protein PBX1 in the SVZ has been reported, but its functional role(s) has not been investigated. Using a genetic loss-of-function mouse model, we now show that Pbx1 is an early regulator of SVZ neurogenesis. Targeted deletion of Pbx1 by retroviral transduction of Cre recombinase into Pbx2-deficient SVZ stem and progenitor cells carrying floxed alleles of Pbx1 significantly reduced the production of neurons and increased the generation of oligodendrocytes. Loss of Pbx1 expression in neuronally committed neuroblasts in the rostral migratory stream in a Pbx2 null background, by contrast, severely compromised cell survival. By chromatin immunoprecipitation from endogenous tissues or isolated cells, we further detected PBX1 binding to known regulatory regions of the neuron-specific genes Dcx and Th days or even weeks before the respective genes are expressed during the normal program of SVZ neurogenesis, suggesting that PBX1 might act as a priming factor to mark these genes for subsequent activation. Collectively, our results establish that PBX1 regulates adult neural cell fate determination in a manner beyond that of its heterodimerization partner MEIS2., (© 2016. Published by The Company of Biologists Ltd.)

When presented with auditory, visual, or bimodal audiovisual stimuli in a discrimination task, adults tend to ignore the auditory component in bimodal stimuli and respond to the visual component only (i.e., Colavita visual dominance effect). The same is true for older children, whereas young children are dominated by the auditory component of bimodal audiovisual stimuli. This suggests a change of sensory dominance during childhood. The aim of the current study was to investigate, in three experimental conditions, whether children and adults show sensory dominance when presented with complex semantic stimuli and whether this dominance can be modulated by stimulus characteristics such as semantic (in)congruency, frequency of bimodal trials, and color information. Semantic (in)congruency did not affect the magnitude of the auditory dominance effect in 6-year-olds or the visual dominance effect in adults, but it was a modulating factor of the visual dominance in 9-year-olds (Conditions 1 and 2). Furthermore, the absence of color information (Condition 3) did not affect auditory dominance in 6-year-olds and hardly affected visual dominance in adults, whereas the visual dominance in 9-year-olds disappeared. Our results suggest that (a) sensory dominance in children and adults is not restricted to simple lights and sounds, as used in previous research, but can be extended to semantically meaningful stimuli and that (b) sensory dominance is more robust in 6-year-olds and adults than in 9-year-olds, implying a transitional stage around this age., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Vesicle formation and fission are tightly regulated at the trans-Golgi network (TGN) during constitutive secretion. Two major protein families regulate these processes: members of the adenosyl-ribosylation factor family of small G-proteins (ARFs) and the protein kinase D (PKD) family of serine/threonine kinases. The functional relationship between these two key regulators of protein transport from the TGN so far is elusive. We here demonstrate the assembly of a novel functional protein complex at the TGN and its key members: cytosolic PKD2 binds ARF-like GTPase (ARL1) and shuttles ARL1 to the TGN. ARL1, in turn, localizes Arfaptin2 to the TGN. At the TGN, where PKD2 interacts with active ARF1, PKD2, and ARL1 are required for the assembly of a complex comprising of ARF1 and Arfaptin2 leading to secretion of matrix metalloproteinase-2 and -7. In conclusion, our data indicate that PKD2 is a core factor in the formation of this multiprotein complex at the TGN that controls constitutive secretion of matrix metalloproteinase cargo., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Introduction: Occipital nerve stimulation (ONS) may provide pain relief in migraine patients. In this double-blinded trial we investigated the significance of paresthesia and possible placebo effects., Methods: Patients already treated with ONS reporting stable treatment effect were included. "Effective stimulation," "subthreshold stimulation" and "no stimulation" were compared. Patients cycled through all three treatment groups. Outcome was measured using the visual analog scale (VAS) for pain, McGill Pain Questionnaire and SF-36., Results: Eight patients were included, mean preoperative VAS was 8.20 ± 1.22. A significant improvement in pain was observed in favor of suprathreshold stimulation compared to subthreshold stimulation (1.98 ± 1.56 vs 5.65 ± 2.11). Pain also significantly improved under subthreshold stimulation compared to no stimulation (5.65 ± 2.11 vs 8.45 ± 0.99). No changes in SF-36 were observed., Conclusions: Paresthesia is not required to achieve pain reduction but suprathreshold stimulation yields better results, underlining the significance of stimulation parameter customization., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: Motor cortex stimulation (MCS) is being offered to patients suffering from neuropathic pain. Outcome prediction, programming and especially sustaining a long-term treatment effect represent major challenges. We report a retrospective long-term analysis of our patients treated with MCS over a median follow-up of 39.1 months., Objectives: To investigate the time course of the treatment effect in MCS for neuropathic pain., Methods: Twenty-three closely followed patients treated with MCS were retrospectively analyzed. Reduction in pain measured on a visual analogue scale (VAS) was defined as the primary outcome parameter. VAS pain level and adverse events were documented at the 1-, 3-, 6-, 12-, 18- and 24-month follow-ups., Results: The mean VAS under best medical treatment was 7.8 (SD 1.2, range 5-9) with escalation to 9.3 (SD 0.9, range 6-10) when the patients' medications were missed or delayed. About half of the patients (47.8%) experienced a satisfactory (>50%) reduction in pain during the first month of treatment. The best treatment results were seen at the 3-month follow-up (mean VAS 4.8, SD 1.9, -37.2% compared to baseline). A decline in the treatment effect was generally observed at the subsequent follow-up assessments. Six patients had their devices explanted during the follow-up period due to loss of treatment effect., Conclusions: In this study, MCS failed to provide long-term pain control for neuropathic pain. Many aspects of MCS still remain unclear, especially the neural circuits involved and their response to long-term stimulation. Means must be developed to overcome the problems in this promising technique.

Objective: Spinal cord stimulation is an interventional treatment for chronic pain syndromes such as failed back surgery syndrome (FBSS), and it utilizes either cylindrical or paddle electrodes placed percutaneously into the epidural space. This prospective nonrandomized single-center study investigated the specific advantages and disadvantages of percutaneously implanted paddle and cylindrical leads in patients with FBSS., Methods: Over a 2-year period, 100 patients with FBSS (43 men; 57 women; mean age: 56.3 years) were included. Paddle leads were placed percutaneously under local anesthesia in 50 patients; conventional percutaneous cylindrical lead implantation was performed in the other 50 patients (one lead permitted per patient). Follow-up included the Visual Analog Scale (VAS) assessment of pain and administration of the Oswestry Disability Questionnaire., Results: Similar significant pain reduction (69%) was demonstrated in both groups (VAS pre/post: paddle: 8.8/3.7; cylindrical: 8.5/3.8). Using the same perioperative protocol for each group, we observed higher dislocation and infection rates for the cylindrical group (14% and 10%, respectively) than for the paddle group (6% and 2%, respectively)., Conclusion: Minimally invasive percutaneous paddle and cylindrical leads are safe and effective, have low complication rates, and perform well in patients with FBSS. Both devices can be implanted using a local anesthetic, so that intraoperative and reproducible testing stimulation can be performed for sufficient paresthesia overlap prior to permanent device fixation., (Georg Thieme Verlag KG Stuttgart · New York.)

We investigate the combined effects of distributed delay and the balance between excitatory and inhibitory nodes on the stability of synchronous oscillations in a network of coupled Stuart-Landau oscillators. To this end a symmetric network model is proposed for which the stability can be investigated analytically. It is found that beyond a critical inhibition ratio, synchronization tends to be unstable. However, increasing distributional widths can counteract this trend, leading to multiple resynchronization transitions at relatively high inhibition ratios. The extended applicability of the results is confirmed by numerical studies on asymmetrically perturbed network topologies. All investigations are performed on two distribution types, a uniform distribution and a Γ distribution.

A new family of cationic ligands, N-alkyl/aryl pyridiniophosphines, has been synthesized through a short, scalable, and highly modular route. Evaluation of their electronic properties evidenced weak σ-donor and quite strong π-acceptor character when used as ancillary ligands. These attributes confer a substantially enhanced π-acidity to the Pt(II) and Au(I) complexes thereof derived and, as result, they depict an improved ability to activate alkynes towards nucleophilic attack. This superior performance has been demonstrated along several mechanistically diverse Pt(II)- and Au(I)-catalyzed transformations., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Patients with Parkinson's disease (PD) deprived of dopaminergic medication to facilitate awake testing during the deep brain stimulation (DBS) procedure are at increased risk of neurologic deterioration.. The aim of this survey was to demonstrate the safety of subcutaneous apomorphine treatment for reducing surgery-related neurologic deterioration in patients undergoing DBS surgery for PD., Methods: Ninety-two patients who underwent DBS surgery for PD between 11/2007 and 10/2011 in our department were retrospectively analyzed for this survey. Demographic data, apomorphine dosage, side-effects and need of ICU/IMC stay were collected and analyzed., Results: Seventy-two out of 92 patients (78.3%) received apomorphine treatment; main reason for omission of treatment was intolerable nausea (16/92, 17.3%). Apomorphine treatment was well tolerated and the most common side effect was nodular panniculitis. No severe complications were observed. No patient required ICU/IMC stay related to dopaminergic deprivation., Conclusions: Perioperative withdrawal of dopaminergic medication in PD patients leads to an increased risk of neurologic and respiratory deterioration during DBS procedures. These complications can likely be tempered using perioperative subcutaneous apomorphine as a substitute. Our 5-year experience indicates a reduction in postoperative neurologic deterioration and ICU/IMC stay need. We consider perioperative apomorphine safe during DBS surgery for PD.

A straightforward synthesis of cyclopropenylidene-stabilized phosphenium cations 1 a-g through the reaction of [(iPr2N)2C3(+)Cl]BF4 with secondary phosphines is described. Their donor ability was evaluated by analysis of the CO stretching frequency in Rh complexes [RhCl(CO)L2](BF4)2 and electrochemical methods. The cyclopropenium ring induces a phosphite-type behavior that can be tuned by the other two substituents attached to the phosphorus atom. Despite of the positive charge that they bear, phosphenium cations 1 a-g still act as two-electron donor ligands, forming adducts with Pd(II) and Pt(II) precursors. Conversely, in the presence of Pd(0) species, an oxidative insertion of the Pd atom into the Ccarbene-phosphorus bond takes place, providing dimeric structures in which each Pd atom is bonded to a cyclopropenyl carbene while two dialkyl/diaryl phosphide ligands serve as bridges between the two Pd centers. The catalytic performance of the resulting library of Pt(II) complexes was tested; all of the cationic phosphines accelerated the prototype 6-endo-dig cyclization of 2-ethynyl-1,1'-biphenyl to afford pentahelicene. The best ligand 1 g was used in the synthesis of two natural products, chrysotoxene and epimedoicarisoside A., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pancreatic cancer cell invasion, metastasis, and angiogenesis are major challenges for the development of novel therapeutic strategies. Protein kinase D (PKD) isoforms are involved in controlling tumor cell motility, angiogenesis, and metastasis. In particular PKD2 expression is up-regulated in pancreatic cancer, whereas PKD1 expression is lowered. We report that both kinases control pancreatic cancer cell invasive properties in an isoform-specific manner. PKD2 enhances invasion in three-dimensional extracellular matrix (3D-ECM) cultures by stimulating expression and secretion of matrix metalloproteinases 7 and 9 (MMP7/9), by which MMP7 is likely to act upstream of MMP9. Knockdown of MMP7/9 blocks PKD2-mediated invasion in 3D-ECM assays and in vivo using tumors growing on chorioallantois membranes. Furthermore, MMP9 enhances PKD2-mediated tumor angiogenesis by releasing extracellular matrix-bound vascular endothelial growth factor A, increasing its bioavailability and angiogenesis. Of interest, specific knockdown of PKD1 in PKD2-expressing pancreatic cancer cells further enhanced the invasive properties in 3D-ECM systems by generating a high-motility phenotype. Loss of PKD1 thus may be beneficial for tumor cells to enhance their matrix-invading abilities. In conclusion, we define for the first time PKD1 and 2 isoform-selective effects on pancreatic cancer cell invasion and angiogenesis, in vitro and in vivo, addressing PKD isoform specificity as a major factor for future therapeutic strategies.

Highly invasive pancreatic tumors are often recognized in late stages due to a lack of clear symptoms and pose major challenges for treatment and disease management. Broad-band Protein Kinase D (PKD) inhibitors have recently been proposed as additional treatment option for this disease. PKDs are implicated in the control of cancer cell motility, angiogenesis, proliferation and metastasis. In particular, PKD2 expression is elevated in pancreatic cancer, whereas PKD1 expression is comparably lower. In our recent study we report that both kinases control PDAC cell invasive properties in an isoform-specific, but opposing manner. PKD1 selectively mediates anti-migratory/anti-invasive features by preferential regulation of the actin-regulatory Cofilin-phosphatase Slingshot1L (SSH1L). PKD2, on the other hand enhances invasion and angiogenesis of PDAC cells in 3D-ECM cultures and chorioallantois tumor models by stimulating expression and secretion of matrix-metalloproteinase 7 and 9 (MMP7/9). MMP9 also enhances PKD2-mediated tumor angiogenesis releasing extracellular matrix-bound VEGF-A. We thus suggest high PKD2 expression and loss of PKD1 may be beneficial for tumor cells to enhance their matrix-invading abilities. In our recent study we demonstrate for the first time PKD1 and 2 isoform-selective effects on pancreatic cancer cell invasion, in-vitro and in-vivo, defining isoform-specific regulation of PKDs as a major future issue.

The carbon (C) balance of boreal peatlands is mainly the sum of three different C fluxes: carbon dioxide (CO2), methane (CH4) and dissolved organic carbon (DOC). Intra- and inter-annual dynamics of these fluxes are differentially controlled by similar factors, such as temperature and water-table. Different climatic conditions within and between years might thus result in varying absolute and relative contributions of each flux to net ecosystem productivity (NEP). In this study CO2 fluxes were measured at a boreal peatland in eastern Finland during a dry year (2006) and a wet year (2007) and combined with DOC and CH4 fluxes from the same site. CO2 uptake in the wet year was 65% higher than in the dry year, caused by higher water table (WT) and subsequently reduced rates of soil respiration. Two to three-fold increases in DOC and CH4 fluxes in the wet year did not completely offset the higher CO2 uptake in that year, resulting in NEP of -83.7±14 g C m(-2) in the dry and -134.5±21 g C m(-2) in the wet year. Thus, in our study, WT was identified as the most important factor responsible for variations in the C balance between the observed years., (© 2013 Elsevier B.V. All rights reserved.)

Objective: The aim of the study was to investigate the predictive value of percutaneous electrical nerve stimulation (PENS) in peripheral nerve stimulation (PNS) for chronic neuropathic pain., Materials and Methods: Twelve patients being evaluated for PNS for chronic neuropathic pain were included in this survey. Stimulation with acupuncture needles was applied with continuous high frequency stimulation. Position, polarity, frequency and amperage threshold of perception, and adverse effects were noted. Additional stimulation side effects were documented. A StimScore was developed to evaluate effects in a standardized manner. This StimScore comprises coverage of the painful area, therapeutic range, and amperage required for successful stimulation. StimScore was determined during PENS, during test stimulation, and under final stimulation., Results: PNS was well tolerated by all patients. Seven of the 12 patients (58%) were classified as successfully treated, and 5/12 patients (42%) as unsuccessful. The mean overall pain reduction in the first group was 4.0 points (SD = 2.87, P = 0.010) and 2.4 points (SD = 1.29, P = 0.014), respectively, on the visual analogue scale. In the successful stimulation group, a mean StimScore of 13.14 (SD 11.19-15.0) was calculated vs. 10.4 (95% CI 8.52-12.28) in the unsuccessful stimulation group (P = 0.033, 95% CI = 0.265-5.220)., Conclusions: Predicting response to PNS is crucial to reduce the number of patients implanted in vain. To adopt PENS via electroacupuncture needles as a percutaneous simulation method for PNS seemed to be feasible. The technique presented herein bears the potential to improve patient selection combined with reduced invasiveness. The presented results are encouraging and deliver a starting point for further trials., (© 2013 International Neuromodulation Society.)

Background: The impact of brain shift on deep brain stimulation surgery is considerable. In DBS surgery, brain shift is mainly caused by CSF loss. CSF loss can be estimated by post-surgical intracranial air. Different approaches and techniques exist to minimize CSF loss and hence brain shift. The aim of this survey was to investigate the extent and dynamics of CSF loss during DBS surgery, analyze its impact on final electrode position, and describe a simple and inexpensive method of burr hole closure., Methods: Sixty-six patients being treated with deep brain stimulation were retrospectively analyzed for this treatise. During surgery, CSF loss was minimized using bone wax as a burr hole closure. Intracranial air volume was calculated based on early post-surgery stereotactic 3D CT and correlated with duration of surgery and electrode deviations derived from post-surgery image fusion., Results: Median early post-surgery intracranial air was 2.1 cm(3) (range 0-35.7 cm(3), SD 8.53 cm(3)). No correlation was found between duration of surgery and CSF-loss (R = 0.078, p = 0.534), indicating that CSF loss mainly occurs early during surgery. Linear regression analysis revealed no significant correlations regarding volume of intracranial air and electrode displacement in any of the three principal axes. No significant difference regarding electrode deviations between first and second side of surgery were observed., Conclusions: CSF loss mainly occurs during the early phase of DBS surgery. CSF loss during a later phase of surgery can be effectively averted by burr hole closure. Postoperative intracranial air volumes up to 35 cm(3) did not result in significant electrode displacement in our series. Comparing our results to studies previously published on this subject, burr hole closure using bone wax is highly effective.

Epstein-Barr virus (EBV) BamHI-A rightward frame 1 (BARF1) is considered a major viral oncogene in epithelial cells and has immune-modulating properties. However, in B cells and lymphomas, BARF1 expression is restricted to the viral lytic replication cycle. In this report, the transcriptional regulation of BARF1 during lytic replication is unraveled. Bisulfite sequencing of various cell lines indicated a high level of methylation of the BARF1 gene control region. A BARF1 promoter luciferase reporter construct was created using a CpG-free vector, enabling true assessment of promoter methylation. Induction of the EBV lytic cycle is mediated by the immediate-early proteins BZLF1 (Z) and BRLF1 (R). R was found to activate expression of the BARF1 promoter up to 250-fold independently of Z and unaffected by BARF1 promoter methylation. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and specific mutagenesis of the R-responsive elements (RREs) demonstrated direct binding of R to RREs between nucleotides -554 and -327 relative to the BARF1 transcriptional ATG start site. The kinetics of BARF1 expression upon transactivation by R showed that BARF1 mRNA was expressed within 6 h in the context of the viral genome. In conclusion, expression of the BARF1 protein during lytic replication is regulated by direct binding of R to multiple RREs in the gene control region and is independent of the promoter methylation status. The early kinetics of BARF1 upon transactivation by R confirm its status as an early gene and emphasize the necessity of early immune modulation during lytic reactivation.

Background: Food-isolated lactic acid bacteria can transform ferulic acid (FA) into several products. Since quantification of these metabolites during the different bacterial growth phases is lacking, the aim of this study was to identify and quantify conversion products of FA and to follow the kinetics of FA metabolism during growth of Lactobacillus plantarum and Lactobacillus collinoides., Results: Lactobacillus plantarum and Lactobacillus collinoides were incubated in MRS broth, to which different amounts of FA were added (final concentrations of 0, 0.5, 1.5 and 3 mmol L⁻¹), at 30 °C until the late stationary phase. Lactobacillus plantarum metabolised FA into 4-vinylguaiacol (4-VG) and hydroferulic acid (HFA). Conversion to 4-VG started simultaneously with the degradation of FA, while formation of HFA started in the mid-exponential phase. Lactobacillus collinoides only formed 4-VG, mainly in the stationary phase. No significant effect of the different amounts of FA was seen on the growth and fermentation characteristics of both bacteria., Conclusion: The results demonstrate that both bacteria are able to convert FA. However, start of conversion differs between the two strains. The different amounts of FA had no influence on the growth and fermentation characteristics of both bacteria., (Copyright © 2012 Society of Chemical Industry.)

Objectives: Spinal cord stimulation (SCS) is an established method for treatment of chronic pain. Cylindrical-type leads can be implanted percutaneously. In contrast, paddle leads (lamitrode) require more invasive surgery (i.e., laminotomy or laminectomy) for placement into the epidural space, thereby offering several advantages over percutaneous leads (octrode), including less lead migration and better paresthesia coverage. The goal of this study was to prospectively demonstrate the safety and efficacy of a percutaneous paddle lead for SCS., Materials and Methods: This prospective trial enrolled 81 patients. The mean age was 57 years (range 27-82 years) with an almost equal sex distribution (male 47%, female 53%). Most patients (90%) had failed back surgery syndrome combined with lower extremity pain and lower back pain. A percutaneous paddle lead was implanted using a novel introduction system for percutaneous implantation. All implantations were performed under local anesthesia. Prior to the final implantation of the impulse generator, all patients underwent seven days of trial stimulation with pain assessment using a visual analog scale (VAS). The median follow-up was 12 months., Results: The data showed favorable clinical outcomes for paresthesia coverage and pain reduction (median VAS 8.4 vs. 2.3), with a risk profile comparable with known percutaneous techniques. Compared with the published data (2-22%), the lead migration rate in this study was low (2.5%). No perioperative complications occurred., Conclusions: This new, minimally invasive percutaneous paddle lead is effective and safe, with a low migration rate. Placement can be done under local anesthesia, allowing an intraoperative assessment of the paresthesia coverage in terms of pain relief. This approach is less invasive and offers a faster and more comfortable procedure compared with laminotomy or laminectomy., (© 2012 International Neuromodulation Society.)

Purpose: To assess the efficacy and tolerability of chronic high-frequency deep brain stimulation (DBS) in adult patients with progressive myoclonic epilepsy (PME) syndromes., Methods: Five adult patients (four male, 28-39 years) with PME underwent chronic high-frequency DBS according to a study protocol that had been approved by the local ethics committee. Electrodes were implanted in the substantia nigra pars reticulata (SNr)/subthalamic nucleus (STN) region in the first patient and additionally in the ventral intermediate nucleus (VIM) bilaterally in the following four cases. Follow-up took place in intervals of 3 months and DBS effects were compared with baseline frequency of passive and activation-induced myoclonic jerks and daily life performance 8 weeks prior to implantation., Key Findings: Follow-up periods ranged from 12-42 months (median 24 months). The best clinical effects were seen with SNr/STN DBS in all patients. VIM stimulation failed to achieve acute therapeutic effects and revealed low side-effect thresholds and even triggering of myoclonia. In all patients the reduction of myoclonic seizures was observed and ranged between 30% and 100% as quantified by a standardized video protocol. All patients reported clinically relevant improvements of various capabilities such as free standing and walking or improved fine motor skills. In one patient with an excellent initial response generalized tonic-clonic seizures increased after 3 months of stimulation following extensive trauma-related surgery. The best effect was seen in the least impaired patient., Significance: DBS of the SNr/STN may be an effective treatment option for patients with PME. Less impaired patients may benefit more markedly., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: The measurement of the CBF is a non-standardized procedure and there are no reliable gold standards. This abstract shows a capillary-based perfusion-phantom for CE-DSC-MRI. It has equivalent flow properties to those within the tissue capillary system of the human brain and allows the validation of the Siemens Perfusion (MR) software., Materials and Methods: The perfusion phantom consists of a dialyzer for the simulation of the capillary system, a feeding tube for simulation of the AIF and a pulsatile pump for simulation of the heart. Using this perfusion phantom, the exact determination of the gold standard CBF due to the well-known geometry of the phantom is easy. It was validated based on different perfusion measurements. These measurements were investigated with standard software (Siemens Perfusion MR). The software determined the CBF within the capillary system. Based on this CBF, a comparison to the gold standard was made with several different flow speeds. After AIF selection, a total of 726 CBF data points were automatically extracted by the software., Results: This results in a comparison of the gold standard CBF to these 726 CBF values. Therefore, a reproducible and reliable deviation estimation between gold standard CBF and measured CBF using the software was computed. It can be shown that the deviation between gold standard and software-based evaluation ranges between 1 and 31 %., Conclusion: There is no significance for any correlation between flow speed and amount of deviation. The mean measured CBF is 11.4 % higher than the gold standard CBF (p-value < 0.001). Using this kind of perfusion-phantom, the validation of different software systems allows reliable conclusions about their quality., (© Georg Thieme Verlag KG Stuttgart · New York.)

Plastoglobules, lipid-protein bodies in the stroma of plant chloroplasts, are enriched in non-polar lipids, in particular prenyl quinols. In the present study we show that, in addition to the thylakoids, plastoglobules also contain a considerable proportion of the plastidial PQ-9 (plastoquinol-9), the redox component of photosystem II, and of the cyclized product of PQ-9, PC-8 (plastochromanol-8), a tocochromanol with a structure similar to gamma-tocopherol and gamma-tocotrienol, but with a C-40 prenyl side chain. PC-8 formation was abolished in the Arabidopsis thaliana tocopherol cyclase mutant vte1, but accumulated in VTE1-overexpressing plants, in agreement with a role of tocopherol cyclase (VTE1) in PC-8 synthesis. VTE1 overexpression resulted in the proliferation of the number of plastoglobules which occurred in the form of clusters in the transgenic lines. Simultaneous overexpression of VTE1 and of the methyltransferase VTE4 resulted in the accumulation of a compound tentatively identified as 5-methyl-PC-8, the methylated form of PC-8. The results of the present study suggest that the existence of a plastoglobular pool of PQ-9, along with the partial conversion of PQ-9 into PC-8, might represent a mechanism for the regulation of the antioxidant content in thylakoids and of the PQ-9 pool that is available for photosynthesis.