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Die BerTA-Studie (englisches Akronym: ReDiCare) verfolgt das Ziel, ein versorgungsnahes Unterstützungsangebot für hoch belastete pflegende Angehörige in einer randomisierten Studie auf seine Wirksamkeit zu überprüfen. Mithilfe eines gestuften Ansatzes sollen unterschiedliche Beratungsbedarfe in dieser Zielgruppe abgedeckt werden. In einem ersten niederschwelligen Schritt erhalten alle pflegenden Angehörigen eine Pflegeberatung mittels strukturiertem Problemlösen durch Pflegeberaterinnen und Pflegeberater der teilnehmenden Pflegekassen. Pflegende Angehörige, die nach drei Monaten weiterhin hoch belastet sind, können im Anschluss ein sechsmonatiges psychotherapeutisches Unterstützungsangebot in Anspruch nehmen. Diese zweite optionale Intervention erfolgt ausschließlich telefonisch durch approbierte PsychotherapeutInnen und beinhaltet Methoden der kognitiven Verhaltenstherapie mit dem Ziel, depressive Symptome (Hauptendpunkt) zu verringern und das Wohlbefinden sowie die subjektiv erlebte Lebensqualität der pflegenden Angehörigen zu verbessern. Einige Charakteristika der bisherigen Stichprobe (N = 231) in der noch laufenden Studie geben einen ersten Einblick in die Studienpopulation und die in den psychotherapeutischen Interventionen adressierten Themen.

The repurposing of existing drugs has emerged as an attractive additional strategy to the development of novel compounds in the fight against cancerous diseases. Inhibition of phosphodiesterase 5 (PDE5) has been claimed as a potential approach to target various cancer subtypes in recent years. However, data on the treatment of tumors with PDE5 inhibitors as well as the underlying mechanisms are as yet very scarce. Here, we report that treatment of tumor cells with low concentrations of Sildenafil was associated with decreased cancer cell proliferation and augmented apoptosis in vitro and resulted in impaired tumor growth in vivo. Notably, incubation of cancer cells with Sildenafil was associated with altered expression of HSP90 chaperone followed by degradation of protein kinase D2, a client protein previously reported to be involved in tumor growth. Furthermore, the involvement of low doses of PU-H71, an HSP90 inhibitor currently under clinical evaluation, in combination with low concentrations of Sildenafil, synergistically and negatively impacted on the viability of cancer cells in vivo. Taken together, our study suggests that repurposing of already approved drugs, alone or in combination with oncology-dedicated compounds, may represent a novel cancer therapeutic strategy.

The efficient analysis of secretomes is important to study the mechanisms of bacterial secretion. However, secretome analysis of bacteria that rely on rich media for optimal secretion via modern quantitative shotgun proteomics workflows is often hampered by the higher degree of sample impurities. This may be a reason for the low number of quantitative secretome investigations in such cases. We assessed the efficiency and amenability for rich media secretome analysis of different workflows including precipitation, SP3, and a combined, serial workflow. Using the model organism Pseudomonas aeruginosa, we found that the combined TCA-SP3 strategy outperformed the other tested methods on all monitored qualitative and quantitative levels. This method proved to be most efficient in the recovery of proteins secreted by the type III secretion system (T3SS), including all known effector proteins and secretion machinery components. We monitored the compositional changes of secretome samples over time, and observed a strong increase in the secreted protein fraction by the T3SS 2 to 3 h after T3SS induction. Our study conceptually illustrates how the combination of TCA precipitation and SP3 results in orthogonality in depleting sample impurities accompanied by improved chromatographic peptide separation, and more efficient MS detection with improved quantification parameters.

Modern automation systems largely rely on closed loop control, wherein a controller interacts with a controlled process via actions, based on observations. These systems are increasingly complex, yet most deployed controllers are linear Proportional-Integral-Derivative (PID) controllers. PID controllers perform well on linear and near-linear systems but their simplicity is at odds with the robustness required to reliably control complex processes. Modern machine learning techniques offer a way to extend PID controllers beyond their linear control capabilities by using neural networks. However, such an extension comes at the cost of losing stability guarantees and controller interpretability. In this paper, we examine the utility of extending PID controllers with recurrent neural networks—–namely, General Dynamic Neural Networks (GDNN); we show that GDNN (neural) PID controllers perform well on a range of complex control systems and highlight how they can be a scalable and interpretable option for modern control systems. To do so, we provide an extensive study using four benchmark systems that represent the most common control engineering benchmarks. All control environments are evaluated with and without noise as well as with and without disturbances. The neural PID controller performs better than standard PID control in 15 of 16 tasks and better than model-based control in 13 of 16 tasks. As a second contribution, we address the lack of interpretability that prevents neural networks from being used in real-world control processes. We use bounded-input bounded-output stability analysis to evaluate the parameters suggested by the neural network, making them understandable for engineers. This combination of rigorous evaluation paired with better interpretability is an important step towards the acceptance of neural-network-based control approaches for real-world systems. It is furthermore an important step towards interpretable and safely applied artificial intelligence.

Many bacteria employ a type III secretion system (T3SS) injectisome to translocate proteins into eukaryotic host cells. Although the T3SS can efficiently export heterologous cargo proteins, a lack of target cell specificity currently limits its application in biotechnology and healthcare. In this study, we exploit the dynamic nature of the T3SS to govern its activity. Using optogenetic interaction switches to control the availability of the dynamic cytosolic T3SS component SctQ, T3SS-dependent effector secretion can be regulated by light. The resulting system, LITESEC-T3SS (Light-induced translocation of effectors through sequestration of endogenous components of the T3SS), allows rapid, specific, and reversible activation or deactivation of the T3SS upon illumination. We demonstrate the light-regulated translocation of heterologous reporter proteins, and induction of apoptosis in cultured eukaryotic cells. LITESEC-T3SS constitutes a new method to control protein secretion and translocation into eukaryotic host cells with unparalleled spatial and temporal resolution., The type III secretion system (T3SS) of bacteria can be used to inject cargo into eukaryotic cells but its lack of target specificity is a disadvantage. Here the authors place the T3SS under the regulation of light by engineering optogenetic switches into the dynamic cytosolic T3SS component SctQ.

Background Pathological anxiety originates from a complex interplay of genetic predisposition and environmental factors, acting via epigenetic mechanisms. Epigenetic processes that can counteract detrimental genetic risk towards innate high anxiety are not well characterized. Methods We used female mouse lines of selectively bred high (HAB)- vs low (LAB)-innate anxiety-related behavior and performed select environmental and pharmacological manipulations to alter anxiety levels as well as brain-specific manipulations and immunohistochemistry to investigate neuronal mechanisms associated with alterations in anxiety-related behavior. Results Inborn hyperanxiety of high anxiety-like phenotypes was effectively reduced by environmental enrichment exposure. c-Fos mapping revealed that hyperanxiety in high anxiety-like phenotypes was associated with blunted challenge-induced neuronal activation in the cingulate-cortex, which was normalized by environmental enrichment. Relating this finding with epigenetic modifications, we found that high anxiety-like phenotypes (compared with low-innate anxiety phenotypes) showed reduced acetylation in the hypoactivated cingulate-cortex neurons following a mild emotional challenge, which again was normalized by environmental enrichment. Paralleling the findings using environmental enrichment, systemic administration of histone-deacetylase-inhibitor MS-275 elicited an anxiolytic-like effect, which was correlated with increased acetylated-histone-3 levels within cingulate-cortex. Finally, as a proof-of-principle, local MS-275 injection into cingulate-cortex rescued enhanced innate anxiety and increased acetylated-histone-3 within the cingulate-cortex, suggesting this epigenetic mark as a biomarker for treatment success. Conclusions Taken together, the present findings provide the first causal evidence that the attenuation of high innate anxiety-like behavior via environmental/pharmacological manipulations is epigenetically mediated via acetylation changes within the cingulate-cortex. Finally, histone-3 specific histone-deacetylase-inhibitor could be of therapeutic importance in anxiety disorders.

// Yang Liu 1, 2 , Konrad Steinestel 3, 4 , Arefeh Rouhi 5 , Milena Armacki 1 , Kristina Diepold 1 , Gabriela Chiosis 6 , Thomas Simmet 7 , Thomas Seufferlein 1 and Ninel Azoitei 1 1 Center for Internal Medicine I, Ulm University, Ulm, Germany 2 Department of Gastroenterology and Hepatology, Zhongda Hospital, Southeast University, Nanjing, China 3 Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, Germany 4 Gerhard-Domagk-Institute of Pathology, University of Munster, Munster, Germany 5 Center for Internal Medicine III, Ulm University, Ulm, Germany 6 Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Institute, New York, NY, USA 7 Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, Ulm, Germany Correspondence to: Ninel Azoitei, email: ninel.azoitei@uni-ulm.de Keywords: tumor angiogenesis, hypoxia, VEGF-A, STK33, HIF-1α Received: May 13, 2017 Accepted: July 31, 2017 Published: August 24, 2017 ABSTRACT Lately, the HSP90 client serine/threonine kinase STK33 emerged to be required by cancer cells for their viability and proliferation. However, its mechanistic contribution to carcinogenesis is not clearly understood. Here we report that elevated STK33 expression correlates with advanced stages of human pancreatic and colorectal carcinomas. Impaired proliferation and augmented apoptosis associated with genetic abrogation of STK33 were paralleled by decreased vascularization in tumor xenografts. In line with this, ectopic STK33 not only promoted tumor growth after pharmacologic inhibition of HSP90 using structurally divergent small molecules currently in clinical development, but also restored blood vessel formation in vivo . Mechanistic studies demonstrated that HSP90-stabilized STK33 interacts with and regulates hypoxia-driven accumulation and activation of HIF-1α as well as secretion of VEGF-A in hypoxic cancer cells. In addition, our study reveals a putative cooperation between STK33 and other HSP90 client protein kinases involved in molecular and cellular events through which cancer cells ensure their survival by securing the oxygen and nutrient supply. Altogether, our findings indicate that STK33 interferes with signals from hypoxia and HSP90 to promote tumor angiogenesis and tumor growth.

The independent naming of components of injectisome-type type III secretion systems in different bacterial species has resulted in considerable confusion, impeding accessibility of the literature and hindering communication between scientists of the same field. A unified nomenclature had been proposed by Hueck more than 20 years ago. It found little attention for many years, but usage was sparked again by recent reviews and an international type III secretion meeting in 2016. Here, we propose that the field consistently switches to an extended version of this nomenclature to be no longer lost in translation.

Bilateral optic neuritis (bilON) is a rare clinical presentation often thought to be associated with relapsing disorders such as neuromyelitis optica spectrum disorders (NMOSD) or multiple sclerosis (MS).To characterize the clinical, radiological phenotype and antibody status of children presenting with bilON.Retrospective multicenter study on children with bilON age18 years with a first episode aquired demyelinating syndrome (ADS), cMRI, AQP4- and serum MOG-antibody status and follow-up data were collected.30 patients (f:m = 15:15, median age 8.0y) with bilON met the inclusion criteria. 22/30 (73%) were MOG-positive (median: 1:1280, range: 1:160-1:1520). No patient showed AQP4-abs. 4/30 patients (13%), all with high MOG-abs titers, had recurrent episodes. No patient developed MS. Improvement after IVMP was observed in most patients (26/30; 87%). Outcome was favorable with no sequelae in 22/30 patients. Serial MOG-abs titers tested in 15/22 patients decreased to a median of 1:160 (range: 0-1:640) over a period of 31 months (range: 2-141 months) in 14/15 (93%) patients. MR imaging showed a predominantly anterior affection of the visual system in seropositive patients with bilateral intraorbital lesions in 68% (15/22), compared to 25% in MOG-negative patients (2/8).Pediatric bilON is associated with high MOG-abs titers in combination with anterior involvement of the visual system. Despite severe loss of vision, the majority of patients shows distinct recovery after IVMP.

Fragestellung: Anhand einer Kadaver-Studie sollte gezeigt werden, welche Zonen des Tibiaplateaus durch welchen chirurgischen Zugang oder durch welche Kombination an Zugängen eingesehen werden können. Methodik: Im Rahmen der Studie wurden an je acht Tibiakopf-Präparaten verschiedene[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2019)

Manual blood smear analysis remains the gold standard to diagnose hematological disorders and infections of blood parasites. However, the analysis and interpretation of peripheral blood smears requires expert users, is time consuming, depends on inter-observer variation, and is not compatible with a high-throughput workflow for clinical routine diagnostics (Dunning & Safo, Biotech. Histochem. 2011, 86, 69–75; Pierre, Clin. Lab. Med., 2002, 22, 279–297). Instead, automated hematology analyzers only flag atypical results which provides no clear classification of diseases and require extensive sample preparation. Label-free image analysis of untouched blood cells would reduce pre-analytical efforts and potentially allows characterization of samples with higher information content compared to both smear analysis and conventional automated flow cytometry, as the blood cell morphology is preserved. Furthermore, preclinical research work is in need for non-invasive analysis of e.g. cancer cells or infected cells to support the discovery of new drugs. We suggest to apply high-throughput and label-free workflows based on digital holographic microscopy for standardizable image analysis relevant for pre- and clinical diagnosis. In the case of parasitic infections, the label-free detection and analysis of malaria parasites has been addressed by various studies (Anand et al., IEEE Photonics J., 2012, 4, 1456-1464; Seo et al., Appl. Phys. Lett., 2014, 104, 1-4; Park et al, PloS One, 2016, 11, 1-19; Ugele et al., Lab Chip, 2018, 18, 1704-1712). The detection of neglected tropical diseases affecting livestock and humans, such as Chagas disease and Leishmaniosis, has not been addressed so far by the community. Our platform technology is based on a customized differential holographic microscopy setup, which has been previously described (Ugele et al., Lab Chip, 2018, 18, 1704-1712; Ugele et al., Adv. Sci., 2018, 5, 1800761). Reference data sets of clinical leukemic samples, cancer cell cultures in solution, and in vitro cultures of various parasites were collected to understand the translational potential for this methodology. Hydrodynamic and viscoelastic focusing in a microfluidics channel was used for high-throughput imaging and enrichment/depletion of cell populations without the need for any autofocusing procedures. Morphological parameters describing the inner consistency were calculated from segmented phase images of the cells/parasites and combined with machine learning algorithms for improved analysis by the discovery of label-free biomarkers. In this way, improved subtyping of acute and chronic leukemias, myeloproliferative neoplasms, and further hematological disorders was achieved. Second, a detection of Trypanosoma and Leishmania parasites could be shown and in vitro cultures of Schistosomia mansoni were classified according to different viability stages. Third, the capability of anti-cancer drug candidate screening was demonstrated by monitoring the mesenchymal-epithelial transition of pancreas cancer cell cultures. We envision, that our platform technology has the potential as a cost-efficient method for automated diagnosis of various hematological disorders, parasitic infections, drug screening and monitoring of therapy efficacy. With further integration effort we also believe that the technology can be applied in resource limited settings.

Flagellar motility is critical for surface attachment and biofilm formation in many bacteria. A key regulator of flagellar motility in Pseudomonas aeruginosa and other microbes is cyclic diguanylate (c-di-GMP). High levels of this second messenger repress motility and stimulate biofilm formation. C-di-GMP levels regulate motility in P. aeruginosa in part by influencing the localization of its two flagellar stator sets, MotAB and MotCD. Here we show that just as c-di-GMP can influence the stators, stators can impact c-di-GMP levels. We demonstrate that the swarming motility-driving stator MotC physically interacts with the transmembrane region of the diguanylate cyclase SadC. Furthermore, we demonstrate that this interaction is capable of stimulating SadC activity. We propose a model by which the MotCD stator set interacts with SadC to stimulate c-di-GMP production in conditions not permissive to motility. This regulation implies a positive feedback loop in which c-di-GMP signaling events cause MotCD stators to disengage from the motor; then disengaged stators stimulate c-di-GMP production to reinforce a biofilm mode of growth. Our studies help define the bidirectional interactions between c-di-GMP and the motility machinery.Importance.The ability of bacterial cells to control motility during early steps in biofilm formation is critical for the transition to a non-motile, biofilm lifestyle. Recent studies have clearly demonstrated the ability of c-di-GMP to control motility via a number of mechanisms, including through controlling transcription of motility-related genes and modulating motor function. Here we provide evidence that motor components can in turn impact c-di-GMP levels. We propose that communication between motor components and c-di-GMP synthesis machinery allows the cell to have a robust and sensitive switching mechanism to control motility during early events in biofilm formation.

A 3-year-old previously healthy boy presented with a fever (39.5°C), tonsillitis, cervical lymphadenopathy and epistaxis. Laboratory testing showed elevated C reactive protein (73 mg/L/695.2 nmol/L), leukocytosis (16 G/L), mild thrombocytopenia (138 G/L) and anaemia (haemoglobin 96 g/L). Within 24 hours, he developed gross haematuria and progressive irregular purpuric skin lesions affecting the lower extremities (figure 1), an elbow and genitals, typical of purpura fulminans. Antimicrobial therapy with third-generation cephalosporin and clindamycin was initiated. Laboratory testing for acute bacterial, fungal and viral infections was negative. Coagulation tests revealed disseminated intravascular coagulation (DIC) with …

Background: Myelin oligodendrocyte glycoprotein (MOG) antibodies have been described in children with acute disseminated encephalomyelitis (ADEM), recurrent optic neuritis, neuromyelitis optica spectrum disorders and more recently in children with multiphasic disseminated encephalomyelitis (MDEM). Objective: To delineate the clinical, cerebrospinal fluid (CSF) and radiological features of paediatric MDEM with MOG antibodies. Methods: Clinical course, serum antibodies, CSF, magnetic resonance imaging (MRI) studies and outcome of paediatric MDEM patients were reviewed. Results: A total of 8 children with two or more episodes of ADEM were identified from a cohort of 295 children with acute demyelinating events. All children had persisting MOG antibodies (median titre: 1:1280). All ADEM episodes included encephalopathy, polyfocal neurological signs and a typical MRI. Apart from ADEM episodes, three children had further clinical attacks without encephalopathy. Median age at initial presentation was 3 years (range: 1–7 years) and median follow-up 4 years (range: 1–8 years). New ADEM episodes were associated with new neurological signs and new MRI lesions. Clinical outcome did range from normal (four of the eight) to mild or moderate impairment (four of the eight). A total of four children received monthly immunoglobulin treatment during the disease course. Conclusion: Children with MDEM and persisting MOG antibodies constitute a distinct entity of relapsing demyelinating events and extend the spectrum of MOG antibody–associated diseases.

One of the major reasons why the elderly lose their ability to live independently at home is the decline in gait performance. A measure to assess gait performance using accelerometers is step counting. The main problem with most step detection algorithms is the loss of accuracy at low speeds ( $ 0.8 m/s) which limits their use in frail elderly populations. In this paper, a step detection algorithm was developed and validated using data from 10 healthy adults and 21 institutionalized seniors, predominantly frail older adults. Data were recorded using a single waist-worn triaxial accelerometer as each of the subjects performed one 10-m-walk trial. The algorithm demonstrated high mean sensitivity (99 $\pm$ 1%) for gait speeds between 0.2–1.5 m/s. False positives were evaluated with a series of motion activities performed by one subject. These activities simulate acceleration patterns similar to those generated near the body's center of mass while walking in terms of amplitude signal and periodicity. Cycling was the activity which led to a higher number of false positives. By applying template matching, we reduced by $73\%$ the number of false positives in the cycling activity and eliminated all false positives in the rest of activities. Using K-means clustering, we obtained two different characteristic step patterns, one for normal and one for frail walking, where particular gait events related to limb impacts and muscle flexions were recognized. The proposed system can help to identify seniors at high risk of functional decline and monitor the progress of patients undergoing exercise therapy interventions.

Fragestellung: Die letale Trias (Koagulopathie, Hypothermie, Azidose) hat ein hohes Letalitätsrisiko - so die gängige Lehrmeinung. Wie stellt sich dieser Umstand im Jahr 2018 dar? Konnte im Zuge der allgemeinen Verbesserung der Schwerstverletztenversorgung auch die letale Trias bekämpft[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2018)

Antibodies against the myelin oligodendrocyte glycoprotein (MOG-Ab) can be detected in various pediatric acquired demyelinating syndromes (ADS). Here, we analyze the spectrum of neuroradiologic findings in children with MOG-Ab and a first demyelinating event. The cerebral and spinal MRI of 69 children with different ADS was assessed in regard to the distribution and characteristics of lesions. Children with acute disseminated encephalomyelitis (n = 36) or neuromyelitis optica spectrum disorder (n = 5) presented an imaging pattern characterized predominantly by poorly demarcated lesions with a wide supra- and infratentorial distribution. Younger children also tended to have poorly defined and widespread lesions. The majority of patients with an isolated optic neuritis (n = 16) only presented small non-specific brain lesions or none at all. A longitudinally extensive transverse myelitis mainly affecting the cervical, and less often so the thoracic, lumbar, and conus regions, was detected in 31 children. The three children of our cohort who were then finally diagnosed with multiple sclerosis had at onset already demarcated white matter lesions as well as transverse myelitis. In conclusion, children with MOG seropositive ADS present disparate, yet characteristic imaging patterns. These patterns have been seen to correlate to the disease entity as well as to age of symptom onset.

In bacterial type 3 secretion, substrate proteins are actively transported from the bacterial cytoplasm into the host cell cytoplasm by a large membrane-embedded machinery called the injectisome. Injectisomes transport secretion substrates in response to specific environmental signals, but the molecular details by which the cytosolic secretion substrates are selected and transported through the type 3 secretion pathway remain unclear. Secretion activity and substrate selectivity are thought to be controlled by a sorting platform consisting of the proteins SctK, SctQ, SctL, and SctN, which together localize to the cytoplasmic side of membrane-embedded injectisomes. However, recent work revealed that sorting platform proteins additionally exhibit substantial cytosolic populations and that SctQ reversibly binds to and dissociates from the cytoplasmic side of membrane-embedded injectisomes. Based on these observations, we hypothesized that dynamic molecular turnover at the injectisome and cytosolic assembly among sorting platform proteins is a critical regulatory component of type 3 secretion. To determine whether sorting platform complexes exist in the cytosol, we measured the diffusive properties of the two central sorting platform proteins, SctQ and SctL, using live cell high-throughput 3D single-molecule tracking microscopy. Single-molecule trajectories, measured in wild-type and mutantYersinia enterocoliticacells, reveal that both SctQ and SctL exist in several distinct diffusive states in the cytosol, indicating that these proteins form stable homo- and hetero-oligomeric complexes in their native environment. Our findings provide the first diffusive state-resolved insights into the dynamic regulatory network that interfaces stationary membrane-embedded injectisomes with the soluble cytosolic components of the type 3 secretion system.

Fragestellung: Etomidate ist, wegen der nachgewiesenen Suppression der Cortisolproduktion umstritten. Nach der S3-Leitlinie Polytrauma sollte Etomidate bei Schwerstverletzten nicht verwendet werden (GoR B). Aber ist das Outcome der mit Etomidate intubierten Schwerstverletzten tatsächlich schlechter?[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017)

Fragestellung: Die Literatur zeigt für die Luftrettung insgeamt eine längere präklinische Versorgungszeit. Der luftgebundene Notarzt wird am Tag oftmals, in der Nacht immer sekundär alarmiert (wenn verfügbar). Sind Unterschiede im präklinischen Ablauf und der Therapie[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017)

Fragestellung: in der Literatur wird Die Inzidenz der Verletzung der hirnversorgenden Gefäße zwischen 0,39% und 4,6% angegeben. Um die gefährdeten Patienten zu identifizieren und diese einer primären Diagnostik zuzuführen werden multiple Algorithmen vorgeschlagen [zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017)

In this paper we propose a challenging new computer vision task of inferring Bread Units (BUs) from food images. Assessing nutritional information and nutrient volume from a meal is an important task for diabetes patients. At the moment, diabetes patients learn the assessment of BUs on a scale of one to ten, by learning correspondence of BU and meals from textbooks. We introduce a large scale data set of around 9k different RGB-D images of 60 western dishes acquired using a Microsoft Kinect v2 sensor. We recruited 20 diabetes patients to give expert assessments of BU values to each dish based on several images. For this task, we set a challenging baseline using state-of-the-art CNNs and evaluated it against the performance of human annotators. In our work we present a CNN architecture to infer the depth from RGB-only food images to be used in BU regression such that the pipeline can operate on RGB data only and compare its performance to RGB-D input data. We show that our inferred depth maps from RGB images can replace RGB-D input data at high significance for the BU regression task. In its best configuration, our proposed method achieves a RMSE of 1.53 BUs using RGB and inferred depth. Considering the variability among the raters themselves of RMSE = 0.89, we can show that our baseline method with depth prediction can extract reasonable nutritional information from RGB image data only.

Objective:To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS).Methods:Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study.Results:Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p < 0.0001) and OCB (p = 0.007). An MOG-ab cutoff titer ≥1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%.Conclusions:Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course.

Fragestellung: Die Überlebensrate nach schwerster Verletzung (Polytrauma) steigt, die Inzidenz der schweren Beckenverletzung nimmt parallel dazu ab. Es könnte postuliert werden, dass durch die Abnahme des Beckentraumas die Überlebensrate steigt, das Beckentrauma jedoch nach wie vor ein[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2016)

Background: Patients with advanced stage non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) often experience multidimensional impairments, affecting quality of life during their course of disease. In lung cancer patients with operable disease, several studies have shown that exercise has a positive impact on quality of life and physical functioning. There is limited evidence regarding efficacy for advanced lung cancer patients undergoing palliative treatment. Therefore, the POSITIVE study aims to evaluate the benefit of a 24-week exercise intervention during palliative treatment in a randomized controlled setting. Methods/design: The POSITIVE study is a randomized, controlled trial investigating the effects of a 24-week exercise intervention during palliative treatment on quality of life, physical performance and immune function in advanced, non-operable lung cancer patients. 250 patients will be recruited in the Clinic for Thoracic Diseases in Heidelberg, enrolment begun in November 2013. Main inclusion criterion is histologically confirmed NSCLC (stage IIIa, IIIb, IV) or SCLC (Limited Disease-SCLC, Extensive Disease-SCLC) not amenable to surgery. Patients are randomized into two groups. Both groups receive weekly care management phone calls (CMPCs) with the goal to assess symptoms and side effects. Additionally, one group receives a combined resistance and endurance training (3x/week). Primary endpoints are quality of life assessed by the Functional Assessment of Cancer Therapy for patients with lung cancer (FACT-L, subcategory Physical Well-Being) and General Fatigue measured by the Multidimensional Fatigue Inventory (MFI-20). Secondary endpoints are physical performance (maximal voluntary isometric contraction, 6-min walk distance), psychosocial (depression and anxiety) and immunological parameters and overall survival. Discussion: The aim of the POSITIVE trial is the evaluation of effects of a 24-week structured and guided exercise intervention during palliative treatment stages. Analysis of various outcomes (such as quality of life, physical performance, self-efficacy, psychosocial and immunological parameters) will contribute to a better understanding of the potential of exercise in advanced lung cancer patients. In contrast to other studies with advanced oncological patients the POSITIVE trial provides weekly phone calls to support patients both in the intervention and control group and to segregate the impact of physical activity on quality of life. Trial registration: ClinicalTrials.gov NCT02055508 (Date: December 12, 2013)

Viele Investitionen in IT-Projekte – insbesondere IT-Infrastrukturinvestitionen – lassen sich in Unternehmen nur dadurch okonomisch rechtfertigen, dass sie notwendige Voraussetzung fur die Durchfuhrung ertragsversprechender Folgeprojekte sind. Solche intertemporalen Abhangigkeiten zwischen IT-Projekten sind bei der Beurteilung von IT-Investitionen im Rahmen eines wertorientierten IT-Portfoliomanagements zu berucksichtigen. In der Literatur wird hierzu haufig auf die Realoptionstheorie und Optionsbewertungsmodelle aus der Finanztheorie wie bspw. das Binomialmodell oder das Black-Scholes-Modell verwiesen. Diese Modelle setzen die Existenz eines vollstandigen Kapitalmarkts voraus. Da IT-Projekte jedoch in der Realitat haufig durch nicht am Kapitalmarkt duplizierbare, projektspezifische Risiken gekennzeichnet sind, ist die direkte Anwendbarkeit der Modelle problematisch. Vor diesem Hintergrund wurden in der Literatur bereits entscheidungstheoretische Erweiterungen des diskreten Binomialmodells entwickelt, die eine korrekte Berucksichtigung projektspezifischer Risiken ermoglichen. In diesem Beitrag werden diese entscheidungstheoretischen Erweiterungen auf das stetige Black-Scholes-Modell ubertragen und erstmalig im Rahmen eines realen Fallbeispiels angewendet. Dabei werden mogliche Auswirkungen der Berucksichtigung projektspezifischer Risiken auf IT-Investitionsentscheidungen veranschaulicht.

Eine Liquiditatsanforderung verlangt bei einer Portfoliooptimierung mit illiquiden Assets die Berucksichtigung deren besonderer Eigenschaften. In der vorliegenden Arbeit werden diese Eigenschaften dadurch definiert, dass illiquide Assets nur vollstandig verkauft werden konnen und ein kurzfristiger Verkauf zu Verlusten fuhrt. Anhand eines einfachen Modells werden signifikante Unterschiede zu einer Optimierung mit lediglich liquiden Assets nachgewiesen. So hat beispielsweise die zufallige Liquiditatsanforderung zur Folge, dass der Portfoliowert auch bei sicheren Renditen der Assets bereits unsicher ist, und damit trotz der sicheren Renditen eine Aufteilung sowohl auf liquide als auch illiquide Assets optimal sein kann. Des Weiteren kann der erwartete Portfoliowert abhangig von der Varianz der Assets sein und sich eine negative Korrelation zwischen Assetklassen nachteilig auf diesen auswirken.

As identified by quantitative electroencephalography, statistically abnormal brain wave patterns were observed when a person thought about a trauma when compared with thinking about a neutral (baseline) event. Reassessment of brain wave patterns (to the traumatic memory) immediately after thought field therapy diagnosis and treatment revealed that the previous abnormal pattern was altered and was no longer statistically abnormal. An 18-month follow-up indicated that the patient continued to be free of all emotional upset regarding the treated trauma. This case study supports the concept that trauma-based negative emotions do have a correlated and measurable abnormal energetic effect. In addition, this study objectively identified an immediate energetic change after thought field therapy in the direction of normalcy and health, which has persisted.

The flagellum and the injectisome are two of the most complex and fascinating bacterial nanomachines. At their core, they share a type III secretion system (T3SS), a transmembrane export complex that forms the extracellular appendages, the flagellar filament and the injectisome needle. Recent advances, combining structural biology, cryo-electron tomography, molecular genetics, in vivo imaging, bioinformatics and biophysics, have greatly increased our understanding of the T3SS, especially the structure of its transmembrane and cytosolic components, the transcriptional, post-transcriptional and functional regulation and the remarkable adaptivity of the system. This review aims to integrate these new findings into our current knowledge of the evolution, function, regulation and dynamics of the T3SS, and to highlight commonalities and differences between the two systems, as well as their potential applications.

The infra-patellar fat pad (IPFP) is composed of intra-articular adipose tissue; it represents a potential source of pro-inflammatory cytokines and has been associated with osteoarthritis of the knee. Yet, to what extent the size of the IPFP differs between healthy men and women, and how sex differences compare to those in inter-muscular and subcutaneous fat tissue content is unknown. We studied healthy reference subjects from the Osteoarthritis Initiative, without knee pain, without radiographic signs or without risk factors of femorotibial osteoarthritis. Sagittal magnetic resonance images (MRIs) of 99 right knees were used to segment the IPFP; in a subset, axial images of the thigh were available to segment inter-muscular and subcutaneous fat. Healthy men (n=40) displayed a 41% greater (p

Background/Objectives: Caring for patients with dementia can be challenging due to emotional contagion. This projected sought to enhance mindfulness and reduce patient-care related stress/anxiety of caregivers to individuals with dementia to foster positive emotional contagion. Design: A mixed method design was used to examine the effects of the mindfulness education. Setting: Continuing Care Retirement Community Participants: Thirty-four long term care staff completed the initial educational activity; 16 completed pre and post survey and practiced the mindfulness activity for one week. Intervention: A 1 hour continuing education program was implemented and evaluated to teach caregivers a mindfulness enhancing technique known as Heart Assisted Therapy-SR (HAT-SR). Measurements: Evaluation focused on caregivers’ responses to the education, the intention to use the technique in practice, and staff experiences regarding the mindfulness enhancing intervention. Caregivers also completed a pre and post CAMS-R mindfulness survey and a post educational activity survey. Results: Mean scores were slightly improved (M=39.00 pre to M=39.73 post) after practicing HAT-SR for one week, however, these results were not statistically significant. The End of Educational Activity survey revealed 100% of participants increased their knowledge base regarding mindfulness, 86% reported the educational activity was helpful in identifying the challenges faced by caregivers of patients with cognitive impairments, and over 85% of participants responded favorably to using HAT-SR as a tool to promote calm and relaxation and to improve their practice. Conclusion

Background: Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established. Methods: Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients. Results: Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age. Conclusions: We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males.

Initially identified as a molecule that catalyzes the phosphorylation from phosphoenolpyruvate to pyruvate in the final step of glycolysis, the M2 isoform of pyruvate kinase (PKM2) was recently reported to have a central role in the metabolic reprogramming of cancer cells as well as participating in the regulation of apoptosis and proliferation. In this study, we have identified PKM2 as a crucial molecule for progression of pancreatic cancer in which tumor microenvironment has been reported to be highly hypoxic. Our data show moderate to strong PKM2 expression in all examined human pancreatic adenocarcinoma samples. Depletion of PKM2 was associated with impaired proliferation and augmented tumor cell death in vitro, while the in vivo tumor xenograft experiments revealed a close association between impaired tumor growth and decreased blood vessel formation. Furthermore, abrogation of PKM2 prevented hypoxia-mediated HIF-1alpha accumulation and HIF-1alpha promoter activity, which negatively impacted VEGF secretion by pancreatic cancer cells deprived of oxygen. Interestingly, PKM2 expression arrest was also mirrored by impaired hypoxia-driven promoter activity of NF-kappaB which also drives the transcription of VEGF. Ectopic expression of p65 restored VEGF transcription after PKM2 ablation inferring that the kinase regulates VEGF via NF-kappaB/p65 subunit. Altogether, our study suggests that in hypoxic pancreatic tumors PKM2 interferes both with NF-kappaB/p65 and HIF-1alpha activation that ultimately triggers VEGF-A secretion and subsequent blood vessel formation. Citation Format: Ninel Azoitei, Alexander Becher, Konrad Steinestel, Arefeh Rouhi, Kristina Diepold, Susanne Bobrovich, Thomas Seufferlein. PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1809. doi:10.1158/1538-7445.AM2017-1809

Objective. In very low birth weight (VLBW) infants, diagnostic and therapeutic decisions depend on hematologic values. As few data are available, we studied the course during the first 6 weeks of life. Design. Four prospective longitudinal cohort studies were retrospectively combined assessing hematologic profiles of 562 VLBW infants. For characterization of red blood cells and iron, infants receiving erythropoietin were excluded. For characterization of white blood cells and platelets, infants receiving antibiotics were excluded. Results. The third (3rd)/median/97th percentiles on day 3 were as follows: hemoglobin: 11.0/15.6/19.8 g/dL; hematocrit: 35/47/60%; red blood cells: 3.2/4.2/5.3 × 1012/L; reticulocytes: .6/7.1/27.8%; platelets: 58/203/430 × 109/L; white blood cells: 3.6/9.5/38.3 × 109/L; neutrophils: .7/4.7/25.3 × 109/L; ferritin: 27/140/504 ng/mL; iron: .8/7.5/26.7 μmol/L; transferrin saturation: 2.6/22.7/79.8%. Transferrin saturation was Conclusions. Iron indices and platelet counts on day 3 and neutrophil counts at 2 to 6 weeks of age are lower than previously assumed in VLBW infants and lower than in larger prematures.

Tapping on acupuncture meridian points for the treatment of psychological problems has persisted over the 18 year period since psychologist Roger J. Callahan, Ph.D. introduced his Callahan TechniquesTM. The Callahan TechniquesTM, also known as Thought Field TherapyTM, have explored a revolutionary conceptualization about the nature of psychological problems, and the rapid alleviation of emotional distress.

During ALL chemotherapy, a 4-year-old patient presented with febrile neutropenia and abdominal pain. Ultrasound examinations were repeatedly normal. Computerized tomography on day 7 demonstrated appendicitis and multiple hepatic foci identified as mucormycosis (Absidia corymbifera). Successful outcome was achieved by aggressive re-surgery, long-term antifungal therapy with serum level-monitored posaconazole, and recovery of neutrophil counts. Considering the interference of posaconazole with CYP3A4, vincristine was administered during 72 hr posaconazole windows. Pediatric intestinal mucormycosis, still associated with a >70% case-fatality rate, calls for early imaging and surgery to establish the diagnosis, reduce the fungal mass, and provide a rationale for using posaconazole.

Human poisoning by organophosphates bearing two methoxy groups, e.g. by malathion, paraoxon-methyl, dimethoate and oxydemeton-methyl, is generally considered to be rather resistant to oxime therapy. Since the oxime effectiveness is influenced not only by its reactivating potential but also by inhibition, aging and spontaneous reactivation kinetics, experiments were performed with human acetyl- (AChE) and butyrylcholinesterase (BChE) to determine the respective kinetic constants. The efficacy of obidoxime in reactivating dimethylphosphoryl-AChE was 40, 9 and 3 times higher than of HI 6, pralidoxime and HLö 7, respectively. Aging (t1/2 3.7 h) and spontaneous reactivation (t1/2 0.7 h) occurred concomitantly, with the portion of the aged enzyme being dependent on the presence of excess inhibitor. Calculation of steady-state AChE activity in the presence of inhibitor and oxime revealed that obidoxime was superior to pralidoxime. In addition, organophosphate concentrations up to 10(-6) M (paraoxon-methyl) and 10(-4) M (oxydemeton-methyl) could be counteracted at clinically relevant oxime concentrations (10 microM). These data indicate that oximes may effectively reactivate human dimethylphosphoryl-AChE. Failure of oximes may be attributed to megadose intoxications and to prolonged time intervals between poison uptake and oxime administration. The potency of the oximes to reactivate dimethylphosphoryl-BChE was much lower and the spontaneous reactivation slower (t1/2 9 h), while aging proceeded at a comparable rate. Thus, BChE activity determination for diagnosis and therapeutic monitoring may give no reliable information on AChE status.

Objective After acute neurological disease due to infection, trauma or other severe damage to the nervous system early neurological rehabilitation is mandatory. Rehabilitation should start during intensive care: early therapy improves the situation and increases the chances of optimal recovery. An interdisciplinary team works together with patients and their families to help regain consciousness, ensuring optimal medical treatment, for a good quality of life and to find their way back to life. We tried a novel way of supporting a patient through this hard, strenuous and emotionally difficult time. Methods Videorecording of steps of rehabilitation and progress in therapies by means of making a music video. Results We here present a music video that depicts the rehabilitation process of a 16 year old girl with severe Guillain-Barre syndrome. The patient was a former singer in a school rockband. On admission to our hospital, she was on mechanical ventilation without any voluntary movements, unable to talk, struck by severe neuropathic pain. Throughout the rehabilitation, even in ICU, she was videorecorded performing to her favourite popsong. All steps of rehabilitation are depicted in this video: first voluntary movements, weaning from the ventilator, enduring neuropathic pain, ability to sit and stand. Conclusion Recording the video was an additional incentive for our patient to work hard during rehabilitation to regain all lost abilities. Because of her passion for singing she could be motivated more easily.

Einleitung: Zahlreiche Institutionen mit unterschiedlichen Interessen sind bei der Entwicklung, Überprüfung und Vermarktung neuer Medikamente/Behandlungsmöglichkeiten beteiligt. In der evidenzbasierten Forschung bergen Interessenkonflikte (IK) – primäre Interessen werden[for full text, please go to the a.m. URL], Prävention zwischen Evidenz und Eminenz; 15. Jahrestagung des Deutschen Netzwerks Evidenzbasierte Medizin

Biotherapeutics are often produced in non-human host cells like Escherichia coli, yeast, and various mammalian cell lines. A major focus of any therapeutic protein purification process is to reduce host cell proteins to an acceptable low level. In this study, various E. coli host cell proteins were identified at different purifications steps by HPLC fractionation, SDS-PAGE analysis, and tryptic peptide mapping combined with online liquid chromatography mass spectrometry (LC-MS). However, no host cell proteins could be verified by direct LC-MS analysis of final drug substance material. In contrast, the application of affinity enrichment chromatography prior to comprehensive LC-MS was adequate to identify several low abundant host cell proteins at the final drug substance level. Bacterial alkaline phosphatase (BAP) was identified as being the most abundant host cell protein at several purification steps. Thus, we firstly established two different assays for enzymatic and immunological BAP monitoring using the cobas® technology. By using this strategy we were able to demonstrate an almost complete removal of BAP enzymatic activity by the established therapeutic protein purification process. In summary, the impact of fermentation, purification, and formulation conditions on host cell protein removal and biological activity can be conducted by monitoring process-specific host cell proteins in a GMP-compatible and high-throughput (> 1000 samples/day) manner.