Characterization and prognostic impact of ACTBL2-positive tumor-infiltrating leukocytes in epithelial ovarian cancer.

Actin beta-like 2 (ACTBL2) was recently identified as a new mediator of migration in ovarian cancer cells. Yet, its impact on tumor-infiltrating and thus migrating leukocytes (TILs) remains to date unknown. This study characterizes the subset of ACTBL2-expressing TILs in epithelial ovarian cancer (EOC) and elucidates their prognostic influence on the overall survival of EOC patients with special regard to different histological subtypes. Comprehensive immunohistochemical analyses of Tissue-Microarrays of 156 ovarian cancer patients revealed, that a tumor infiltration by ACTBL2-positive leukocytes was significantly associated with an improved overall survival (OS) (61.2 vs. 34.4 months; p = 0.006) and was identified as an independent prognostic factor (HR = 0.556; p = 0.038). This significant survival benefit was particularly evident in patients with low-grade serous carcinoma (OS: median not reached vs. 15.6 months, p < 0.001; HR = 0.058, p = 0.018). In the present cohort, ACTBL2-positive TILs were mainly composed of CD44-positive cytotoxic T-cells (CD8+) and macrophages (CD68+), as depicted by double-immunofluorescence and various immunohistochemical serial staining. Our results provide significant evidence of the prognostic impact and cellular composition of ACTBL2-expressing TILs in EOC. Complementary studies are required to analyze the underlying molecular mechanisms of ACTBL2 as a marker for activated migrating leukocytes and to further characterize its immunological impact on ovarian carcinogenesis.

A route for the top-down fabrication of ordered ultrathin GaN nanowires.

We introduce a facile route for the top-down fabrication of ordered arrays of GaN nanowires with aspect ratios exceeding 10 and diameters below 20 nm. Highly uniform thin GaN nanowires are first obtained by lithographic patterning a bilayer Ni/SiNxhard mask, followed by a combination of dry and wet etching in KOH. The SiNxis found to work as an etch stop during wet etching, which eases reproducibility. Arrays with nanowire diameters down to (33 ± 5) nm can be achieved with a uniformity suitable for photonic applications. Next, a scheme for digital etching is demonstrated to further reduce the nanowire diameter down to 5 nm. However, nanowire breaking or bundling is observed for diameters below ≈20 nm, an effect that is associated to capillary forces acting on the nanowires during sample drying in air. Explicit calculations of the nanowire buckling states under capillary forces indicate that nanowire breaking is favored by the incomplete wetting of water on the substrate surface during drying. The observation of intense nanowire photoluminescence at room-temperature indicates good compatibility of the fabrication route with optoelectronic applications. The process can be principally applied to any GaN/SiNxnanostructures and allows regrowth after removal of the SiNxmask.

Synchronized beamline at FLASH2 based on high-order harmonic generation for two-color dynamics studies.

We present the design, integration, and operation of the novel vacuum ultraviolet (VUV) beamline installed at the free-electron laser (FEL) FLASH. The VUV source is based on high-order harmonic generation (HHG) in gas and is driven by an optical laser system synchronized with the timing structure of the FEL. Ultrashort pulses in the spectral range from 10 to 40 eV are coupled with the FEL in the beamline FL26, which features a reaction microscope (REMI) permanent endstation for time-resolved studies of ultrafast dynamics in atomic and molecular targets. The connection of the high-pressure gas HHG source to the ultra-high vacuum FEL beamline requires a compact and reliable system, able to encounter the challenging vacuum requirements and coupling conditions. First commissioning results show the successful operation of the beamline, reaching a VUV focused beam size of about 20 µm at the REMI endstation. Proof-of-principle photo-electron momentum measurements in argon indicate the source capabilities for future two-color pump-probe experiments.

[Strategies for digitalizing the hospital of the future]. / Digitalisierungsstrategien für das Krankenhaus der Zukunft.

Digitalization cannot be understood as an off-the-shelf product, bought as a one-time purchase in a warehouse. It rather requires a constantly developing vision, which comes with a continuous transformation process, hand in hand with strategic innovation management. Thus, digitalization means understanding the digital maturity level of an enterprise and the digital skills of the employees. Besides an investment in products, a successful digitalization process also necessitates consideration of the cost to release employees from their obligations in order to contribute to the process as well as for a dedicated and continuing staff training and education program. While digitalization in Germany is underdeveloped regarding both the national health infrastructure and the level of digitalization in hospitals, German clinics are recognizing more and more the importance of digitalization and are initiating digitalization strategies. In this regard, we can learn from our European partners, who have partially established advanced and innovative solutions. Looking into these flagship projects can help to see potentials and to identify valuable building blocks for our own strategy.

[Diagnostic Workup and Treatment of Antibody-Related Encephalomyelitis]. / Diagnostik und Therapie von autoantikörpervermittelten Enzephalomyelitiden.

The results of laboratory tests for antineuronal antibodies in immune-mediated encephalitis nowadays are not only relevant for diagnostic purposes but are instead closely connected to outcome measures and treatment response. Besides the mere detection of antibodies, investigating the cerebrospinal fluid is indispensible to rule out an infectious etiology of encephalitis prior to the initiation of immunosuppressive treatment, whereas imaging studies are relevant to gain information on the temporal course of disease and for ruling out other etiologies, e. g. hippocampal gliomas. This work gives an overview on the clinical course and findings of laboratory, electroencephalography (EEG) and imaging studies in relevant types of autoimmune mediated encephalitis. Furthermore, it gives a synopsis on contemporary treatment strategies.

A Case Report of a Carbamazepine Overdose With Focus on Pharmacokinetic Aspects.

In this article a case of carbamazepine overdose is reported. It is common to use immuno-based methods in the field of therapeutic drug monitoring but it might be difficult to adapt such values to toxicological cases. For carbamazepine overdoses it is recommended also to determine the metabolite carbamazepine-10,11-epoxide. Especially for critical conditions a definite substance identification should be performed. In addition, quantifying main metabolites is recommended for an acute clinical toxicological assessment.

Dose-response relationship between light exposure and cycling performance.

Light has a stimulating effect on physical performance if scheduled according to the chronotype, but dose-dependent effects on performance have not yet been examined. Three groups of healthy men (25.1 ± 3.1 years) were exposed to light for different durations in a parallel group design before a 40-min time-trial. In each group, subjects were exposed to either bright light (BL, 4420 lx) or moderate light (ML, 230 lx) in a randomized order in a crossover design. The durations of light exposure were 120 min prior to and during exercise (2HEX; n = 16), 60 min prior to and during exercise (1HEX; n = 10), or only for 60 min prior to exercise (1H; n = 15). Total work performed during the time-trial in kJ in the 2HEX group was significantly higher in the BL setting (527 kJ) than in ML (512 kJ) (P = 0.002), but not in 1HEX (BL: 485 kJ; ML: 498 kJ) or 1H (BL: 519 kJ; ML: 514 kJ) (P = 0.770; P = 0.485). There was a significant (P = 0.006) positive dose-response relationship between the duration of light exposure and the work performed over the three doses of light exposure. A long duration light exposure is an effective tool to increase total work in a medium length time-trial in subjects normalized for their individual chronotype.

Synthesis and characterization of a trinuclear iridium(III) based catalyst for the photocatalytic reduction of CO2.

A trimetallic Ir(iii) based complex () was synthesized and fully characterized by spectroscopic and electrochemical methods. A detailed comparison to its mono- () and bimetallic () analogue regarding the photocatalytic reduction of CO2 is outlined. In particular, the effect of intramolecular quenching, provided by ethyl tethers, was investigated. Moreover, the relationship between the photophysical properties, the lifetime of the excited state, the quenching efficiency and the catalytic performance is presented. Notably, the covalent linkage of the Ir(iii) moieties within the three-armed ligand structure (complex ) leads to a twofold increase of the turn over number (TON) compared to its monometallic analogue . Taking in account the quantum efficiency of 10% and the TONCO = 60 (per Ir(iii) center), complex is a highly active Ir(iii) based photocatalyst.

Self-Lubricity of WSex Nanocomposite Coatings.

Transition metal chalcogenides with lamellar structure are known for their use in tribological applications although limited to vacuum due to their easy degradation in the presence of oxygen and/or moisture. Here we present a tailored WSex coating with low friction (0.07) and low wear rates (3×10(-7) mm3 Nm(-1)) even in ambient air. To understand the low friction behavior and lower chemical reactivity a tribological study is carried out in a high-vacuum tribometer under variable pressure (atmospheric pressure to 1×10(-8) mbar). A detailed investigation of the film nanostructure and composition by advanced transmission electron microscopy techniques with nanoscale resolution determined that the topmost layer is formed by nanocrystals of WSe2 embedded in an amorphous matrix richer in W, a-W(Se). After the friction test, an increased crystalline order and orientation of WSe2 lamellas along the sliding direction were observed in the interfacial region. On the basis of high angle annular dark field, scanning transmission electron microscopy, and energy dispersive X-ray analysis, the release of W atoms from the interstitial basal planes of the a-W(Se) phase is proposed. These W atoms reaching the surface, play a sacrificial role preventing the lubricant WSe2 phase from oxidation. The increase of the WSe2 crystalline order and the buffer effect of W capturing oxygen atoms would explain the enhanced chemical and tribological response of this designed nanocomposite material.

Indicators for high physical strain and overload in elite football players.

Laboratory, psychological and performance parameters as possible indicators of physical strain and overload during highly demanding competition phases were evaluated in elite male football players. In two studies with the same objective, periods of high (HE: >270 min during 3 weeks before testing) and low (LE: <270 min) match exposure were compared over the course of an entire season. In study 1 (n=88 players of the first and second German leagues; age: 25.6 ± 4.3 years; body mass index (BMI): 23.2 ± 1.0 kg/m(2) ), blood count, CK, urea, uric acid, CRP and ferritin were determined. In study 2, 19 players of the third German league and the highest under-19 league (age: 19.7 ± 2.8 years; BMI: 22.8 ± 1.7 kg/m(2) ) were screened for individual vertical jump height, maximal velocity and by the Recovery-Stress-Questionnaire for Athletes (REST-Q Sport). The mean differences in exposure times were 180 min (study 1: quartiles: 105, 270 min) and 247 min (study 2: 180, 347 min), respectively. Significant differences were found neither in blood parameters (study 1; P>0.36) nor in physiological testing results or in REST-Q scores (study 2; P>0.20). A 3-week period of high match exposure in elite football players does not affect laboratory, psychometric and performance parameters.

Routine blood parameters in elite soccer players.

UNLABELLED: Often blood screening is repeatedly done in elite athletes although training and competition can affect its results and normal ranges for highly active individuals are widely unknown. This study was conducted to provide reference data in professional soccer players. 467 male soccer players of the 2 highest German leagues were observed over an entire season. Venous blood sampling was conducted 4 times in a standardized manner to determine complete blood count, AST, ALT, CK, creatinine, urea, uric acid, cholesterol, electrolytes, ferritin, CRP and TSH.There were significant changes during the season in hematocrit, creatinine, uric acid (decrease), CK, AST, urea, sodium, potassium, magnesium, and TSH (increase). Only the changes in hematocrit and CK were large enough to possibly interfere with clinical decisions in soccer players. Upper limits of the 95% confidence intervals exceeded population reference ranges slightly in AST, urea, creatinine, and potassium. The mean intraindividual coefficient of variation was below 10% in complete blood count (except leukocytes), creatinine, uric acid, total cholesterol, and all electrolytes. There seems to be a profound effect of elite soccer training and competition on hematocrit (plasma volume) and CK only. Spontaneous variability of most parameters is too small to justify repeated sampling only for routine screening. TRIAL REGISTRATION: NCT00946855 Effect of Elite Soccer Training on Routine Laboratory Parameters (SOCCERLAB), http://www.clinicaltrials.gov/ct2/show/NCT00946855?term=soccerlab&rank=1.

Influence of storage on the position of the germinal disc in the fertilized unincubated chicken egg.

The breeding of male layer chickens is currently considered to be highly uneconomical. In Germany alone, 40 to 50 million newly hatched male chickens were killed annually immediately after hatching. Therefore, it is necessary to find a method for sexing chickens early in the embryonic development, preferably before incubation. The genotypic sex of an egg can be determined using information found in the germinal disc, so knowledge of the exact position of the germinal disc is essential for further sexing, or for other actions such as the in ovo injection of agents. Previous studies have shown that the germinal disc is located somewhere on top of the yolk. However, no studies have yet been performed that investigate the influence of time spent in horizontal storage on the position of the germinal disc. Magnetic resonance imaging was chosen to determine this influence on the position of the germinal disc. It was found that eggs placed horizontally for long periods of time before scanning had significant changes in the positions of their germinal discs compared with those of eggs scanned minutes after positioning. The position of the germinal disc in eggs, minutes after horizontal positioning, deviated 14.7 ± 0.6 mm from the maximum vertical plane of the egg (zero position) in the z-direction; eggs scanned after 96 h of horizontal positioning showed a deviation of only 4.9 ± 1.6 mm. The x-axis also exhibited changes in the position of the germinal disc over time. Immediately after horizontal positioning, the eggs showed a deviation of 0.4 ± 0.4 mm in the x-direction, whereas the deviation after 96 h was 2.9 ± 0.5 mm. These results show that horizontal positioning of the egg hours before the measurement is necessary.

High hydrostatic pressure treatment generates inactivated mammalian tumor cells with immunogeneic features.

Most of the classical therapies for solid tumors have limitations in achieving long-lasting anti-tumor responses. Therefore, treatment of cancer requires additional and multimodal therapeutic strategies. One option is based on the vaccination of cancer patients with autologous inactivated intact tumor cells. The master requirements of cell-based therapeutic tumor vaccines are the: (a) complete inactivation of the tumor cells; (b) preservation of their immunogenicity; and (c) need to remain in accordance with statutory provisions. Physical treatments like freeze-thawing and chemotherapeutics are currently used to inactivate tumor cells for vaccination purposes, but these techniques have methodological, therapeutic, or legal restrictions. For this reason, we have proposed the use of a high hydrostatic pressure (HHP) treatment (p >or= 100 MPa) as an alternative method for the inactivation of tumor cells. HHP is a technique that has been known for more than 100 years to successfully inactivate micro-organisms and to alter biomolecules. In the studies here, we show that the treatment of MCF7, B16-F10, and CT26 tumor cells with HHP >or= 300 MPa results in mainly necrotic tumor cell death forms displaying degraded DNA. Only CT26 cells yielded a notable amount of apoptotic cells after the application of HHP. All tumor cells treated with >or= 200 MPa lost their ability to form colonies in vitro. Furthermore, the pressure-inactivated cells retained their immunogenicity, as tested in a xenogeneic as well as syngeneic mouse models. We conclude that the complete tumor cell inactivation, the degradation of the cell's nuclei, and the retention of the immunogeneic potential of these dead tumor cells induced by HHP favor the use of this technique as a powerful and low-cost technique for the inactivation of tumor cells to be used as a vaccine.

Activation-induced cell death and total Akt content of granulocytes show a biphasic course after low-dose radiation.

Low-dose radiation (single doses from 0.3 to 1.0 Gy) in clinical practice is mostly used to treat patients with several inflammatory diseases and painful degenerative disorders. Low-dose radiation is known to exert anti-inflammatory effects. However, the molecular and cellular mechanism are not fully analysed and most of the observed effects are based on empirical studies. We investigated the effects of low-dose radiation on the activation-induced cell death of polymorph nuclear granulocytes (PMN). A biphasic appearance of cell death in irradiated PMN was observed, displaying a relative maximum at 0.3 Gy and minimum at 0.5 Gy, respectively. This biphasic course of cell death was coincident with the protein level of total cellular Akt. We conclude that low-dose radiation exerts immunomodulatory effects on PMN contributing to the observed anti-inflammatory effects in clinical applications.

Proteasome inhibition drastically but reversibly impairs murine lymphocyte development.

The proteasome inhibitor bortezomib, which induces cell death in various cancer cell lines including lymphatic neoplasias, has recently been approved for the treatment of relapsed multiple myeloma. Important mechanisms of proteasome inhibitor-mediated tumor cell death are the inhibition of NF-kappaB activation and induction of the terminal unfolded protein response (UPR). However, little is known about effects of bortezomib on developing and mature lymphocytes. Therefore, Balb/C mice were injected with bortezomib and lymphocyte subsets were analyzed. This treatment resulted in dramatically decreased numbers of T and B lymphocyte precursors, while mature lymphocytes were only partially affected. Thymocytes were almost depleted 3 days after a single bortezomib injection, pro-B and pre-B cells already after 2 days. Thymocytes and B cell precursors recovered within 2 weeks. The decreased numbers of developing lymphocytes were due to apoptotic cell death accompanied by strongly increased caspase 3/7 activity. Within 8 h after bortezomib injection, there was a strong induction of heat shock protein 70 and C/EBP homologous protein in bone marrow B cells, indicating endoplasmic reticulum stress and activation of the terminal UPR, respectively. Hence, induction of apoptosis by proteasome inhibition can dramatically affect lymphocyte development, a fact which has important implications for the clinical use of bortezomib, especially in situations with ongoing lymphopoiesis.

The Plasmodium parasite--a 'new' challenge for insect innate immunity.

Though lacking adaptive immunity, insects possess a powerful innate immune system, a genome-encoded defence machinery used to confront infections. Studies in the fruit fly Drosophila melanogaster revealed a remarkable capacity of the innate immune system to differentiate between and subsequently respond to different bacteria and fungi. However, hematophagous compared to non-hematophagous insects encounter additional blood-borne infectious agents, such as parasites and viruses, during their lifetime. Anopheles mosquitoes become infected with the malaria parasite Plasmodium during feeding on infected human hosts and may then transmit the parasite to new hosts during subsequent bites. Whether Anopheles has developed mechanisms to confront these infections is the subject of this review. Initially, we review our current understanding of innate immune reactions and give an overview of the Anopheles immune system as revealed through comparative genomic analyses. Then, we examine and discuss the capacity of mosquitoes to recognize and respond to infections, especially to Plasmodium, and finally, we explore approaches to investigate and potentially utilize the vector immune competence to prevent pathogen transmission. Such approaches constitute a new challenge for insect immunity research, a challenge for global health.

[Resources in schizophrenic patients. Validity testing of a new rating scale to assess health features]. / Ressourcen schizophrener Patienten. Validitätsprüfung des Erhebungsbogens zur Erfassung gesunder Anteile.

Biopsychosocial concepts and Antonovsky's salutogenesis model gave rise to new treatment approaches and research prospects in health-related fields. Also in psychiatry, there is increasing interest to obtain information on patients' resources. There are, nevertheless, only a few instruments developed particularly for this assessment. The new EGA rating scale offers the possibility to assess patient resources as abilities and health-maintaining features in four areas of life. To test the validity of the EGA, 39 schizophrenic patients participated in the current study. Those with more health-maintaining features in the EGA showed significantly fewer psychic and somatic symptoms (SCL-90 R), better social and occupational functioning (SOFAS), higher sense of coherence (SOC), and better social adjustment(FSI). They were significantly younger at the beginning of their disease and had more frequently held jobs during the previous 12 months. The findings point to satisfactory concept- and criterion-related validity and reliability of the EGA rating scale as well as to its possible application in course studies, individual diagnosis, therapy evaluation, and indication. Early medical and therapeutic intervention and increased use of working aid programs are recommended.

Ultrastructural, immunohistochemical and biochemical investigations of the rat liver exposed to experimental diabetes und acute hypoxia with and without application of Ginkgo extract.

The aim of this paper was to investigate the effect of streptozotocin-induced diabetes by i.p. bolus injection of streptozotocin at 60 mg per kg bodyweight over four months and additional acute respiratory hypoxia (20 min. duration, 5% oxygen v/v), and also the protective effect of Ginkgo biloba extract (EGb 761) on Wistar rat liver under these experimental conditions. Diabetic and additional hypoxic alterations in histology and ultrastructure were subjected to qualitative and quantitative analysis, collagen was investigated by immunohistochemistry, and some biochemical parameters of oxidative stress were determined. Diabetes caused an increase in the size of the hepatocytes and their nuclei with a decrease in nucleus-to-plasma ratio and glycogen content. Connective tissue was variably increased in individual cases as shown by routine histological staining. EGb did not influence these data. Ultrastructural morphometry revealed a significant reduction in rough endoplasmic reticulum (rER) and a significant increase in smooth endoplasmic reticulum (sER) through diabetes, an increase under EGb protection, with no significant alteration under hypoxia. The volume fraction of mitochondria was significantly increased after induction of diabetes but less increased in the protected group. Additional hypoxia reduced this parameter. The mean cross-section area of mitochondria was significantly elevated in all diabetic groups compared to controls. Volume density of mitochondrial cristae was significantly diminished in all diabetic groups; EGb could only improve this parameter in the diabetic-hypoxic group.

Immunohistochemical analysis of B-cell lymphoma using tissue microarrays identifies particular phenotypic profiles of B-cell lymphomas.

AIMS: To validate the applicability of tissue microarray (TM) in immunohistochemical profiling of B-cell lymphoma and to identify particular phenotypic profiles of B-cell neoplasms. METHODS AND RESULTS: Eighty-two diffuse large B-cell lymphomas (DLBL), 54 follicular lymphomas (FL) and 74 mantle cell lymphomas (MCL) were arrayed. Immunohistochemical stains of TM were compared with immunostains of conventional, formalin-fixed and frozen material sections. Concordant staining results were obtained in more than 88% of cases for CD20, CD3, CD5, CD10, CD23, Bcl-2, IgD, secretory differentiation, p53 and p21 expression. Prognostically relevant hot-spot expression of Ki67 yielded concordant results in 71%. Applying TM for characterization of p27KIP1 expression, both typical and blastoid MCL only rarely showed p27KIP1 expression (9% and 15%), whereas 32% of nodal DLBL were p27KIP1-positive, irrespective of high proliferative activity. Among 22 B-cell lymphomas investigated genetically, a p53 + p21- immunophenotype in >20% of tumour cells correlated with p53 locus deletion. CONCLUSIONS: Lymphoma TM allows for immunohistochemical profiling of human B-cell lymphoma with a comparable accuracy to immunohistochemical studies performed on conventional tissue sections. Nodal DLBLs showed significantly more frequent expression of IgD and p27KIP1 than extranodal DLBL. MCL and DLBL frequently showed aberrant p27KIP1 expression. A p53 + p21- immunophenotype in >20% of tumour cells in B-cell non-Hodgkin's lymphoma correlates with p53 gene deletion.