Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study.

Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to the similar mechanism of action of these two drugs. Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 AEDs who received placebo or BRV 50-200mg/day without titration over a 12-week treatment period. Patients taking concomitant LEV at enrollment were excluded from this analysis. Patients were categorized by their status of prior exposure to LEV, carbamazepine (CBZ), topiramate (TPM), or lamotrigine (LTG), to investigate any consistent trend towards reduced response in AED-exposed subgroups compared to AED-naïve subgroups, regardless of the mechanism of action. Study completion rates, percent reduction from baseline in focal seizure frequency over placebo, ≥50% responder rates, and tolerability were evaluated for each subgroup. A total of 1160 patients were investigated. Study completion rates were similar in the AED-exposed subgroups and AED-naïve subgroups. In subgroups with (531 patients) or without (629 patients) prior LEV exposure, ≥50% responder rates for each dose of BRV compared with placebo were generally higher among the LEV-naïve subgroups than the previously LEV-exposed subgroups. LEV-exposed subgroups receiving BRV doses ≥50mg/day showed greater ≥50% responder rates than those receiving placebo. Similar results were observed for CBZ, TPM, and LTG. Previous treatment failure with commonly prescribed AEDs (LEV, CBZ, TPM, or LTG) is associated with a reduced response to BRV irrespective of the mechanism of action. Hence, this post-hoc analysis indicates that previous treatment failure with LEV does not preclude the use of BRV in patients with epilepsy

Subtropical westerly jet influence on occurrence of western disturbances and Tibetan plateau vortices

Western disturbances (WDs) are mid-to-upper-tropospheric mesoscale vortices, which typically propagate along the subtropical westerly jet stream and bring heavy rainfall to Pakistan and northern India during boreal winter. They are dynamically similar to Tibetan Plateau vortices (TPVs), which affect southwest China during spring and summer and emanate from the Tibetan Plateau. Here, we propose that their similarity implies the existence of a more general group of upper-tropospheric vortices featuring interactions with the orography of the Hindu Kush-Himalaya-Tibetan Plateau region. Using existing track databases for WDs and TPVs derived from ERA-Interim reanalysis, we show that their respective occurrence frequencies are highly anticorrelated with each other through the seasonal cycle, yet both are strongly correlated with jet latitude. Our findings imply that the incidence of hazards due to WDs and TPVs is correlated on intra- and interannual timescales, particularly through upper-level baroclinicity

Two-Color Coherent Photodissociation of Nitrogen Oxide in Intense Laser Fields

A simple one-dimensional semi-classical model with a Morse potential is used to investigate the possibility of two-color infrared multi-photon dissociation of vibrationally excited nitrogen oxide. The amplitude ratio effects and adiabatic effects are investigated. Some initial states are found to have thresholds smaller than expected from single-mode considerations and multiple thresholds exist for initial states up to 32. PACS: 42.50.HzComment: 3 pages, old papers, add source files to replace original postscrip

Extended microsatellite analysis in microsatellite stable, MSH2 and MLH1 mutation-negative HNPCC patients: Genetic reclassification and correlation with clinical features

Background: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder predisposing to predominantly colorectal cancer (CRC) and endometrial cancer frequently due to germline mutations in DNA mismatch repair (MMR) genes, mainly MLH1, MSH2 and also MSH6 in families seen to demonstrate an excess of endometrial cancer. As a consequence, tumors in HNPCC reveal alterations in the length of simple repetitive genomic sequences like poly-A, poly-T, CA or GT repeats (microsatellites) in at least 90% of the cases. Aim of the Study: The study cohort consisted of 25 HNPCC index patients ( 19 Amsterdam positive, 6 Bethesda positive) who revealed a microsatellite stable (MSS) - or low instable (MSI-L) - tumor phenotype with negative mutation analysis for the MMR genes MLH1 and MSH2. An extended marker panel (BAT40, D10S197, D13S153, D18S58, MYCL1) was analyzed for the tumors of these patients with regard to three aspects. First, to reconfirm the MSI-L phenotype found by the standard panel; second, to find minor MSIs which might point towards an MSH6 mutation, and third, to reconfirm the MSS status of hereditary tumors. The reconfirmation of the MSS status of tumors not caused by mutations in the MMR genes should allow one to define another entity of hereditary CRC. Their clinical features were compared with those of 150 patients with sporadic CRCs. Results: In this way, 17 MSS and 8 MSI-L tumors were reclassified as 5 MSS, 18 MSI-L and even 2 MSI-H ( high instability) tumors, the last being seen to demonstrate at least 4 instable markers out of 10. Among all family members, 87 malignancies were documented. The mean age of onset for CRCs was the lowest in the MSI-H-phenotyped patients with 40.5 +/- 4.9 years (vs. 47.0 +/- 14.6 and 49.8 +/- 11.9 years in MSI-L- and MSS-phenotyped patients, respectively). The percentage of CRC was the highest in families with MSS-phenotyped tumors (88%), followed by MSI-L-phenotyped ( 78%) and then by MSI-H-phenotyped (67%) tumors. MSS tumors were preferentially localized in the distal colon supposing a similar biologic behavior like sporadic CRC. MSH6 mutation analysis for the MSI-L and MSI-H patients revealed one truncating mutation for a patient initially with an MSS tumor, which was reclassified as MSI-L by analyzing the extended marker panel. Conclusion: Extended microsatellite analysis serves to evaluate the sensitivity of the reference panel for HNPCC detection and permits phenotype confirmation or upgrading. Additionally, it confirms the MSS status of hereditary CRCs not caused by the common mutations in the MMR genes and provides hints to another entity of hereditary CRC. Copyright (C) 2004 S. Karger AG, Basel

The Antitumorigenic Function of EGFR in Metastatic Breast Cancer is Regulated by Expression of Mig6

Numerous studies by our lab and others demonstrate that epidermal growth factor receptor (EGFR) plays critical roles in primary breast cancer (BC) initiation, growth and dissemination. However, clinical trials targeting EGFR function in BC have lead to disappointing results. In the current study we sought to identify the mechanisms responsible for this disparity by investigating the function of EGFR across the continuum of the metastatic cascade. We previously established that overexpression of EGFR is sufficient for formation of in situ primary tumors by otherwise nontransformed murine mammary gland cells. Induction of epithelial-mesenchymal transition (EMT) is sufficient to drive the metastasis of these EGFR-transformed tumors. Examining growth factor receptor expression across this and other models revealed a potent downregulation of EGFR through metastatic progression. Consistent with diminution of EGFR following EMT and metastasis EGF stimulation changes from a proliferative to an apoptotic response in in situ versus metastatic tumor cells, respectively. Furthermore, overexpression of EGFR in metastatic MDA-MB-231 BC cells promoted their antitumorigenic response to EGF in three dimensional (3D) metastatic outgrowth assays. In line with the paradoxical function of EGFR through EMT and metastasis we demonstrate that the EGFR inhibitory molecule, Mitogen Induced Gene-6 (Mig6), is tumor suppressive in in situ tumor cells. However, Mig6 expression is absolutely required for prevention of apoptosis and ultimate metastasis of MDA-MB-231 cells. Further understanding of the paradoxical function of EGFR between primary and metastatic tumors will be essential for application of its targeted molecular therapies in BC

Determination of intrarenal resistance index (RI) in patients with multiple myeloma

<p>Abstract</p> <p>Background</p> <p>Renal impairment is a common complication of multiple myeloma occuring in up to 50% of patients at some stage in their disease. Due to occurrence of cast nephropathies we hypothesized circulatory dysregulation (vasoconstriction) in the kidneys with measurable elevation of the resistance index among these patients which would have a diagnostic impact.</p> <p>Subjects and methods</p> <p>36 patients with treated multiple myeloma (21 females, 15 males, mean age 61.6 ± 8.5 years) were prospectively examined by conventional abdominal ultrasound with focussed investigation of the kidneys. First, length of the organs, parenchymal width and characterization of parenchymal echogenicity were determined. Then, intrarenal RI values were measured in segmental and arcuate arteries, respectively, in both kidneys. Additionally, serum creatinine, BUN and GFR of each patient were evaluated. RI values were compared to values of 78 healthy control subjects.</p> <p>Results</p> <p>Mean renal RI was 0.68 ± 0.07 which was slightly higher than in controls with 0.62 ± 0.05, but without statistical significance. Due to the laboratory analyses patients were subdivided in those with normal (group 1, n = 21) and those with impaired (group 2, n = 15) renal function. In both groups kidney size and parenchymal width were normal. Significant more group 2 patients (60%) revealed hyperechogenic par enchyma than group 1 patients (24%) (p < 0.01). Mean renal RI indices were 0.67 ± 0.06 (right) and 0.69 ± 0.06 (left) in group 1 patients and 0.71 ± 0.08 (right) and 0.71 ± 0.07 (left) in group 2 patients and showed no significant difference (p = 0.06 and 0.15).</p> <p>Conclusion</p> <p>Renal RI values are not significantly elevated in patients with multiple myeloma even in those with renal impairment so that no hints to a relevant vasoconstriction could be evaluated. RI seems not to be a relevant parameter for the diagnosis of cast nephro pathy of multiple myeloma patients. Routinely performed ultrasound examination should be more focussed on the qualification of parenchymal echogenicity.</p

Geostatistical radar-raingauge combination with nonparametric correlograms: methodological considerations and application in Switzerland

Modelling spatial covariance is an essential part of all geostatistical methods. Traditionally, parametric semivariogram models are fit from available data. More recently, it has been suggested to use nonparametric correlograms obtained from spatially complete data fields. Here, both estimation techniques are compared. Nonparametric correlograms are shown to have a substantial negative bias. Nonetheless, when combined with the sample variance of the spatial field under consideration, they yield an estimate of the semivariogram that is unbiased for small lag distances. This justifies the use of this estimation technique in geostatistical applications. Various formulations of geostatistical combination (Kriging) methods are used here for the construction of hourly precipitation grids for Switzerland based on data from a sparse realtime network of raingauges and from a spatially complete radar composite. Two variants of Ordinary Kriging (OK) are used to interpolate the sparse gauge observations. In both OK variants, the radar data are only used to determine the semivariogram model. One variant relies on a traditional parametric semivariogram estimate, whereas the other variant uses the nonparametric correlogram. The variants are tested for three cases and the impact of the semivariogram model on the Kriging prediction is illustrated. For the three test cases, the method using nonparametric correlograms performs equally well or better than the traditional method, and at the same time offers great practical advantages. Furthermore, two variants of Kriging with external drift (KED) are tested, both of which use the radar data to estimate nonparametric correlograms, and as the external drift variable. The first KED variant has been used previously for geostatistical radar-raingauge merging in Catalonia (Spain). The second variant is newly proposed here and is an extension of the first. Both variants are evaluated for the three test cases as well as an extended evaluation period. It is found that both methods yield merged fields of better quality than the original radar field or fields obtained by OK of gauge data. The newly suggested KED formulation is shown to be beneficial, in particular in mountainous regions where the quality of the Swiss radar composite is comparatively low. An analysis of the Kriging variances shows that none of the methods tested here provides a satisfactory uncertainty estimate. A suitable variable transformation is expected to improve this

Rachis brittleness in a hybrid–parent barley (Hordeum vulgare) breeding germplasm with different combinations at the non‐brittle rachis genes

Two dominant, closely linked and complementary genes, Btr1 and Btr2, control rachis brittleness in barley. Recessive mutations in any of these genes turn the fragile rachis (brittle) into a tough rachis phenotype (non‐brittle). The cross of parents with alternative mutations in the btr genes leads to a brittle F1 hybrid that presents grain retention problems. We evaluated rachis fragility through a mechanical test and under natural conditions, in F1 crosses with different compositions at the btr genes. Brittleness was significantly higher in Btr1btr1Btr2btr2 crosses compared to hybrids and inbred parents carrying one of the mutations (btr1btr1Btr2Btr2/Btr1Btr1btr2btr2). This fact could jeopardize the efficient harvest of hybrids bearing alternative mutations, reducing the choice of possible crosses for hybrid barley breeding and hindering the exploitation of potential heterotic patterns. Furthermore, non‐brittle hybrids showed higher brittleness than inbreds, suggesting the presence of other dominant factors affecting the trait. In conclusion, this work encourages a deeper study of the genetic control of the rachis brittleness trait and urges the consideration of rachis tenacity as a target for hybrid barley breeding.This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness grants RFP2015 00006‐00‐00, and RTA2012‐00033‐C03‐02, and by the contract “Iberia region hybrid barley variety development and understanding effects of adaptation genes in hybrids,” between CSIC and Syngenta Crop Protection AG, which included funding for MFC PhD scholarship

Guidelines for stakeholder engagement in systematic reviews of environmental management

Abstract: People have a stake in conservation and environmental management both for their own interests and the sake of the environment itself. Environmental decision-making has changed somewhat in recent decades to account for unintentional impacts on human wellbeing. The involvement of stakeholders in environmental projects has been recognised as critical for ensuring their success and equally for the syntheses of evidence of what works, where, and for whom, providing key benefits and challenges. As a result of increased interest in systematic reviews of complex management issues, there is a need for guidance in best practices for stakeholder engagement. Here, we propose a framework for stakeholder engagement in systematic reviews/systematic maps, highlighting recommendations and advice that are critical for effective, efficient and meaningful engagement of stakeholders. The discussion herein aims to provide a toolbox of stakeholder engagement activities, whilst also recommending approaches from stakeholder engagement research that may prove to be particularly useful for systematic reviews and systematic maps

COST 733 - WG4: Applications of weather type classification

The main objective of the COST Action 733 is to achieve a general numerical method for assessing, comparing and classifying typical weather situations in the European regions. To accomplish this goal, different workgroups are established, each with their specific aims: WG1: Existing methods and applications (finished); WG2: Implementation and development of weather types classification methods; WG3: Comparison of selected weather types classifications; WG4: Testing methods for various applications. The main task of Workgroup 4 (WG4) in COST 733 implies the testing of the selected weather type methods for various classifications. In more detail, WG4 focuses on the following topics:• Selection of dedicated applications (using results from WG1), • Performance of the selected applications using available weather types provided by WG2, • Intercomparison of the application results as a results of different methods • Final assessment of the results and uncertainties, • Presentation and release of results to the other WGs and external interested • Recommend specifications for a new (common) method WG2 Introduction In order to address these specific aims, various applications are selected and WG4 is divided in subgroups accordingly: 1.Air quality 2. Hydrology (& Climatological mapping) 3. Forest fires 4. Climate change and variability 5. Risks and hazards Simultaneously, the special attention is paid to the several wide topics concerning some other COST Actions such as: phenology (COST725), biometeorology (COST730), agriculture (COST 734) and mesoscale modelling and air pollution (COST728). Sub-groups are established to find advantages and disadvantages of different classification methods for different applications. Focus is given to data requirements, spatial and temporal scale, domain area, specifi