Early Major Worsening in Ischemic Stroke: Predictors and Outcome

Introduction: We aimed to investigate the characteristics and outcome of patients suffering early major worsening (EMW) after acute ischemic stroke (AIS) and assess the parameters associated with it. Methods: All consecutive patients with AIS in the ASTRAL registry until 10/2010 were included. EMW was defined as an NIHSS increase of ≥8 points within the first 24h after admission. The Bootstrap version of the Kolmogorov-Smirnov test and the χ 2-test were used for the comparison of continuous and categorical covariates, respectively, between patients with and without EMW. Multiple logistic regression analysis was performed to identify independent predictors of EMW. Results: Among 2155 patients, 43 (2.0%) had an EMW. EMW was independently associated with hemorrhagic transformation (OR 22.6, 95% CI 9.4-54.2), cervical artery dissection (OR 9.5, 95% CI 4.4-20.6), initial dysarthria (OR 3.7, 95% CI 1.7-8.0), and intravenous thrombolysis (OR 2.1, 95% CI 1.1-4.3), whereas a negative association was identified with initial eye deviation (OR 0.4, 95% CI 0.2-0.9). Favorable outcome at 3 and 12months was less frequent in patients with EMW compared to patients without (11.6 vs. 55.3% and 16.3 vs. 50.7%, respectively), and case fatality was higher (53.5 vs. 12.9% and 55.8 vs. 16.8%, respectively). Stroke recurrence within 3months in surviving patients was similar between patients with and without EMW (9.3 vs. 9.0%, respectively). Conclusions: Worsening of ≥8 points in the NIHSS score during the first 24h in AIS patients is related to cervical artery dissection and hemorrhagic transformation. It justifies urgent repeat parenchymal and arterial imaging. Both conditions may be influenced by targeted interventions in the acute phase of strok

3D Tangibles Facilitate Joint Visual Attention in Dyads

We report results from a dual eye-tracking study around a Tangible User Interface (TUI). Participants (N=54) worked in groups of two and solved optimization problems on the TinkerTable, a TUI designed for students in logistics. The TinkerTable features tangible shelves that students can manipulate to build and optimize the layout of a warehouse while the system provides feedback with a projector above the table. Using mobile eye-trackers, we examined participants’ visual coordination when solving those problems. We describe two contributions to the CSCL community: first, we propose a methodology for synchronizing two eye-tracking goggles and computing measures of joint visual attention (JVA) in a co-located setting. Second, we report preliminary findings suggesting that participants were more likely to have moments of joint attention when looking at 3D, realistic objects compared to 2D, abstract ones. JVA was also found to be a significant predictor of students’ learning gains and performance during the optimization tasks. We discuss implications of these findings for supporting interactions around a TUI

A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

The recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.We analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation

Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells

BACKGROUND: With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to correlate with anaplasia and unfavorable prognosis. In neuroblastoma – an embryonal tumor with biological similarities to MB – the quassinoid NBT-272 has been demonstrated to inhibit cellular proliferation and to down-regulate c-MYC protein expression. METHODS: To study MB cell responses to NBT-272 and their dependence on the level of c-MYC expression, DAOY (wild-type, empty vector transfected or c-MYC transfected), D341 (c-MYC amplification) and D425 (c-MYC amplification) human MB cells were used. The cells were treated with different concentrations of NBT-272 and the impact on cell proliferation, apoptosis and c-MYC expression was analyzed. RESULTS: NBT-272 treatment resulted in a dose-dependent inhibition of cellular proliferation (IC50 in the range of 1.7 – 9.6 ng/ml) and in a dose-dependent increase in apoptotic cell death in all human MB cell lines tested. Treatment with NBT-272 resulted in up to 90% down-regulation of c-MYC protein, as demonstrated by Western blot analysis, and in a significant inhibition of c-MYC binding activity. Anti-proliferative effects were slightly more prominent in D341 and D425 human MB cells with c-MYC amplification and slightly more pronounced in c-MYC over-expressing DAOY cells compared to DAOY wild-type cells. Moreover, treatment of synchronized cells by NBT-272 induced a marked cell arrest at the G1/S boundary. CONCLUSION: In human MB cells, NBT-272 treatment inhibits cellular proliferation at nanomolar concentrations, blocks cell cycle progression, induces apoptosis, and down-regulates the expression of the oncogene c-MYC. Thus, NBT-272 may represent a novel drug candidate to inhibit proliferation of human MB cells in vivo

Simple quantitative tests to validate sampling from thermodynamic ensembles

It is often difficult to quantitatively determine if a new molecular simulation algorithm or software properly implements sampling of the desired thermodynamic ensemble. We present some simple statistical analysis procedures to allow sensitive determination of whether a de- sired thermodynamic ensemble is properly sampled. We demonstrate the utility of these tests for model systems and for molecular dynamics simulations in a range of situations, includ- ing constant volume and constant pressure simulations, and describe an implementation of the tests designed for end users.Comment: 48 pages, 4 figure

Potential use of deodorised water extracts: polyphenol-rich extract of Thymus pannonicus All. as a chemopreventive agent

Deodorised water extracts of aromatic plants are obtained as by-products of essential oil isolation and usually discarded as waste. However, phytochemical composition of these extracts encourages their further utilization as food additives or functional food ingredients. In this study we investigated phytochemical composition, antioxidant and in vivo antiproliferative activity of deodorised water extract of Thymus pannonicus All. (DWE). HPLC analysis revealed rosmarinic acid (RA) (71.11 +/- 1.54 mg/g) as the most abundant constituent of the extract, followed by salvianolic acid H (14.83 +/- 0.79 mg/g, calculated as RA). DWE exhibited pronounced antioxidant activity in vitro, in FRAP and DPPH tests (FRAP value: 7.41 mmol Fe/g and SC50: 3.80 mu g/g, respectively). Using the model of Ehrlich carcinoma cells in mice that were treated with DWE prior, at the time, and after tumour cells implantation, the tumour growth suppression and redox status of malignant cells (i.e., activities of antioxidant enzymes, level of glutathione and intensity of lipid peroxidation) were followed. DWE applied as pretreatment caused disturbance of antioxidant equilibrium as well as apoptosis/necrosis of up to 90% EAC cells. Results obtained in the present study revealed chemopreventive potential and possibility of T. pannonicus DWE usage. High content of RA and other phenolic compounds explains, at least in part, the observed effects

Using metadynamics to explore complex free-energy landscapes

Metadynamics is an atomistic simulation technique that allows, within the same framework, acceleration of rare events and estimation of the free energy of complex molecular systems. It is based on iteratively \u2018filling\u2019 the potential energy of the system by a sum of Gaussians centred along the trajectory followed by a suitably chosen set of collective variables (CVs), thereby forcing the system to migrate from one minimum to the next. The power of metadynamics is demonstrated by the large number of extensions and variants that have been developed. The first scope of this Technical Review is to present a critical comparison of these variants, discussing their advantages and disadvantages. The effectiveness of metadynamics, and that of the numerous alternative methods, is strongly influenced by the choice of the CVs. If an important variable is neglected, the resulting estimate of the free energy is unreliable, and predicted transition mechanisms may be qualitatively wrong. The second scope of this Technical Review is to discuss how the CVs should be selected, how to verify whether the chosen CVs are sufficient or redundant, and how to iteratively improve the CVs using machine learning approaches