Effects of aflatoxin and fumonisin on gene expression of growth factors and inflammation-related genes in a human hepatocyte cell line

Aflatoxin B1 (AFB1) and fumonisin B1 (FB1) are mycotoxins widely distributed in maize and maized-based products, often occurring together. The implications of co-exposure to aflatoxin and fumonsin for human health are numerous, but a particular concern is the potential of FB1 to modulate AFB1 hepatotoxicity. This study evaluated the toxicity of these mycotoxins, alone or combined, in a human non-tumorigenic liver cell line, HHL-16 cells, and assessed the effects of AFB1 and FB1 on expression of genes involved in immune and growth factor pathways. The results demonstrated that in HHL-16 cells, both AFB1 and FB1 had dose-dependent and time-dependent toxicity, and the combination of them showed a synergistic toxicity in the cells. Moreover, AFB1 caused upregulation of IL6, CCL20, and BMP2, and downregulation of NDP. In combination of AFB1 with FB1, gene expression levels of IL6 and BMP2 were significantly higher compared to individual FB1 treatment, and had a tendency to be higher than individual AFB1 treatment. This study shows that FB1 may increase the hepatoxicity of AFB1 through increasing the inflammatory response and disrupting cell growth pathways

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .)

Genome-wide functional perturbation of human microsatellite repeats using engineered zinc finger transcription factors.

Repeat elements can be dysregulated at a genome-wide scale in human diseases. For example, in Ewing sarcoma, hundreds of inert GGAA repeats can be converted into active enhancers when bound by EWS-FLI1. Here we show that fusions between EWS and GGAA-repeat-targeted engineered zinc finger arrays (ZFAs) can function at least as efficiently as EWS-FLI1 for converting hundreds of GGAA repeats into active enhancers in a Ewing sarcoma precursor cell model. Furthermore, a fusion of a KRAB domain to a ZFA can silence GGAA microsatellite enhancers genome wide in Ewing sarcoma cells, thereby reducing expression of EWS-FLI1-activated genes. Remarkably, this KRAB-ZFA fusion showed selective toxicity against Ewing sarcoma cells compared with non-Ewing cancer cells, consistent with its Ewing sarcoma-specific impact on the transcriptome. These findings demonstrate the value of ZFAs for functional annotation of repeats and illustrate how aberrant microsatellite activities might be regulated for potential therapeutic applications

Brane-bulk energy exchange : a model with the present universe as a global attractor

The role of brane-bulk energy exchange and of an induced gravity term on a single braneworld of negative tension and vanishing effective cosmological constant is studied. It is shown that for the physically interesting cases of dust and radiation a unique global attractor which can realize our present universe (accelerating and 0<Omega_{m0}<1) exists for a wide range of the parameters of the model. For Omega_{m0}=0.3, independently of the other parameters, the model predicts that the equation of state for the dark energy today is w_{DE,0}=-1.4, while Omega_{m0}=0.03 leads to w_{DE,0}=-1.03. In addition, during its evolution, w_{DE} crosses the w_{DE}=-1 line to smaller values.Comment: 8 pages, 2 figures, RevTex; references added, to appear in JHE

Measurement of W Polarisation at LEP

The three different helicity states of W bosons produced in the reaction e+ e- -> W+ W- -> l nu q q~ at LEP are studied using leptonic and hadronic W decays. Data at centre-of-mass energies \sqrt s = 183-209 GeV are used to measure the polarisation of W bosons, and its dependence on the W boson production angle. The fraction of longitudinally polarised W bosons is measured to be 0.218 \pm 0.027 \pm 0.016 where the first uncertainty is statistical and the second systematic, in agreement with the Standard Model expectation

Search for Anomalous Couplings in the Higgs Sector at LEP

Anomalous couplings of the Higgs boson are searched for through the processes e^+ e^- -> H gamma, e^+ e^- -> e^+ e^- H and e^+ e^- -> HZ. The mass range 70 GeV < m_H < 190 GeV is explored using 602 pb^-1 of integrated luminosity collected with the L3 detector at LEP at centre-of-mass energies sqrt(s)=189-209 GeV. The Higgs decay channels H -> ffbar, H -> gamma gamma, H -> Z\gamma and H -> WW^(*) are considered and no evidence is found for anomalous Higgs production or decay. Limits on the anomalous couplings d, db, Delta(g1z), Delta(kappa_gamma) and xi^2 are derived as well as limits on the H -> gamma gamma and H -> Z gamma decay rates

Measurement of W Polarisation at LEP

The three different helicity states of W bosons produced in the reaction e+ e- -> W+ W- -> l nu q q~ at LEP are studied using leptonic and hadronic W decays. Data at centre-of-mass energies \sqrt s = 183-209 GeV are used to measure the polarisation of W bosons, and its dependence on the W boson production angle. The fraction of longitudinally polarised W bosons is measured to be 0.218 \pm 0.027 \pm 0.016 where the first uncertainty is statistical and the second systematic, in agreement with the Standard Model expectation

Neutral-Current Four-Fermion Production in e+e- Interactions at LEP

Neutral-current four-fermion production, e+e- -> ffff is studied in 0.7/fb of data collected with the L3 detector at LEP at centre-of-mass energies root(s)=183-209GeV. Four final states are considered: qqvv, qqll, llll and llvv, where l denotes either an electron or a muon. Their cross sections are measured and found to agree with the Standard Model predictions. In addition, the e+e- -> Zgamma* -> ffff process is studied and its total cross section at the average centre-of-mass energy 196.6GeV is found to be 0.29 +/- 0.05 +/- 0.03 pb, where the first uncertainty is statistical and the second systematic, in agreement with the Standard Model prediction of 0.22 pb. Finally, the mass spectra of the qqll final states are analysed to search for the possible production of a new neutral heavy particle, for which no evidence is found

Measurement of Exclusive rho+rho- Production in Mid-Virtuality Two-Photon Interactions and Study of the gamma gamma* -> rho rho Process at LEP

Exclusive rho+rho- production in two-photon collisions between a quasi-real photon, gamma, and a mid-virtuality photon, gamma*, is studied with data collected at LEP at centre-of-mass energies root(s)=183-209GeV with a total integrated luminosity of 684.8pb^-1. The cross section of the gamma gamma* -> rho+ rho- process is determined as a function of the photon virtuality, Q^2, and the two-photon centre-of-mass energy, W_gg, in the kinematic region: 0.2GeV^2 < Q^2 <0.85GeV^2 and 1.1GeV < W_gg < 3GeV. These results, together with previous L3 measurements of rho0 rho0 and rho+ rho- production, allow a study of the gamma gamma* -> rho rho process over the Q^2-region 0.2GeV^2 < Q^2 < 30 GeV^2

Bose-Einstein Correlations of Neutral and Charged Pions in Hadronic Z Decays

Bose-Einstein correlations of both neutral and like-sign charged pion pairs are measured in a sample of 2 million hadronic Z decays collected with the L3 detector at LEP. The analysis is performed in the four-momentum difference range 300 MeV < Q < 2 GeV. The radius of the neutral pion source is found to be smaller than that of charged pions. This result is in qualitative agreement with the string fragmentation model