Varying efficacy of intermittent preventive treatment for malaria in infants in two similar trials: public health implications.

BACKGROUND\ud \ud Intermittent preventive treatment (IPTi) with sulphadoxine-pyrimethamine (SP) in infants resulted in different estimates of clinical malaria protection in two trials that used the same protocol in Ifakara, Tanzania, and Manhiça, Mozambique. Understanding the reasons for the discrepant results will help to elucidate the action mechanism of this intervention, which is essential for rational policy formulation.\ud \ud METHODS\ud \ud A comparative analysis of two IPTi trials that used the same study design, follow-up, intervention, procedures and assessment of outcomes, in Tanzania and Mozambique was undertaken. Children were randomised to receive either SP or placebo administered 3 times alongside routine vaccinations delivered through the Expanded Program on Immunisation (EPI). Characteristics of the two areas and efficacy on clinical malaria after each dose were compared.\ud \ud RESULTS\ud \ud The most relevant difference was in ITN's use ; 68% in Ifakara and zero in Manhiça. In Ifakara, IPTi was associated with a 53% (95% CI 14.0; 74.1) reduction in the risk of clinical malaria between the second and the third dose; during the same period there was no significant effect in Manhiça. Similarly, protection against malaria episodes was maintained in Ifakara during 6 months after dose 3, but no effect of IPTi was observed in Manhiça.\ud \ud CONCLUSION\ud \ud The high ITN coverage in Ifakara is the most likely explanation for the difference in IPTi efficacy on clinical malaria. Combination of IPTi and ITNs may be the most cost-effective tool for malaria control currently available, and needs to be explored in current and future studies.\ud \ud TRIAL REGISTRATION\ud \ud Manhiça study registration number: NCT00209795Ifakara study registration number: NCT88523834

Ground-State Electromagnetic Moments of Calcium Isotopes

High-resolution bunched-beam collinear laser spectroscopy was used to measure the optical hyperfine spectra of the $^{43-51}$Ca isotopes. The ground state magnetic moments of $^{49,51}$Ca and quadrupole moments of $^{47,49,51}$Ca were measured for the first time, and the $^{51}$Ca ground state spin $I=3/2$ was determined in a model-independent way. Our results provide a critical test of modern nuclear theories based on shell-model calculations using phenomenological as well as microscopic interactions. The results for the neutron-rich isotopes are in excellent agreement with predictions using interactions derived from chiral effective field theory including three-nucleon forces, while lighter isotopes illustrate the presence of particle-hole excitations of the $^{40}$Ca core in their ground state.Comment: Accepted as a Rapid Communication in Physical Review

tabAnti-HER2 (erbB-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO)

<p>Abstract</p> <p>Background</p> <p>The effects of the olive oil-rich Mediterranean diet on breast cancer risk might be underestimated when HER2 (<it>ERB</it>B2) oncogene-positive and HER2-negative breast carcinomas are considered together. We here investigated the anti-HER2 effects of phenolic fractions directly extracted from Extra Virgin Olive Oil (EVOO) in cultured human breast cancer cell lines.</p> <p>Methods</p> <p>Solid phase extraction followed by semi-preparative high-performance liquid chromatography (HPLC) was used to isolate phenolic fractions from commercial EVOO. Analytical capillary electrophoresis coupled to mass spectrometry was performed to check for the composition and to confirm the identity of the isolated fractions. EVOO polyphenolic fractions were tested on their tumoricidal ability against HER2-negative and HER2-positive breast cancer <it>in vitro </it>models using MTT, crystal violet staining, and Cell Death ELISA assays. The effects of EVOO polyphenolic fractions on the expression and activation status of HER2 oncoprotein were evaluated using HER2-specific ELISAs and immunoblotting procedures, respectively.</p> <p>Results</p> <p>Among the fractions mainly containing the <it>single phenols </it>hydroxytyrosol and tyrosol, the <it>polyphenol acid </it>elenolic acid, the <it>lignans </it>(+)-pinoresinol and 1-(+)-acetoxypinoresinol, and the <it>secoiridoids </it>deacetoxy oleuropein aglycone, ligstroside aglycone, and oleuropein aglycone, all the major EVOO polyphenols (<it>i.e. </it>secoiridoids and lignans) were found to induce strong tumoricidal effects within a micromolar range by selectively triggering high levels of apoptotic cell death in HER2-overexpressors. Small interfering RNA-induced depletion of HER2 protein and lapatinib-induced blockade of HER2 tyrosine kinase activity both significantly prevented EVOO polyphenols-induced cytotoxicity. EVOO polyphenols drastically depleted HER2 protein and reduced HER2 tyrosine autophosphorylation in a dose- and time-dependent manner. EVOO polyphenols-induced HER2 downregulation occurred regardless the molecular mechanism contributing to HER2 overexpression (<it>i.e</it>. naturally by gene amplification and ectopically driven by a viral promoter). Pre-treatment with the proteasome inhibitor MG132 prevented EVOO polyphenols-induced HER2 depletion.</p> <p>Conclusion</p> <p>The ability of EVOO-derived polyphenols to inhibit HER2 activity by promoting the proteasomal degradation of the HER2 protein itself, together with the fact that humans have safely been ingesting secoiridoids and lignans as long as they have been consuming olives and OO, support the notion that the stereochemistry of these phytochemicals might provide an excellent and safe platform for the design of new HER2-targeting agents.</p

The Toll-Like Receptor Gene Family Is Integrated into Human DNA Damage and p53 Networks

In recent years the functions that the p53 tumor suppressor plays in human biology have been greatly extended beyond “guardian of the genome.” Our studies of promoter response element sequences targeted by the p53 master regulatory transcription factor suggest a general role for this DNA damage and stress-responsive regulator in the control of human Toll-like receptor (TLR) gene expression. The TLR gene family mediates innate immunity to a wide variety of pathogenic threats through recognition of conserved pathogen-associated molecular motifs. Using primary human immune cells, we have examined expression of the entire TLR gene family following exposure to anti-cancer agents that induce the p53 network. Expression of all TLR genes, TLR1 to TLR10, in blood lymphocytes and alveolar macrophages from healthy volunteers can be induced by DNA metabolic stressors. However, there is considerable inter-individual variability. Most of the TLR genes respond to p53 via canonical as well as noncanonical promoter binding sites. Importantly, the integration of the TLR gene family into the p53 network is unique to primates, a recurrent theme raised for other gene families in our previous studies. Furthermore, a polymorphism in a TLR8 response element provides the first human example of a p53 target sequence specifically responsible for endogenous gene induction. These findings—demonstrating that the human innate immune system, including downstream induction of cytokines, can be modulated by DNA metabolic stress—have many implications for health and disease, as well as for understanding the evolution of damage and p53 responsive networks

Residual Expression of the Reprogramming Factors Prevents Differentiation of iPSC Generated from Human Fibroblasts and Cord Blood CD34+ Progenitors

Human induced pluripotent stem cells (hiPSC) have been generated from different tissues, with the age of the donor, tissue source and specific cell type influencing the reprogramming process. Reprogramming hematopoietic progenitors to hiPSC may provide a very useful cellular system for modelling blood diseases. We report the generation and complete characterization of hiPSCs from human neonatal fibroblasts and cord blood (CB)-derived CD34+ hematopoietic progenitors using a single polycistronic lentiviral vector containing an excisable cassette encoding the four reprogramming factors Oct4, Klf4, Sox2 and c-myc (OKSM). The ectopic expression of OKSM was fully silenced upon reprogramming in some hiPSC clones and was not reactivated upon differentiation, whereas other hiPSC clones failed to silence the transgene expression, independently of the cell type/tissue origin. When hiPSC were induced to differentiate towards hematopoietic and neural lineages those hiPSC which had silenced OKSM ectopic expression displayed good hematopoietic and early neuroectoderm differentiation potential. In contrast, those hiPSC which failed to switch off OKSM expression were unable to differentiate towards either lineage, suggesting that the residual expression of the reprogramming factors functions as a developmental brake impairing hiPSC differentiation. Successful adenovirus-based Cre-mediated excision of the provirus OKSM cassette in CB-derived CD34+ hiPSC with residual transgene expression resulted in transgene-free hiPSC clones with significantly improved differentiation capacity. Overall, our findings confirm that residual expression of reprogramming factors impairs hiPSC differentiation

Can changes in malaria transmission intensity explain prolonged protection and contribute to high protective efficacy of intermittent preventive treatment for malaria in infants?

BACKGROUND: Intermittent preventive (or presumptive) treatment of infants (IPTi), the administration of a curative anti-malarial dose to infants whether or not they are known to be infected, is being considered as a new strategy for malaria control. Five of the six trials using sulphadoxine-pyrimethamine (SP) for IPTi showed protective efficacies (PEs) against clinical malaria ranging from 20.1 - 33.3% whilst one, the Ifakara study, showed a protective efficacy of 58.6%. MATERIALS AND METHODS: The possible mechanisms that could explain the differences in the reported PE of IPTi were examined by comparing output from a mathematical model to data from the six published IPTi trials. RESULTS: Under stable transmission, the PE of IPTi predicted by the model was comparable with the observed PEs in all but the Ifakara study (ratio of the mean predicted PE to that observed was 1.02, range 0.39 - 1.59). When a reduction in the incidence of infection during the study was included in the model, the predicted PE of IPTi increased and extended into the second year of life, as observed in the Ifakara study. CONCLUSION: A decrease in malaria transmission during the study period may explain part of the difference in observed PEs of IPTi between sites and the extended period of protection into the second year of life observed in the Ifakara study. This finding of continued benefit of interventions in settings of decreasing transmission may explain why rebound of clinical malaria was absent in the large scale trials of insecticide-treated bed nets

EUROnu-WP6 2010 Report

This is a summary of the work done by the Working Package 6 (Physics) of the EU project "EUROnu" during the second year of activity of the project.Comment: 82 pages, 51 eps figure

Extreme Starbursts in the Local Universe

The "Extreme starbursts in the local universe" workshop was held at the Insituto de Astrofisica de Andalucia in Granada, Spain on 21-25 June 2010. Bearing in mind the advent of a new generation of facilities such as JWST, Herschel, ALMA, eVLA and eMerlin, the aim of the workshop was to bring together observers and theorists to review the latest results. The purpose of the workshop was to address the following issues: what are the main modes of triggering extreme starbursts in the local Universe? How efficiently are stars formed in extreme starbursts? What are the star formation histories of local starburst galaxies? How well do the theoretical simulations model the observations? What can we learn about starbursts in the distant Universe through studies of their local counterparts? How important is the role of extreme starbursts in the hierarchical assembly of galaxies? How are extreme starbursts related to the triggering of AGN in the nuclei of galaxies? Overall, 41 talks and 4 posters with their corresponding 10 minutes short talks were presented during the workshop. In addition, the workshop was designed with emphasis on discussions, and therefore, there were 6 discussion sessions of up to one hour during the workshop. Here is presented a summary of the purposes of the workshop as well as a compilation of the abstracts corresponding to each of the presentations. The summary and conclusions of the workshop along with a description of the future prospects by Sylvain Veilleux can be found in the last section of this document. A photo of the assistants is included.Comment: worksho

Numerical study of anharmonic vibrational decay in amorphous and paracrystalline silicon

The anharmonic decay rates of atomic vibrations in amorphous silicon (a-Si) and paracrystalline silicon (p-Si), containing small crystalline grains embedded in a disordered matrix, are calculated using realistic structural models. The models are 1000-atom four-coordinated networks relaxed to a local minimum of the Stillinger-Weber interatomic potential. The vibrational decay rates are calculated numerically by perturbation theory, taking into account cubic anharmonicity as the perturbation. The vibrational lifetimes for a-Si are found to be on picosecond time scales, in agreement with the previous perturbative and classical molecular dynamics calculations on a 216-atom model. The calculated decay rates for p-Si are similar to those of a-Si. No modes in p-Si reside entirely on the crystalline cluster, decoupled from the amorphous matrix. The localized modes with the largest (up to 59%) weight on the cluster decay primarily to two diffusons. The numerical results are discussed in relation to a recent suggestion by van der Voort et al. [Phys. Rev. B {\bf 62}, 8072 (2000)] that long vibrational relaxation inferred experimentally may be due to possible crystalline nanostructures in some types of a-Si.Comment: 9 two-column pages, 13 figure