Publication bias in animal research: a systematic review protocol.

BACKGROUND: Systematic reviews and meta-analyses of pre-clinical studies, in vivo animal experiments in particular, can influence clinical care. Publication bias is one of the major threats of validity in systematic reviews and meta-analyses. Previous empirical studies suggested that systematic reviews and meta-analyses have become more prevalent until 2010 and found evidence for compromised methodological rigor with a trend towards improvement. We aim to comprehensively summarize and update the evidence base on systematic reviews and meta-analyses of animal studies, their methodological quality and assessment of publication bias in particular. METHODS/DESIGN: The objectives of this systematic review are as follows: âeuro¢To investigate the epidemiology of published systematic reviews of animal studies until present. âeuro¢To examine methodological features of systematic reviews and meta-analyses of animal studies with special attention to the assessment of publication bias. âeuro¢To investigate the influence of systematic reviews of animal studies on clinical research by examining citations of the systematic reviews by clinical studies. Eligible studies for this systematic review constitute systematic reviews and meta-analyses that summarize in vivo animal experiments with the purpose of reviewing animal evidence to inform human health. We will exclude genome-wide association studies and animal experiments with the main purpose to learn more about fundamental biology, physical functioning or behavior. In addition to the inclusion of systematic reviews and meta-analyses identified by other empirical studies, we will systematically search Ovid Medline, Embase, ToxNet, and ScienceDirect from 2009 to January 2013 for further eligible studies without language restrictions. Two reviewers working independently will assess titles, abstracts, and full texts for eligibility and extract relevant data from included studies. Data reporting will involve a descriptive summary of meta-analyses and systematic reviews. DISCUSSION: Results are expected to be publicly available later in 2013 and may form the basis for recommendations to improve the quality of systematic reviews and meta-analyses of animal studies and their use with respect to clinical care.

Oligogalacturonide defense signals in plants: large fragments interact with the plasma membrane in vitro.

Oligogalacturonides are plant cell wall-derived regulatory molecules which stimulate defense gene expression during pathogenesis. In vitro, these compounds enhance the phosphorylation of an approximately 34-kDa protein (pp34) in purified plasma membranes from potato and tomato leaves. We now show that polygalacturonate-enhanced phosphorylation of pp34 occurs in plasma membranes purified from tomato roots, hypocotyls, and stems and from undifferentiated potato cells. Furthermore, a similar phosphorylation is detected in leaf plasma membranes from soybean, a plant distantly related to tomato. Purified oligogalacturonides 13 to at least 26 residues long stimulate pp34 thiophosphorylation in vitro. This stimulation pattern differs from the induction of many known defense responses in vivo, where a narrower range of smaller fragments, between approximately 10 and 15 residues long, are active. On the basis of these differences we suggest that observed effects of applied exogenous oligogalacturonides on defense responses may not necessarily reflect the situation during pathogenesis. The cell wall could act as a barrier to many exogenous oligo- and polygalacturonides as well as other large regulatory ligands.

Crystal size distribution of periclase in contact metamorphic dolomite marbles from the southern Adamello Massif, Italy

Crystal size distributions (CSD) of periclase in contact metamorphic dolomite marbles are presented for two profiles near the Cima Uzza summit in the southern Adamello Massif (Italy). The database was combined with geochemical and petrological information to deduce the controls on the periclase-forming reaction. The contact metamorphic dolomite marbles are exposed at the contact of mafic intrusive rocks and are partially surrounded by them. Brucite is retrograde and pseudomorphs spherical periclase crystals. Prograde periclase growth is the consequence of limited infiltration of water-rich fluid at T near 605C. Stable isotope data show depletion in (13)C and (18)O over a narrow region (40 cm) near the magmatic contact, whereas the periclase-forming reaction front extends up to 4 m from the contact. CSD analyses along the two profiles show that the median grain size of the periclase crystals does not change, but that there is a progressively greater distribution of grain sizes, including a greater proportion of larger grains, with increasing distance from the contact. A qualitative model, based on the textural and geochemical data, attributes these variations in grain size to changing reaction affinities along a kinetically dispersed infiltration front. This study highlights the need to invoke disequilibrium processes for metamorphic mineral growth and expands the use of CSDs to systems of mineral formation driven by fluid infiltration.

Feasibility of direct mapping of cerebral fluorodeoxy-D-glucose metabolism in situ at subcellular resolution using soft X-ray fluorescence.

Glucose metabolism is difficult to image with cellular resolution in mammalian brain tissue, particularly with (18) fluorodeoxy-D-glucose (FDG) positron emission tomography (PET). To this end, we explored the potential of synchrotron-based low-energy X-ray fluorescence (LEXRF) to image the stable isotope of fluorine (F) in phosphorylated FDG (DG-6P) at 1 μm(2) spatial resolution in 3-μm-thick brain slices. The excitation-dependent fluorescence F signal at 676 eV varied linearly with FDG concentration between 0.5 and 10 mM, whereas the endogenous background F signal was undetectable in brain. To validate LEXRF mapping of fluorine, FDG was administered in vitro and in vivo, and the fluorine LEXRF signal from intracellular trapped FDG-6P over selected brain areas rich in radial glia was spectrally quantitated at 1 μm(2) resolution. The subsequent generation of spatial LEXRF maps of F reproduced the expected localization and gradients of glucose metabolism in retinal Müller glia. In addition, FDG uptake was localized to periventricular hypothalamic tanycytes, whose morphological features were imaged simultaneously by X-ray absorption. We conclude that the high specificity of photon emission from F and its spatial mapping at ≤1 μm resolution demonstrates the ability to identify glucose uptake at subcellular resolution and holds remarkable potential for imaging glucose metabolism in biological tissue. © 2012 Wiley Periodicals, Inc.

The histone-interacting domain of nuclear factor I activates simian virus 40 DNA replication in vivo.

Efficient initiation of SV40 DNA replication requires transcription factors that bind auxiliary sequences flanking the minimally required origin. To evaluate the possibility that transcription factors may activate SV40 replication by acting on the chromatin structure of the origin, we used an in vivo replication system in which we targeted GAL4 fusion proteins to the minimally required origin. We found that the proline-rich transcriptional activation domain of nuclear factor I (NF-I), which has been previously shown to interact with histone H3, specifically activates replication. Evaluation of a series of deletion and point mutants of NF-I indicates that the H3-binding domain and the replication activity coincide perfectly. Assays with other transcription factors, such as Sp1, confirmed the correlation between the interaction with H3 and the activation of replication. These findings imply that transcription factors such as NF-I can activate SV40 replication via direct interaction with chromatin components, thereby contributing to the relief of nucleosomal repression at the SV40 origin.

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

The human Rad52 protein exists as a heptameric ring.

The RAD52 epistasis group was identified in yeast as a group of genes required to repair DNA damaged by ionizing radiation [1]. Genetic evidence indicates that Rad52 functions in Rad51-dependent and Rad51-independent recombination pathways [2] [3] [4]. Consistent with this, purified yeast and human Rad52 proteins have been shown to promote single-strand DNA annealing [5] [6] [7] and to stimulate Rad51-mediated homologous pairing [8] [9] [10] [11]. Electron microscopic examinations of the yeast [12] and human [13] Rad52 proteins have revealed their assembly into ring-like structures in vitro. Using both conventional transmission electron microscopy and scanning transmission electron microscopy (STEM), we found that the human Rad52 protein forms heptameric rings. A three-dimensional (3D) reconstruction revealed that the heptamer has a large central channel. Like the hexameric helicases such as Escherichia coli DnaB [14] [15], bacteriophage T7 gp4b [16] [17], simian virus 40 (SV40) large T antigen [18] and papilloma virus E1 [19], the Rad52 rings show a distinctly chiral arrangement of subunits. Thus, the structures formed by the hexameric helicases may be a more general property of other proteins involved in DNA metabolism, including those, such as Rad52, that do not bind and hydrolyze ATP.

Ethique économique (d'Arthur Rich)

Enfin traduite en français, l'éthique économique d'Arthur Rich est une somme magistrale, une synthèse unique en son genre, due à l'un des représentants éminents de l'éthique sociale contemporaine. Puisant son inspiration dans la théologie, l'éthique contemporaine et les grands travaux de recherche en économie, l'auteur montre que si le système de l'économie de marché a l'avantage d'être foncièrement réformable, au contraire de toute économie planifiée, il exige des régulations équitables et responsables. Ni marxiste, ni sauvagement libéral, l'auteur ne fait pas non plus de concessions à l'écologie qu'il soumet aux normes de l'éthique sociale et de la justice économique. La synthèse puissante qu'il offre au long des 680 pages de son ouvrage est une des références majeures d'un discours économique d'inspiration chrétienne. Né en 1910 en Suisse alémanique, mort en 1992, Arthur Rich a étudié la théologie après un apprentissage en usine. Ses intérêts l'ont mené vers l'éthique sociale et économique dont il est une figure reconnue dans le monde anglo-saxon.