Detecting Signals of Disproportionate Reporting from Singapore's Spontaneous Adverse Event Reporting System: An Application of the Sequential Probability Ratio Test.

INTRODUCTION: The ability to detect safety concerns from spontaneous adverse drug reaction reports in a timely and efficient manner remains important in public health. OBJECTIVE: This paper explores the behaviour of the Sequential Probability Ratio Test (SPRT) and ability to detect signals of disproportionate reporting (SDRs) in the Singapore context. METHODS: We used SPRT with a combination of two hypothesised relative risks (hRRs) of 2 and 4.1 to detect signals of both common and rare adverse events in our small database. We compared SPRT with other methods in terms of number of signals detected and whether labelled adverse drug reactions were detected or the reaction terms were considered serious. The other methods used were reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN) and Gamma Poisson Shrinker (GPS). RESULTS: The SPRT produced 2187 signals in common with all methods, 268 unique signals, and 70 signals in common with at least one other method, and did not produce signals in 178 cases where two other methods detected them, and there were 403 signals unique to one of the other methods. In terms of sensitivity, ROR performed better than other methods, but the SPRT method found more new signals. The performances of the methods were similar for negative predictive value and specificity. CONCLUSIONS: Using a combination of hRRs for SPRT could be a useful screening tool for regulatory agencies, and more detailed investigation of the medical utility of the system is merited

Shape memory characteristics of woven glass fibre fabric reinforced epoxy composite in flexure

Shape memory characteristics of a woven glass fibre (GF) fabric reinforced epoxy composite (reinforcement content: 38 vol.%) were assessed in three point bending mode in a dynamic-mechanical analysis device and compared to those of the parent epoxy resin (EP). From unconstrained tests the shape fixity and recovery ratios and the recovery rate, whereas from constrained tests the recovery stress were determined. The shape fixity and recovery rate decreased due to the GF reinforcement which had, however, no effect on the shape recovery. Major benefit of the woven GF fabric was that the recovery stress could be enhanced by two orders of magnitude in comparison to the neat EP. GF reinforcement was accompanied with a substantial decrease in the failure-free flexural deformability of the composite specimen

Cruciferous vegetable supplementation in a controlled diet study alters the serum peptidome in a GSTM1-genotype dependent manner

<p>Abstract</p> <p>Background</p> <p>Cruciferous vegetable intake is inversely associated with the risk of several cancers. Isothiocyanates (ITC) are hypothesized to be the major bioactive constituents contributing to these cancer-preventive effects. The polymorphic glutathione-<it>S</it>-transferase (GST) gene family encodes several enzymes which catalyze ITC degradation <it>in vivo</it>.</p> <p>Methods</p> <p>We utilized high throughput proteomics methods to examine how human serum peptides (the "peptidome") change in response to cruciferous vegetable feeding in individuals of different <it>GSTM1 </it>genotypes. In two randomized, crossover, controlled feeding studies (EAT and 2EAT) participants consumed a fruit- and vegetable-free basal diet and the basal diet supplemented with cruciferous vegetables. Serum samples collected at the end of the feeding period were fractionated and matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry spectra were obtained. Peak identification/alignment computer algorithms and mixed effects models were used to analyze the data.</p> <p>Results</p> <p>After analysis of spectra from EAT participants, 24 distinct peaks showed statistically significant differences associated with cruciferous vegetable intake. Twenty of these peaks were driven by their <it>GSTM1 </it>genotype (i.e., <it>GSTM1+ </it>or <it>GSTM1- </it>null). When data from EAT and 2EAT participants were compared by joint processing of spectra to align a common set, 6 peaks showed consistent changes in both studies in a genotype-dependent manner. The peaks at 6700 <it>m/z </it>and 9565 <it>m/z </it>were identified as an isoform of transthyretin (TTR) and a fragment of zinc α2-glycoprotein (ZAG), respectively.</p> <p>Conclusions</p> <p>Cruciferous vegetable intake in <it>GSTM1+ </it>individuals led to changes in circulating levels of several peptides/proteins, including TTR and a fragment of ZAG. TTR is a known marker of nutritional status and ZAG is an adipokine that plays a role in lipid mobilization. The results of this study present evidence that the <it>GSTM1</it>-genotype modulates the physiological response to cruciferous vegetable intake.</p

Type IV Pili of Acidithiobacillus ferrooxidans Are Necessary for Sliding, Twitching Motility, and Adherence

We used conventional methods to investigate the mechanism by which Acidithiobacillus ferrooxidans colonizes a solid surface by assessing pili-mediated sliding, twitching motility, and adherence. A. ferrooxidans slided to form circular oxidized zones around each colony. This suggested that slide motility occurs through pili or flagella, though A. ferrooxidans strains ATCC 19859 and ATCC 23270 lack flagella. The results of reverse transcription-PCR demonstrated that the putative major pili gene of A. ferrooxidans strains ATCC 19859, ATCC 23270, and BY3 genes were transcribed. Culture of A. ferrooxidans between silicone gel and glass led to the production of type IV pili and the formation of rough twitching motility zones. When the bacteria were grown on lean ore cubes, pyrite was colonized readily by A. ferrooxidans and there is a correlation between pilus expression and strong attachment. However, non-pili bacteria attached minimally to the mineral surface. The results show a correlation between these functions and pilus expression

Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

34 pages, 6 additional files, 5 tables, 4 figures.[Background ] Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity.[Results] Fifteen antitumor agents, which are in clinical use or being evaluated as part of the National Cancer Institute’s drug screening effort, were analyzed in silico to assess the contribution of various molecular descriptors to their DNA-binding affinity, and the capacity of the descriptors and DNA-binding constants for predicting cell cytotoxicity. Equations to predict drug-DNA binding constants and growth-inhibitory concentrations were obtained by multiple regression following rigorous statistical procedures.[Conclusions] For drugs binding reversibly to DNA, both their strength of binding and their cytoxicity are fairly predicted from molecular descriptors by using multiple regression methods. The equations derived may be useful for rational drug design. The results obtained agree with that compounds more active across the National Cancer Institute’s 60-cell line data set tend to have common structural features.Supported by a grant from the former Spanish Ministry of Education and Science (BFU2007-60998) and the FEDER program of the European Community.Peer reviewe

ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner

<p>Abstract</p> <p>Background</p> <p>Tumor cells adapt to endoplasmic reticulum (ER) stress through a set of conserved intracellular pathways, as part of a process termed the unfolded protein response (UPR). The expression of UPR genes/proteins correlates with increasing progression and poor clinical outcome of several tumor types, including prostate cancer. UPR signaling can activate NF-κB, a master regulator of transcription of pro-inflammatory, tumorigenic cytokines. Previous studies have shown that Lipocalin 2 (Lcn2) is upregulated in several epithelial cancers, including prostate cancer, and recently Lcn2 was implicated as a key mediator of breast cancer progression. Here, we hypothesize that the tumor cell UPR regulates Lcn2 production.</p> <p>Methods</p> <p>We interrogated Lcn2 regulation in murine and human prostate cancer cells undergoing pharmacological and physiological ER stress, and tested UPR and NF-κB dependence by using pharmacological inhibitors of these signaling pathways.</p> <p>Results</p> <p>Induction of ER stress using thapsigargin (Tg), a canonical pharmacologic ER stress inducer, or via glucose deprivation, a physiologic ER stressor present in the tumor microenvironment, upregulates LCN2 production in murine and human prostate cancer cells. Inhibition of the UPR using 4-phenylbutyric acid (PBA) dramatically decreases Lcn2 transcription and translation. Inhibition of NF-κB in prostate cancer cells undergoing Tg-mediated ER stress by BAY 11-7082 abrogates Lcn2 upregulation.</p> <p>Conclusions</p> <p>We conclude that the UPR activates Lcn2 production in prostate cancer cells in an NF-κB-dependent manner. Our results imply that the observed upregulation of Lipocalin 2 in various types of cancer cells may be the direct consequence of concomitant UPR activation, and that the ER stress/Lipocalin 2 axis is a potential new target for intervention in cancer progression.</p

HIV-1 is budded from CD4+ T lymphocytes independently of exosomes

The convergence of HIV-1 budding and exosome biogenesis at late endosomal compartments called multivesicular bodies has fueled the debate on whether HIV-1 is budded from its target cells and transmitted in the form of exosomes. The point of contention appears to primarily derive from the types of target cells in question and lack of a well-defined protocol to separate exosomes from HIV-1. In this study, we adapted and established a simplified protocol to define the relationship between HIV-1 production and exosome biogenesis. Importantly, we took advantage of the newly established protocol to unequivocally show that HIV-1 was produced from CD4+ T lymphocytes Jurkat cells independently of exosomes. Thus, this study not only presents a simplified way to obtain highly purified HIV-1 virions for identification of host proteins packaged into virions, but also provides a technical platform that can be employed to define the relationship between exosome biogenesis and budding of HIV-1 or other viruses and its contributions to viral pathogenesis

The influence of different helminth infection phenotypes on immune responses against HIV in co-infected adults in South Africa

<p>Abstract</p> <p>Background</p> <p>The convergent distribution of the Human Immunodeficiency Virus (HIV) and helminth infections has led to the suggestion that infection with helminths exacerbates the HIV epidemic in developing countries. In South Africa, it is estimated that 57% of the population lives in poverty and carries the highest burden of both HIV and helmith infections, however, the disease interactions are under-researched.</p> <p>Methods</p> <p>We employed both coproscopy and <it>Ascaris lumbricoides</it>-specific serum IgE to increase diagnostic sensitivity and to distinguish between different helminth infection phenotypes and their effects on immune responses in HIV co-infected individuals. Coproscopy was done by formol ether and Kato Katz methods. HIV positive and negative adults were stratified according to the presence or absence of <it>A. lumbricoides </it>and/or <it>Trichuris trichuria </it>eggs with or without elevated <it>Ascaris </it>IgE. Lymphocyte subsets were phenotyped by flow cytometry. Viral loads, serum total IgE and eosinophils were also analysed. Lymphocyte activation markers (CCR5, HLA-DR, CD25, CD38 and CD71) were determined. Non parametric statistics were used to describe differences in the variables between the subgroups.</p> <p>Results</p> <p>Helminth prevalence ranged between 40%-60%. Four distinct subgroups of were identified, and this included egg positive/high <it>Ascaris</it>-specific IgE (egg⁺IgE^hi), egg positive/low IgE (egg⁺IgE^lo), egg negative/high IgE (egg^-IgE^hi) and egg negative/low IgE (egg^-IgE^lo) individuals. The egg⁺IgE^hisubgroup displayed lymphocytopenia, eosinophilia, (low CD4⁺counts in HIV^-group), high viral load (in HIV⁺group), and an activated lymphocyte profile. High <it>Ascaris </it>IgE subgroups (egg⁺IgE^hiand egg^-IgE^hi) had eosinophilia, highest viral loads, and lower CD4⁺counts in the HIV^-group). Egg excretion and low IgE (egg⁺IgE^lo) status demonstrated a modified Th₂immune profile with a relatively competent response to HIV.</p> <p>Conclusions</p> <p>People with both helminth egg excretion and high <it>Ascaris</it>-IgE levels had dysregulated immune cells, high viral loads with more immune activation. A modified Th₂helminth response in individuals with egg positive stools and low <it>Ascaris </it>IgE showed a better HIV related immune profile. Future research on helminth-HIV co-infection should include parasite-specific IgE measurements in addition to coproscopy to delineate the different response phenotypes. Helminth infection affects the immune response to HIV in some individuals with high IgE and egg excretion in stool.</p

Methane production in ruminant animals

Agriculture is a significant source of GHGs globally and ruminant livestock animals are one of the largest contributors to these emissions, responsible for an estimated 14% of GHGs (CH4 and N2O combined) worldwide. A large portion of GHG fluxes from agricultural activities is related to CH4 emissions from ruminants. Both direct and indirect methods are available. Direct methods include enclosure techniques, artificial (e.g. SF6) or natural (e.g. CO2) tracer techniques, and micrometeorological methods using open-path lasers. Under the indirect methods, emission mechanisms are understood, where the CH4 emission potential is estimated based on the substrate characteristics and the digestibility (i.e. from volatile fatty acids). These approximate methods are useful if no direct measurement is possible. The different systems used to quantify these emission potentials are presented in this chapter. Also, CH4 from animal waste (slurry, urine, dung) is an important source: methods pertaining to measuring GHG potential from these sources are included

Practicing a Musical Instrument in Childhood is Associated with Enhanced Verbal Ability and Nonverbal Reasoning

Background: In this study we investigated the association between instrumental music training in childhood and outcomes closely related to music training as well as those more distantly related. Methodology/Principal Findings: Children who received at least three years (M = 4.6 years) of instrumental music training outperformed their control counterparts on two outcomes closely related to music (auditory discrimination abilities and fine motor skills) and on two outcomes distantly related to music (vocabulary and nonverbal reasoning skills). Duration of training also predicted these outcomes. Contrary to previous research, instrumental music training was not associated with heightened spatial skills, phonemic awareness, or mathematical abilities. Conclusions/Significance: While these results are correlational only, the strong predictive effect of training duration suggests that instrumental music training may enhance auditory discrimination, fine motor skills, vocabulary, and nonverba