Intracluster correlation coefficients and coefficients of variation for perinatal outcomes from five cluster-randomised controlled trials in low and middle-income countries: results and methodological implications

Background: Public health interventions are increasingly evaluated using cluster-randomised trials in which groups rather than individuals are allocated randomly to treatment and control arms. Outcomes for individuals within the same cluster are often more correlated than outcomes for individuals in different clusters. This needs to be taken into account in sample size estimations for planned trials, but most estimates of intracluster correlation for perinatal health outcomes come from hospital-based studies and may therefore not reflect outcomes in the community. In this study we report estimates for perinatal health outcomes from community-based trials to help researchers plan future evaluations.Methods: We estimated the intracluster correlation and the coefficient of variation for a range of outcomes using data from five community-based cluster randomised controlled trials in three low-income countries: India, Bangladesh and Malawi. We also performed a simulation exercise to investigate the impact of cluster size and number of clusters on the reliability of estimates of the coefficient of variation for rare outcomes.Results: Estimates of intracluster correlation for mortality outcomes were lower than those for process outcomes, with narrower confidence intervals throughout for trials with larger numbers of clusters. Estimates of intracluster correlation for maternal mortality were particularly variable with large confidence intervals. Stratified randomisation had the effect of reducing estimates of intracluster correlation. The simulation exercise showed that estimates of intracluster correlation are much less reliable for rare outcomes such as maternal mortality. The size of the cluster had a greater impact than the number of clusters on the reliability of estimates for rare outcomes.Conclusions: The breadth of intracluster correlation estimates reported here in terms of outcomes and contexts will help researchers plan future community-based public health interventions around maternal and newborn health. Our study confirms previous work finding that estimates of intracluster correlation are associated with the prevalence of the outcome of interest, the nature of the outcome of interest ( mortality or behavioural) and the size and number of clusters. Estimates of intracluster correlation for maternal mortality need to be treated with caution and a range of estimates should be used in planning future trials

Forgetting having denied: The "amnesic" consequences of denial

The concept of denial has its roots in psychoanalysis. Denial has been assumed to be effective in blocking unwanted memories. In two experiments, we report that denial has unique consequences for remembering. In two experiments, participants viewed a video of a theft and half of the participants had to deny seeing certain details in the video whereas the other half had to tell the truth. One day later, all participants were given a source monitoring recognition or recall task. In these tasks, they were instructed to indicate (1) whether they could remember talking about certain details and (2) whether they could recollect seeing those details in the video. In both experiments, we found that denial made participants forget that they talked about these details while leaving memory for the video unaffected. This denial-induced forgetting was evident for both the source monitoring recognition and recall tests. Furthermore, when we asked participants after the experiment whether they could still not remember talking about these details, participants who had to deny were most likely to report that they forgot this. In contrast to a widely held belief, we show that denial does not impair memory for the experienced stimuli, but that it has a unique ability to undermine memory for what was talked about

Identification of a Novel Calotropis procera Protein That Can Suppress Tumor Growth in Breast Cancer through the Suppression of NF-κB Pathway

10.1371/journal.pone.0048514PLoS ONE712

Cannabinoid Regulation of Nitric Oxide Synthase I (nNOS) in Neuronal Cells

In our previous studies, CB1 cannabinoid receptor agonists stimulated production of cyclic GMP and translocation of nitric oxide (NO)-sensitive guanylyl cyclase in neuronal cells (Jones et al., Neuropharmacology 54:23–30, 2008). The purpose of these studies was to elucidate the signal transduction of cannabinoid-mediated neuronal nitric oxide synthase (nNOS) activation in neuronal cells. Cannabinoid agonists CP55940 (2-[(1S,2R,5S)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), WIN55212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), and the metabolically stable analog of anandamide, (R)-(+)-methanandamide stimulated NO production in N18TG2 cells over a 20-min period. Rimonabant (N-(piperidin-lyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-H-pyrazole-3-carboxamide), a CB1 receptor antagonist, partially or completely curtailed cannabinoid-mediated NO production. Inhibition of NOS activity (NG-nitro-l-arginine) or signaling via Gi/o protein (pertussis toxin) significantly limited NO production by cannabinoid agonists. Ca2+ mobilization was not detected in N18TG2 cells after cannabinoid treatment using Fluo-4 AM fluorescence. Cannabinoid-mediated NO production was attributed to nNOS activation since endothelial NOS and inducible NOS protein and mRNA were not detected in N18TG2 cells. Bands of 160 and 155 kDa were detected on Western blot analysis of cytosolic and membrane fractions of N18TG2 cells, using a nNOS antibody. Chronic treatment of N18TG2 cells with cannabinoid agonists downregulated nNOS protein and mRNA as detected using Western blot analysis and real-time polymerase chain reaction, respectively. Cannabinoid agonists stimulated NO production via signaling through CB1 receptors, leading to activation of Gi/o protein and enhanced nNOS activity. The findings of these studies provide information related to cannabinoid-mediated NO signal transduction in neuronal cells, which has important implications in the ongoing elucidation of the endocannabinoid system in the nervous system

Kinome Profiling Reveals an Interaction Between Jasmonate, Salicylate and Light Control of Hyponastic Petiole Growth in Arabidopsis thaliana

Plants defend themselves against infection by biotic attackers by producing distinct phytohormones. Especially jasmonic acid (JA) and salicylic acid (SA) are well known defense-inducing hormones. Here, the effects of MeJA and SA on the Arabidopsis thaliana kinome were monitored using PepChip arrays containing kinase substrate peptides to analyze posttranslational interactions in MeJA and SA signaling pathways and to test if kinome profiling can provide leads to predict posttranslational events in plant signaling. MeJA and SA mediate differential phosphorylation of substrates for many kinase families. Also some plant specific substrates were differentially phosphorylated, including peptides derived from Phytochrome A, and Photosystem II D protein. This indicates that MeJA and SA mediate cross-talk between defense signaling and light responses. We tested the predicted effects of MeJA and SA using light-mediated upward leaf movement (differential petiole growth also called hyponastic growth). We found that MeJA, infestation by the JA-inducing insect herbivore Pieris rapae, and SA suppressed low light-induced hyponastic growth. MeJA and SA acted in a synergistic fashion via two (partially) divergent signaling routes. This work demonstrates that kinome profiling using PepChip arrays can be a valuable complementary ∼omics tool to give directions towards predicting behavior of organisms after a given stimulus and can be used to obtain leads for physiological relevant phenomena in planta

ICAR: endoscopic skull‐base surgery

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Drug discovery in advanced prostate cancer: translating biology into therapy.

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. We review the evolving therapeutic landscape of CRPC and discuss issues associated with precision medicine as well as challenges encountered with immunotherapy for this disease. Finally, we envision the future management of CRPC, highlighting the use of circulating biomarkers and modern clinical trial designs