An investigation of minimisation criteria

Minimisation can be used within treatment trials to ensure that prognostic factors are evenly distributed between treatment groups. The technique is relatively straightforward to apply but does require running tallies of patient recruitments to be made and some simple calculations to be performed prior to each allocation. As computing facilities have become more widely available, minimisation has become a more feasible option for many. Although the technique has increased in popularity, the mode of application is often poorly reported and the choice of input parameters not justified in any logical way

Transition of plasmodium sporozoites into liver stage-like forms is regulated by the RNA binding protein pumilio

Many eukaryotic developmental and cell fate decisions that are effected post-transcriptionally involve RNA binding proteins as regulators of translation of key mRNAs. In malaria parasites (Plasmodium spp.), the development of round, non-motile and replicating exo-erythrocytic liver stage forms from slender, motile and cell-cycle arrested sporozoites is believed to depend on environmental changes experienced during the transmission of the parasite from the mosquito vector to the vertebrate host. Here we identify a Plasmodium member of the RNA binding protein family PUF as a key regulator of this transformation. In the absence of Pumilio-2 (Puf2) sporozoites initiate EEF development inside mosquito salivary glands independently of the normal transmission-associated environmental cues. Puf2- sporozoites exhibit genome-wide transcriptional changes that result in loss of gliding motility, cell traversal ability and reduction in infectivity, and, moreover, trigger metamorphosis typical of early Plasmodium intra-hepatic development. These data demonstrate that Puf2 is a key player in regulating sporozoite developmental control, and imply that transformation of salivary gland-resident sporozoites into liver stage-like parasites is regulated by a post-transcriptional mechanism

Significant associations of PAI-1 genetic polymorphisms with osteonecrosis of the femoral head

<p>Abstract</p> <p>Background</p> <p>The pathogenesis of osteonecrosis of the femoral head (ONFH) has been implicated in hypofibrinolysis and blood supply interruption. Previous studies have demonstrated that decreased fibrinolytic activity due to elevated plasminogen activator inhibitor-1 (PAI-1) levels correlates with ONFH pathogenesis. The -675 4G/5G single nucleotide polymorphism (SNP rs1799889) in the PAI-1 gene promoter is associated with PAI-1 plasma level. We investigated whether rs1799889 and two other SNPs of the PAI-1 gene (rs2227631, -844 G/A in the promoter; rs11178, +10700 C/T in the 3'UTR) are associated with increased ONFH risk.</p> <p>Methods</p> <p>Three SNPs in PAI-1 were genotyped in 206 ONFH patients and 251 control subjects, using direct sequencing and a TaqMan^®5' allelic discrimination assay. We performed association analysis for genotyped SNPs and haplotypes with ONFH.</p> <p>Results</p> <p>The 4G allele of rs1799889, A allele of rs2227631, and C allele of rs11178 were significantly associated with increased ONFH risk (p = 0.03, p = 0.003, and p = 0.002, respectively). When we divided the population according to gender, an association between the three SNPs and increased risk of ONFH was found only in men. In another subgroup analysis based on the etiology of ONFH, rs2227631 (A allele) and rs11178 (C allele) in the idiopathic subgroup (p = 0.007 and p = 0.021) and rs1799889 (4G allele) and rs11178 (C allele) in the alcohol-induced subgroup (p = 0.042 and p = 0.015) were associated with increased risk of ONFH. In addition, a certain haplotype (A-4G-C) of PAI-1 was also significantly associated with ONFH (p < 0.001).</p> <p>Conclusion</p> <p>Our findings demonstrated that three SNPs (rs1799889, rs2227631, and rs11178) of the PAI-1 gene were associated with ONFH risk. This study also suggests that PAI-1 SNPs may play an important role in ONFH.</p

Atorvastatin reduces lipopolysaccharide-induced expression of cyclooxygenase-2 in human pulmonary epithelial cells

OBJECTIVE: To explore the effects of atorvastatin on expression of cyclooxygenase-2 (COX-2) in human pulmonary epithelial cells (A549). METHODS: A549 cells were incubated in DMEM medium containing lipopolysaccharide (LPS) in the presence or absence of atorvastatin. After incubation, the medium was collected and the amount of prostaglandin E(2 )(PGE(2)) was measured by enzyme-linked immunosorbent assay (ELISA). The cells were harvested, and COX-2 mRNA and protein were analyzed by RT-PCR and western-blot respectively. RESULTS: LPS increased the expression of COX-2 mRNA and production of PGE(2 )in a dose- and time-dependent manner in A549. Induction of COX-2 mRNA and protein by LPS were inhibited by atorvastatin in a dose-dependent manner. Atorvastatin also significantly decreased LPS-induced production of PGE(2). There was a positive correlation between reduced of COX-2 mRNA and decreased of PGE(2 )(r = 0.947, P < 0.05). CONCLUSION: Atorvastatin down-regulates LPS-induced expression of the COX-2 and consequently inhibits production of PGE(2 )in cultured A549 cells

The convective storm initiation project

Copyright @ 2007 AMSThe Convective Storm Initiation Project (CSIP) is an international project to understand precisely where, when, and how convective clouds form and develop into showers in the mainly maritime environment of southern England. A major aim of CSIP is to compare the results of the very high resolution Met Office weather forecasting model with detailed observations of the early stages of convective clouds and to use the newly gained understanding to improve the predictions of the model. A large array of ground-based instruments plus two instrumented aircraft, from the U.K. National Centre for Atmospheric Science (NCAS) and the German Institute for Meteorology and Climate Research (IMK), Karlsruhe, were deployed in southern England, over an area centered on the meteorological radars at Chilbolton, during the summers of 2004 and 2005. In addition to a variety of ground-based remote-sensing instruments, numerous rawin-sondes were released at one- to two-hourly intervals from six closely spaced sites. The Met Office weather radar network and Meteosat satellite imagery were used to provide context for the observations made by the instruments deployed during CSIP. This article presents an overview of the CSIP field campaign and examples from CSIP of the types of convective initiation phenomena that are typical in the United Kingdom. It shows the way in which certain kinds of observational data are able to reveal these phenomena and gives an explanation of how the analyses of data from the field campaign will be used in the development of an improved very high resolution NWP model for operational use.This work is funded by the National Environment Research Council following an initial award from the HEFCE Joint Infrastructure Fund

Coordinated airborne studies in the tropics (CAST)

This is the final version of the article. It first appeared from the American Meteorological Society via http://dx.doi.org/10.1175/BAMS-D-14-00290.1Abstract The main field activities of the Coordinated Airborne Studies in the Tropics (CAST) campaign took place in the west Pacific during January–February 2014. The field campaign was based in Guam (13.5°N, 144.8°E), using the U.K. Facility for Airborne Atmospheric Measurements (FAAM) BAe-146 atmospheric research aircraft, and was coordinated with the Airborne Tropical Tropopause Experiment (ATTREX) project with an unmanned Global Hawk and the Convective Transport of Active Species in the Tropics (CONTRAST) campaign with a Gulfstream V aircraft. Together, the three aircraft were able to make detailed measurements of atmospheric structure and composition from the ocean surface to 20 km. These measurements are providing new information about the processes influencing halogen and ozone levels in the tropical west Pacific, as well as the importance of trace-gas transport in convection for the upper troposphere and stratosphere. The FAAM aircraft made a total of 25 flights in the region between 1°S and 14°N and 130° and 155°E. It was used to sample at altitudes below 8 km, with much of the time spent in the marine boundary layer. It measured a range of chemical species and sampled extensively within the region of main inflow into the strong west Pacific convection. The CAST team also made ground-based measurements of a number of species (including daily ozonesondes) at the Atmospheric Radiation Measurement Program site on Manus Island, Papua New Guinea (2.1°S, 147.4°E). This article presents an overview of the CAST project, focusing on the design and operation of the west Pacific experiment. It additionally discusses some new developments in CAST, including flights of new instruments on board the Global Hawk in February–March 2015.CAST is funded by NERC and STFC, with grant NE/ I030054/1 (lead award), NE/J006262/1, NE/J006238/1, NE/J006181/1, NE/J006211/1, NE/J006061/1, NE/J006157/1, NE/J006203/1, NE/J00619X/1, and NE/J006173/1. N. R. P. Harris was supported by a NERC Advanced Research Fellowship (NE/G014655/1). P. I. Palmer acknowledges his Royal Society Wolfson Research Merit Award. The BAe-146-301 Atmospheric Research Aircraft is flown by Directflight Ltd and managed by the Facility for Airborne Atmospheric Measurements, which is a joint entity of the Natural Environment Research Council and the Met Office. The authors thank the staff at FAAM, Directflight and Avalon Aero who worked so hard toward the success of the aircraft deployment in Guam, especially for their untiring efforts when spending an unforeseen 9 days in Chuuk. We thank the local staff at Chuuk and Palau, as well as the authorities in the Federated States of Micronesia for their help in facilitating our research flights. Special thanks go to the personnel associated with the ARM facility at Manus, Papua New Guinea without whose help the ground-based measurements would not have been possible. Thanks to the British Atmospheric Data Centre (BADC) for hosting our data and the NCAS Atmospheric Measurement Facility for providing the radiosonde and ground-based ozone equipment. Chlorophyll-a data used in Figure 1 were extracted using the Giovanni online data system, maintained by the NASA GES DISC. We acknowledge the MODIS mission scientists and associated NASA personnel for the production of this data set. Finally we thank many individuals associated with the ATTREX and CONTRAST campaigns for their help in the logistical planning, and we would like to single out Jim Bresch for his excellent and freely provided meteorological advice

Acute atomoxetine treatment of younger and older children with ADHD: A meta-analysis of tolerability and efficacy

<p>Abstract</p> <p>Background</p> <p>Atomoxetine is FDA-approved as a treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6 years to adult. Among pediatric clinical trials of atomoxetine to date, six with a randomized, double-blind, placebo-controlled design were used in this meta-analysis. The purpose of this article is to describe and compare the treatment response and tolerability of atomoxetine between younger children (6–7 years) and older children (8–12 years) with ADHD, as reported in these six acute treatment trials.</p> <p>Methods</p> <p>Data from six clinical trials of 6–9 weeks duration were pooled, yielding 280 subjects, ages 6–7 years, and 860 subjects, ages 8–12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-diagnosed ADHD. Efficacy was analyzed using the ADHD Rating Scale-IV (ADHD-RS), Conners' Parent Rating Scale-revised (CPRS-R:S), and the Clinical Global Impression of ADHD Severity (CGI-ADHD-S).</p> <p>Results</p> <p>Atomoxetine was superior to placebo in both age categories for mean (SD) change in ADHD-RS total, total T, and subscale scores; 3 CPRS-R:S subscales; and CGI-ADHD-S from baseline. Although there were no significant treatment differentials between the age groups for these efficacy measures, the age groups themselves, regardless of treatment, were significantly different for ADHD-RS total (younger: ATX = -14.2 [13.8], PBO = -4.6 [10.4]; older: ATX = -15.4 [13.2], PBO = -7.3 [12.0]; p = .001), total T (younger: ATX = -15.2 [14.8], PBO = -4.9 [11.2]; older: ATX = -16.4 [14.6], PBO = -7.9 [13.1]; p = .003), and subscale scores (Inattentive: younger: ATX = -7.2 [7.5], PBO = -2.4 [5.7]; older: ATX = -8.0 [7.4], PBO = -3.9 [6.7]; p = .043; Hyperactive/Impulsive: younger: ATX = -7.0 [7.2], PBO = -2.1 [5.4]; older: ATX = -7.3 [7.0], PBO = -3.4 [6.3]; p < .001), as well as the CGI-ADHD-S score (younger: ATX = -1.2 [1.3], PBO = -0.5 [0.9]; older: ATX = -1.4 [1.3], PBO = -0.7 [1.1]; p = .010). Although few subjects discontinued from either age group due to adverse events, a significant treatment-by-age-group interaction was observed for abdominal pain (younger: ATX = 19%, PBO = 6%; older: ATX = 15%, PBO = 13%; p = .044), vomiting (younger: ATX = 14%, PBO = 2%; older: ATX = 9%, PBO = 6%; p = .053), cough (younger: ATX = 10%, PBO = 6%; older: ATX = 3%, PBO = 9%; p = .007), and pyrexia (younger: ATX = 5%, PBO = 2%; older: ATX = 3%, PBO = 5%; p = .058).</p> <p>Conclusion</p> <p>Atomoxetine is an effective and generally well-tolerated treatment of ADHD in both younger and older children as assessed by three recognized measures of symptoms in six controlled clinical trials.</p> <p>Trial Registration</p> <p>Not Applicable.</p

Parainfluenza virus infection associated with posterior reversible encephalopathy syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Posterior reversible encephalopathy syndrome is a clinical and radiological entity. The most accepted theory of posterior reversible encephalopathy syndrome is a loss of autoregulation in cerebral blood flow with a subsequent increase in vascular permeability and leakage of blood plasma and erythrocytes, producing vasogenic edema. In infection-associated posterior reversible encephalopathy syndrome, a clinical pattern consistent with systemic inflammatory response syndrome develops. Parainfluenza virus has not been reported in the medical literature to be associated with posterior reversible encephalopathy syndrome.</p> <p>Case presentation</p> <p>We report herein the case of a 54-year-old Caucasian woman with posterior reversible encephalopathy syndrome associated with parainfluenza virus infection who presented with generalized headache, blurring of vision, new-onset seizure and flu-like symptoms.</p> <p>Conclusion</p> <p>Infection-associated posterior reversible encephalopathy syndrome as well as hypertension-associated posterior reversible encephalopathy syndrome favor the contribution of endothelial dysfunction to the pathophysiology of this clinicoradiological syndrome. In view of the reversible nature of this clinical entity, it is important that all physicians are well aware of posterior reversible encephalopathy syndrome in patients presenting with headache and seizure activity. A detailed clinical assessment leading to the recognition of precipitant factors in posterior reversible encephalopathy syndrome is paramount.</p

Aviation effects on already-existing cirrus clouds.

Determining the effects of the formation of contrails within natural cirrus clouds has proven to be challenging. Quantifying any such effects is necessary if we are to properly account for the influence of aviation on climate. Here we quantify the effect of aircraft on the optical thickness of already-existing cirrus clouds by matching actual aircraft flight tracks to satellite lidar measurements. We show that there is a systematic, statistically significant increase in normalized cirrus cloud optical thickness inside mid-latitude flight tracks compared with adjacent areas immediately outside the tracks