Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

Objectives: One third of the world population is considered latently infected with Mycobacterium tuberculosis(LTBI) and sterilizing this reservoir of bacteria that may reactivate is required for tuberculosis (TB) elimination. Thegroup of individuals with LTBI is heterogeneous with some of them being more at risk to develop TB disease thanothers. Improved diagnosis of subjects with LTBI is needed, allowing to differentiate subjects with LTBI from thosewith active TB, and to select among LTBI subjects those who are more at risk to develop active TB. We havecharacterized at the cellular level both the quantitative and qualitative T cell responses to different mycobacterialantigens in selected populations of infected subjects in order to identify new biomarkers that could help to identify M.tuberculosis-infected subjects and to stratify them in risk groups for reactivation of the infection.Methods: Lymphoblast frequencies and cytokine production (IFN-γ, TNF-α, IL-2) among CD4+ and CD8+ T cellswere analyzed by flow cytometry after in vitro stimulation with the latency antigen heparin-binding haemagglutinin(HBHA) or early-secreted antigen Target-6 (ESAT-6) of peripheral blood mononuclear cells from clinically wellcharacterized M. tuberculosis-infected humans (28 LTBI, 22 TB disease,12 controls). The LTBI group definedaccording to the Center for Disease Control guidelines was subdivided into QuantiFERON-TB Gold in-Tube (QFT)positive and negative subgroups.Results: Similar to TB patients, QFT+ LTBI subjects had higher proportions of HBHA-induced TNF-αsingle+ CD4+lymphocytes than QFT- LTBI subjects (p<0.05). Compared to LTBI subjects, TB patients had higher frequencies ofESAT-6-induced CD8+ lymphoblasts (p<0.001), higher proportions of ESAT-6-induced IFN-γ+TNF-α+ CD4+ Tlymphocytes (p<0.05), and lower proportions of HBHA-induced IFN-γ+TNF-α+IL-2+ (p<0.05) CD4+ T lymphocytes.Conclusions: These data provide new biomarkers to discriminate active TB from LTBI, and more interestingly,help to identify LTBI subjects with increased likelihood to develop TB disease.

A price worth paying?: Women and work – choice, constraint or satisficing

Purpose – Are women held back or holding back? Do women choose their jobs/careers or are they structurally or normatively constrained? The purpose of this paper is to shed fresh light on these questions and contribute to an on-going debate that has essentially focused on the extent to which part-time work is women’s choice, the role of structural and organisational constraints and the role of men in excluding women. Design/methodology/approach – The paper uses data from interviews with 80 working women – both full-time and part-time – performing diverse work roles in a range of organisations in the south east of England. Findings – It was found that many women do not make strategic job choices, rather they often ‘‘fall into’’ jobs that happen to be available to them. Some would not have aspired to their present jobs without male encouragement; many report incidents of male exclusion; and virtually all either know or suspect that they are paid less than comparable men. Those working reduced hours enjoy that facility, yet they are aware that reduced hours and senior roles are seen as incompatible. In short, they recognise both the positive and negative aspects of their jobs, whether they work full or part-time, whether they work in male-dominated or female-dominated occupations, and whatever their position in the organisational hierarchy. Accordingly, the paper argues that the concept of ‘‘satisficing’’, i.e. a decision which is good enough but not optimal, is a more appropriate way to view women’s working lives than are either choice or constraint theories. Originality/value – There is an ongoing, and often polarised, debate between those who maintain that women choose whether to give preference to work or home/family and others who maintain that women, far from being self-determining actors, are constrained structurally and normatively. Rather than supporting these choice or constraint theories, this paper argues that ‘‘satisficing’’ is a more appropriate and nuanced concept to explain women’s working lives.

Marine biodiversity and ecosystem function relationships:the potential for practical monitoring applications

There is an increasing demand for environmental assessments of the marine environment to include ecosystem function. However, existing schemes are predominantly based on taxonomic (i.e. structural) measures of biodiversity. Biodiversity and Ecosystem Function (BEF) relationships are suggested to provide a mechanism for converting taxonomic information into surrogates of ecosystem function. This review assesses the evidence for marine BEF relationships and their potential to be used in practical monitoring applications (i.e. operationalized). Five key requirements were identified for the practical application of BEF relationships: (1) a complete understanding of strength, direction and prevalence of marine BEF relationships, (2) an understanding of which biological components are influential within specific BEF relationships, (3) the biodiversity of the selected biological components can be measured easily, (4) the ecological mechanisms that are the most important for generating marine BEF relationships, i.e. identity effects or complementarity, are known and (5) the proportion of the overall functional variance is explained by biodiversity, and hence BEF relationships, has been established. Numerous positive and some negative BEF relationships were found within the literature, although many reproduced poorly the natural species richness, trophic structures or multiple functions of real ecosystems (requirement 1). Null relationships were also reported. The consistency of the positive and negative relationships was often low that compromised the ability to generalize BEF relationships and confident application of BEF within marine monitoring. Equally, some biological components and functions have received little or no investigation. Expert judgement was used to attribute biological components using spatial extent, presence and functional rate criteria (requirement 2). This approach highlighted the main biological components contributing the most to specific ecosystem functions, and that many of the particularly influential components were found to have received the least amount of research attention. The need for biodiversity to be measureable (requirement 3) is possible for most biological components although difficult within the functionally important microbes. Identity effects underpinned most marine BEF relationships (requirement 4). As such, processes that translated structural biodiversity measures into functional diversity were found to generate better BEF relationships. The analysis of the contribution made by biodiversity, over abiotic influences, to the total expression of a particular ecosystem function was rarely measured or considered (requirement 5). Hence it is not possible to determine the overall importance of BEF relationships within the total ecosystem functioning observed. In the few studies where abiotic factors had been considered, it was clear that these modified BEF relationships and have their own direct influence on functional rate. Based on the five requirements, the information required for immediate ‘operationalization’ of BEF relationships within marine functional monitoring is lacking. However, the concept of BEF inclusion within practical monitoring applications, supported by ecological modelling, shows promise for providing surrogate indicators of functioning.

Rinderpest and peste de petits ruminants viruses exhibit neurovirulence in mice

Members of the morbillivirus genus, canine distemper (CDV), phocine distemper virus (PDV), and the cetacean viruses of dolphins and porpoises exhibit high levels of CNS infection in their natural hosts. CNS complications are rare for measles virus (MV) and are not associated with rinderpest virus (RPV) and peste des petits ruminants virus (PPRV) infection. However, it is possible that all morbilliviruses infect the CNS but in some hosts are rapidly cleared by the immune response. In this study, we assessed whether RPV and PPRV have the potential to be neurovirulent. We describe the outcome of infection, of selected mouse strains, with isolates of RPV, PPRV, PDV, porpoise morbillivirus (PMV), dolphin morbillivirus (DMV), and a wild-type strain of MV. In the case of RPV virus, strains with different passage histories have been examined. The results of experiments with these viruses were compared with those using neuroadapted and vaccine strains of MV, which acted as positive and negative controls respectively. Intracerebral inoculation with RPV (Saudi/81) and PPRV (Nigeria75/1) strains produced infection in Balb/C and Cd1, but not C57 suckling mice, whereas the CAM/RB rodent-adapted strain of MV infected all three strains of mice. Weanling mice were only infected by CAM/RB. Intranasal and intraperitoneal inoculation failed to produce infection with any virus strains. We have shown that, both RPV and PPRV, in common with other morbilliviruses are neurovirulent in a permissive system. Transient infection of the CNS of cattle and goats with RPV and PPRV, respectively, remains a possibility, which could provide relevant models for the initial stages of MV infection in humans.

A prospective clinical trial of a real-time polymerase chain reaction assay for the diagnosis of candidemia in nonneutropenic, critically ill adults

Background. Invasive Candida infection among nonneutropenic, critically ill adults is a clinical problem that has received increasing attention in recent years. Poor performance of extant diagnostic modalities has promoted risk-based, preemptive prescribing in view of the poor outcomes associated with inadequate or delayed antifungal therapy; this risks unnecessary overtreatment. A rapid, reliable diagnostic test could have a substantial impact on therapeutic practice in this patient population.

Methods. Three TaqMan-based real-time polymerase chain reaction assays were developed that are capable of detecting the main medically important Candida species, categorized according to the likelihood of fluconazole susceptibility. Assay 1 detected Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida dubliniensis. Assays 2 and 3 detected Candida glabrata and Candida krusei, respectively. The clinical performance of these assays, applied to serum, was evaluated in a prospective trial of nonneutropenic adults in a single intensive care unit.

Results. In all, 527 specimens were obtained from 157 participants. All 3 assays were run in parallel for each specimen; they could be completed within 1 working day. Of these, 23 specimens were obtained from 23 participants categorized as having proven Candida infection at the time of sampling. If a single episode of Candida famata candidemia was excluded, the estimated clinical sensitivity, specificity, and positive and negative predictive values of the assays in this trial were 90.9%, 100%, 100% and 99.8%, respectively.

Conclusions. These data suggest that the described assays perform well in this population for enhancing the diagnosis of candidemia. The extent to which they may affect clinical outcomes, prescribing practice, and cost-effectiveness of care remains to be ascertained.

Mineralogy of selected geological deposits from the United Kingdom and the Republic of Ireland as possible capping materials for low-level radioactive waste disposal facilities

Solid low-level radioactive waste (LLW) is currently being disposed at a number of facilities in the United Kingdom (UK). The safety of these facilities relies to some extent on the use of engineered barriers, such as a cap, to isolate the waste and protect the environment. Generally, the material used as the barrier layer within such a cap should be of low permeability and it should retain this property over long timescales (beyond a few decades normally required for facilities containing non-radioactive wastes). The objective of this research is to determine the mineralogy of selected geological deposits from the UK and Ireland as part of a larger project to examine their suitability as a capping material, particularly on LLW sites. Mineral transformations, as a result of future climate change, may impact on the long-term performance of the cap and even the disposal facility. X-ray diffraction (XRD) was carried-out on the sand, silt and clay fractions of the London Clay, Belfast Upper Boulder Clay, Irish Glacial Till, Belfast Sleech, and Ampthill Clay geological deposits. Minerals were present that could pose both positive and negative effects on the long-term performance of the cap. Smectite, which has a high shrink swell potential, may produce cracks in London Clay, Belfast Upper Boulder Clay and Ampthill Clay capping material during dry, hotter periods as a possible consequence of future climate change; thus, resulting in higher permeability. Ampthill Clay and Belfast Sleech had elevated amounts of organic matter (OM) at 5.93% and 5.88%, respectively, which may also contribute to cracking. Over time, this OM may decompose and result in increased permeability. Gypsum (CaSO4) in the silt and sand fractions of Ampthill Clay may reduce the impact of erosion during wetter periods if it is incorporated into the upper portion of the cap. There are potential negative effects from the acidity created by the weathering of pyrite (FeS2) present in the silt and sand fractions of Belfast Sleech and Ampthill Clay that could impede the growth of grasses used to stabilize the surface of the capping material if this material is used as part of the vegetative soil layer. Additionally, acidic waters generated from pyrite weathering could negatively impact the lower lying capping layers and the disposal facility in general. However, the calcium carbonate (CaCO3) present in the silt and sand fractions of these deposits, and dolomite (CaMg(CO3)2) in Belfast Sleech, may counter act the acidity.

Determinants of human rights attitudes and behavior: A comparison and integration of psychological perspectives

Following several political-psychological approaches, the present research analyzed whether orientations toward human rights are a function of right-wing authoritarianism (RWA), social dominance orientation (SDO), basic human values in the sense of Schwartz (1992), and political ideology. Three dimensions of human rights attitudes (endorsement, restriction, and enforcement) were differentiated from human rights knowledge and behavior. In a time-lagged Internet survey (N = 479), using structural equation modeling, RWA, universalism and power values, and political ideology (measured at Time 1) differentially predicted dimensions of human rights attitudes (measured at Time 2 five months later). RWA and universalism values also predicted self-reported human rights behavior, with the effects mediated through human rights endorsement. Human rights knowledge also predicted behavior. The psychological roots of positive and negative orientations toward human rights, consequences for human rights education, and the particular role of military enforcement of human rights are discussed.

Coordinated control of DFIG’s rotor and grid side converters during network unbalance

This paper proposes a coordinated control of the rotor and grid side converters (RSC & GSC) of doubly-fed induction generator (DFIG) based wind generation systems under unbalanced voltage conditions. System behaviors and operations of the RSC and GSC under unbalanced voltage are illustrated. To provide enhanced operation, the RSC is controlled to eliminate the torque oscillations at double supply frequency under unbalanced stator supply. The oscillation of the stator output active power is then cancelled by the active power output from the GSC, to ensure constant active power output from the overall DFIG generation system. To provide the required positive and negative sequence currents control for the RSC and GSC, a current control strategy containing a main controller and an auxiliary controller is analyzed. The main controller is implemented in the positive (dq)+ frame without involving positive/negative sequence decomposition whereas the auxiliary controller is implemented in the negative sequence (dq)? frame with negative sequence current extracted. Simulation results using EMTDC/PSCAD are presented for a 2MW DFIG wind generation system to validate the proposed control scheme and to show the enhanced system operation during unbalanced voltage supply.

Rapid confirmatory method for the determination of sixteen synthetic growth promoters and bisphenol A in bovine milk using dispersive solid-phase extraction and liquid chromatography-tandem mass spectrometry

A rapid liquid chromatographic-tandem mass spectrometric (LC-MS/MS) multi-residue method for the simultaneous quantitation and identification of sixteen synthetic growth promoters and bisphenol A in bovine milk has been developed and validated. Sample preparation was straightforward, efficient and economically advantageous. Milk was extracted with acetonitrile followed by phase separation with NaCl. After centrifugation, the extract was purified by dispersive solid-phase extraction with C18 sorbent material. The compounds were analysed by reversed-phase LC-MS/MS using both positive and negative ionization and operated in multiple reaction monitoring (MRM) mode, acquiring two diagnostic product ions from each of the chosen precursor ions for unambiguous confirmation. Total chromatographic run time was less than 10 min for each sample. The method was validated at a level of 1 mu g L-1. A wide variety of deuterated internal standards were used to improve method performance. The accuracy and precision of the method were satisfactory for all analytes. The confirmative quantitative liquid chromatographic tandem mass spectrometric (LC-MS/MS) method was validated according to Commission Decision 2002/657/EC. The decision limit (CC alpha) and the detection capability (CC beta) were found to be below the chosen validation level of 1 mu g L-1 for all compounds. (C) 2010 Elsevier B.V. All rights reserved.

Association Analysis of the PIP4K2A Gene on Chromosome 10p12 and Schizophrenia in the Irish Study of High Density Schizophrenia Families (ISHDSF) and the Irish Case-Control Study of Schizophrenia (ICCSS)

Molecular studies support pharmacological evidence that phosphoinositide signaling is perturbed in schizophrenia and bipolar disorder. The phosphatidylinositol-4-phosphate-5-kinase type-II alpha (PIP4K2A) gene is located on chromosome 10p12. This region has been implicated in both diseases by linkage, and PIP4K2A directly by association. Given linkage evidence in the Irish Study of High Density Schizophrenia Families (ISHDSF) to a region including 10p12, we performed an association study between genetic variants at PIP4K2A and disease. No association was detected through single-marker or haplotype analysis of the whole sample. However, stratification into families positive and negative for the ISHDSF schizophrenia high-risk haplotype (HRH) in the DTNBP1 gene and re-analysis for linkage showed reduced amplitude of the 10p12 linkage peak in the DTNBP1 HRH positive families. Association analysis of the stratified sample showed a trend toward association of PIP4K2A SNPs rs1417374 and rs1409395 with schizophrenia in the DTNBP1 HRH positive families. Despite this apparent paradox, our data may therefore suggest involvement of PIP4K2A in schizophrenia in those families for whom genetic variation in DTNBP1 appears also to be a risk factor. This trend appears to arise from under-transmission of common alleles to female cases. Follow-up association analysis in a large Irish schizophrenia case-control control sample (ICCSS) showed significant association with disease of a haplotype comprising these same SNPs rs1417374-rs1409395, again more so in affected females, and in cases with negative family history of the disease. This study supports a minor role for PIP4K2A in schizophrenia etiology in the Irish population. (C) 2009 Wiley-Liss, Inc.

A Preference for Mephedrone: Drug Markets, Drugs of Choice, and the Emerging “Legal High” Scene

This study focuses on individuals' preferences for mephedrone, a new psychoactive substance that has emerged in several countries. We examine the reasons for mephedrone preferences, and describe the positive and negative effects of the drug experience, route of administration and consumers' views about the legality of mephedrone. Data were collected through semi-structured interviews with 45 adults who had used mephedrone since January 2010. Respondents resided in one of two jurisdictions that were characterized by different legislative controls over mephedrone. The findings suggest the importance of macro-level drug market factors that shaped people's preferences for mephedrone. Additionally, respondents' preferences were guided by pharmacological properties that helped them conceal the effects of mephedrone in public and semi-public spaces. Respondents were not deterred by the (impending) change from legal to illicit drug. The findings have implications for the study of localized drug markets, and in particular, legislative controls over emerging legal highs.

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl) benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phen-cyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl) phenyl) methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl) ethynyl) nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

STUDY OF THE DISCHARGE OF A MULTICUSP ION-SOURCE OPERATING WITH H2 AND D2

The plasma parameters and relative positive and negative ion concentrations in a small, filtered, multicusp ion source, operating at low plasma density (

ELECTRON-ENERGY DISTRIBUTION-FUNCTIONS AND NEGATIVE-ION CONCENTRATIONS IN TANDEM AND HYBRID MULTICUSP NEGATIVE HYDROGEN-ION SOURCES

The second derivative of a Langmuir probe characteristic is used to establish the electron energy distribution function (EEDF) in both a tandem and hybrid multicusp H- ion source. Moveable probes are used to establish the spatial variation of the EEDF. The negative ion density is measured by laser induced photo-detachment. In the case of the hybrid source the EEDF consists of a cold Maxwellian in the central region of the source; the electron temperature increases with increasing discharge current (rising from 0.3 eV at 1 A to 1.2 eV at 50 A when the pressure is 0.4 Pa). A hot-electron tail exists in the EEDF of the driver region adjacent to each filament which is shown to consist of a distinct group of primary electrons at low pressure (0.08 Pa) but becomes degraded mainly through inelastic collisions at higher pressures (0.27 Pa). The tandem source, on the other hand, has a single driver region which extends throughout the central region. The primary electron confinement times are much longer so that even at the lowest pressure considered (0.07 Pa) the primaries are degraded. In both cases the measured EEDF at specific locations and values of discharge operating parameters are used to establish the rate coefficients for the processes of importance in H- production and destruction.