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Terms modified by Suggested Selected Abstracts"IT'S GETTING CRAZY OUT THERE": CAN A CIVIL GANG INJUNCTION CHANGE A COMMUNITY?*CRIMINOLOGY AND PUBLIC POLICY, Issue 3 2005CHERYL L. MAXSON Research Summary: Civil gang injunctions are an increasingly popular gang suppression tactic. This article reports on the first scientific evaluation of the community impact of this strategy. San Bernardino residents in five neighborhoods were surveyed about their perceptions and experience of crime, gang activity, and neighborhood quality 18 months before and 6 months after the issuance of an injunction. Analyses indicated positive evidence of short-term effects in the disordered, primary injunction area, including less gang presence, fewer reports of gang intimidation, and less fear of confrontation with gang members, but no significant changes in intermediate or long-term outcomes except lower fear of crime. Comparison of this injunction area with a previous one suggested that improvements in neighborhood dynamics might accrue over the long term. Negative effects were observed in the secondary, less disordered injunction area. Policy Implications: This study suggests that the strategic suppression of gang member activities may translate into modest immediate improvements in community safety and well-being. Furthermore, the findings suggest that law enforcement use caution regarding the size of an injunction area and the type of gang targeted by the tactic. Coupling an injunction with efforts to improve neighborhood social organization and provide positive alternatives for gang members might substantially improve its effectiveness. [source] Cell distribution of stress fibres in response to the geometry of the adhesive environmentCYTOSKELETON, Issue 6 2006Manuel Théry Abstract Cells display a large variety of shapes when plated in classical culture conditions despite their belonging to a common cell type. These shapes are transitory, since cells permanently disassemble and reassemble their cytoskeleton while moving. Adhesive micropatterns are commonly used to confine cell shape within a given geometry. In addition the micropattern can be designed so as to impose cells to spread upon adhesive and nonadhesive areas. Modulation of the pattern geometry allows the analysis of the mechanisms governing the determination of cell shape in response to external adhesive conditions. In this study, we show that the acquisition of cell shape follows two stages where initially the cell forms contact with the micropattern. Here, the most distal contacts made by the cell with the micropattern define the apices of the cell shape. Then secondly, the cell borders that link two apices move so as to minimise the distance between the two apices. In these cell borders, the absence of an underlying adhesive substrate is overcome by stress fibres forming between the apices, which in turn are marked by an accumulation of focal adhesions. By inhibiting myosin function, cell borders on nonadhesive zones become more concave, suggesting that the stress fibres work against the membrane tension in the cell border. Moreover, this suggested that traction forces are unevenly distributed in stationary, nonmigrating, cells. By comparing the stress fibres in cells with one, two, or three nonadherent cell borders it was reasoned that stress fibre strength is inversely proportional to number. We conclude that cells of a given area can generate the same total sum of tractional forces but that these tractional forces are differently spaced depending on the spatial distribution of its adherence contacts. Cell Motil. Cytoskeleton 2006. © 2006 Wiley-Liss, Inc. [source] Structural and functional effects of hydrostatic pressure on centrosomes from vertebrate cellsCYTOSKELETON, Issue 4 2001A. Rousselet Abstract In an attempt to better understand the role of centrioles in vertebrate centrosomes, hydrostatic pressure was applied to isolated centrosomes as a means to disassemble centriole microtubules. Treatments of the centrosomes were monitored by analyzing their protein composition, ultrastructure, their ability to nucleate microtubules from pure tubulin, and their capability to induce parthenogenetic development of Xenopus eggs. Moderate hydrostatic pressure (95 MPa) already affected the organization of centriole microtubules in isolated centrosomes, and also impaired microtubule nucleation. At higher pressure, the protein composition of the peri-centriolar matrix (PCM) was also altered and the capacity to nucleate microtubules severely impaired. Incubation of the treated centrosomes in Xenopus egg extract could restore their capacity to nucleate microtubules after treatment at 95 MPa, but not after higher pressure treatment. However, the centriole structure was in no case restored. It is noteworthy that centrosomes treated with mild pressure did not allow parthenogenetic development after injection into Xenopus eggs, even if they had recovered their capacity to nucleate microtubules. This suggested that, in agreement with previous results, centrosomes in which centriole architecture is impaired, could not direct the biogenesis of new centrioles in Xenopus eggs. Centriole structure could also be affected by applying mild hydrostatic pressure directly to living cells. Comparison of the effect of hydrostatic pressure on cells at the G1/S border or on the corresponding cytoplasts suggests that pro-centrioles are very sensitive to pressure. However, cells can regrow a centriole after pressure-induced disassembly. In that case, centrosomes eventually recover an apparently normal duplication cycle although with some delay. Cell Motil. Cytoskeleton 48:262,276, 2001. © 2001 Wiley-Liss, Inc. [source] How fantasy benefits young children's understanding of pretenseDEVELOPMENTAL SCIENCE, Issue 1 2006David M. Sobel Sobel and Lillard (2001) demonstrated that 4-year-olds' understanding of the role that the mind plays in pretending improved when children were asked questions in a fantasy context. The present study investigated whether this fantasy effect was motivated by children recognizing that fantasy contains violations of real-world causal structure. In Experiment 1, 4-year-olds were shown a fantasy character engaged in ordinary actions or actions that violated causal knowledge. Children were more likely to say that a troll doll who was acting like but ignorant of the character was not pretending to be that character when read the violation story. Experiment 2 suggested that this difference was not caused by a greater interest in the violation story. Experiment 3 demonstrated a similar difference for characters engaged in social and functional violations that were possible in the real world. These data are consistent with the hypothesis that preschoolers use actions and appearance more than mental states to make judgments about pretense, but that those judgments can be influenced by the context in which the questions are presented. [source] Orlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight lossDIABETES OBESITY & METABOLISM, Issue 4 2009S. Jacob Background:, Both obesity and type 2 diabetes are associated with increased morbidity and mortality. Published data suggest that orlistat 120 mg, a lipase inhibitor used to treat obesity, may improve glycaemic parameters through weight loss,independent effects. Aim:, To investigate the effect of orlistat 120 mg on weight loss, and assess whether changes in glycaemic parameters [fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c)] are independent of weight loss. Methods:, This retrospective analysis of pooled data from seven multicentre, double-blind, placebo-controlled studies involved overweight or obese patients with type 2 diabetes (aged 18,70 years). Patients were required to have a body mass index of 27,43 kg/m2, HbA1c of 6.5 to <13%, and stable weight for ,3 months. Subjects received orlistat 120 mg tid or placebo for 6 or 12 months. Results:, A total of 2550 overweight or obese patients with type 2 diabetes were enrolled and randomized to treatment with orlistat 120 mg tid (n = 1279) or placebo (n = 1271). For the whole population, patients treated with orlistat 120 mg had significantly greater mean decreases in FPG compared with placebo-treated patients (,1.39 mmol/l vs. ,0.47 mmol/l; p < 0.0001). In addition, orlistat 120 mg provided significantly larger mean decreases in HbA1c compared with placebo (,0.74% vs. ,0.31%; p < 0.0001). For patients with minimal weight loss (,1% of baseline body weight), orlistat 120 mg still provided a significantly greater decrease in the least squares mean value for both FPG (,0.83 mmol/l vs. ±0.02 mmol/l; p = 0.0052) and HbA1c,0.29% vs. ±0.14%; p = 0.0008). This suggested that the improvement of glycaemic control with orlistat 120 mg was independent of weight loss. Using linear regression analysis, improvement in glycaemic control (FPG and HbA1c) with orlistat 120 mg was less strongly correlated with weight loss than for placebo. Conclusion:, Orlistat 120 mg appears to improve glycaemic control more than would be predicted by weight loss alone in overweight or obese patients with type 2 diabetes. Postulated mechanisms underlying this effect include an improvement of insulin sensitivity, a slower and incomplete digestion of dietary fat, reduction of postprandial plasma non-esterified fatty acids, decreased visceral adipose tissue, and stimulation of glucagon-like peptide-1 secretion in the lower small intestine. [source] Relationship of glucose regulation to changes in weight: a systematic review and guide to future researchDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2010Ching-Ju Chiu Abstract Although weight gain and obesity are risk factors for poor glucose regulation, the relationship, if any, of glucose regulation to changes in weight is not well understood. The purpose of this study was to conduct a systematic review of research examining the relationship of glucose regulation to changes in weight in human-based studies and to provide guidelines for future research in this area. We searched electronic databases and reference sections of relevant articles, including both diabetic and non-diabetic populations, to locate all the literature published before February 2010, and then conducted a systematic review across studies to compare the research designs and findings. The 22 studies meeting our criteria for review generally supported the relationship of glucose regulation to changes in weight. Three studies reported that poor glucose regulation is associated with weight gain; 12 studies concluded that poor glucose regulation is associated with weight loss; 5 showed complex relationships depending on age, sex, or race/ethnicity; and 2 suggested no relationship. The diverse findings may imply that the direction (negative or positive) of the relationship may depend on specific conditions. More research focused on different subpopulations may provide more definitive information supplemental to the current preliminary findings. Recommendations regarding future research in this particular area are provided in the discussion. Copyright © 2010 John Wiley & Sons, Ltd. [source] Recanting of life-time inhalant use: how big a problem and what to make of itADDICTION, Issue 8 2009Steven C. Martino ABSTRACT Aims To establish the prevalence of recanting of life-time inhalant use, identify correlates of recanting to gain insight to its causes and develop a method for distinguishing recanters who truly are versus are not life-time users of inhalants. Design and setting Longitudinal survey data from students in 62 South Dakota middle schools who were participating in a field trial to evaluate a school-based drug prevention program. Measurements At grades 7,8, participants reported on their life-time inhalant use, other drug use and drug-related beliefs, attitudes and behaviors. Findings Forty-nine per cent of students who reported life-time inhalant use at grade 7 recanted their reports a year later. Comparison of students who recanted inhalant use with those who did or did not report inhalant use consistently on drug-related beliefs, attitudes and behaviors at grades 7 and 8 suggested that, whereas some inhalant use recanting reflects denial of past behavior, some reflects erroneous initial reporting. Based on a latent mixture model fitted to the multivariate distribution of grade 7 and grade 8 responses of recanters and consistent reporters, we calculated the probability that each recanter was, in fact, a life-time inhalant user. An estimated 67% of the recanters in our sample appear to be life-time inhalant users who admitted use in grade 7 and then denied that use at grade 8; 33% appear to be students who reported use incorrectly at grade 7 and then corrected that error at grade 8. Conclusions Inhalant use recanting is a significant problem that, if not handled carefully, is likely to have a considerable impact on our understanding of the etiology of inhalant use and efforts to prevent it. [source] Linking metal bioaccumulation of aquatic insects to their distribution patterns in a mining-impacted riverENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 6 2004Daniel J. Cain Abstract Although the differential responses of stream taxa to metal exposure have been exploited for bioassessment and monitoring, the mechanisms affecting these responses are not well understood. In this study, the subcellular partitioning of metals in operationally defined metal-sensitive and detoxified fractions were analyzed in five insect taxa. Samples were collected in two separate years along an extensive metal contamination gradient in the Clark Fork River (MT, USA) to determine if interspecific differences in the metal concentrations of metal-sensitive fractions and detoxified fractions were linked to the differences in distributions of taxa relative to the gradient. Most of the Cd, Cu, and Zn body burdens were internalized and potentially biologically active in all taxa, although all taxa appeared to detoxify metals (e.g., metal bound to cytosolic metal-binding proteins). Metal concentrations associated with metal-sensitive fractions were highest in the mayflies Epeorus albertae and Serratella tibialis, which were rare or absent from the most contaminated sites but occurred at less contaminated sites. Relatively low concentrations of Cu were common to the tolerant taxa Hydropsyche spp. and Baetis spp., which were widely distributed and dominant in the most contaminated sections of the river. This suggested that distributions of taxa along the contamination gradient were more closely related to the bioaccumulation of Cu than of other metals. Metal bioaccumulation did not appear to explain the spatial distribution of the caddisfly Arctopsyche grandis, considered to be a bioindicator of metal effects in the river. Thus, in this system the presence/absence of most of these taxa from sites where metal exposure was elevated could be differentiated on the basis of differences in metal bioaccumulation. [source] Applying species-sensitivity distributions in ecological risk assessment: Assumptions of distribution type and sufficient numbers of species,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2000Michael C. Newman Abstract Species-sensitivity distribution methods assemble single-species toxicity data to predict hazardous concentrations (HCps) affecting a certain percentage (p) of species in a community. The fit of the lognormal model and required number of individual species values were evaluated with 30 published data sets. The increasingly common assumption that a lognormal model best fits these data was not supported. Fifteen data sets failed a formal test of conformity to a lognormal distribution; other distributions often provided better fit to the data than the lognormal distribution. An alternate bootstrap method provided accurate estimates of HCp without the assumption of a specific distribution. Approximate sample sizes producing HC5 estimates with minimal variance ranged from 15 to 55, and had a median of 30 species-sensitivity values. These sample sizes are higher than those suggested in recent regulatory documents. A bootstrap method is recommended that predicts with 95% confidence the concentration affecting 5% or fewer species. [source] Avian Risk Assessment: Effects of Perching Height and DetectabilityETHOLOGY, Issue 4 2004Daniel T. Blumstein We studied two components of predator risk assessment in birds. While many species are limited to seeking safety under cover or under ground, some birds can fly away from their predators and escape to trees. If birds in fact ,feel' safer (e.g. perceive less risk) in trees, we would expect them to tolerate closer approach by a potential terrestrial predator. Another component of safety is at which point the animal detects an approaching threat, which we expected to increase with eye size, assuming eye size is a surrogate for visual acuity. We used the distance birds moved away from an approaching human [flight initiation distance (FID)] as a metric to determine whether birds associated a lower risk of predation by being in trees, and we used the distance at which birds first displayed alert behaviors from an approaching human (alert distance) to determine if birds with larger eyes had higher detection distances. Although some species were affected by tree height, we found no clear pattern that birds assessed themselves to be at a lower risk of predation when they were ,3 m above the ground compared with being <3 m above ground. In the 10 species for which height had any significant effect on FID, birds ,3 m off the ground had greater FIDs in six species, but the remaining three species had the opposite response. While we found a significant positive relationship between eye size and alert distance in 23 species, the relationship was not present in a phylogenetic analysis using independent contrasts, which suggests that the apparent relationship was influenced strongly by the association between the studied species. Together, these results suggest that birds do not obviously associate being in a tree with safety, and that variations in visual acuity, per se, cannot be used as a general indicator of differences in alert distances, as previously suggested in the literature. [source] Wavelet analysis of the scale- and location-dependent correlation of modelled and measured nitrous oxide emissions from soilEUROPEAN JOURNAL OF SOIL SCIENCE, Issue 1 2005A. E. Milne Summary We used the wavelet transform to quantify the performance of models that predict the rate of emission of nitrous oxide (N2O) from soil. Emissions of N2O and other soil variables that influence emissions were measured on soil cores collected at 256 locations across arable land in Bedfordshire, England. Rate-limiting models of N2O emissions were constructed and fitted to the data by functional analysis. These models were then evaluated by wavelet variance and wavelet correlations, estimated from coefficients of the adapted maximal overlap discrete wavelet transform (AMODWT), of the fitted and measured emission rates. We estimated wavelet variances to assess whether the partition of the variance of modelled rates of N2O emission between scales reflected that of the data. Where the relative distribution of variance in the model is more skewed to coarser scales than is the case for the observation, for example, this indicates that the model predictions are too smooth spatially, and fail adequately to represent some of the variation at finer scales. Scale-dependent wavelet correlations between model and data were used to quantify the model performance at each scale, and in several cases to determine the scale at which the model description of the data broke down. We detected significant changes in correlation between modelled and predicted emissions at each spatial scale, showing that, at some scales, model performance was not uniform in space. This suggested that the influence of a soil variable on N2O emissions, important in one region but not in another, had been omitted from the model or modelled poorly. Change points usually occurred at field boundaries or where soil textural class changed. We show that wavelet analysis can be used to quantify aspects of model performance that other methods cannot. By evaluating model behaviour at several scales and positions wavelet analysis helps us to determine whether a model is suitable for a particular purpose. [source] Plakoglobin-dependent disruption of the desmosomal plaque in pemphigus vulgarisEXPERIMENTAL DERMATOLOGY, Issue 6 2007Alain De Bruin Abstract:, We recently reported that the pathogenesis of pemphigus vulgaris (PV), an autoimmune blistering skin disorder, is driven by the accumulation of c-Myc secondary to abrogation of plakoglobin (PG)-mediated transcriptional c-Myc suppression. PG knock-out mouse keratinocytes express high levels of c-Myc and resemble PVIgG-treated wild-type keratinocytes in most respects. However, they fail to accumulate nuclear c-Myc and loose intercellular adhesion in response to PVIgG-treatment like wild-type keratinocytes. This suggested that PG is also required for propagation of the PVIgG-induced events between augmented c-Myc expression and acantholysis. Here, we addressed this possibility by comparing PVIgG-induced changes in the desmosomal organization between wild-type and PG knock-out keratinocytes. We found that either bivalent PVIgG or monovalent PV-Fab (known to trigger blister formation in vivo) disrupt the linear organization of all major desmosomal components along cell borders in wild-type keratinocytes, simultaneously with a reduction in intercellular adhesive strength. In contrast, PV-Fab failed to affect PG knock-out keratinocytes while PVIgG cross-linked their desmosomal cadherins without significantly affecting desmoplakin. These results identify PG as a principle effector of the PVIgG-induced signals downstream of c-Myc that disrupt the desmosomal plaque at the plasma membrane. [source] Increased glucose metabolism and ATP level in brain tissue of Huntington's disease transgenic miceFEBS JOURNAL, Issue 19 2008Judit Oláh Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by multifarious dysfunctional alterations including mitochondrial impairment. In the present study, the formation of inclusions caused by the mutation of huntingtin protein and its relationship with changes in energy metabolism and with pathological alterations were investigated both in transgenic and 3-nitropropionic acid-treated mouse models for HD. The HD and normal mice were characterized clinically; the affected brain regions were identified by immunohistochemistry and used for biochemical analysis of the ATP-producing systems in the cytosolic and the mitochondrial compartments. In both HD models, the activities of some glycolytic enzymes were somewhat higher. By contrast, the activity of glyceraldehyde-3-phosphate dehydrogenase was much lower in the affected region of the brain compared to that of the control. Paradoxically, at the system level, glucose conversion into lactate was enhanced in cytosolic extracts from the HD brain tissue, and the level of ATP was higher in the tissue itself. The paradox could be resolved by taking all the observed changes in glycolytic enzymes into account, ensuing an experiment-based detailed mathematical model of the glycolytic pathway. The mathematical modelling using the experimentally determined kinetic parameters of the individual enzymes and the well-established rate equations predicted the measured flux and concentrations in the case of the control. The same mathematical model with the experimentally determined altered Vmax values of the enzymes did account for an increase of glycolytic flux in the HD sample, although the extent of the increase was not predicted quantitatively. This suggested a somewhat altered regulation of this major metabolic pathway in HD tissue. We then used the mathematical model to develop a hypothesis for a new regulatory interaction that might account for the observed changes; in HD, glyceraldehyde-3-phosphate dehydrogenase may be in closer proximity (perhaps because of the binding of glyceraldehyde-3-phosphate dehydrogenase to huntingtin) with aldolase and engage in channelling for glyceraldehyde-3-phosphate. By contrast to most of the speculation in the literature, our results suggest that the neuronal damage in HD tissue may be associated with increased energy metabolism at the tissue level leading to modified levels of various intermediary metabolites with pathological consequences. [source] Transcription of individual tRNAGly1 genes from within a multigene family is regulated by transcription factor TFIIIBFEBS JOURNAL, Issue 20 2005Akhila Parthasarthy Members of a multigene family from the silkworm Bombyx mori have been classified based on their transcriptions in homologous nuclear extracts, into three groups of highly, moderately and poorly transcribed genes. Because all these gene copies have identical coding sequences and consequently identical promoter elements (the A and B boxes), the flanking sequences modulate their expression levels. Here we demonstrate the interaction of transcription factor TFIIIB with these genes and its role in regulating differential transcriptions. The binding of TFIIIB to the poorly transcribed gene -6,7 was less stable compared with binding of TFIIIB to the highly expressed copy, -1. The presence of a 5, upstream TATA sequence closer to the coding region in -6,7 suggested that the initial binding of TFIIIC to the A and B boxes sterically hindered anchoring of TFIIIB via direct interactions, leading to lower stability of TFIIIC,B-DNA complexes. Also, the multiple TATATAA sequences present in the flanking regions of this poorly transcribed gene successfully competed for TFIIIB reducing transcription. The transcription level could be enhanced to some extent by supplementation of TFIIIB but not by TATA box binding protein. The poor transcription of -6,7 was thus attributed both to the formation of a less stable transcription complex and the sequestration of TFIIIB. Availability of the transcription factor TFIIIB in excess could serve as a general mechanism to initiate transcription from all the individual members of the gene family as per the developmental needs within the tissue. [source] Connection of transport and sensing by UhpC, the sensor for external glucose-6-phosphate in Escherichia coliFEBS JOURNAL, Issue 7 2003Christian Schwöppe UhpC is a membrane-bound sensor protein in Escherichia coli required for recognizing external glucose-6-phosphate (Glc6P) and induction of the transport protein UhpT. Recently, it was shown that UhpC is also able to transport Glc6P. In this study we investigated whether these transport and sensing activities are obligatorily coupled in UhpC. We expressed a His-UhpC protein in a UhpC-deficient E. coli strain and verified that this construct does not alter the basic biochemical properties of the Glc6P sensor system. The effects of arginine replacements, mutations of the central loop, and introduction of a salt bridge in UhpC on transport and sensing were compared. The exchanges R46C, R266C and R149C moderately affected transport by UhpC but strongly decreased the sensing ability. This suggested that the affinity for Glc6P as a transported substrate is uncoupled in UhpC from its affinity for Glc6P as an inducer. Four of the 11 arginine mutants showed a constitutive phenotype but had near wild-type transport activity suggesting that Glc6P can be transported by a molecule locked in the inducing conformation. Introduction of an intrahelical salt bridge increased the transport activity of UhpC but abolished sensing. Three conserved residues from the central loop were mutated and although none of these showed transport, one exhibited increased affinity for sensing. Taken together, these data show that transport by UhpC is not required for sensing, that conserved arginine residues are important for sensing and not for transport, and that residues located in the central hydrophilic loop are critical for transport and for sensing. [source] Monitoring bacterial and archaeal community shifts in a mesophilic anaerobic batch reactor treating a high-strength organic wastewaterFEMS MICROBIOLOGY ECOLOGY, Issue 3 2008Changsoo Lee Abstract Shifts in bacterial and archaeal communities, associated with changes in chemical profiles, were investigated in an anaerobic batch reactor treating dairy-processing wastewater prepared with whey permeate powder. The dynamics of bacterial and archaeal populations were monitored by quantitative real-time PCR and showed good agreement with the process data. A rapid increase in bacterial populations and a high rate of substrate fermentation were observed during the initial period. Growth and regrowth of archaeal populations occurred with biphasic production of methane, corresponding to the diauxic consumption of acetate and propionate. Bacterial community structure was examined by denaturing gel gradient electrophoresis (DGGE) targeting 16S rRNA genes. An Aeromonas -like organism was suggested to be mainly responsible for the rapid fermentation of carbohydrate during the initial period. Several band sequences closely related to the Clostridium species, capable of carbohydrate fermentation, lactate or ethanol fermentation, and/or homoacetogenesis, were also detected. Statistical analyses of the DGGE profiles showed that the bacterial community structure, as well as the process performance, varied with the incubation time. Our results demonstrated that the bacterial community shifted, reflecting the performance changes and, particularly, that a significant community shift corresponded to a considerable process event. This suggested that the diagnosis of an anaerobic digestion process could be possible by monitoring bacterial community shifts. [source] Quantification and correction of bias in tagging SNPs caused by insufficient sample size and marker density by means of haplotype-dropping,GENETIC EPIDEMIOLOGY, Issue 1 2008Mark M. Iles Abstract Tagging single nucleotide polymorphisms (tSNPs) are commonly used to capture genetic diversity cost-effectively. It is important that the efficacy of tSNPs is correctly estimated, otherwise coverage may be inadequate and studies underpowered. Using data simulated under a coalescent model, we show that insufficient sample size can lead to overestimation of tSNP efficacy. Quantifying this we find that even when insufficient marker density is adjusted for, estimates of tSNP efficacy are up to 45% higher than the true values. Even with as many as 100 individuals, estimates of tSNP efficacy may be 9% higher than the true value. We describe a novel method for estimating tSNP efficacy accounting for limited sample size. The method is based on exclusion of haplotypes, incorporating a previous adjustment for insufficient marker density. We show that this method outperforms an existing Bootstrap approach. We compare the efficacy of multimarker and pairwise tSNP selection methods on real data. These confirm our findings with simulated data and suggest that pairwise methods are less sensitive to sample size, but more sensitive to marker density. We conclude that a combination of insufficient sample size and overfitting may cause overestimation of tSNP efficacy and underpowering of studies based on tSNPs. Our novel method corrects much of this bias and is superior to a previous method. However, sample sizes larger than previously suggested may be required for accurate estimation of tSNP efficacy. This has obvious ramifications for tSNP selection both in candidate regions and using HapMap or SNP chips for genomewide studies. Genet. Epidemiol. 31, 2007. © 2007 Wiley-Liss, Inc. [source] Interactions between TLR7 and TLR9 agonists and receptors regulate innate immune responses by astrocytes and microglia,GLIA, Issue 6 2010Niranjan B. Butchi Abstract Toll-like receptors 7 (TLR7) and 9 (TLR9) are important mediators of innate immune responses. Both receptors are located in endosomal compartments, recognize nucleic acids, and signal via Myeloid differentiation factor 88 (MyD88). In the current study, we analyzed TLR7 and TLR9 induced activation of astrocytes and microglia, two cell types that contribute to innate immune responses in the CNS. TLR7 and TLR9 agonists induced similar cytokine profiles within each cell type. However, there were notable differences in the cytokine profile between astrocytes and microglia, including the production of the anti-inflammatory cytokine IL-10 and antiapoptotic cytokines G-CSF and IL-9 by microglia but not astrocytes. Costimulation studies demonstrated that the TLR7 agonist, imiquimod, could inhibit TLR9 agonist-induced innate immune responses, in both cell types, in a concentration-dependent manner. Surprisingly, this inhibition was not mediated by TLR7, as deficiency in TLR7 did not alter suppression of the TLR9 agonist-induced responses. The suppression of innate immune responses was also not due to an inhibition of TLR9 agonist uptake. This suggested that imiquimod suppression may be a direct effect, possibly by blocking CpG-ODN binding and/or signaling with TLR9, thus limiting cell activation. An antagonistic relationship was also observed between the two receptors in microglia, with TLR7 deficiency resulting in enhanced cytokine responses to CpG-ODN stimulation. Thus, both TLR7 and its agonist can have inhibitory effects on TLR9-induced cytokine responses in glial cells. © 2009 Wiley-Liss, Inc. [source] Social deprivation and the outcomes of crisis resolution and home treatment for people with mental health problems: a historical cohort studyHEALTH & SOCIAL CARE IN THE COMMUNITY, Issue 5 2010Richard Kingsford BA (Hons) MA DipSW MSc Abstract The development of crisis resolution and home treatment (CRHT) teams has been central to the UK Government's objective of reducing reliance on hospital-based care and is supported by a growing body of evidence. However, there has been no research specifically exploring the relationship between social deprivation and CRHT teams, in spite of evidence of an association between social deprivation and increased pressure on inpatient services. This article reports a study which tested the hypothesis that social deprivation is associated with the outcome of CRHT interventions. Using a historical cohort study design, we examined a total of 260 accepted referrals to a CRHT. Social deprivation was measured by the Index of Multiple Deprivation (Office of the Deputy Prime Minister 2004) as a predictor of CRHT interventions outcomes. CRHT outcomes were dichotomised into successful and unsuccessful and were defined with reference to the CRHT operational policy. Univariate analysis found that people who lived in more socially deprived areas had a poorer outcome, as did older people and those referred from the enhanced community mental health team (CMHT). Logistic regression analysis found that age and referral source were independently associated with outcome. Analysis of the demographic data also suggested a non-significant trend towards men having less successful outcomes. Further analysis exploring the characteristics of the different referral sources to the CRHT found that those referred from the enhanced CMHT were significantly more likely to be from the most deprived area. This suggested a relationship between an enhanced level of mental health need, social deprivation and poor outcome of CRHT intervention. [source] CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice,HEPATOLOGY, Issue 4 2010Tomonori Aoyama Chronic liver disease is associated with hepatocyte injury, inflammation, and fibrosis. Chemokines and chemokine receptors are key factors for the migration of inflammatory cells such as macrophages and noninflammatory cells such as hepatic stellate cells (HSCs). The expression of CX3CR1 and its ligand, CX3CL1, is up-regulated in chronic liver diseases such as chronic hepatitis C. However, the precise role of CX3CR1 in the liver is still unclear. Here we investigated the role of the CX3CL1-CX3CR1 interaction in a carbon tetrachloride (CCl4),induced liver inflammation and fibrosis model. CX3CR1 was dominantly expressed in Kupffer cells in the liver. In contrast, the main source of CX3CL1 was HSCs. Mice deficient in CX3CR1 showed significant increases in inflammatory cell recruitment and cytokine production [including tumor necrosis factor , (TNF-,); monocyte chemoattractant protein 1; macrophage inflammatory protein 1,; and regulated upon activation, normal T cell expressed, and secreted (RANTES)] after CCl4 treatment versus wild-type (WT) mice. This suggested that CX3CR1 signaling prevented liver inflammation. Kupffer cells in CX3CR1-deficient mice after CCl4 treatment showed increased expression of TNF-, and transforming growth factor , and reduced expression of the anti-inflammatory markers interleukin-10 (IL-10) and arginase-1. Coculture experiments showed that HSCs experienced significantly greater activation by Kupffer cells from CCl4 -treated CX3CR1-deficient mice versus WT mice. Indeed, augmented fibrosis was observed in CX3CR1-deficient mice versus WT mice after CCl4 treatment. Finally, CX3CL1 treatment induced the expression of IL-10 and arginase-1 in WT cultured Kupffer cells through CX3CR1, which in turn suppressed HSC activation. Conclusion: The CX3CL1-CX3CR1 interaction inhibits inflammatory properties in Kupffer cells/macrophages and results in decreased liver inflammation and fibrosis. (Hepatology 2010) [source] A role for the pregnane X receptor in flucloxacillin-induced liver injury,HEPATOLOGY, Issue 5 2010Elise Andrews Drug-induced liver injury (DILI) due to flucloxacillin is a rare but serious complication of treatment. There is some evidence that flucloxacillin is a human pregnane X receptor (PXR) agonist. This study was designed to investigate the relevance of PXR to flucloxacillin toxicity and to identify genes changing in expression in response to flucloxacillin. Changes in gene expression in human hepatocytes after treatment with 500 ,M flucloxacillin for 72 hours were examined by expression microarray analysis. The ability of flucloxacillin to act as a PXR agonist was investigated with reporter gene experiments. Flucloxacillin DILI cases (n = 51), drug-exposed controls without toxicity (n = 64), and community controls (n = 90) were genotyped for three common PXR polymorphisms. Luciferase reporter assays were used to assess the significance of a promoter region PXR polymorphism. Seventy-two probe sets representing 50 different genes showed significant changes in expression of 1.2-fold or higher. Most genes showing changes greater than 3-fold were known to be rifampicin-responsive, and this suggested a PXR-dependent mode of regulation. Using a luciferase-everted repeat separated by 6 base pairs element construct, we confirmed that flucloxacillin was a PXR agonist. We found a difference in the distribution of a PXR polymorphism (rs3814055; C-25385T) between flucloxacillin DILI cases and controls with the CC genotype associated with an increased risk of disease (odds ratio = 3.37, 95% confidence interval = 1.55-7.30, P = 0.0023). Reporter gene experiments showed lower promoter activity for the C allele than the T allele. Conclusion: Flucloxacillin is a PXR agonist at pharmacologically relevant concentrations, and a functionally significant upstream PXR polymorphism is a risk factor for flucloxacillin-induced DILI. Hepatology 2010 [source] Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines,HEPATOLOGY, Issue 4 2008Arnhild Schrage Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells (LSEC) inhibit or support the chemokine-driven transmigration and differentially influence the transmigration of pro-inflammatory or anti-inflammatory CD4+ T cells, indicating a mechanism of hepatic immunoregulation. Finally, the results shed light on the molecular mechanisms by which LSEC modulate chemokine-dependent transmigration. LSEC significantly enhanced the chemotactic effect of CXC-motif chemokine ligand 12 (CXCL12) and CXCL9, but not of CXCL16 or CCL20, on naive and memory CD4+ T cells of a T helper 1, T helper 2, or interleukin-10,producing phenotype. In contrast, brain and lymphatic endothelioma cells and ex vivo isolated lung endothelia inhibited chemokine-driven transmigration. As for the molecular mechanisms, chemokine-induced activation of LSEC was excluded by blockage of Gi -protein,coupled signaling and the use of knockout mice. After preincubation of CXCL12 to the basal side, LSEC took up CXCL12 and enhanced transmigration as efficiently as in the presence of the soluble chemokine. Blockage of transcytosis in LSEC significantly inhibited this effect, and this suggested that chemokines taken up from the basolateral side and presented on the luminal side of endothelial cells trigger T cell transmigration. Conclusion: Our findings demonstrate a unique capacity of LSEC to present chemokines to circulating lymphocytes and highlight the importance of endothelial cells for the in vivo effects of chemokines. Chemokine presentation by LSEC could provide a future therapeutic target for inhibiting lymphocyte immigration and suppressing hepatic inflammation. (HEPATOLOGY 2008.) [source] The potential role of ER, isoforms in the clinical management of breast cancerHISTOPATHOLOGY, Issue 4 2008C A Green The discovery of a second oestrogen receptor, ER,, was a subject of much interest, as this suggested a means to improve the prognostic stratification of invasive breast cancer, better predict response to endocrine therapy, develop new chemotherapeutic/chemopreventative drugs and perhaps prevent inappropriate treatment. However, this has not proved to be straightforward with the discovery of five ER, isoforms and numerous exon deletion variants. This review sets out to identify the present state of knowledge regarding the clinicopathological role of ER, isoforms and discusses possible reasons for conflicting results arising from recent research findings. [source] Functional analysis of promoter variants in the microsomal triglyceride transfer protein (MTTP) gene,HUMAN MUTATION, Issue 1 2008Diana Rubin Abstract The microsomal triglyceride transfer protein (MTTP) is required for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins from the intestine and liver. According to this function, polymorphic sites in the MTTP gene showed associations to low-density lipoprotein (LDL) cholesterol and related traits of the metabolic syndrome. Here we studied the functional impact of common MTTP promoter polymorphisms rs1800804:T>C (,164T>C), rs1800803:A>T (,400A>T), and rs1800591:G>T (,493G>T) using gene-reporter assays in intestinal Caco-2 and liver Huh-7 cells. Significant results were obtained in Huh-7 cells. The common MTTP promoter haplotype ,164T/,400A/,493G showed about two-fold lower activity than the rare haplotype ,164C/,400T/,493T. MTTP promoter mutant constructs ,164T/,400A/,493T and ,164T/,400T/,493T exhibited similar activity than the common haplotype. Activities of mutants ,164C/,400A/,493G and ,164C/,400A/,493T resembled the rare MTTP promoter haplotype. Electrophoretic mobility shift assays (EMSAs) revealed higher binding capacity of the transcriptional factor Sterol regulatory element binding protein1a (SREBP1a) to the ,164T probe in comparison to the ,164C probe. In conclusion, our study indicates that the polymorphism ,164T>C mediates different activities of common MTTP promoter haplotypes via SREBP1a. This suggested that the already described SREBP-dependent modulation of MTTP expression by diet is more effective in ,164T than in ,164C carriers. Hum Mutat 29(1), 123,129, 2008. © 2007 Wiley-Liss, Inc. [source] Lost in translation: exploring the link between HRM and performance in healthcareHUMAN RESOURCE MANAGEMENT JOURNAL, Issue 1 2007Timothy Bartram Using data collected in 2004 from 132 Victorian (Australia) public healthcare providers, comprising metropolitan and regional hospital networks, rural hospitals and community health centres, we investigated the perceptions of HRM from the experiences of chief executive officers, HR directors and other senior managers. We found some evidence that managers in healthcare organisations reported different perceptions of strategic HRM and a limited focus on collection and linking of HR performance data with organisational performance management processes. Using multiple moderator regression and multivariate analysis of variance, significant differences were found in perceptions of strategic HRM and HR priorities between chief executive officers, HR directors and other senior managers in the large organisations. This suggested that the strategic human management paradigm is ,lost in translation', particularly in large organisations, and consequently opportunities to understand and develop the link between people management practices and improved organisational outcomes may be missed. There is some support for the relationship between strategic HRM and improved organisational outcomes. Implications of these findings are drawn for managerial practice. [source] Evaluation of spatial variability in snow water equivalent for a high mountain catchmentHYDROLOGICAL PROCESSES, Issue 3 2004S. P. Anderton Abstract Multivariate statistical analysis was used to explore relationships between catchment topography and spatial variability in snow accumulation and melt processes in a small headwater catchment in the Spanish Pyrenees. Manual surveys of snow depth and density provided information on the spatial distribution of snow water equivalent (SWE) and its depletion over the course of the 1997 and 1998 melt seasons. A number of indices expressing the topographic control on snow processes were extracted from a detailed digital elevation model of the catchment. Bivariate screening was used to assess the relative importance of these topographic indices in controlling snow accumulation at the start of the melt season, average melt rates and the timing of snow disappearance. This suggested that topographic controls on the redistribution of snow by wind are the most important influence on snow distribution at the start of the melt season. Furthermore, it appeared that spatial patterns of snow disappearance were largely determined by the distribution of snow water equivalent (SWE) at the start of the melt season, rather than by spatial variability in melt rates during the melt season. Binary regression tree models relating snow depth and disappearance date to terrain indices were then constructed. These explained 70,80% of the variance in the observed data. As well as providing insights into the influence of topography on snow processes, it is suggested that the techniques presented herein could be used in the parameterization of distributed snowmelt models, or in the design of efficient stratified snow surveys. Copyright © 2003 John Wiley & Sons, Ltd. [source] Diagnosing the environmental causes of the decline in Grey Partridge Perdix perdix survival in FranceIBIS, Issue 1 2001ELISABETH BRO We studied Grey Partridge Perdix perdix mortality during breeding to identify the environmental causes of a long-term decline in adult survival. We radiotagged and monitored daily from mid-March to mid-September 1009 females on ten contrasting study sites in 1995-97. Simultaneously, we recorded habitat features and estimated the abundance of Hen and Marsh Harriers Circus cyaneus and C. aeruginosus Red Fox Vulpes vulpes and mustelids. We experimentally tested whether scavenging could have biased predation rates. We also examined, through the necropsy of 80 carcasses of Grey Partridge, whether disease, parasites or poisoning could have been ultimate causes of high predation rates. The survival rate of radiotagged females during spring and summer ranged from 0.25 to 0.65 across study areas. Mortality peaked in May, June and July when females were laying and incubating. The direct negative impact of farming practices was low (6%). Predation was the main proximate cause of female mortality during breeding (73%) and determined the survival rate, suggesting no compensation by other causes of mortality. Ground carnivores were responsible for 64% of predation cases, and raptors for 29%, but this proportion varied across study sites. Disease and poisoning did not appear to favour predation, and scavenging was not likely to have substantially overestimated predation rates. The predation rate on breeding females was positively correlated with the abundance of Hen and Marsh Harriers, suggesting an additional mortality in areas where harriers were abundant. The proportion of raptor predation was linearly related to harrier abundance. The predation rate was not correlated with the abundance of the Red Fox and mustelids. A potential density-dependent effect on the predation rate was confounded by the abundance of harriers. We found no convincing relationship between the predation rate and habitat features, but we observed a positive relationship between the abundance of Hen and Marsh Harriers and the mean field size. This suggested that habitat characteristics may contribute to high predation rates through predator abundance or habitat-dependent predation. [source] Development of chromatic induction in infancyINFANT AND CHILD DEVELOPMENT, Issue 6 2007Hiromi Okamura Abstract The perception of colour in an embedded field is affected by the surround colour. This phenomenon is known as chromatic induction. In the present study we investigated whether the colour perception by infants aged 5,7 months could be affected by the surround colour. In Experiments 1 and 2 each stimulus was composed of an array of six squares in tandem. The colour appearance of the array in the familiarization stimulus was established by chromatic induction. In Experiment 1 we used familiarization stimuli that were perceived as two-colour array with a two-colour surround. In Experiment 2 we used a familiarization stimulus that was perceived as a uniform-colour array with a two-colour surround. In the test phase, the uniform-colour array and the two-colour array were presented on a white uniform-colour surround in both experiments. The results showed that in Experiment 1 the 5- and 7-month-old infants had novelty preference for the uniform-colour test array. This suggested that the infants' colour perception could be affected by surround colour. The results of Experiment 2 showed that the 7-month-olds showed a novelty preference for the two-colour test array, but the 5-month-olds showed no novelty preference. This suggested that 7-month-olds' colour perception could be affected by surround colour, but that of 5-month-olds could not. We discuss the contradiction of the results between Experiments 1 and 2. Copyright © 2007 John Wiley & Sons, Ltd. [source] Chronic hypothyroidism only marginally affects adult-type Leydig cell regeneration after EDS administrationINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 1 2010Eddy Rijntjes Summary Chronic prenatally induced dietary hypothyroidism delays adult-type Leydig cell development, but does not block this process. Using a chemical model to induce hypothyroidism, it was suggested that development of a new population of Leydig cells was completely inhibited following the addition of the cytotoxic compound ethane-1,2-dimethyl sulphonate (EDS). In this study, we used a dietary approach to induce hypothyroidism and reinvestigated the regeneration of the Leydig cell population following EDS administration. Eighty-four day old euthyroid and chronically hypothyroid rats received an injection of EDS and were killed directly before or at regular intervals up to 77 days after EDS. In some control and hypothyroid animals, the first progenitor-type Leydig cells were observed at day 12 after EDS. At day 16, Leydig cell progenitors were present in all rats. The percentage of proliferating Leydig cells peaked in the euthyroid animals at day 21 after EDS. In the hypothyroid testis such a peak was not observed, although the percentage of proliferating regenerating Leydig cells was significantly higher from days 35 to 56 compared with the controls. This suggested that the wave of Leydig cell proliferation was delayed in the hypothyroid animals as compared with the euthyroid controls. On the day of EDS injection, the Leydig/Sertoli cell ratio was 37% lower in the hypothyroid rats compared with the controls. The Leydig/Sertoli cell ratio remained lower in the EDS-treated hypothyroid animals compared with the controls at all time points investigated. At day 77 after EDS, the Leydig cell population had returned to its pre-treatment size in both groups. Plasma testosterone production was reduced to below detectable levels immediately after EDS injection, and started to increase again on day 16, reaching pre-treatment values on day 21 in both groups. Taken together, severely reduced thyroid hormone levels did not block the regeneration of the adult-type Leydig cell population following EDS, as has been suggested previously. [source] PPAR, and PP2A are involved in the proapoptotic effect of conjugated linoleic acid on human hepatoma cell line SK-HEP-1INTERNATIONAL JOURNAL OF CANCER, Issue 11 2007Giuliana Muzio Abstract Conjugated linoleic acid (CLA), found in dairy products, in beef and lamb has been demonstrated to possess anticancer properties protecting several tissues from developing cancer. Moreover, it has been shown to modulate apoptosis in several cancer cell lines. The aim of this study was to investigate which signaling transduction pathways were modulated in CLA-induced apoptosis in human hepatoma SK-HEP-1 cells. The cells exposed to CLA were evaluated for PPAR,, PP2A, pro-apoptotic proteins Bak, Bad and caspases, and anti-apoptotic proteins Bcl-2 and Bcl-XL. Cells were also treated with okadaic acid, a PP2A inhibitor, or with Wy-14643, a specific PPAR, agonist. The CLA-induced apoptosis was concomitant to the increase of percentage of cells in the S phase, PPAR,, PP2A and pro-apoptotic proteins; simultaneously, antiapoptotic proteins decreased. Inhibition of PP2A prevented apoptosis, and PPAR, agonist showed similar effect as CLA. The increased PP2A could be responsible for the dephosphorylation of Bcl-2 and Bad, permitting apoptotic activity of Bax and Bad. The increase of caspase 8 and 9 suggested that both the intrinsic and extrinsic apoptotic pathways were induced. PP2A was probably increased by PPAR,, since putative PPRE sequences were found in genes encoding its subunits. In conclusion, CLA induces apoptosis in human hepatoma SK-HEP-1 cells, by increasing PPAR,, PP2A and pro-apoptotic proteins. © 2007 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||||||||||||||