A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Background

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties by gene expression profile. Lamb et al first proposed the Connectivity Map [Lamb et al (2006), Science 313, 1929–1935] to make successful connections among small molecules, genes, and diseases using genomic signatures.

Results

Here we have built on the principles of the Connectivity Map to present a simpler and more robust method for the construction of reference gene-expression profiles and for the connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with two randomly generated gene signatures and three experimentally derived gene signatures (for HDAC inhibitors, estrogens, and immunosuppressive drugs, respectively). Our testing with this method indicates that it achieves a higher level of specificity and sensitivity and so advances the original method.

Conclusion

The method presented here not only offers more principled statistical procedures for testing connections, but more importantly it provides effective safeguard against false connections at the same time achieving increased sensitivity. With its robust performance, the method has potential use in the drug development pipeline for the early recognition of pharmacological and toxicological properties in chemicals and new drug candidates, and also more broadly in other 'omics sciences.

Expression of the counter-regulatory peptide intermedin is augmented in the presence of oxidative stress in hypertrophied cardiomyocytes.

Background: Intermedin (IMD), a novel cardiac peptide related to adrenomedullin (AM), protects against myocardial ischemia-reperfusion injury and attenuates ventricular remodelling. IMD’s actions are mediated by a calcitonin receptor-like receptor in association with receptor activity modifying proteins (RAMPs 1-3). Aim/method: using the spontaneously hypertensive rat (SHR) and normotensive Wistar Kyoto (WKY) rat at 20 weeks of age, to examine (i) the presence of myocardial oxidative stress and concentric hypertrophy; (ii) expression of IMD, AM and receptor components. Results: In left and right ventricular cardiomyocytes from SHR vs. WKY cell width (26% left, 15% right) and mRNA expression of hypertrophic markers ANP (2.7 fold left, 2.7 fold right) and BNP (2.2 fold left, 2.0 fold right) were enhanced. In left ventricular cardiomyocytes only (i) oxidative stress was indicated by increased membrane protein carbonyl content (71%) and augmented production of O2- anion (64%); (ii) IMD (6.8 fold), RAMP1 (2.5 fold) and RAMP3 (2.0 fold) mRNA was increased while AM and RAMP2 mRNA was not altered; (iii) abundance of RAMP1 (by 48%), RAMP2 (by 41%) and RAMP3 (by 90%) monomers in cell membranes was decreased. Conclusion: robust augmentation of IMD expression in hypertrophied left ventricular cardiomyocytes indicates a prominent role for this counter-regulatory peptide in the adaptation of the SHR myocardium to the stresses imposed by chronic hypertension. The local concentration and action of IMD may be further enhanced by down-regulation of NEP within the left ventricle.

Evaluation of the Q-method as a method of public participation in the selection of sustainable development indicators

The complexity of sustainable development means that it is often difficult to evaluate and communicate the concept effectively. One standard method to reduce complexity and improve Communication, while maintaining scientific objectivity, is to use selected indicators. The aim of this paper is to describe and evaluate a process Of public participation in the selection of sustainable development indicators that utilised the Q-method for discourse analysis. The Q-method was Utilised to combine public opinion with technical expertise to create a list of technically robust indicators that would be relevant to the public, The method comprises statement collection, statement analysis, Q-sorts and Q-sort analysis. The results of the Q-method generated a list of statements for which a preliminary list of indicators was then developed by a team of experts from the fields of environmental science, sustainable development and Psychology. Subsequently members of the public evaluated the preliminary list of indicators, to select a final list of indicators that were both technically sound and incorporated the views of the public. The Utilisation of the Q-method in this process was evaluated using previously published criteria. The application of the Q-method in this context needs to be considered not only by the quality of the indicators developed, but also from the perspective of the benefit of the process to the participants. it was concluded that the Q-method provided an effective framework for public participation in the selection of indicators as it allowed the public to discuss Sustainable development in familiar language and in the context of their daily lives. By combining this information with expert input, a list of technically robust indicators that resonate with the public was developed. The results demonstrated that many citizens are not aware Of Sustainable development, and if it is to be successfully communicated to them, then indicators and policy need to be couched in terms familiar and relevant to citizen and communities. (C) 2009 Elsevier Ltd. All rights reserved.

The effect of increased dietary fruit and vegetable consumption on endothelial activation, inflammation and oxidative stress in hypertensive volunteers

Background and aims

Public health campaigns recommend increased fruit and vegetable (FV) consumption as an effective means of cardiovascular risk reduction. During an 8 week randomised control trial among hypertensive volunteers, we noted significant improvements in endothelium-dependent vasodilatation with increasing FV consumption. Circulating indices of inflammation, endothelial activation and insulin resistance are often employed as alternative surrogates for systemic arterial health. The responses of several such biomarkers to our previously described FV intervention are reported here.
Methods and results

Hypertensive volunteers were recruited from medical outpatient clinics. After a common 4 week run-in period during which FV consumption was limited to 1 portion per day, participants were randomised to 1, 3 or 6 portions daily for 8 weeks. Venous blood samples for biomarker analyses were collected during the pre and post-intervention vascular assessments. A total of 117 volunteers completed the 12 week study. Intervention-related changes in circulating levels of high sensitivity C-reactive protein (hsCRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) did not differ significantly between FV groups. Similarly, there were no significant between group differences of change in homeostasis model assessment (HOMA) scores.
Conclusions

Despite mediating a significant improvement in acetylcholine induced vasodilatation, increased FV consumption did not affect a calculated measure of insulin resistance or concentrations of the circulating biomarkers measured during this study. Functional indices of arterial health such as endothelium-dependent vasomotion are likely to provide more informative cardiovascular end-points during short-term dietary intervention trials.

Effective collision strengths for transitions of Ni XVII

Electron impact excitation collision strengths are required for the analysis and interpretation of stellar observations. This calculation aims to provide fine structure effective collision strengths for the Ni XVII ion using a method which includes contributions from resonances. A DARC calculation has been performed, involving 37 J pi states. The effective collision strengths are calculated by averaging the electron collision strengths over a Maxwellian distribution of electron velocities. The non-zero effective collision strengths for transitions between the fine structure levels are given for electron temperatures (T(e)) in the range log(10) T(e)(K) = 4.5 - 8.5. Data for several transitions from the ground state are discussed in this paper.

Effective collision strengths for electron-impact excitation of S X

Effective collision strengths computed by the R-matrix method are presented for the electron-impact excitation of nitrogen-like S X. The total wave function used in the expansion includes the lowest 11 eigenstates of S X which arise from the 2s(2)2p(3), 2s2p(4), 2p(5) and 2s(2)2p(2)3s configurations. These 11 LS target states correspond to 22 fine-structure levels, giving 231 possible transitions. All the effective collision strengths for these transitions are tabulated in the range log T(K) = 4.6 to log T(K) = 6.7. The energy level values and oscillator strengths for allowed transitions are also tabulated. The effective collision strengths were calculated by averaging the electron collision strengths over a Maxwellian distribution of velocities. The present effective collision strengths are the only results currently available for these fine-structure transition rates. (C) 2000 Academic Press.

Dealing with post-traumatic stress disorder: The psychological sequelae of bloody Sunday and the response of state services

Objective: This article describes the political context of health and social care services in Northern Ireland at a the of intense social conflict. Method: Concepts from post-traumatic stress disorder (PTSD) and other relevant international psychological literature are then used to study the experience of the Bloody Sunday families, victims of a traumatic event that happened in Derry in January 1972. Results: High levels of psychological morbidity within this population are reported, alongside some evidence that families had not received services that may have helped resolve the trauma. Conclusions: The authors noted that new services planned as a result of the current peace process may offer social workers and other professionals new ways to address the unmet needs of people traumatized by the Troubles.

The health of children with cerebral palsy and stress in their parents

Aim.  This paper is a report of a study conducted to describe the health of children with cerebral palsy and investigate predictors of stress in their parents. Background.  Children with severe cerebral palsy tend to have poorer health than their able-bodied peers, and their parents are more likely to be stressed and have poorer health. Method.  A cross-sectional survey with home visits using standard questionnaires was administered to parents in 2004–05. A total of 102/199 (51%) children and parents participated. The children were compared with a normative sample. Results.  Children with cerebral palsy had poorer physical health, and 79% of parents reported that their child had moderate to severe pain. Their poorer health, in comparison with the normal sample and measured by the Child Health Questionnaire, was related to feeding problems and seizures, general health perceptions to intellectual and feeding impairment, and family activities with severe motor, intellectual and feeding impairment. Poorer psychological well-being on the hyperactivity domain of the Strengths & Difficulties Questionnaire was related to feeding difficulties, on the prosocial domain to more severe forms of all child impairments, and on the social impairment scale to intellectual impairment. Children with psychological problems had statistically significantly increased odds (OR = 7·2, 95% CIs 2·6–20·3) of having parents with high stress. Conclusion.  Children with cerebral palsy and associated impairments are at higher risk of poorer health and family well-being. A family-centred approach to the care of children with cerebral palsy and their families is essential to ensure both receive adequate care and support.

Evaluation of effective groundwater recharge of freshwater lens in small islands by the combined modeling of geoelectrical data and water heads

In small islands, a freshwater lens can develop due to the recharge induced by rain. Magnitude and spatial distribution of this recharge control the elevation of freshwater and the depth of its interface with salt water. Therefore, the study of lens morphology gives useful information on both the recharge and water uptake due to evapotranspiration by vegetation. Electrical resistivity tomography was applied on a small coral reef island, giving relevant information on the lens structure. Variable density groundwater flow models were then applied to simulate freshwater behavior. Cross validation of the geoelectrical model and the groundwater model showed that recharge exceeds water uptake in dunes with little vegetation, allowing the lens to develop. Conversely, in the low-lying and densely vegetated sectors, where water uptake exceeds recharge, the lens cannot develop and seawater intrusion occurs. This combined modeling method constitutes an original approach to evaluate effective groundwater recharge in such environments.
[Comte, J.-C., O. Banton, J.-L. Join, and G. Cabioch (2010), Evaluation of effective groundwater recharge of freshwater lens in small islands by the combined modeling of geoelectrical data and water heads, Water Resour. Res., 46, W06601, doi:10.1029/2009WR008058.]

Stress, coping and satisfaction in nursing students

Aim. This article is a report of a study conducted to explore the relationship between sources of stress and psychological well-being and to consider how different sources of stress and coping resources might function as moderators and mediators on well-being.


Background. In most research exploring sources of stress and coping in nursing students, stress has been construed as psychological distress. Sources of stress likely to enhance well-being and, by implication, learning have not been considered.


Method. A questionnaire was administered to 171 final year nursing students in 2008. Questions were asked to measure sources of stress when rated as likely to contribute to distress (a hassle) and rated as likely to help one achieve (an uplift). Support, control, self-efficacy and coping style were also measured, along with their potential moderating and mediating effects on well-being, operationalized using the General Health Questionnaire and measures of course and career satisfaction.


Findings. Sources of stress likely to lead to distress were more often predictors of well-being than were sources of stress likely to lead to positive, eustress states, with the exception of clinical placement demands. Self-efficacy, dispositional control and support were important predictors, and avoidance coping was the strongest predictor of adverse well-being. Approach coping was not a predictor of well-being. The mere presence of support appeared beneficial as well as the utility of that support to help a student cope.


Conclusion. Initiatives to promote support and self-efficacy are likely to have immediate benefits for student well-being. In course reviews, nurse educators need to consider how students’ experiences might contribute not just to potential distress, but to eustress as well.

Residual stress due to curing can initiate damage in porous bone cement: experimental and theoretical evidence

Residual stress due to shrinkage of polymethylmethacrylate bone cement after polymerisation is possibly one factor capable of initiating cracks in the mantle of cemented hip replacements. No relationship between residual stress and observed cracking of cement has yet been demonstrated. To investigate if any relationship exists, a physical model has been developed which allows direct observation of damage in the cement layer on the femoral side of total hip replacement. The model contains medial and lateral cement layers between a bony surface and a metal stem; the tubular nature of the cement mantle is ignored. Five specimens were prepared and examined for cracking using manual tracing of stained cracks, observed by transmission microscopy: cracks were located and measured using image analysis. A mathematical approach for the prediction of residual stress due to shrinkage was developed which uses the thermal history of the material to predict when stress-locking occurs, and estimates subsequent thermal stress. The residual stress distribution of the cement layer in the physical model was then calculated using finite element analysis. Results show maximum tensile stresses normal to the observed crack directions, suggesting a link between residual stress and preload cracking. The residual stress predicted depends strongly on the definition of the reference temperature for stress-locking. The highest residual stresses (4-7 MPa) are predicted for shrinkage from maximum temperature, in this case, magnitudes are sufficiently high to initiate cracks when the influence of stress raisers such as pores or interdigitation at the bone/cement interface are taken into account (up to 24 MPa when calculating stress around a pore according to the method of Harrigan and Harris (J. Biomech. 24(11) (1991) 1047-1058)). We conclude that the damage accumulation failure scenario begins before weight-bearing due to cracking induced by residual stress around pores or stress raisers. (C) 2002 Elsevier Science Ltd. All rights reserved.

Parenting stress and children with cerebral palsy: A European cross-sectional survey

Aim
The aim of this study was to describe stress in the parents of children with cerebral palsy and investigate associations with very high stress.

Method
A cross-sectional survey was conducted of parents of 818 children aged 8 to 12 years from nine regions in Europe. Families were eligible to participate if they were living in one of the specified geographic areas. Parental stress was captured using the Parenting Stress Index Short Form, which has 36 items and takes 10 minutes to complete. Parents rate items on a 5-point Likert scale, with higher scores indicating higher stress. The Short Form yields scores on three subscales and a Total Stress score. A trained research associate administered the questionnaire in the child’s home and visits lasted 90 to 120 minutes. All data collected were reported by parents unless otherwise stated.

Results
The Total Stress score on the Parenting Stress Index was dichotomized into scores of less than 99 or 99 or more, the latter indicating ‘very high’ stress. Most respondents were mothers (94%), and 26% reported very high stress levels. The parents of children with communication impairment had higher odds for very high stress (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.2–3.0) than those whose child had no such impairment; the parents of children with moderate or severe pain had higher odds for very high stress (OR 1.7 [95% CI 1.1–2.4] and 2.5 [95% CI 1.5–4.3] respectively) than those whose child had no pain; and the parents of children with an intellectual impairment had higher odds for very high stress (OR 1.8; 95% CI 1.2–2.9) than those whose child had none. There was no association between very high stress and motor impairment. The subscales ‘parent–child dysfunctional interaction’ and ‘difficult child’ contributed most to the Total Stress score.

Interpretation
Parents of children with communication difficulties, intellectual impairment, or pain are at very high risk of stress. The final model explained 12% of the observed variation in very high stress.

The development of a rapid immunobiosensor screening method for the detection of residues of sulphadiazine

A rapid imununoassay using an optical biosensor (BIAcore(TM)) for determining the presence of sulphadiazine (SDZ) residues in pig bile was developed. SDZ,cas immobilised onto the surface of a dextran-coated silicon chip and a solution containing SDZ antibody, sample and buffer was injected over the chip surface. The level of antibody binding to the chip was determined after 20 s and the surface of the chip was then regenerated over a 1-min period prior to another sample injection taking place. Standard curves were constructed to allow quantification of SDZ presence in sample. Concentrations ranging from 0 to 10.64 mu g ml(-1) SDZ were detected in bile samples taken from experimentally fed pigs and randomly selected pigs taken from a local slaughterhouse. These results were compared to the concentrations of SDZ detected by high-performance liquid chromatography: in associated tissues. When concentrations in bile exceeded 0.6 mu g ml(-1) SDZ, the corresponding edible tissue was above the maximum residue level (MRL), i.e. 0.1 mu g g(-1) in 13 out of 14 cases. Wizen the bile concentration was less than 0.6 mu ml(-1) the associated tissue concentrations never exceeded rite MRL. This experiment has indicated that biosensor analysis of bile is a highly effective method for detecting violative SDZ residues in meat.

Investigation of the effect of the preparation method on the activity and stability of Au/CeZrO4 catalysts for the low temperature water gas shift reaction

The impact of the preparation method on the activity and stability of gold supported on ceria-zirconia low temperature water-gas shift (WGS) catalysts have been investigated. The influence of the gold deposition method, nature of the gold precursor, nature of the washing solution, drying method, Ce: Zr ratio of the support and sulfation of the support have been evaluated. The highest activity catalysts were obtained using a support with a Ce: Zr mole ratio 1: 1, HAuCl4 as the gold precursor deposited via deposition precipitation using sodium carbonate as the precipitation agent and the catalyst washed with water or 0.1 M NH4OH solution. In addition, the drying used was found to be critical with drying under vacuum at room temperature found to be most effective.

Predicting die life from die temperature for high pressure dies casting

The objective of this research was to determine the surface temperature of a high pressure die casting die during casting conditions. This was achieved by instrumentation of an insert which was placed in the shotplate region of the die. This research overcame the challenge of directly measuring the die surface temperature during a HPDC production casting cycle and shows that this is an effective method to determine the die surface temperature during the casting cycle. The instrumentation results gave a peak and minimum temperature of 500 C and 240 C respectively during steady state running conditions with a molten aluminium casting temperature of 660 C. Stress analysis from the steady state measured temperature of the die surface was calculated through a simple FEA model and the resulting stress uctuation was applied to a fatigue equation for the die material, the predicted number of cycles for cracking to start was found to correlate well with observed die damage.