Safe fabrication of sharp gold tips for light emission in scanning tunnelling microscopy

Gold is the optimal tip metal for light emission in scanning tunnelling microscopy (LESTM) under ambient conditions. Sharp Au-tips of similar to 10nm radius were produced reliably using a safe, two-step etching method in 20% (w/w) CaCl2 solution. Previous CaCl2-based methods have tended to produce blunter tips, while other etching techniques that do produce sharp Au-tips, do so with the use of toxic or hazardous electrolytes. The tips are characterised using scanning electron microscopy and their efficacy in LESTM is evidenced by high-resolution, simultaneous topographic and photon mapping of Au(1 1 1)- and polycrystalline Au-surfaces. Spectra of the optical emission exhibit only one or two peaks with etched tips in contrast to the more complex spectra typical of cut tips; this feature, together with the highly symmetric geometry of the tips, facilitates a definitive analysis of the light emission process. (c) 2007 Elsevier B. V.. All rights reserved.

Child abuse as a complex and wicked problem: Reflecting on policy developments in the United Kingdom in working with children and families with multiple problems

In spite of significant public concern, professional efforts and financial expenditure, there has been a perceived lack of progress in reducing the incidence of child abuse, and in improving the outcomes for children in both the short and longer term. In this article the authors reflect on recent policy developments in the United Kingdom relating to children and families experiencing multiple adversities, and argue that the current conceptualisation of child abuse is flawed. In adopting a rational technical approach to the management of child abuse, there is a tendency to focus on shorter term outcomes for the child, such as immediate safety, that primarily reflect the outputs of the child protection system. However, by viewing child abuse as a wicked problem, that is complex and less amenable to being solved, then child welfare professionals can be supported to focus on achieving longer term outcomes for children that are more likely to meet their needs. The authors argue for an earlier identification of and intervention with children who are experiencing multiple adversity, such as those living with parents misusing substances and exposed to intimate partner violence.

Short interfering RNA-mediated gene silencing in Globodera pallida and Meloidogyne incognita infective stage juveniles

The analysis of gene function through RNA interference (RNAi)-based reverse genetics in plant parasitic nematodes (PPNs) remains inexplicably reliant on the use of long double-stranded RNA (dsRNA) silencing triggers; a practice inherently disadvantageous due to the introduction of superfluous dsRNA sequence. increasing chances of aberrant or off-target gene silencing through interactions between nascent short interfering RNAs (siRNAs) and non-cognate mRNA targets. Recently, we have shown that non-nematode, long dsRNAs have a propensity to elicit profound impacts on the phenotype and migrational abilities of both root knot and cyst nematodes. This study presents, to our knowledge for the first time, gene-specific knockdown of FMRFamide-like peptide (flp) transcripts, using discrete 21 bp siRNAs in potato cyst nematode Globodera pallida, and root knot nematode Meloidogyne incognita infective (J2) stage juveniles. Both knockdown at the transcript level through quantitative (q)PCR analysis and functional data derived from migration assay, indicate that siRNAs targeting certain areas of the FMRFamide-like peptide (FLP) transcripts are potent and specific in the silencing of gene function. In addition, we present a method of manipulating siRNA activity through the management of strand thermodynamics. Initial evaluation of strand thermodynamics as a determinant of RNA-induced Silencing Complex (RISC) strand selection (inferred from knockdown efficacy) in the siRNAs presented here suggested that the purported influence of 5' stand stability on guide incorporation may be somewhat promiscuous. However, we have found that on strategically incorporating base mismatches in the sense strand of a G. pallida-specific siRNA we could specifically increase or decrease the knockdown of its target (specific to the antisense strand), presumably through creating more favourable thermodynamic profiles for incorporation of either the sense (non-target-specific) or antisense (target-specific) strand into a cleavage-competent RISC. Whilst the efficacy of similar approaches to siRNA modification has been demonstrated in the context of Drosophila whole-cell lysate preparations and in mammalian cell cultures, it remained to be seen how these sense strand mismatches may impact on gene silencing in vivo, in relation to different targets and in different sequence contexts. This work presents the first application of such an approach in a whole organism; initial results show promise. (C) 2009 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Willingness to use functional breads. Applying the Health Belief Model across four European countries

The present study focused on the role of the Health Belief Model (HBM) in predicting willingness to use functional breads, across four European countries: UK (N = 552), Italy (N = 504), Germany (N = 525) and Finland (N = 513). The behavioural evaluation components of the HBM (the perceived benefits and barriers conceptualized respectively as perceived healthiness and pleasantness) and the health motivation component were good predictors of willingness to use functional breads whereas threat perception components (perceived susceptibility and perceived anticipated severity) failed as predictors. This result was common in all four countries and across products. The role of 'cue to action' was marginal. On the whole the HBM fit was similar across the countries and products in terms of significant predictors (the perceived benefits, barriers and health motivation) with the exception of self-efficacy which was significant only in Finland. Young consumers seemed more interested in the functional bread with a health claim promoting health rather than in reducing risk of disease, whereas the opposite was true for older people. However, functional staple foods, such as bread in this European study, are still perceived as common foods rather than as a means of avoiding diseases. Consumers seek these foods for their healthiness (the perceived benefits) as they expect them to be healthier than regular foods and for the pleasantness (the perceived barriers) as they do not expect any change in the sensory characteristics due to the addition of the functional ingredients. The importance of health motivation in willingness to use products with health claims implies that there is an opening for developing better models for explaining health-promoting food choices that take into account both food and health-related factors without making a reference to disease-related outcome. (C) 2008 Elsevier Ltd. All rights reserved.

Salbutamol up-regulates matrix metalloproteinase-9 in the alveolar space in the acute respiratory distress syndrome.

Objectives: Acute respiratory distress syndrome (ARDS) is characterized by alveolar-capillary barrier damage. Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of ARDS. In the Beta Agonists in Acute Lung Injury Trial, intravenous salbutamol reduced extravascular lung water (EVLW) in patients with ARDS at day 4 but not inflammatory cytokines or neutrophil recruitment. We hypothesized that salbutamol reduces MMP activity in ARDS.

Methods: MMP-1/-2/-3/-7/-8/-9/-12/-13 was measured in supernatants of distal lung epithelial cells, type II alveolar cells, and bronchoalveolar lavage (BAL) fluid from patients in the Beta Agonists in Acute Lung Injury study by multiplex bead array and tissue inhibitors of metalloproteinases (TIMPs)-1/-2 by enzyme-linked immunosorbent assay. MMP-9 protein and activity levels were further measured by gelatin zymography and fluorokine assay.

Measurements and Main Results: BAL fluid MMP-1/-2/-3 declined by day 4, whereas total MMP-9 tended to increase. Unexpectedly, salbutamol augmented MMP-9 activity. Salbutamol induced 33.7- and 13.2-fold upregulation in total and lipocalin-associated MMP-9, respectively at day 4, compared with 2.0- and 1.3-fold increase in the placebo group, p < 0.03. Salbutamol did not affect BAL fluid TIMP-1/-2. Net active MMP-9 was higher in the salbutamol group (4222 pg/mL, interquartile range: 513-7551) at day 4 compared with placebo (151 pg/mL, 124-2108), p = 0.012. Subjects with an increase in BAL fluid MMP-9 during the 4-day period had lower EVLW measurements than those in whom MMP-9 fell (10 vs. 17 mL/kg, p = 0.004): change in lung water correlated inversely with change in MMP-9, r = -.54, p = 0.0296. Salbutamol up-regulated MMP-9 and down-regulated TIMP-1/-2 secretion in vitro by distal lung epithelial cells. Inhibition of MMP-9 activity in cultures of type II alveolar epithelial cells reduced wound healing.

Conclusions: Salbutamol specifically up-regulates MMP-9 in vitro and in vivo in patients with ARDS. Up-regulated MMP-9 is associated with a reduction in EVLW. MMP-9 activity is required for alveolar epithelial wound healing in vitro. Data suggest MMP-9 may have a previously unrecognized beneficial role in reducing pulmonary edema in ARDS by improving alveolar epithelial healing.

Genetic testing and the relationship between specific and general self-efficacy

The study examined the extent to which variations in health-specific self-efficacy could affect general self-efficacy. In a repeated measures design, 300 participants were administered an efficacy questionnaire, before and after an alleged news report, aimed at increasing or decreasing self-efficacy over genetic-testing decision making. The results found that self-efficacy over testing was significantly reduced after reading the negative news report in those participants who felt personal efficacy over testing decisions was important. Levels of general self-efficacy were also significantly decreased. The findings suggest that being denied control over a specific area of self-efficacy can have a wider impact, with a lack of perceived efficacy over testing decision making adversely impacting on levels of general well-being. The wider implications of this generalization effect and the processes involved in efficacy generalization are discussed.

Differential expression of steroid 5 alpha-reductase isozymes and association with disease severity and angiogenic genes predict their biological role in prostate cancer

The biological role of steroid 5 alpha-reductase isozymes (encoded by the SRD5A1 and SRD5A2 genes) and angiogenic factors that play important roles in the pathogenesis and vascularization of prostate cancer (PC) is poorly understood. The sub-cellular expression of these isozymes and vascular endothelial growth factor (VEGF) in PC tissue microarrays (n=62) was examined using immunohistochemistry. The effect of SRD5A inhibition on the angiogenesis pathway genes in PC was also examined in prostate cell lines, LNCaP, PC3, and RWPE-1, by treating them with the SRD5A inhibitors finasteride and dutasteride, followed by western blot, quantitative PCR, and ELISA chip array techniques. In PC tissues, nuclear SRD5A1 expression was strongly associated with higher cancer Gleason scores (P=0.02), higher cancer stage (P=0.01), and higher serum prostate specific antigen (PSA) levels (P=0.01), whereas nuclear SRD5A2 expression was correlated with VEGF expression (P=0.01). Prostate tumor cell viability was significantly reduced in dutasteride-treated PC3 and RWPE-1 cells compared with finasteride-treated groups. Expression of the angiogenesis pathway genes transforming growth factor beta 1 (TGFB1), endothelin (EDN1), TGF alpha (TGFA), and VEGFR1 was upregulated in LNCaP cells, and at least 7 out of 21 genes were upregulated in PC3 cells treated with finasteride (25 mu M). Our findings suggest that SRD5A1 expression predominates in advanced PC, and that inhibition of SRD5A1 and SRD5A2 together was more effective in reducing cell numbers than inhibition of SRD5A2 alone. However, these inhibitors did not show any significant difference in prostate cell angiogenic response. Interestingly, some angiogenic genes remained activated after treatment, possibly due to the duration of treatment and tumor resistance to inhibitors. Endocrine-Related Cancer (2010) 17 757-770

Platelet Redox Balance in Diabetic Patients with Hypertension improved by n-3 fatty acids

OBJECTIVE:
Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing cardiovascular disease, largely as a result of defective production of cardioprotective nitric oxide and a concomitant rise in oxidative stress. Dietary interventions that could reverse this trend would be extremely beneficial. Here we investigated whether dietary n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation positively affected platelet nitroso-redox imbalance.
RESEARCH DESIGN AND METHODS:
We randomized hypertensive T2DM patients (T2DM HT; n = 22) and age-and-sex matched hypertensive study participants without diabetes (HT alone; n = 23) in a double-blind, crossover fashion to receive 8 weeks of n-3 PUFAs (1.8 g eicosapentaenoic acid and 1.5 g docosahexaenoic acid) or identical olive oil capsules (placebo), with an intervening 8-week washout period. Platelet nitrite and superoxide were measured and compared before and after treatment; 8-isoprostane was determined by ELISA and subcellular compartmentalization of the NAD(P)H oxidase subunit p47-phox examined by Western blotting.
RESULTS:
The n-3 PUFA supplementation reduced 8-isoprostane and superoxide levels in platelets from T2DM HT, but not HT alone, participants, without effect on nitrite production. This coincided with a significant decrease in p47-phox membrane localization and a similar reduction in superoxide to that achieved with apocynin. At baseline, a subcohort of T2DM HT and HT alone participants showed evidence of nitric oxide synthase (NOS)-derived superoxide production, indicating defective enzymatic activity. This was reversed significantly in T2DM HT participants after treatment, demonstrating improved NOS function.
CONCLUSIONS:
Our finding that n-3 PUFAs diminish platelet superoxide production in T2DM HT patients in vivo suggests a therapeutic role for these agents in reducing the vascular-derived oxidative stress associated with diabetes.

Parenting Control in Contexts of Political Violence: Testing Bidirectional Relations Between Violence Exposure and Control in Post-Accord Belfast

Objective. The authors examined bidirectional relations between youth exposure to sectarian and nonsectarian antisocial behavior and mothers' efforts to control youths' exposure to community violence in Belfast, Northern Ireland. Design. Mother-child dyads (N = 773) were interviewed in their homes twice over 2 years regarding youths' exposure to sectarian and nonsectarian community antisocial behavior and mothers' use of control strategies, including behavioral and psychological control. Results. Youths' exposure to nonsectarian antisocial behavior was related to increases in mothers' use of behavioral and psychological control strategies over time, controlling for earlier levels of these constructs. Reflecting bidirectional relations, mothers' behavioral control strategies were associated with youths' reduced exposure to nonsectarian and sectarian antisocial behavior over time, whereas psychological control was not related to reduced exposure. Conclusion. Only nonsectarian community violence was associated longitudinally with mothers' increased use of control strategies, and only behavioral control strategies were effective in reducing youths' exposure to community antisocial behavior, including sectarian and nonsectarian antisocial behavior.

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for prevention of sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of the entry inhibitors maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously over 28 days from rings in vitro, at rates of 100-2500 µg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady state fluid concentrations were ~106 fold greater than IC50 values for SHIV-162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. Pretreatment of macaques with Depo-Provera® (DP), as commonly used in macaque challenge studies, was shown to significantly modify the bio-distribution of the inhibitors, but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments, and also for ring performance during the human female menstrual cycle. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Job characteristics and burnout among aging professionals in information and communications technology

The aim of this Study was to examine the relationship between job characteristics and burnout, i.e., exhaustion, cynicism and lack of professional efficacy, in a sample of 115 (49- to 61-yr.-old) information and communications technology professionals. Questionnaire survey data were collected at two time points. In 1995 (Time 1), higher quantitative overload and lower job control were associated with higher exhaustion. Job control was negatively associated with lack of professional efficacy. In 2001 (Time 2), quantitative overload and information overload were positively associated with exhaustion, but with job control negatively. Use of new information Was negatively associated with cynicism. In addition, job control and use of new information were negatively associated with lack of professional efficacy. job characteristics at Time 1 were not significantly associated with burnout at Time 2 when job characteristics at Time 2 were controlled.

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.

Cognitive-behavioural interventions for children who have been sexually abused

Background: Despite differences in how it is defined, there is a general consensus amongst clinicians and researchers that the sexual abuse of children and adolescents (’child sexual abuse’) is a substantial social problem worldwide. The effects of sexual abuse manifest in a wide range of symptoms, including fear, anxiety, post-traumatic stress disorder and various externalising and internalising behaviour problems, such as inappropriate sexual behaviours. Child sexual abuse is associated with increased risk of psychological problems in adulthood. Cognitive-behavioural approaches are used to help children and their non-offending or ’safe’ parent tomanage the sequelae of childhood sexual abuse. This review updates the first Cochrane review of cognitive-behavioural approaches interventions for children who have been sexually abused, which was first published in 2006.

Objectives: To assess the efficacy of cognitive-behavioural approaches (CBT) in addressing the immediate and longer-term sequelae of sexual abuse on children and young people up to 18 years of age.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011 Issue 4); MEDLINE (1950 to November Week
3 2011); EMBASE (1980 to Week 47 2011); CINAHL (1937 to 2 December 2011); PsycINFO (1887 to November Week 5 2011); LILACS (1982 to 2 December 2011) and OpenGrey, previously OpenSIGLE (1980 to 2 December 2011). For this update we also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP).

Selection criteria: We included randomised or quasi-randomised controlled trials of CBT used with children and adolescents up to age 18 years who had experienced being sexually abused, compared with treatment as usual, with or without placebo control.

Data collection and analysis: At least two review authors independently assessed the eligibility of titles and abstracts identified in the search. Two review authors independently extracted data from included studies and entered these into Review Manager 5 software. We synthesised and presented data in both written and graphical form (forest plots).

Main results: We included 10 trials, involving 847 participants. All studies examined CBT programmes provided to children or children and a nonoffending parent. Control groups included wait list controls (n = 1) or treatment as usual (n = 9). Treatment as usual was, for the most part, supportive, unstructured psychotherapy. Generally the reporting of studies was poor. Only four studies were judged ’low risk of bias’ with regards to sequence generation and only one study was judged ’low risk of bias’ in relation to allocation concealment. All studies were judged ’high risk of bias’ in relation to the blinding of outcome assessors or personnel; most studies did not report on these, or other issues of bias. Most studies reported results for study completers rather than for those recruited.

Depression, post-traumatic stress disorder (PTSD), anxiety and child behaviour problems were the primary outcomes. Data suggest that CBT may have a positive impact on the sequelae of child sexual abuse, but most results were not statistically significant. Strongest evidence for positive effects of CBT appears to be in reducing PTSD and anxiety symptoms, but even in these areas effects tend to be 'moderate’ at best. Meta-analysis of data from five studies suggested an average decrease of 1.9 points on the Child Depression Inventory immediately after intervention (95% confidence interval (CI) decrease of 4.0 to increase of 0.4; I2 = 53%; P value for heterogeneity = 0.08), representing a small to moderate effect size. Data from six studies yielded an average decrease of 0.44 standard deviations on a variety of child post-traumatic stress disorder scales (95% CI 0.16 to 0.73; I2 = 46%; P value for heterogeneity = 0.10). Combined data from five studies yielded an average decrease of 0.23 standard deviations on various child anxiety scales (95% CI 0.3 to 0.4; I2=0%; P value for heterogeneity = 0.84). No study reported adverse effects.

Authors’ conclusions: The conclusions of this updated review remain the same as those when it was first published. The review confirms the potential of CBT to address the adverse consequences of child sexual abuse, but highlights the limitations of the evidence base and the need for more carefully conducted and better reported trials.

Fasciolicides: Efficacy, actions, resistance and its management

The modes of action of fasciolicides are described. Closantel and other salicylanilides interfere with energy metabolism by uncoupling oxidative phosphorylation in the fluke. Other fasciolicides are believed to have a metabolic action-halogenated phenols (via uncoupling) and clorsulon (via inhibition of glycolysis)-but direct evidence is lacking. Benzimidazoles (in particular, riclabendazole) bind to fluke tubulin and disrupt microtubule-based processes. Diamphenethide inhibits protein synthesis in the fluke. Other potential drug actions may contribute to overall drug efficacy. In particular, a number of fasciolicides-salicylanilides, phenols, diamphenethide-induce a rapid paralysis of the fluke, so their action may have a neuromuscular basis, although the actions remain ill-defined. Resistance to salicylanilides and triclabendazole has been detected in the field, although drug resistance does not appear to be a major problem yet. Strategies to minimize the development of resistance include the use of synergistic drug combinations, together with the design of integrated management programmes and the search for alternatives to drugs, in particular, vaccines. (C) 1999 Harcourt Publishers Ltd.

Dielectronic recombination in Li+

Dielectronic recombination has been investigated for ground-state Li+(1s2s) and metastable Li+(1s2s) ions. Absolute recombination rates for the convoluted sum of these configurations are obtained and compared with theoretical calculations. Also, the effect of the space charge on the energy of the observed resonances is investigated as well as the effect of trapped residual, ions in reducing the effect of the space charge.