Structural studies on acridine derivatives binding to telomeric DNA

Acridine derivatives can inhibit a variety of nuclear enzymes by binding or intercalating to DNA. This class of compounds is of great interest in the development of novel anticancer agents. Despite the availability of crystallographic data for some of the compounds complexed with DNA, uncertainties remain about the mechanisms of action, binding preferences and biological targets. To investigate the intercalation of several acridine derivatives, a variety of techniques are being employed. Single-crystal X-ray diffraction is being used to determine the high resolution three-dimensional structure of short sequences of quadruplex telomeric DNA with bound drug. This will be compared to the effect of drug binding to long segments of double-stranded DNA using fibre diffraction, with neutron diffraction studies planned to analyse the hydrogen bonding patterns of the DNA-drug complexes. Small-angle neutron scattering (SANS) will also be applied to study drug binding to both short and long sequences of quadruplex and double-stranded DNA in solution. Initial SANS measurements of the telomeric repeat d(TGGGGT) imply that this hexamer is present as a quadruplex. (c) 2006 Elsevier B.V. All rights reserved.

Using bargaining-game theory for negotiating concession period for BOT-type contract

This paper extends the build-operate-transfer (BOT) concession model (BOTCcM) to a new method for identifying a concession period by using bargaining-game theory. Concession period is one of the most important decision variables in arranging a BOT-type contract, and there are few methodologies available for helping to determine the value of this variable. The BOTCcM presents an alternative method by which a group of concession period solutions are produced. Nevertheless, a typical weakness in using BOTCcM is that the model cannot recommend a specific time span for concessionary. This paper introduces a new method called BOT bargaining concession model (BOTBaC) to enable the identification of a specific concession period, which takes into account the bargaining behavior of the two parties concerned in engaging a BOT contract, namely, the investor and the government concerned. The application of BOTBaC is demonstrated through using an example case.

An optimized reverse-phase high performance liquid chromatographic method for evaluating percutaneous absorption of glucosamine hydrochloride

A relatively simple, selective, precise and accurate high performance liquid chromatography (HPLC) method based on a reaction of phenylisothiocyanate (PITC) with glucosamine (GL) in alkaline media was developed and validated to determine glucosamine hydrochloride permeating through human skin in vitro. It is usually problematic to develop an accurate assay for chemicals traversing skin because the excellent barrier properties of the tissue ensure that only low amounts of the material pass through the membrane and skin components may leach out of the tissue to interfere with the analysis. In addition, in the case of glucosamine hydrochloride, chemical instability adds further complexity to assay development. The assay, utilising the PITC-GL reaction was refined by optimizing the reaction temperature, reaction time and PITC concentration. The reaction produces a phenylthiocarbarnyl-glucosamine (PTC-GL) adduct which was separated on a reverse-phase (RP) column packed with 5 mu m ODS (C-18) Hypersil particles using a diode array detector (DAD) at 245 nm. The mobile phase was methanol-water-glacial acetic acid (10:89.96:0.04 v/v/v, pH 3.5) delivered to the column at 1 ml min(-1) and the column temperature was maintained at 30 degrees C Using a saturated aqueous solution of glucosamine hydrochloride, in vitro permeation studies were performed at 32 +/- 1 degrees C over 48 h using human epidermal membranes prepared by a heat separation method and mounted in Franz-type diffusion cells with a diffusional area 2.15 +/- 0.1 cm(2). The optimum derivatisation reaction conditions for reaction temperature, reaction time and PITC concentration were found to be 80 degrees C, 30 min and 1 % v/v, respectively. PTC-Gal and GL adducts eluted at 8.9 and 9.7 min, respectively. The detector response was found to be linear in the concentration range 0-1000 mu g ml(-1). The assay was robust with intra- and inter-day precisions (described as a percentage of relative standard deviation, %R.S.D.) < 12. Intra- and inter-day accuracy (as a percentage of the relative error, %RE) was <=-5.60 and <=-8.00, respectively. Using this assay, it was found that GL-HCI permeates through human skin with a flux 1.497 +/- 0.42 mu g cm(-2) h(-1), a permeability coefficient of 5.66 +/- 1.6 x 10(-6) cm h(-1) and with a lag time of 10.9 +/- 4.6 h. (c) 2005 Elsevier B.V. All rights reserved.

Description of a multifaceted strategy for recruiting general practitioners and community pharmacists to talk about medication errors

Objective: To describe the use of a multifaceted strategy for recruiting general practitioners (GPs) and community pharmacists to talk about medication errors which have resulted in preventable drug-related admissions to hospital. This is a potentially sensitive subject with medicolegal implications. Setting: Four primary care trusts and one teaching hospital in the UK. Method: Letters were mailed to community pharmacists and general practitioners asking for provisional consent to be interviewed and permission to contact them again should a patient be admitted to hospital as a result of a medication error. In addition, GPs were asked for permission to approach their patients should they be admitted to hospital. A multifaceted approach to recruitment was used including gaining support for the study from professional defence agencies and local champions. Key findings: Eighty-five percent (310/385) of GPs and 62% (93/149) of community pharmacists responded to the letters. Eighty-five percent (266/310) of GPs who responded and 81% (75/93) of community pharmacists who responded gave provisional consent to participate in interviews. All GPs (14 out of 14) and community pharmacists (10 out of 10) who were subsequently asked to participate, when patients were admitted to hospital, agreed to be interviewed. Conclusion: The multifaceted approach to recruitment was associated with an impressive response when asking healthcare professionals to be interviewed about medication errors which have resulted in preventable drug-related morbidity.

Huntington's disease patients have selective problems with insight

The objective of this study was to determine insight in patients with Huntington's disease (HD) by contrasting patients' ability to rate their own behavior with their ability to rate a person other than themselves. HD patients and carers completed the Dysexecutive Questionnaire (DEX), rating themselves and each other at two time points. The temporal stability of these ratings was initially examined using these two time points since there is no published test-retest reliability of the DEX with this Population to date. This was followed by a comparison of patients' self-ratings and carer's independent ratings of patients by performing correlations with patients' disease variables, and in exploratory factor analysis was conducted on both sets of ratings. The DEX showed good test-retest reliability, with patients consistently and persistently underestimating the degree of their dysexecutive behavior, but not that of their carers. Patients' self-ratings and caters' ratings of patients both showed that dysexecutive behavior in HD can be fractionated into three underlying components (Cognition, Self-regulation, Insight), and the relative ranking of these factors was similar for both data sets. HD patients consistently underestimated the extent of only their own dysexecutive behaviors relative to carers' ratings by 26%, but were similar in ascribing ranks to the components of dysexecutive behavior. (c) 2005 Movement Disorder Society.

Future directions for child anxiety theory and treatment

The aim of this introductory paper, and of this special issue of Cognition and Emotion, is to stimulate debate about theoretical issues that will inform child anxiety research in the coming years. Papers included in this special issue have arisen from an Economic and Social Research Council (ESRC, UK) funded seminar series, which we called Child Anxiety Theory and Treatment (CATTS). We begin with an overview of the CATTS project before discussing (1) the application of adult models of anxiety to children, and (2) the role of parents in child anxiety. We explore the utility of adult models of anxiety for child populations before discussing the problems that are associated with employing them uncritically in this context. The study of anxiety in children provides the opportunity to observe the trajectory of anxiety and to identify variables that causally influence its development. Parental influences are of particular interest and new and imaginative strategies are required to isolate the complex network of causal relationships therein. We conclude by suggesting that research into the causes and developmental course of anxiety in children should be developed further. We also propose that, although much is known about the role of parents in the development of anxiety, it would be useful for research in this area to move towards an examination of the specific processes involved. We hope that these views represent a constructive agenda for people in the field to consider when planning future research.

Strategies and biases in location memory in Williams syndrome

Individuals with Williams syndrome (WS) demonstrate impaired visuo-spatial abilities in comparison to their level of verbal ability. In particular, visuo-spatial construction is an area of relative weakness. It has been hypothesised that poor or atypical location coding abilities contribute strongly to the impaired abilities observed on construction and drawing tasks [Farran, E. K., & Jarrold, C. (2005). Evidence for unusual spatial location coding in Williams syndrome: An explanation for the local bias in visuo-spatial construction tasks? Brain and Cognition, 59, 159-172; Hoffman, J. E., Landau, B., & Pagani, B. (2003). Spatial breakdown in spatial construction: Evidence from eye fixations in children with Williams syndrome. Cognitive Psychology, 46, 260-301]. The current experiment investigated location memory in WS. Specifically, the precision of remembered locations was measured as well as the biases and strategies that were involved in remembering those locations. A developmental trajectory approach was employed; WS performance was assessed relative to the performance of typically developing (TD) children ranging from 4- to 8-year-old. Results showed differential strategy use in the WS and TD groups. WS performance was most similar to the level of a TD 4-year-old and was additionally impaired by the addition of physical category boundaries. Despite their low level of ability, the WS group produced a pattern of biases in performance which pointed towards evidence of a subdivision effect, as observed in TD older children and adults. In contrast, the TD children showed a different pattern of biases, which appears to be explained by a normalisation strategy. In summary, individuals with WS do not process locations in a typical manner. This may have a negative impact on their visuo-spatial construction and drawing abilities. (c) 2007 Elsevier Ltd. All rights reserved.

Evaluating the intonation of non-native speakers of English using a computerised test battery

This study investigates the intonation of Chinese and Arabic learners of English using the computerized test battery Profiling Elements of Prosody for Speech and Communication (PEPS-C). The aims were to ascertain which aspects of intonation are difficult for these learners, and to determine whether PEPS-C can be used to assess the intonation of adult learners. Although some results were significantly different from native-speaker data, raw scores showed that the learner groups performed well in most tasks, which may indicate that the learners' level is too high for the PEPS-C to be useful. However, the PEPS-C did reveal that Arabic learners performed significantly worse at contrastive stress placement, and Chinese learners performed significantly worse assessing likes and dislikes.

Adiposity, insulin and lipid metabolism in post-menopausal women

OBJECTIVE: To investigate relationships between body fat and its distribution and carbohydrate and lipid tolerance using statistical comparisons in post-menopausal women. DESIGN: Sequential meal, postprandial study (600 min) which included a mixed standard breakfast (30 g fat) and lunch (44 g fat) given at 0 and 270 min, respectively, after an overnight fast. SUBJECTS: Twenty-eight post-menopausal women with a diverse range of body weight (body mass index (BMI), mean 27.2, range 20.5-38.8 kg/m2) and abdominal fat deposition (waist, mean 86.4, range 63.5-124.0 cm). Women with BMI <18 or >37 kg/m2, age>80 y and taking hormone replacement therapy (HRT) were excluded. MEASUREMENTS: Anthropometric measurements were performed to assess total and regional fat deposits. The concentrations of plasma total cholesterol, high density lipoprotein (HDL) cholesterol, triacylglycerol (TAG), glucose, insulin (ins), non-esterified fatty acids (NEFA) and apolipoprotein (apo) B-48 were analysed in plasma collected at baseline (fasted state) and at 13 postprandial time points for a 600 min period. RESULTS: Insulin concentrations in the fasted and fed state were significantly correlated with all measures of adiposity (BMI, waist, waist-hip ratio (W/H), waist-height ratio (W/Ht) and sum of skinfold thickness (SSk)). After controlling for BMI, waist remained significantly and positively associated with fasted insulin (r=0.559) with waist contributing 53% to the variability after multiple regression analysis. After controlling for waist, BMI remained significantly correlated with postprandial (IAUC) insulin (r=0.535) contributing 66% of the variability of this measurement. No association was found between any measures of adiposity and glucose concentrations, although insulin concentration in relation to glucose concentration (glucose-insulin ratio) was significantly negatively correlated with all measures of adiposity. A significant positive correlation was found between fasted TAG and BMI (r=0.416), waist (r=0.393) and Ssk (r=0.457) and postprandial (AUC) TAG with BMI (r=0.385) and Ssk (r=0.406). A significantly higher postprandial apolipoprotein (apo) B-48 response was observed in those women with high BMI (>27 kg/m2). Fasting levels of NEFA were significantly and positively correlated with all measures of adiposity (except W/H). No association was found between cholesterol containing particles and any measure of adiposity. CONCLUSION: Hyperinsulinaemia associated with increasing body fat and central fat distribution is associated with normal glucose but not TAG or NEFA concentrations in postmenopausal women.