Microsatellite analysis for determination of the mutagenicity of extremely low-frequency electromagnetic fields and ionising radiation in vitro.

Extremely low-frequency electromagnetic fields (ELF-EMF) have been reported to induce lesions in DNA and to enhance the mutagenicity of ionising radiation. However, the significance of these findings is uncertain because the determination of the carcinogenic potential of EMFs has largely been based on investigations of large chromosomal aberrations. Using a more sensitive method of detecting DNA damage involving microsatellite sequences, we observed that exposure of UVW human glioma cells to ELF-EMF alone at a field strength of 1 mT (50 Hz) for 12 h gave rise to 0.011 mutations/locus/cell. This was equivalent to a 3.75-fold increase in mutation induction compared with unexposed controls. Furthermore, ELF-EMF increased the mutagenic capacity of 0.3 and 3 Gy gamma-irradiation by factors of 2.6 and 2.75, respectively. These results suggest not only that ELF-EMF is mutagenic as a single agent but also that it can potentiate the mutagenicity of ionising radiation. Treatment with 0.3 Gy induced more than 10 times more mutations per unit dose than irradiation with 3 Gy, indicating hypermutability at low dose.

Radiation induced bystander signals are independent of DNA damage and DNA repair capacity of the irradiated cells.

Evidence is accumulating that irradiated cells produce signals, which interact with non-exposed cells in the same population. Here, we analysed the mechanism for bystander signal arising in wild-type CHO cells and repair deficient varients, focussing on the relationship between DNA repair capacity and bystander signal arising in irradiated cells. In order to investigate the bystander effect, we carried out medium transfer experiments after X-irradiation where micronuclei were scored in non-targeted DSB repair deficient xrs5 cells. When conditioned medium from irradiated cells was transferred to unirradiated xrs5 cells, the level of induction was independent of whether the medium came from irradiated wild-type, ssb or dsb repair deficient cells. This result suggests that the activation of a bystander signal is independent of the DNA repair capacity of the irradiated cells. Also, pre-treatment of the irradiated cells with 0.5% DMSO, which suppresses micronuclei induction in CHO but not in xrs5 cells, suppressed bystander effects completely in both conditioned media, suggesting that DMSO is effective for suppression of bystander signal arising independently of DNA damage in irradiated cells. Overall the work presented here adds to the understanding that it is the repair phenotype of the cells receiving bystander signals, which determines overall response rather than that of the cell producing the bystander signal.

Radiotherapy in the presence of contrast agents: a general figure of merit and its application to gold nanoparticles

Delivering sufficient dose to tumours while sparing surrounding tissue is one of the primary challenges of radiotherapy, and in common practice this is typically achieved by using highly penetrating MV photon beams and spatially shaping dose. However, there has been a recent increase in interest in the possibility of using contrast agents with high atomic number to enhance the dose deposited in tumours when used in conjunction with kV x-rays, which see a significant increase in absorption due to the heavy element's high-photoelectric cross-section at such energies. Unfortunately, the introduction of such contrast agents significantly complicates the comparison of different source types for treatment efficacy, as the dose deposited now depends very strongly on the exact composition of the spectrum, making traditional metrics such as beam quality less valuable. To address this, a 'figure of merit' is proposed, which yields a value which enables the direct comparison of different source types for tumours at different depths inside a patient. This figure of merit is evaluated for a 15 MV LINAC source and two 150 kVp sources (both of which make use of a tungsten target, one with conventional aluminium filtration, while the other uses a more aggressive thorium filter) through analytical methods as well as numerical models, considering tissue treated with a realistic concentration and uptake ratio of gold nanoparticle contrast agents (10 mg ml(-1) concentration in 'tumour' volume, 10: 1 uptake ratio). Finally, a test case of human neck phantom is considered with a similar contrast agent to compare the abstract figure to a more realistic treatment situation. Good agreement was found both between the different approaches to calculate the figure of merit, and between the figure of merit and the effectiveness in a more realistic patient scenario. Together, these observations suggest that there is the potential for contrast-enhanced kilovoltage radiation to be a useful therapeutic tool for a number of classes of tumour on dosimetric considerations alone, and they point to the need for further research in this area.

Co-regulation of Gremlin and Notch signalling in diabetic nephropathy

Diabetic nephropathy is currently the leading cause of end-stage renal disease worldwide, and occurs in approximately one third of all diabetic patients. The molecular pathogenesis of diabetic nephropathy has not been fully characterized and novel mediators and drivers of the disease are still being described. Previous data from our laboratory has identified the developmentally regulated gene Gremlin as a novel target implicated in diabetic nephropathy in vitro and in vivo. We used bioinformatic analysis to examine whether Gremlin gene sequence and structure could be used to identify other genes implicated in diabetic nephropathy. The Notch ligand Jagged1 and its downstream effector, hairy enhancer of split-1 (Hes1), were identified as genes with significant similarity to Gremlin in terms of promoter structure and predicted microRNA binding elements. This led us to discover that transforming growth factor-beta (TGFß1), a primary driver of cellular changes in the kidney during nephropathy, increased Gremlin, Jagged1 and Hes1 expression in human kidney epithelial cells. Elevated levels of Gremlin, Jagged1 and Hes1 were also detected in extracts from renal biopsies from diabetic nephropathy patients, but not in control living donors. In situ hybridization identified specific upregulation and co-expression of Gremlin, Jagged1 and Hes1 in the same tubuli of kidneys from diabetic nephropathy patients, but not controls. Finally, Notch pathway gene clustering showed that samples from diabetic nephropathy patients grouped together, distinct from both control living donors and patients with minimal change disease. Together, these data suggest that Notch pathway gene expression is elevated in diabetic nephropathy, co-incident with Gremlin, and may contribute to the pathogenesis of this disease.

Integrated structure selection and parameter optimisation for eng-genes neural models

The eng-genes concept involves the use of fundamental known system functions as activation functions in a neural model to create a 'grey-box' neural network. One of the main issues in eng-genes modelling is to produce a parsimonious model given a model construction criterion. The challenges are that (1) the eng-genes model in most cases is a heterogenous network consisting of more than one type of nonlinear basis functions, and each basis function may have different set of parameters to be optimised; (2) the number of hidden nodes has to be chosen based on a model selection criterion. This is a mixed integer hard problem and this paper investigates the use of a forward selection algorithm to optimise both the network structure and the parameters of the system-derived activation functions. Results are included from case studies performed on a simulated continuously stirred tank reactor process, and using actual data from a pH neutralisation plant. The resulting eng-genes networks demonstrate superior simulation performance and transparency over a range of network sizes when compared to conventional neural models. (c) 2007 Elsevier B.V. All rights reserved.

Reducing Drifts in the Inertial Measurements of Wrist and Elbow Positions

In this paper, we present an inertial-sensor-based monitoring system for measuring the movement of human upper limbs. Two wearable inertial sensors are placed near the wrist and elbow joints, respectively. The measurement drift in segment orientation is dramatically reduced after a Kalman filter is applied to estimate inclinations using accelerations and turning rates from gyroscopes. Using premeasured lengths of the upper and lower arms, we compute the position of the wrist and elbow joints via a proposed kinematic model. Experimental results demonstrate that this new motion capture system, in comparison to an optical motion tracker, possesses an RMS position error of less than 0.009 m, with a drift of less than 0.005 ms-1 in five daily activities. In addition, the RMS angle error is less than 3??. This indicates that the proposed approach has performed well in terms of accuracy and reliability.

Neuropeptides Regulate Expression of Angiogenic Growth Factors in Human Dental Pulp Fibroblasts

Abstract
INTRODUCTION:
Neuropeptides play an important role in inflammation and repair and have been implicated in mediating angiogenesis. Pulp fibroblasts express neuropeptide receptors, and the aim of this research was to investigate whether neuropeptides could regulate angiogenic growth factor expression in vitro
METHODS:
An angiogenic array was used to determine the levels of 10 angiogenic growth factors expressed by human pulp fibroblasts.
RESULTS:
Pulp fibroblasts were shown to express angiogenin, angiopoietin-2, epidermal growth factor, basic fibroblast growth factor, heparin-binding epidermal growth factor, hepatocyte growth factor, leptin, platelet-derived growth factor, placental growth factor, and vascular endothelial growth factor. Furthermore, the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide, and neuropeptide Y altered angiogenic growth factor expression in vitro.
CONCLUSIONS:
The regulation of angiogenic growth factor expression by neuropeptides suggests a novel role for neuropeptides in pulpal inflammation and repair.

When some is actually all: Scalar inferences in face-threatening contexts

Accounts of the scalar inference from 'some X-ed' to 'not all X-ed' are central to the debate between contemporary theories of conversational pragmatics. An important contribution to this debate is to identify contexts that decrease the endorsement rate of the inference. We suggest that the inference is endorsed less often in face-threatening contexts, i.e., when X implies a loss of face for the listener. This claim is successfully tested in Experiment 1. Experiment 2 rules out a possible confound between face-threatening contexts and lower-bound contexts. Experiment 3 shows that whilst saying 'some X-ed' when one knew for a fact that all X-ed is always perceived as an underinformative utterance, it is also seen as a nice and polite thing to do when X threatens the face of the listener. These findings are considered from the perspective of Relevance Theory as well as that of the Generalized Conversational Inference approach. (C) 2009 Elsevier B.V. All rights reserved.

Fragmentation and plasmid strand breaks in pure and gold-doped DNA irradiated by beams of fast hydrogen atoms

The results of an investigation into the damage caused to dry plasmid DNA after irradiation by fast (keV) hydrogen atoms are presented. Agarose gel electrophoresis was used to assess single and double strand break yields as a function of dose in dry DNA samples deposited on a mica substrate. Damage levels were observed to increase with beam energy. Strand break yields demonstrated a considerable dependence on sample structure and the method of sample preparation. Additionally, the effect of high-Z nanoparticles on damage levels was investigated by irradiating DNA samples containing controlled amounts of gold nanoparticles. In contrast to previous (photonic) studies, no enhancement of strand break yields was observed with the particles showing a slight radioprotective effect. A model of DNA damage as a function of dose has been constructed in terms of the probability for the creation of single and double strand breaks, per unit ion flux. This model provides quantitative conclusions about the effects of both gold nanoparticles and the different buffers used in performing the assays and, in addition, infers the proportion of multiply damaged fragments.

A Profile of Adolescent Cocaine Use in Northern Ireland.

Background: The image of cocaine as a 'party' drug used by more affluent members of society has begun to change as the levels of use of the drug rise amongst school aged young people. Methods: Cocaine use patterns amongst young people aged 13-16 years who were participating in the Belfast Youth Development Study, a longitudinal study of adolescent drug use was explored. Data was collected through an annual datasweep in participating schools. This paper includes data collected in years 3, 4 and 5 of the study. Results: The results show higher levels of cocaine use amongst this age group than reported in much of the existing harm reduction literature. Lifetime use was 3.8% at age 13-14 years, rising to 7.5% at 15-16 years. The profile indicated that adolescent cocaine users were more likely to be female, live in disrupted families and experience social deprivation which is similar to existing adolescent drug use profiles. There was also some evidence of experimental cocaine use amongst the sample. Conclusions: These findings provide further evidence for the development of age appropriate school focused harm reduction initiatives and continued monitoring of contemporary trends of use of cocaine amongst school aged young people.

Length of Stay-Based Patient Flow Models: Recent Developments and Future Directions

Modelling patient flow in health care systems is vital in understanding the system activity and may therefore prove to be useful in improving their functionality. An extensively used measure is the average length of stay which, although easy to calculate and quantify, is not considered appropriate when the distribution is very long-tailed. In fact, simple deterministic models are generally considered inadequate because of the necessity for models to reflect the complex, variable, dynamic and multidimensional nature of the systems. This paper focuses on modelling length of stay and flow of patients. An overview of such modelling techniques is provided, with particular attention to their impact and suitability in managing a hospital service.