Uncommon genetic syndromes and narrative production - Case Studies with Williams, Smith-Magenis and Prader- Willi Syndromes

This study compares narrative production among three syndromes with genetic microdeletions: Williams syndrome (WS), Smith-Magenis syndrome (SMS), and Prader-Willi syndrome (PWS), characterized by intellectual disabilities and relatively spared language abilities. Our objective is to study the quality of narrative production in the context of a common intellectual disability. To elicit a narrative production, the task Frog! Where Are You was used. Then, structure, process, and content of the narrative process were analysed in the three genetic disorders:WS (n52), SMS (n52), and PWS (n52). Data show evidence of an overall low narrative quality in these syndromes, despite a high variability within different measures of narrative production. Results support the hypothesis that narrative is a highly complex cognitive process and that, in a context of intellectual disability, there is no evidence of particular ‘hypernarrativity’ in these syndromes.This research was supported by the grants FEDER –

The BSR-PsA:study protocol for the British Society for Rheumatology psoriatic arthritis register

Acknowledgements We acknowledge contribution of BSR-PsA study staff, under the supervision of KFK: Maureen Heddle, Barry Morris, Jonathan Lock and Jane Brady. We also acknowledge the support from the Centre for Healthcare Randomised Trials (CHaRT) at the University of Aberdeen, especially Mark Forrest and Brian Taylor, for database and IT support. We would like to thank Professor Iain McInnes from the University of Glasgow, and our International Advisory Committee (Professors Merete Hetland, Oliver Fitzgerald and Philip Mease), for their comments when developing the protocol and for advice in harmonising data collection with other international studies, and the staff at the British Society for Rheumatology, in particular Alan Roach, Ross Matthews, Chris Hiley and Debbie MacDonald. Finally, we are indebted to the staff at all participating NHS trusts (details of which are available from www.abdn.ac.uk/bsr-psa) and especially the NIHR Clinical Research Network research nurses for their assistance with participant recruitment and data collection. Funding The BSR-PsA is funded by the BSR as part of its rheumatology registers portfolio and, in turn, receives funding for this from pharmaceutical companies. At the time of publication, only Amgen (previously Celgene) have contributed to the funding of the BSR-PsA. Pharmaceutical companies providing funds to BSR do not participant in the conduct or oversight of the study. However, they do receive advance notice of publications on which they are able to comment. Companies contributing to the funding of the register can request anonymised data on clinically confirmed serious adverse events and some events of special interest (e.g. pregnancy) among participants prescribed the specific bDMARD or tsDMARD agents that they manufacture. Other than this information, they do not have access to any raw data. They may, however, request specific analyses to be performed, for which a pre-specific analysis plan is discussed, and additional funds are provided.Peer reviewedPublisher PD

Nuclear localization and function of polypeptide ligands and their receptors: a new paradigm for hormone specificity within the mammary gland?

The specific effects triggered by polypeptide hormone/growth factor stimulation of mammary cells were considered mediated solely by receptor-associated signaling networks. A compelling body of new data, however, clearly indicates that polypeptide ligands and/or their receptors are transported into the nucleus, where they function directly to regulate the expression of specific transcription factors and gene loci. The intranuclear function of these complexes may contribute to the explicit functions associated with a given ligand, and may serve as new targets for pharmacologic intervention

Quantum dynamics in strong fluctuating fields

A large number of multifaceted quantum transport processes in molecular systems and physical nanosystems can be treated in terms of quantum relaxation processes which couple to one or several fluctuating environments. A thermal equilibrium environment can conveniently be modelled by a thermal bath of harmonic oscillators. An archetype situation provides a two-state dissipative quantum dynamics, commonly known under the label of a spin-boson dynamics. An interesting and nontrivial physical situation emerges, however, when the quantum dynamics evolves far away from thermal equilibrium. This occurs, for example, when a charge transferring medium possesses nonequilibrium degrees of freedom, or when a strong time-dependent control field is applied externally. Accordingly, certain parameters of underlying quantum subsystem acquire stochastic character. Herein, we review the general theoretical framework which is based on the method of projector operators, yielding the quantum master equations for systems that are exposed to strong external fields. This allows one to investigate on a common basis the influence of nonequilibrium fluctuations and periodic electrical fields on quantum transport processes. Most importantly, such strong fluctuating fields induce a whole variety of nonlinear and nonequilibrium phenomena. A characteristic feature of such dynamics is the absence of thermal (quantum) detailed balance.Comment: review article, Advances in Physics (2005), in pres

A participatory parent-focused intervention promoting physical activity in preschools: design of a cluster-randomized trial

<p>Abstract</p> <p>Background</p> <p>With rates of childhood obesity increasing, physical activity (PA) promotion especially in young children has assumed greater importance. Given the limited effectiveness of most interventions to date, new approaches are needed. The General Systems theory suggests that involving parents as intervention targets may be effective in fostering healthier life styles in children. We describe the development of a parent-focused participatory intervention and the procedures used to evaluate its effectiveness in increasing daily PA in preschoolers.</p> <p>Methods/Design</p> <p>Thirty-seven South German preschools were identified for this study and agreed to participate. Using a two-armed, controlled cluster-randomized trial design we test a participatory intervention with parents as the primary target group and potential agents of behavioural change. Specifically, the intervention is designed to engage parents in the development, refinement and selection of project ideas to promote PA and in incorporating these ideas into daily routines within the preschool community, consisting of children, teachers and parents. Our study is embedded within an existing state-sponsored programme providing structured gym lessons to preschool children. Thus, child-based PA outcomes from the study arm with the parent-focused intervention and the state-sponsored programme are compared with those from the study arm with the state-sponsored programme alone. The evaluation entails baseline measurements of study outcomes as well as follow-up measurements at 6 and 12 months. Accelerometry measures PA intensity over a period of six days, with the mean over six days used as the primary outcome measure. Secondary outcomes include childrens' BMI, a sum of averaged skin fold thickness measurements across multiple sites, and PA behaviour. Longitudinal multilevel models are used to assess within-subject change and between-group differences in study outcomes, adjusted for covariates at the preschool and individual levels. Teacher qualitative interviews monitor the intervention implementation process.</p> <p>Discussion</p> <p>Participatory approaches that actively involve parents have the potential to promote PA in ways that might be better tailored to local needs and more sustainable. Our mixed methods approach to assess the intervention efficacy and implementation employing both quantitative and qualitative measures within a cluster-randomized controlled trial may serve as a framework for evaluating public health interventions in preschool settings.</p> <p>Trial Registration</p> <p><b>clinicaltrials.gov No: NCT00987532</b></p

Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials

Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand– foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs

The relationship between lung function impairment and quantitative computed tomography in chronic obstructive pulmonary disease

Contains fulltext : 109919.pdf (Publisher’s version ) (Open Access)OBJECTIVES: To determine the relationship between lung function impairment and quantitative computed tomography (CT) measurements of air trapping and emphysema in a population of current and former heavy smokers with and without airflow limitation. METHODS: In 248 subjects (50 normal smokers; 50 mild obstruction; 50 moderate obstruction; 50 severe obstruction; 48 very severe obstruction) CT emphysema and CT air trapping were quantified on paired inspiratory and end-expiratory CT examinations using several available quantification methods. CT measurements were related to lung function (FEV(1), FEV(1)/FVC, RV/TLC, Kco) by univariate and multivariate linear regression analysis. RESULTS: Quantitative CT measurements of emphysema and air trapping were strongly correlated to airflow limitation (univariate r-squared up to 0.72, p < 0.001). In multivariate analysis, the combination of CT emphysema and CT air trapping explained 68-83% of the variability in airflow limitation in subjects covering the total range of airflow limitation (p < 0.001). CONCLUSIONS: The combination of quantitative CT air trapping and emphysema measurements is strongly associated with lung function impairment in current and former heavy smokers with a wide range of airflow limitation.01 januari 201

Estrogen receptor transcription and transactivation: Estrogen receptor knockout mice - what their phenotypes reveal about mechanisms of estrogen action

Natural, synthetic and environmental estrogens have numerous effects on the development and physiology of mammals. Estrogen is primarily known for its role in the development and functioning of the female reproductive system. However, roles for estrogen in male fertility, bone, the circulatory system and immune system have been established by clinical observations regarding sex differences in pathologies, as well as observations following menopause or castration. The primary mechanism of estrogen action is via binding and modulation of activity of the estrogen receptors (ERs), which are ligand-dependent nuclear transcription factors. ERs are found in highest levels in female tissues critical to reproduction, including the ovaries, uterus, cervix, mammary glands and pituitary gland. Since other affected tissues have extremely low levels of ER, indirect effects of estrogen, for example induction of pituitary hormones that affect the bone, have been proposed. The development of transgenic mouse models that lack either estrogen or ER have proven to be valuable tools in defining the mechanisms by which estrogen exerts its effects in various systems. The aim of this article is to review the mouse models with disrupted estrogen signaling and describe the associated phenotypes

Performance related factors are the main determinants of the von Willebrand factor response to exhaustive physical exercise

Background: Physical stress triggers the endothelium to release von Willebrand Factor (VWF) from the Weibel Palade bodies. Since VWF is a risk factor for arterial thrombosis, it is of great interest to discover determinants of VWF response to physical stress. We aimed to determine the main mediators of the VWF increase by exhaustive physical exercise. Methods: 105 healthy individuals (18-35 years) were included in this study. Each participant performed an incremental exhaustive exercise test on a cycle ergometer. Respiratory gas exchange measurements were obtained while cardiac function was continuously monitored. Blood was collected at baseline and directly after exhaustion. VWF antigen (VWF:Ag) levels, VWF collagen binding (VWF:CB) levels, ADAMTS13 activity and common variations in Syntaxin Binding Protein-5 (STXBP5, rs1039084 and rs9399599), Syntaxin-2 (STX2, rs7978987) and VWF (promoter, rs7965413) were determined. Results: The median VWF:Ag level at baseline was 0.94 IU/mL [IQR 0.8-1.1] and increased with 47% [IQR 25-73] after exhaustive exercise to a median maximum VWF:Ag of 1.38 IU/mL [IQR 1.1-1.8] (p<0.0001). VWF:CB levels and ADAMTS13 activity both also increased after exhaustive exercise (median increase 43% and 12%, both p<0.0001). The strongest determinants of the VWF:Ag level increase are performance related (p<0.0001). We observed a gender difference in VWF:Ag response to exercise (females 1.2 IU/mL; males 1.7 IU/mL, p = 0.001), which was associated by a difference in performance. Genetic variations in STXBP5, STX2 and the VWF promoter were not associated with VWF:Ag levels at baseline nor with the VWF:Ag increase. Conclusions: VWF:Ag levels strongly increase upon exhaustive exercise and this increase is strongly determined by physical fitness level and the intensity of the exercise, while there is no clear effect of genetic variation in STXBP5, STX2 and the VWF promoter

Surface functionalisation of nanodiamonds for human neural stem cell adhesion and proliferation.

Biological systems interact with nanostructured materials on a sub-cellular level. These interactions may govern cell behaviour and the precise control of a nanomaterial's structure and surface chemistry allow for a high degree of tunability to be achieved. Cells are surrounded by an extra-cellular matrix with nano-topographical properties. Diamond based materials, and specifically nanostructured diamond has attracted much attention due to its extreme electrical and mechanical properties, chemical inertness and biocompatibility. Here the interaction of nanodiamond monolayers with human Neural Stem Cells (hNSCs) has been investigated. The effect of altering surface functionalisation of nanodiamonds on hNSC adhesion and proliferation has shown that confluent cellular attachment occurs on oxygen terminated nanodiamonds (O-NDs), but not on hydrogen terminated nanodiamonds (H-NDs). Analysis of H and O-NDs by Atomic Force Microscopy, contact angle measurements and protein adsorption suggests that differences in topography, wettability, surface charge and protein adsorption of these surfaces may underlie the difference in cellular adhesion of hNSCs reported here