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Background: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family., Methods: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed., Results: We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype., Conclusions: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study was undertaken in order to determine the extent of the use of CAM in a UK headache clinic., Design: Ninety-two patients attending a headache clinic were given a questionnaire containing questions regarding their headaches and their use of CAM for headaches., Setting: Outpatient headache clinic, Birmingham, UK. Main outcome measures. The use of complementary and alternative therapies and predictive factors., Results: 32% of respondents had used a median of 3 different CAM therapies for their headache. The commonest source of recommendation of CAM use was a friend or relative (72%) and the commonest reason given for using CAM was as a last resort after trying all conventional therapies offered (48%). CAM therapies were perceived as beneficial by 60% of CAM users and no users perceived the CAM therapy to worsen their headache. 42% of CAM users had not disclosed it to their doctor or nurse, 80% of these giving the reason that the doctor or nurse never asked, rather than fear of discouragement or lack of understanding. Individuals who were in employment were more likely to have used CAM than those who were not. Binary logistic regression revealed Headache Impact Test (HIT-6) score to be a significant predictor of CAM use (Odds Ratio=1.38 [95% CI 1.05-1.81])., Conclusions: As a matter of desperation, headache clinic patients try CAM therapies. Health care professionals involved in the management of headache should be aware of this. There is a need for evaluation of the benefits and safety of CAM therapies for headache., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Here, we describe the Interactorium, a tool in which a Virtual Cell is used as the context for the seamless visualisation of the yeast protein interaction network, protein complexes and protein 3-D structures. The tool has been designed to display very complex networks of up to 40 000 proteins or 6000 multiprotein complexes and has a series of toolboxes and menus to allow real-time data manipulation and control the manner in which data are displayed. It incorporates new algorithms that reduce the complexity of the visualisation by the generation of putative new complexes from existing data and by the reduction of edges through the use of protein "twins" when they occur in multiple locations. Since the Interactorium permits multi-level viewing of the molecular biology of the cell, it is a considerable advance over existing approaches. We illustrate its use for Saccharomyces cerevisiae but note that it will also be useful for the analysis of data from simpler prokaryotes and higher eukaryotes, including humans. The Interactorium is available for download at http://www.interactorium.net.

Genes encoding the olfactory receptors of the "OR37" subfamily of the mouse are characterized by special features including a clustered expression pattern, assembly in two distinct gene clusters, and highly conserved putative promoter motifs. Mining the rat and dog databases revealed that these two species possess highly conserved clusters of OR37 genes at two syntenic genomic loci. In a prototherian mammal, the platypus (Ornithorhynchus anatinus), none of the characteristic OR37 genes were found. Examination of a metatherian mammal, the gray short-tailed opossum (Monodelphis domestica) revealed seven canonical OR37 genes, all phylogenetically related to cluster II genes and also organized similar to cluster II of eutherian species. In addition, their 5' upstream regions comprised sequence motifs related to the putative regulatory sequences of cluster II genes. Typical cluster I OR37 genes were identified only in the eutherian mammals examined, including the evolutionary ancient anteater, wherein OR37 genes related to both clusters were present. Together, these results reveal novel information concerning the phylogenetic origin and important evolutionary steps of the mammalian-specific OR37 olfactory receptor family.

Ferromagnetic embolization hyperthermia (FEH) is a novel treatment for liver cancer. Magnetic microspheres are injected into the hepatic artery and cluster in the periphery of tumours and are heated with externally applied magnetic fields. In order to more accurately simulate FEH, we modelled a three-dimensional heterogeneous distribution of heat sources. We constructed a fractal model of the vasculature in the periphery of a tumour. We used this model to compute the spatial distribution of the microspheres that lodge in capillaries. We used the distribution model as input to a finite-element heat transfer model of the FEH treatment. The overall appearance of the vascular tree is subjectively similar to that of the disorganized vascular network which encapsulates tumours. The microspheres are distributed in the tumour periphery in similar patterns to experimental observations. We expect the vasculature and microsphere deposition models to also be of interest to researchers of any targeted cancer therapies such as localized intra-arterial chemotherapy and selective internal radiotherapy. Our results show that heterogeneous microsphere distributions give significantly different results to those for a homogeneous model and thus are preferable when accurate results are required.

The hatchling Xenopus laevis tadpole was used to study the brain neurons controlling responsiveness. Tadpoles have reduced motor activity and responsiveness when they hang at rest, attached by cement gland mucus. Afferent input from cement gland mechanosensory neurons has both a phasic role in stopping swimming and a tonic role in reducing responsiveness while tadpoles hang attached. Both these roles depend on GABA(A)-mediated inhibition. We provide evidence supporting the hypothesis that long-term reduced responsiveness in attached tadpoles results from tonic activity in the reticulospinal GABAergic pathway mediating the stopping response. Two groups of putative stopping pathway interneurons were recorded in the caudal and rostral hindbrain of immobilised tadpoles. Both groups showed a sustained increase in activity during simulated attachment. This attached activity was irregular and unstructured. We consider whether low-level firing in cement gland afferents (at approximately 1 Hz) during simulated attachment is sufficient to explain the low-level firing (at approximately 0.5 Hz) in reticulospinal neurons. We then ask if a small population of these neurons (approximately 20) could produce sufficient inhibition of spinal neurons to reduce the whole tadpole's responsiveness. We conclude that for most of their 1st day of life GABAergic brainstem neurons could produce inhibition continuously while the tadpole is at rest.

Hatchling Xenopus laevis tadpoles spend most of their time attached to objects or the water surface by mucus secreted by a gland on the head. While attached, swimming activity and responsiveness to swim-initiating stimuli are reduced over long periods of time. We have investigated the mechanisms and significance of this apparent long-term inhibition. In behavioural experiments we show, firstly, that innervation of the cement gland and GABA(A)-mediated inhibition are necessary for attachment to reduce responsiveness, and secondly, that denervation of the cement gland increases tadpole activity and increases their predation by damselfly nymphs (Zygoptera). To investigate the neuronal pathway from the cement gland to GABA(A) inhibition, we have devised an immobilized, inverted tadpole preparation where a weight attached to the mucus simulates the force as it hangs. Simulated attachment reduces responsiveness and spontaneous fictive swimming activity. We have recorded the activity and responses of trigeminal neurons innervating the cement gland. They are spontaneously active and simulating attachment results in a sustained increase in this activity. We propose that hanging from a mucus strand increases firing in cement gland afferents. This leads to tonic GABA inhibition that reduces tadpole activity and responses, and leads to fewer attacks by predators.

We constructed a three-dimensional fractal model of the vascular network in a tumour periphery. We model the highly disorganised structure of the neoplastic vasculature by using a high degree of variation in segment properties such as length, diameter and branching angle. The overall appearance of the vascular tree is subjectively similar to that of the disorganised vascular network which encapsulates tumours. The fractal dimension of the model is within the range of clinically measured values.

The holy grail of biomedical modelling is an integrated model of the entire human body. To this end, research groups around the world need to interchange experimental data, models and model results. A good interchange will have an efficient representation for storage and sharing and will have tools for modelling, data verification, authoring, data conversions and so on. A field is a spatially varying properly. In this paper we present the abstract field layer (AFL) and the field representation language (FRL). The AFL provides the field abstraction together with a set of common field operations. The FRL provides an efficient means for field representation and storage. We show how fields can be used to interchange information between modelling systems and between modelling and visualisation systems. We are currently developing a software system that composes multiple single cell solvers to create a tissue solver.

The manner in which terrestrial ecosystems are regulated is controversial. The "top-down" school holds that predators limit herbivores and thereby prevent them from overexploiting vegetation. "Bottom-up" proponents stress the role of plant chemical defenses in limiting plant depredation by herbivores. A set of predator-free islands created by a hydroelectric impoundment in Venezuela allows a test of these competing world views. Limited area restricts the fauna of small (0.25 to 0.9 hectare) islands to predators of invertebrates (birds, lizards, anurans, and spiders), seed predators (rodents), and herbivores (howler monkeys, iguanas, and leaf-cutter ants). Predators of vertebrates are absent, and densities of rodents, howler monkeys, iguanas, and leaf-cutter ants are 10 to 100 times greater than on the nearby mainland, suggesting that predators normally limit their populations. The densities of seedlings and saplings of canopy trees are severely reduced on herbivore-affected islands, providing evidence of a trophic cascade unleashed in the absence of top-down regulation.