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University College London , formerly styled University College, London, is a public research university in London, England and a constituent college of the federal University of London. Founded in 1826 as London University, UCL was the first university institution established in London and the first in England to be entirely secular, to admit students regardless of their religion, and to admit women on equal terms with men. The philosopher Jeremy Bentham is commonly regarded as the spiritual father of UCL, as his radical ideas on education and society were the inspiration to its founders, although his direct involvement in its foundation was limited. UCL became one of the two founding colleges of the University of London in 1836. It has grown through mergers, including with the Institute of Neurology , the Eastman Dental Institute , the School of Slavonic and East European Studies , the School of Pharmacy and the Institute of Education .UCL's main campus is located in the Bloomsbury area of central London, with a number of institutes and teaching hospitals elsewhere in central London, and satellite campuses in Adelaide, Australia and Doha, Qatar. UCL is organised into 11 constituent faculties, within which there are over 100 departments, institutes and research centres. UCL has around 36,000 students and 11,000 staff and had a total income of £1.02 billion in 2013/14, of which £374.5 million was from research grants and contracts. Measured by number of students it is both the largest higher education institution in London and largest postgraduate institution in the UK. UCL is responsible for several museums and collections in a wide range of fields including the Petrie Museum of Egyptian Archaeology, a leading collection of Egyptian and Sudanese archaeology, and the Grant Museum of Zoology and Comparative Anatomy.UCL ranks highly in domestic and global league tables; it is 20th in the world in the 2014 Academic Ranking of World Universities, joint 5th in the world in the 2014 QS World University Rankings and 22nd in the world in the 2014/15 Times Higher Education World University Rankings. For the period 1999 to 2009 it was the 13th most-cited university in the world . There are 32 Nobel Prize winners and three Fields Medalists amongst UCL's alumni and current and former staff. UCL alumni include the "Father of the Nation" of each of India, Kenya and Mauritius, the inventor of the telephone, and one of the co-discoverers of the structure of DNA. All five of the naturally-occurring noble gases were discovered at UCL by William Ramsay.UCL is part of three of the 11 biomedical research centres established by the NHS in England and is a founding member of the Francis Crick Institute and UCL Partners, the world's largest academic health science centre. UCL has hundreds of research and teaching partnerships, including a major collaboration with Yale University, the Yale UCL Collaborative. UCL is a member of numerous academic organisations including the G5, the League of European Research Universities and the Russell Group and forms part of the 'golden triangle' of British universities. Wikipedia.


The current synthesis of the 'hygiene hypothesis' suggests that the recent increase in chronic inflammatory disorders is at least partly attributable to immunodysregulation resulting from lack of exposure to microorganisms that have evolved an essential role in the establishment of the immune system. This document provides a background for discussion of the following propositions. 1. The essential role of these organisms is an example of 'evolved dependence'. 2. The most relevant organisms are those that co-evolved with mammals, and already accompanied early hominids in the Paleolithic. 3. More recently evolved 'childhood infections' are not likely to have evolved this role, and recent epidemiology supports this contention. 4. This mechanism is interacting with other modern environmental changes that also lead to enhanced inflammatory responses [inappropriate diet, obesity, psychological stress, vitamin D deficiency, pollution (dioxins), etc.]. 5. The range of chronic inflammatory disorders that is affected is potentially larger than usually assumed [allergies, autoimmunity, inflammatory bowel disease, but also vascular disease, some cancers, depression/anxiety (when accompanied by raised inflammatory cytokines), and perhaps neurodegenerative disorders and type 2 diabetes]. © 2010 British Society for Immunology. Source


Rossier B.C.,University of Lausanne | Baker M.E.,University of California at San Diego | Studer R.A.,University College London
Physiological Reviews | Year: 2015

Transcription and translation require a high concentration of potassium across the entire tree of life. The conservation of a high intracellular potassium was an absolute requirement for the evolution of life on Earth. This was achieved by the interplay of P- and V-ATPases that can set up electrochemical gradients across the cell membrane, an energetically costly process requiring the synthesis of ATP by F-ATPases. In animals, the control of an extracellular compartment was achieved by the emergence of multicellular organisms able to produce tight epithelial barriers creating a stable extracellular milieu. Finally, the adaptation to a terrestrian environment was achieved by the evolution of distinct regulatory pathways allowing salt and water conservation. In this review we emphasize the critical and dual role of Na+-K+-ATPase in the control of the ionic composition of the extracellular fluid and the renin-angiotensin-aldosterone system (RAAS) in salt and water conservation in vertebrates. The action of aldosterone on transepithelial sodium transport by activation of the epithelial sodium channel (ENaC) at the apical membrane and that of Na+-K+-ATPase at the basolateral membrane may have evolved in lungfish before the emergence of tetrapods. Finally, we discuss the implication of RAAS in the origin of the present pandemia of hypertension and its associated cardiovascular diseases. © 2015 the American Physiological Society. Source


Gleeson P.,University College London
PLoS computational biology | Year: 2010

Biologically detailed single neuron and network models are important for understanding how ion channels, synapses and anatomical connectivity underlie the complex electrical behavior of the brain. While neuronal simulators such as NEURON, GENESIS, MOOSE, NEST, and PSICS facilitate the development of these data-driven neuronal models, the specialized languages they employ are generally not interoperable, limiting model accessibility and preventing reuse of model components and cross-simulator validation. To overcome these problems we have used an Open Source software approach to develop NeuroML, a neuronal model description language based on XML (Extensible Markup Language). This enables these detailed models and their components to be defined in a standalone form, allowing them to be used across multiple simulators and archived in a standardized format. Here we describe the structure of NeuroML and demonstrate its scope by converting into NeuroML models of a number of different voltage- and ligand-gated conductances, models of electrical coupling, synaptic transmission and short-term plasticity, together with morphologically detailed models of individual neurons. We have also used these NeuroML-based components to develop an highly detailed cortical network model. NeuroML-based model descriptions were validated by demonstrating similar model behavior across five independently developed simulators. Although our results confirm that simulations run on different simulators converge, they reveal limits to model interoperability, by showing that for some models convergence only occurs at high levels of spatial and temporal discretisation, when the computational overhead is high. Our development of NeuroML as a common description language for biophysically detailed neuronal and network models enables interoperability across multiple simulation environments, thereby improving model transparency, accessibility and reuse in computational neuroscience. Source


Scanlon D.O.,University College London | Walsh A.,University of Bath
Applied Physics Letters | Year: 2012

ZnSnP 2, an absorber material for solar cells, transitions from an ordered chalcopyrite to a disordered sphalerite structure at high temperatures. We investigate the electronic structure of both phases, combining a screened hybrid density functional with the special quasi-random structure method. We predict a bandgap reduction of 0.95 eV between the ordered and fully disordered materials. Experimental reports are consistent with partial disorder. Tuning of the order parameter would lead to a family of ZnSnP 2 phases with bandgaps ranging from 0.75 eV to 1.70 eV, thus providing graded solar cell absorbers from a single material system. © 2012 American Institute of Physics. Source


Maguire E.A.,University College London
Experimental Physiology | Year: 2014

New Findings: What is the topic of this review? This lecture is concerned with autobiographical memory representations, how they evolve and change over time, and the brain regions that support them. What advances does it highlight? The use of high resolution structural and functional magnetic resonance imaging combined with methods such as multi-voxel pattern analysis are opening up new opportunities to study memory consolidation in vivo in humans. We are endlessly fascinated by memory; we desire to improve it and fear its loss. While it has long been recognized that brain regions such as the hippocampus are vital for supporting memories of our past experiences (autobiographical memories), we still lack fundamental knowledge about the mechanisms involved. This is because the study of specific neural signatures of autobiographical memories in vivo in humans presents a significant challenge. However, recent developments in high-resolution structural and functional magnetic resonance imaging coupled with advanced analytical methods now permit access to the neural substrates of memory representations that has hitherto been precluded in humans. Here, I describe how the application of 'decoding' techniques to brain-imaging data is beginning to disclose how individual autobiographical memory representations evolve over time, deepening our understanding of systems-level consolidation. In particular, this prompts new questions about the roles of the hippocampus and ventromedial prefrontal cortex and offers new opportunities to interrogate the elusive memory trace that has for so long confounded neuroscientists. © 2013 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. Source


Hunter A.,University College London
International Journal of Approximate Reasoning | Year: 2013

Argumentation can be modelled at an abstract level using a directed graph where each node denotes an argument and each arc denotes an attack by one argument on another. Since arguments are often uncertain, it can be useful to quantify the uncertainty associated with each argument. Recently, there have been proposals to extend abstract argumentation to take this uncertainty into account. This assigns a probability value for each argument that represents the degree to which the argument is believed to hold, and this is then used to generate a probability distribution over the full subgraphs of the argument graph, which in turn can be used to determine the probability that a set of arguments is admissible or an extension. In order to more fully understand uncertainty in argumentation, in this paper, we extend this idea by considering logic-based argumentation with uncertain arguments. This is based on a probability distribution over models of the language, which can then be used to give a probability distribution over arguments that are constructed using classical logic. We show how this formalization of uncertainty of logical arguments relates to uncertainty of abstract arguments, and we consider a number of interesting classes of probability assignments. © 2012 Elsevier Inc. All rights reserved. Source


Wells J.C.K.,University College London
American Journal of Physical Anthropology | Year: 2012

In the 19th century, two "ecogeographical rules" were proposed hypothesizing associations of climate with mammalian body size and proportions. Data on human body weight and relative leg length support these rules; however, it is unknown whether such associations are attributable to lean tissue (the heat-producing component) or fat (energy stores). Data on weight, height, and two skinfold thickness were obtained from the literature for 137 nonindustrialized populations, providing 145 male and 115 female individual samples. A variety of indices of adiposity and lean mass were analyzed. Preliminary analyses indicated secular increases in skinfolds in men but not women, and associations of age and height with lean mass in both sexes. Decreasing annual temperature was associated with increasing body mass index (BMI), and increasing triceps but not subscapular skinfold. After adjusting for skinfolds, decreasing temperature remained associated with increasing BMI. These results indicate that colder environments favor both greater peripheral energy stores, and greater lean mass. Contrasting results for triceps and subscapular skinfolds might be due to adaptive strategies either constraining central adiposity in cold environments to reduce cardiovascular risk, or favoring central adiposity in warmer environments to maintain energetic support of the immune system. Polynesian populations were analyzed separately and contradicted all of the climate trends, indicating support for the hypothesis that they are cold-adapted despite occupying a tropical region. It is unclear whether such associations emerge through natural selection or through trans-generational and life-course plasticity. These findings nevertheless aid understanding of the wide variability in human physique and adiposity. Copyright © 2011 Wiley Periodicals, Inc. Source


Oberhofer H.,University of Cambridge | Blumberger J.,University College London
Angewandte Chemie - International Edition | Year: 2010

The distance dependences of all electrontransfer parameters, including electronic coupling, were computed for the Ru2+Ru3+ electron self-exchange reaction in aqueous solution. It was found that the probability for electron exchange is a maximum at a Ru2+-Ru 3+ distance of 5.6 Aring; (see free-energy surface), which is significantly smaller than the envelopes of the [Ru(H2O) 6]n+ complexes (Figure Presented). © 2010 Wiley-VCH Verlag GmbH & Co. KCaA. Source


Weiss R.A.,University College London
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Endogenous retrovirus (ERV) genomes integrated into the chromosomal DNA of the host were first detected in chickens and mice as Mendelian determinants of Gag and Env proteins and of the release of infectious virus particles. The presence of ERV was confirmed by DNA hybridization. With complete host genomes available for analysis, we can now see the great extent of viral invasion into the genomes of numerous vertebrate species, including humans. ERVs are found at many loci in host DNA and also in the genomes of large DNA viruses, such as herpesviruses and poxviruses. The evolution of xenotropism and cross-species infection is discussed in the light of the dynamic relationship between exogenous and endogenous retroviruses. Source


Recent years have seen interest in approaches for directly generating fibers and scaffolds following a rising trend for their exploration in the health sciences. In this review the author wishes to briefly highlight the many approaches explored to date for generating such structures, while underlining their advantages and disadvantages, and their contribution in particular to the biomedical sciences. Such structures have been demonstrated as having implications in both the laboratory and the clinic, as they mimic the native extra cellular matrix. Interestingly the only materials investigated until very recently for generating fibrous architectures employed either natural or synthetic polymers with or without the addition of functional molecule(s). Arguably although such constructs have been demonstrated to have many applications, they lack the one unit most important for carrying out the ability to directly reconstruct a three-dimensional functional tissue, namely living cells. Therefore recent findings have demonstrated the ability to directly form cell-laden fibers and scaffolds in useful quantities from which functional three-dimensional living tissues can be conceived. These recent developments have far-reaching ramifications to many areas of research and development, a few of which range from tissue engineering and regenerative medicine, a novel approach to analyzing cell behavior and function in real time in three-dimensions, to the advanced controlled and targeted delivery of experimental and/or medical cells and/or genes for localized treatment. At present these developments have passed all in vitro and in vivo mouse model based challenge trials and are now spearheading their journey towards initiating human clinical trials. Source


Bernabe E.,Kings College London | Sheiham A.,University College London
American Journal of Public Health | Year: 2014

Objectives. We assessed the relative influences of age, period, and cohort effects on trends in caries experience of permanent teeth in 4 different populations. Methods. We used data from England and Wales, United States, Japan, and Sweden in which numerous cross-sectional, nationally representative surveys have been conducted periodically since the early 1960s. For each country, trends in caries experience (measured by DMFT index-the number of decayed, missing, and filled permanent teeth) were analyzed in an age, period, and cohort (APC) analysis using partial least square regression. Results. A strong effect of age manifested in caries experience, period and cohort effects aside. Caries levels increased through to adolescence; thereafter, there was a larger increase in DMFT in adulthood. Compared with the aging effect, period and cohort effects on caries experience were small. Population DMFT scores decreased over time in all countries except Japan. Cohort effects on caries experience displayed a nonlinear pattern in all 4 countries, with slightly lower caries levels among the oldest and most recent generations. Conclusions. Despite marked recent declines in caries among children, caries levels increase with age and remain problematic in adults. Source


Probably the greatest challenge to those managing patients with oral diseases is the dilemma of attempting to predict which oral erythroplakias, leukoplakias, lichenoid and other potentially malignant mucosal disease (PMD) such as oral submucous fibrosis will progress to neoplasia - notably oral squamous cell carcinoma (OSCC). The paper reviews progress over the past decade and the application to the clinical situation. © 2013 John Wiley & Sons A/S. Source


Attridge K.,University of Oxford | Walker L.S.K.,University College London
Immunological Reviews | Year: 2014

The identification of CD25 and subsequently Forkhead box protein 3 (Foxp3) as markers for regulatory T cells (Tregs) has revolutionized our ability to explore this population experimentally. In a similar vein, our understanding of antigen-specific Treg responses in vivo owes much to the fortuitous generation of T-cell receptor (TCR)-transgenic Tregs. This has permitted tracking of Tregs with a defined specificity in vivo, facilitating analysis of how encounter with cognate antigen shapes Treg homeostasis and function. Here, we review the key lessons learned from a decade of analysis of TCR-transgenic Tregs and set this in the broader context of general progress in the field. Use of TCR-transgenic Tregs has led to an appreciation that Tregs are a highly dynamic proliferative population in vivo, rather than an anergic population as they were initially portrayed. It is now clear that Treg homeostasis is positively regulated by encounter with self-antigen expressed on peripheral tissues, which is likely to be relevant to the phenomenon of peripheral repertoire reshaping that has been described for Tregs and the observation that the Treg TCR specificities vary by anatomical location. Substantial evidence has also accumulated to support the role of CD28 costimulation and interleukin-2 in Treg homeostasis. The availability of TCR-transgenic Tregs has enabled analysis of Treg populations that are sufficient or deficient in particular genes, without the comparison being confounded by repertoire alterations. This approach has yielded insights into genes required for Treg function in vivo, with particular progress being made on the role of ctla-4 in this context. As the prospect of manipulating Treg populations in the clinic becomes reality, a full appreciation of the rules governing their homeostasis will prove increasingly important. © 2014 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd. Source


Jenner R.G.,University College London
Briefings in Functional Genomics | Year: 2013

The differentiation of CD4 helperT cells into specialized effector lineages has provided a powerful model for understanding immune cell differentiation. Distinct lineages have been defined by differential expression of signature cytokines and the lineage-specifying transcription factors necessary and sufficient for their production. The traditional paradigm of differentiation towards Th1 and Th2 subtypes driven by T-bet and GATA3, respectively, has been extended to incorporate additional T cell lineages and transcriptional regulators. Technological advances have expanded our view of these lineage-specifying transcription factors to the whole genome and revealed unexpected interplay between them. From these data, it is becoming clear that lineage specification is more complex and plastic than previous models might have suggested. Here, we present an overview of the different forms of transcription factor interplay that have been identified and how T cell phenotypes arise as a product of this interplay within complex regulatory networks.We also suggest experimental strategies that will provide further insight into the mechanisms that underlieT cell lineage specification and plasticity. © The Author 2013. Published by Oxford University Press. All rights reserved. Source


Lee J.-M.,U.S. National Cancer Institute | Ledermann J.A.,University College London | Kohn E.C.,U.S. National Cancer Institute
Annals of Oncology | Year: 2014

Poly(ADP-ribose)polymerase inhibitors (PARPis) have shown promising activity in patients with BRCA1/2 mutation-associated (BRCA1/2MUT+) ovarian and breast cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of sporadic high-grade serous ovarian cancer, and cancers defective in DNA repair pathways, such as prostate, endometrial, and pancreatic cancers. Several PARPis are currently in phase 1/2 clinical investigation, with registration trials now being designed. Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2MUT+ and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers. Understanding more about the molecular abnormalities involved in BRCA-like tumors, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers, is critical to rapidly advancing the field of PARPi therapy and improve clinical outcomes. Source


Marshall M.N.,University College London
International Journal for Quality in Health Care | Year: 2014

Decisions about how to organize and deliver health services are often more complex and seemingly less rational than decisions about what clinical care to provide. The concept of 'Evidence-Based Management', or what might more appropriately be termed 'Evidence-Informed Improvement', does not seem to have captured the hearts and minds of the people responsible for managing health-care provision. Organizational decision-making is more likely to be influenced by political, ideological and pragmatic factors, and by the personal experience of the decision-makers, than by science. Whilst some people would regard the messiness of management decision-making as inevitable, most would accept that decisions could be improved by making greater use of the established health service research evidence, and through a stronger commitment to developing new evidence. Over the last two or more decades the evidence base created by Health Service Researchers has grown in quantity and in quality and yet much of it remains invisible to the people who most need to use it. This paper explores how the disconnect between the traditional 'producers' of research evidence in academia, and the managerial and clinical 'consumers' of that evidence, has contributed to the challenge of embedding an evidence-informed approach to service improvement. The advantages of a closer working relationship between academia and health services are outlined and three approaches to evidence creation and utilization are described which attempt to maximize the influence of scientific evidence on managerial practice. © The Author 2013. Published by Oxford University Press in association with the International Society for Quality in Health Care; all rights reserved. Source


Peitsidis P.,University College London
Archives of gynecology and obstetrics | Year: 2011

To perform an extensive systematic review to examine all the available literature reporting iatrogenic acquired arteriovenous malformation (AVM) induced after diagnostic curettage and to describe a further case of a 34-year-old woman presenting with acute vaginal bleeding due to AVM induced after uterine curettage for termination of pregnancy. We searched the electronic databases: MEDLINE (1950-2011), Embase (1980-2011), Cochrane Library (2004-2011), Cinahl (1981-2011), Popline (2004-2011). Initial search extracted 333 relevant articles. Final assessment resulted to the inclusion of 91 studies, 85 case reports and 6 observational studies. Studies are dated between 1954 and 2011. A metanalysis of the 85 case reports reporting 100 patients was performed. The mean age of the women diagnosed with AVM was 30 ± 9.1 years, range (16-72) years, 96 women were premenopausal (96%) and 4 were postmenopausal (4%). Ultrasound imaging was applied in 86 patients (86%), and ultrasound combined with angiography was performed in 51 patients (51%). Uterine artery embolization (UAE) was the most common treatment option performed in 59 patients (59%). Total abdominal hysterectomy was performed in 29 patients (29%). Spontaneous resolution of AVM occurred in six patients (6%). In 17 patients (17%), recurrence occurred after treatment with UAE. Twenty-four articles reported pregnancies in 27 patients (27%). Ultrasound imaging with appropriate knowledge of color Doppler features minimizes the use of inappropriate interventional procedures such as diagnostic curettage. UAE is effective in treatment, and rarely leads to complications. Source


Dumontheil I.,Birkbeck, University of London | Dumontheil I.,University College London
Developmental Cognitive Neuroscience | Year: 2014

Rostral prefrontal cortex (RPFC) has increased in size and changed in terms of its cellular organisation during primate evolution. In parallel emerged the ability to detach oneself from the immediate environment to process abstract thoughts and solve problems and to understand other individuals' thoughts and intentions. Rostrolateral prefrontal cortex (RLPFC) is thought to play an important role in supporting the integration of abstract, often self-generated, thoughts. Thoughts can be temporally abstract and relate to long term goals, or past or future events, or relationally abstract and focus on the relationships between representations rather than simple stimulus features. Behavioural studies have provided evidence of a prolonged development of the cognitive functions associated with RLPFC, in particular logical and relational reasoning, but also episodic memory retrieval and prospective memory. Functional and structural neuroimaging studies provide further support for a prolonged development of RLPFC during adolescence, with some evidence of increased specialisation of RLPFC activation for relational integration and aspects of episodic memory retrieval. Topics for future research will be discussed, such as the role of medial RPFC in processing abstract thoughts in the social domain, the possibility of training abstract thinking in the domain of reasoning, and links to education. © 2014 Published by Elsevier Ltd. Source


Kirkbride J.B.,University College London
Health and Place | Year: 2014

Recent research published in Health and Place (Ngamini Ngui et al., 2013b) found that one third of people with first episode psychosis [FEP] will have made a large-scale migration six years after initial diagnosis. Here, I extend this discussion around three important observations. Namely, at first presentation the most disadvantaged communities already shoulder the burden of psychotic morbidity; people with FEP in more rural communities migrate less often, and people with FEP exhibit both upwards and downwards social mobility after onset. Understanding the reasons for (non-)migration before and after psychosis onset is now required for effective public mental health and service provision. © 2014 The Author. Source


Wells J.C.K.,University College London
European Journal of Clinical Nutrition | Year: 2013

The aetiology of obesity is seemingly simple to understand: individuals consume more energy than they expend, with the excess energy being stored in adipose tissue. Public health campaigns therefore promote dietary restraint and physical exercise, and emphasize individual responsibility for these behaviours. Increasingly, however, researchers are switching from thermodynamic to metabolic models of obesity, thereby clarifying how specific environmental factors promote lipogenesis. Obesity can best be explained not by counting 'calories in and out', but by understanding how specific dietary products and activity behaviours perturb cellular metabolism and promote net lipogenesis. This metabolic approach can furthermore be integrated with more sophisticated models of how commercial practices drive the consumer trends that promote obesogenic behaviours. Notably, obesity treatment has proven more effective if it bypasses individual responsibility, suggesting that a similar approach placing less emphasis on individual responsibility would improve the efficacy of obesity prevention. Successful obesity prevention campaigns are likely to emerge only when the public receive better 'protection' from the commercial practices that are driving the global obesity epidemic. Rather than populations failing to heed governments' public health advice, governments are currently failing the public by abandoning their responsibility for regulating commercial activities. © 2013 Macmillan Publishers Limited. Source


Rahman S.,University College London
Journal of Inherited Metabolic Disease | Year: 2013

Inherited defects of oxidative phosphorylation lead to heterogeneous, often multisystem, mitochondrial diseases. This review highlights those mitochondrial syndromes with prominent gastrointestinal and hepatic symptoms, categorised according to underlying disease mechanism. Mitochondrial encephalopathies with major gastrointestinal involvement include mitochondrial neurogastrointestinal encephalopathy and ethylmalonic encephalopathy, which are each associated with highly specific clinical and metabolic profiles. Mitochondrial hepatopathies are most frequently caused by defects of mitochondrial DNA maintenance and expression. Although mitochondrial disorders are notorious for extreme clinical, biochemical and genetic heterogeneity, there are some pathognomonic clinical and metabolic clues that suggest a specific diagnosis, and these are highlighted. An approach to diagnosis of these complex disorders is presented, together with a genetic classification, including mitochondrial DNA disorders and nuclear-encoded defects of mitochondrial DNA maintenance and translation, OXPHOS complex assembly and mitochondrial membrane lipids. Finally, supportive and experimental therapeutic options for these currently incurable diseases are reviewed, including liver transplantation, allogeneic haematopoietic stem cell transplantation and gene therapy. © 2013 SSIEM and Springer Science+Business Media Dordrecht. Source


Hitchings R.,University College London
Wiley Interdisciplinary Reviews: Climate Change | Year: 2011

This article reviews work from across various disciplines that illuminates the changing ways in which people around the world manage their experience of local climate with particular reference to temperature. This topic is important because it has implications for issues that range from the rising energy demands associated with the spread of air-conditioning to the idea that future societies may eventually forget about the climates outside the buildings into which they have retreated. My purpose is neither to critique the various ways of conceptualizing the relation between human comfort and thermal environment nor to champion any particular argument about the mechanism that guides its development over time. Rather the aim is to integrate a diverse set of studies into an evaluative account that foregrounds the cultural differences and geographical dynamics now characterizing the ways in which people relate to outdoor temperature. Many of us now spend a great deal of our time surrounded by controlled bodies of ambient air which may superficially seem appropriately civilized. Yet this same situation could easily end up making us less willing to experience our local climates and more reliant on some quite resource hungry technologies. Changing practices of coping with outdoor temperature should be examined further. © 2011 John Wiley & Sons, Ltd. Source


Price S.L.,University College London
Chemical Society Reviews | Year: 2014

Currently, organic crystal structure prediction (CSP) methods are based on searching for the most thermodynamically stable crystal structure, making various approximations in evaluating the crystal energy. The most stable (global minimum) structure provides a prediction of an experimental crystal structure. However, depending on the specific molecule, there may be other structures which are very close in energy. In this case, the other structures on the crystal energy landscape may be polymorphs, components of static or dynamic disorder in observed structures, or there may be no route to nucleating and growing these structures. A major reason for performing CSP studies is as a complement to solid form screening to see which alternative packings to the known polymorphs are thermodynamically feasible. This journal is © the Partner Organisations 2014. Source


Ekins P.,University College London
Progress in Physical Geography | Year: 2011

This paper reflects on the extensive literature on environmental sustainability that has been produced over the last two decades, and proposes a new approach for environmental policy that goes beyond the cost-benefit analysis that has proved so difficult to implement for non-marginal environmental issues. This approach combines the Safe Minimum Standard approach, which was proposed many years ago, with the concepts of environmental functions and ecosystem goods and services, which have been developed much more recently. It is shown that this approach provides the basis for a robust calculation of sustainability across different environmental themes, following which a 'sustainability gap', showing the extent to which this standard is not being met, may be computed. This gap may be expressed in both physical and monetary terms, which permits the formulation of sustainability performance in a scientifically robust, easily communicable indicator that may be compared with GDP. While there appear to be no insurmountable scientific or practical obstacles to the full operationalization of this approach, it remains to be seen whether human societies are sufficiently concerned about the implications of continuing environmental unsustainability to make the resources available for such operationalization, and to enact the policies to allow the sustainability standards to be met. © The Author(s) 2011. Source


Scully C.,University College London
Medicina Oral, Patologia Oral y Cirugia Bucal | Year: 2011

Oral cancer appears to be increasing in incidence, and mortality has hardly improved over the past 25 years. Better understanding of the aetiopatho genesis should lead to more accurate and earlier diagnosis and more effective treatments with fewer adverse effects. Cancer is the result of DNA mutations arising spontaneously and from the action of various mutagens, especially in tobacco and alcohol. A sequence of genetic changes leads eventually to loss of growth control and autonomy. Countering these changes are mechanisms to metabolise carcinogens, repair DNA damage, control growth, and defend against cancer. Cancer is a consequence of an interaction of these many factors. Diagnosis is increasingly aided by detection of cellular and now molecular changes. Treatment is increasingly looking towards chemotherapy and now gene therapy. However, there is no doubt that prevention is the most important aspect, particularly patient education and the reduction of lifestyle risk habits and environmental factors. © Medicina Oral S. L. C.I.F. Source


Savory S.J.,University College London
IEEE Journal on Selected Topics in Quantum Electronics | Year: 2010

Digital coherent receivers have caused a revolution in the design of optical transmission systems, due to the subsystems and algorithms embedded within such a receiver. After giving a high-level overview of the subsystems, the optical front end, the analog-to-digital converter (ADC) and the digital signal processing (DSP) algorithms, which relax the tolerances on these subsystems are discussed. Attention is then turned to the compensation of transmission impairments, both static and dynamic. The discussion of dynamic-channel equalization, which forms a significant part of the paper, includes a theoretical analysis of the dual-polarization constant modulus algorithm, where the control surfaces several different equalizer algorithms are derived, including the constant modulus, decision-directed, trained, and the radially directed equalizer for both polarization division multiplexed quadriphase shift keyed (PDM-QPSK) and 16 level quadrature amplitude modulation (PDM-16-QAM). Synchronization algorithms employed to recover the timing and carrier phase information are then examined, after which the data may be recovered. The paper concludes with a discussion of the challenges for future coherent optical transmission systems. © 2010 IEEE. Source


Berghe T.V.,Vlaams Institute for Biotechnology | Linkermann A.,University of Kiel | Jouan-Lanhouet S.,Vlaams Institute for Biotechnology | Walczak H.,University College London | Vandenabeele P.,Vlaams Institute for Biotechnology
Nature Reviews Molecular Cell Biology | Year: 2014

Cell death research was revitalized by the understanding that necrosis can occur in a highly regulated and genetically controlled manner. Although RIPK1 (receptor-interacting protein kinase 1)-and RIPK3-MLKL (mixed lineage kinase domain-like)-mediated necroptosis is the most understood form of regulated necrosis, other examples of this process are emerging, including cell death mechanisms known as parthanatos, oxytosis, ferroptosis, NETosis, pyronecrosis and pyroptosis. Elucidating how these pathways of regulated necrosis are interconnected at the molecular level should enable this process to be therapeutically targeted. © 2014 Macmillan Publishers Limited. Source


Gems D.,University College London
Aging | Year: 2014

Why do humans live longer than other higher primates? Why do women live longer than men? What is the significance of the menopause? Answers to these questions may be sought by reference to the mechanisms by which human aging might have evolved. Here, an evolutionary hypothesis is presented that could answer all three questions, based on the following suppositions. First, that the evolution of increased human longevity was driven by increased latelife reproduction by men in polygynous primordial societies. Second, that the lack of a corresponding increase in female reproductive lifespan reflects evolutionary constraint on late-life oocyte production. Third, that antagonistic pleiotropy acting on androgen-generated secondary sexual characteristics in men increased reproductive success earlier in life, but shortened lifespan. That the gender gap in aging is attributable to androgens appears more likely given a recent report of exceptional longevity in eunuchs. Yet androgen depletion therapy, now used to treat prostatic hyperplasia, appears to accelerate other aspects of aging (e.g. cardiovascular disease). One possibility is that low levels of androgens throughout life reduces aging rate, but late-life androgen depletion does not. © Gems. Source


Zeki S.,University College London
Frontiers in Human Neuroscience | Year: 2013

Though first published almost one century ago, and though its premise has been disputed, Clive Bell's essay on aesthetics in his book Art still provides fertile ground for discussing problems in aesthetics, especially as they relate to neuroesthetics. In this essay, I begin with a brief account of Bell's ideas on aesthetics, and describe how they focus on problems of importance to neuroesthetics. I also examine where his premise falls short, and where it provides significant insights, from a neuroesthetic and general neurobiological point of view. © 2013 Zeki. Source


Bateman A.,Anna Freud Center | Fonagy P.,University College London
British Journal of Psychiatry | Year: 2013

Background: Evidence of remission from borderline personality disorder (BPD) without specialised treatment is accumulating. Aims: To establish whether specialised treatments are indicated for patients with clinically severe disorder. Method: The impact of clinical severity on outcomes of a randomised controlled trial of mentalisation-based treatment (MBT) was contrasted with structured clinical management (SCM). Severity indicators were defined as severity of comorbid psychiatric syndromes, severity of BPD, severity of personality disturbance and severity of symptom distress. Logistic regressions were used to predict the likelihood of recovery at 18 months, and mixed-effects regression analysis was applied to examine the association of severity and rates of improvement across time in the two treatment groups. Results: None of the severity criteria predicted outcome at the end of treatment on logistic regression. However, testing the significance of distribution of cases of recovery v. nonrecovery suggested that multiple Axis II diagnoses and symptom distress influenced outcomes. Conclusions: Borderline personality disorder with significant Axis II comorbidity is a possible but uncertain indicator for specialist treatment. Patients whose only personality disorder diagnosis is BPD do equally well with SCM. Prospective studies are needed. Source


Ethnic groups vary in cardiometabolic risk, but the underlying mechanisms remain unclear. Several components of body composition variability (fat/lean ratio, fat distribution, lean mass composition and metabolism, and adipose tissue biology) are increasingly linked with cardiometabolic risk and vary substantially across ethnic groups. Constituents of lean mass are proposed to contribute to 'metabolic capacity', a generic trait favouring the maintenance of homeostasis. Adiposity is proposed to contribute to 'metabolic load', which at higher levels challenges metabolic homeostasis, elevating cardiometabolic risk. Ethnic differences in body composition, representing different load-capacity ratios, may therefore contribute to ethnic variability in cardiometabolic risk. Ecological and evolutionary factors potentially contributing to ethnic variability in body composition are explored. In contemporary populations, clinicians encounter an increasing range of ethnicity, along with many individuals of mixed-ethnic ancestry. Increasing understanding of the contribution of body composition to cardiometabolic risk may reduce the need to treat ethnic groups as qualitatively different. A conceptual model is proposed, treating insulin sensitivity and stroke risk as composite functions of body composition variables. Operationalizing this model may potentially improve the ability to assess cardiovascular risk across the full ethnicity spectrum, and to predict cardiometabolic consequences of excess weight gain. © 2012 International Association for the Study of Obesity. Source


Pembrey M.E.,University College London
Human Fertility | Year: 2010

Genomic imprinting establishes the principle of epigenetic marks placed in one generation influencing gene expression in the next generation. This led to speculation that epigenetic gametic inheritance might underlie a form of transgenerational adaptation to major environmental challenges, such that exposures in one generation correlate with outcomes in the next generation(s). An ongoing collaboration between Ume University, Sweden and the Avon Longitudinal Study of Parents and Childhood, Bristol University, UK has documented transgenerational correlations between food supply during the early life of the paternal grandparents and the grandchild's longevity, including associations with cardiovascular and diabetic deaths, and correlations between the onset of paternal smoking in mid-childhood and the body mass index of future sons. Whilst the mediating molecular mechanism(s) is unknown, the sex-specific transmission patterns and exposure-sensitive periods suggest a pre-evolved transgenerational response mechanism. © 2010 The British Fertility Society. Source


Chen S.,University College London
Nature Photonics | Year: 2016

Reliable, efficient electrically pumped silicon-based lasers would enable full integration of photonic and electronic circuits, but have previously only been realized by wafer bonding. Here, we demonstrate continuous-wave InAs/GaAs quantum dot lasers directly grown on silicon substrates with a low threshold current density of 62.5 A cm2, a room-temperature output power exceeding 105 mW and operation up to 120 °C. Over 3,100 h of continuous-wave operating data have been collected, giving an extrapolated mean time to failure of over 100,158 h. The realization of high-performance quantum dot lasers on silicon is due to the achievement of a low density of threading dislocations on the order of 105 cm-2 in the III–V epilayers by combining a nucleation layer and dislocation filter layers with in situ thermal annealing. These results are a major advance towards reliable and cost-effective silicon-based photonic–electronic integration. © 2016 Nature Publishing Group Source


Panicker J.N.,University College London
Clinical rehabilitation | Year: 2010

This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is 'the trainee consistent demonstrates a knowledge of the pathophysiology of various specific impairments including bladder dysfunction' and 'management approaches for specific impairments including bladder dysfunction'. The lower urinary tract (bladder and urethra) has two roles: storage of urine and emptying at appropriate times. The optimal and coordinated activity of the lower urinary tract is subject to a complex neural control which involves all levels of the nervous system, from cortex to peripheral innervation. The complexity of the neural control of lower urinary tract explains the high prevalence of urinary disturbances in neurologic disease. Information obtained from history taking and supplemented by use of a bladder diary forms the cornerstone of evaluation. Ultrasonography is used to assess the degree of incomplete bladder emptying, and for assessing the upper tracts. Urodynamic tests, with or without simultaneous fluoroscopic monitoring, assess detrusor and bladder outlet function and give fundamental information about detrusor pressure and thus the risk factor for upper tract damage. Impaired emptying is most often managed by clean intermittent self-catheterization and this should be initiated if the post-void residual urine is greater than 100 mL or exceeds one third of bladder capacity, or rarely if spontaneous voiding is dangerous due to high detrusor pressure. Storage symptoms are most often managed using antimuscarinic medications. Other options include desmopressin to reduce urine output or intra-detrusor injection of botulinum toxin type A to reduce detrusor overactivity. Understanding of the underlying mechanism of lower urinary tract dysfunction is crucial for effective management. Source


Mullin S.,University College London
Molecular neurobiology | Year: 2013

α-Synuclein (SNCA) is a substantive component of Lewy bodies, the pathological hallmark of Parkinson's disease (PD). The discovery and subsequent derivation of its role in PD has led to a suprising but fruitful convergence of the fields of biochemistry and molecular genetics. In particular, the manipulation of the cell lines of a number of forms of familial PD has implicated SNCA in distinct and diverse biochemical pathways related to its pathogenesis. This current and rapidly evolving concept indicates PD is a disease in which interacting pathways of oxidative stress, mitochondrial dysfunction and impaired regulation of protein turnover interact to cause dopaminergic cell dysfunction and death. SNCA has a central role in these processes and manipulation of its expression, degradation and aggregation appear to be promising neuroprotective therapeutic targets. Source


Stone J.,University of Edinburgh | Edwards M.,University College London
Neurology | Year: 2012

Functional (psychogenic) motor symptoms are diagnosed on the basis of positive signs of inconsistency or incongruity with known neurologic disease. These signs, such as Hoover sign or tremor entrainment, are often regarded by neurologists as 'tricks of the trade,' to 'catch the patient out, ' and certainly not to be shared with them. In this reflective article, the authors suggest that showing the patient with functional motor symptoms their physical signs, if done in the right way, is actually one of the most useful things a neurologist can do for these patients in persuading them of the accuracy of their diagnosis and the potential reversibility of their symptoms. Copyright © 2012 by AAN Enterprises, Inc. Source


Hausdorf B.,University of Hamburg | Hennig C.,University College London
Systematic Biology | Year: 2010

We propose a method for delimiting species based on dominant or codominant multilocus data using Gaussian clustering with a noise component for outliers. Case studies show that provisional species delimited using Gaussian clustering based on dominant multilocus data correspond well with provisional species delimited based on other data. However, the performance of Gaussian clustering in delimiting species based on few codominant markers was only moderate. Species represented by few individuals are usually included in the noise component because clusters are difficult to recognize with limited data. As alternative methods, we evaluated two model-based clustering methods originally proposed to infer population structure and assign individuals to populations based on the assumption of Hardy-Weinberg equilibrium within populations, namely STRUCTURE and STRUCTURAMA, as well as the "fields for recombination" approach. The latter resulted in lumping all individuals of each data set with codominant markers together, and whereas STRUCTURE often provides no decision about the number of clusters, STRUCTURAMA usually yields correct or almost correct numbers of clusters. The classification success of STRUCTURAMA analyses based on codominant markers was very good, but its performance with dominant markers was less consistent. Based on the classification success of the different methods for delimiting species with dominant and codominant multilocus markers in the case studies, we recommend using Gaussian clustering for data sets with dominant markers and STRUCTURAMA for data sets with codominant markers. © 2010 The Author(s). Source


Roiser J.P.,University College London
CNS spectrums | Year: 2013

We discuss the importance of cognitive abnormalities in unipolar depression, drawing the distinction between "hot" (emotion-laden) and "cold" (emotion-independent) cognition. "Cold" cognitive impairments are present reliably in unipolar depression, underscored by their presence in the diagnostic criteria for major depressive episodes. There is good evidence that some "cold" cognitive abnormalities do not disappear completely upon remission, and that they predict poor response to antidepressant drug treatment. However, in many studies the degree of impairment is moderately related to symptoms. We suggest that "cold" cognitive deficits in unipolar depression may in part be explicable in terms of alterations in "hot" processing, particularly on tasks that utilize feedback, on which depressed patients have been reported to exhibit a "catastrophic response to perceived failure." Other abnormalities in "hot" cognition are commonly observed on tasks utilizing emotionally valenced stimuli, with numerous studies reporting mood-congruent processing biases in depression across a range of cognitive domains. Additionally, an emerging literature indicates reliable reward and punishment processing abnormalities in depression, which are especially relevant for hard-to-treat symptoms such as anhedonia. Both emotional and reward biases are strongly influenced by manipulations of the neurochemical systems targeted by antidepressant drugs. Such a pattern of "hot" and "cold" cognitive abnormalities is consistent with our cognitive neuropsychological model of depression, which proposes central roles for cognitive abnormalities in the generation, maintenance, and treatment of depressive symptoms. Future work should examine in greater detail the role that "hot" and "cold" cognitive processes play in mediating symptomatic improvement following pharmacological, psychological, and novel brain circuit-level interventions. Source


Gilbert S.J.,University College London
Quarterly Journal of Experimental Psychology | Year: 2015

In everyday life, we often use external artefacts such as diaries to help us remember intended behaviours. In addition, we commonly manipulate our environment, for example by placing reminders in noticeable places. Yet strategic offloading of intentions to the external environment is not typically permitted in laboratory tasks examining memory for delayed intentions. What factors influence our use of such strategies, and what behavioural consequences do they have? This article describes four online experiments (N = 1196) examining a novel web-based task in which participants hold intentions for brief periods, with the option to strategically externalize these intentions by creating a reminder. This task significantly predicted participants' fulfilment of a naturalistic intention embedded within their everyday activities up to one week later (with greater predictive ability than more traditional prospective memory tasks, albeit with weak effect size). Setting external reminders improved performance, and it was more prevalent in older adults. Furthermore, participants set reminders adaptively, based on (a) memory load, and (b) the likelihood of distraction. These results suggest the importance of metacognitive processes in triggering intention offloading, which can increase the probability that intentions are eventually fulfilled. © 2014, The Author. Published by Taylor & Francis. Source


Bays P.M.,University College London
Trends in Cognitive Sciences | Year: 2015

This opinion article argues that noise (randomness) in neural activity is the limiting factor in visual working memory (WM), determining how accurately we can maintain stable internal representations of external stimuli. Sharing of a fixed amount of neural activity between items in memory explains why WM can be successfully described as a continuous resource. This contrasts with the popular conception of WM as comprising a limited number of memory slots, each holding a representation of one stimulus - I argue that this view is challenged by computational theory and the latest neurophysiological evidence. © 2015 Elsevier Ltd. Source


Dein S.,University College London
The Journal of nervous and mental disease | Year: 2012

Although studies examining religion, spirituality, and mental health generally indicate positive associations, there is a need for more sophisticated methodology, greater discrimination between different cultures and traditions, more focus on situated experiences of individuals belonging to particular traditions, and, in particular, greater integration of theological contributions to this area. We suggest priorities for future research based on these considerations. Source


Candy B.,University College London
Cochrane database of systematic reviews (Online) | Year: 2012

This is an update of the review published on 'Drug therapy for anxiety in adult palliative care patients' in Issue 1, 2004 of The Cochrane Library. Anxiety is common in palliative care patients. It can be a natural response to impending death, but it may represent a clinically significant issue in its own right. It may also result from pain, or other untreated or poorly managed symptoms. When anxiety is severe or distressing drug therapy may be considered in addition to supportive care. This review aimed to identify and evaluate randomised controlled trials examining the effectiveness of drug therapy for symptoms of anxiety in adult palliative care patients. We searched the following sources: CENTRAL (The Cochrane Library 2012, Issue 2), MEDLINE (1966 to 2012), EMBASE (1980 to 2012), CINAHL (1982 to 2012), PsycLit (1974 to 2000) and PsycInfo (1990 to 2012) for literature pertaining to this topic published in any language using a detailed search strategy. We sought prospective, randomised trials, with or without blinding, involving the use of drug therapy for the treatment of symptoms of anxiety in adult palliative care patients. Pharmacological agents included 5-HT3 receptor antagonists, anxiolytic agents, antiepileptic agents, antidepressive agents, antipsychotic agents, benzodiazepines, butyrophenones, phenothiazines, antihistamines, barbiturates, sedative hypnotics, antiepileptic drugs and beta-blockers. We identified and excluded six studies using the original search strategy, with a further two studies being identified and excluded for this 2012 update. We therefore identified a total of eight potential studies but none met the criteria for inclusion in this review. No data were available to enable an assessment to be made of the effectiveness of drugs to treat symptoms of anxiety in palliative care patients. There remains insufficient evidence to draw a conclusion about the effectiveness of drug therapy for symptoms of anxiety in adult palliative care patients. To date no studies have been found that meet the inclusion criteria for this review. Prospective controlled clinical trials are required in order to establish the benefits and harms of drug therapy for the treatment of anxiety in palliative care. Source


Ke X.,University College London
American Journal of Human Genetics | Year: 2012

Many genetic loci and SNPs associated with many common complex human diseases and traits are now identified. The total genetic variance explained by these loci for a trait or disease, however, has often been very small. Much of the "missing heritability" has been revealed to be hidden in the genome among the large number of variants with small effects. Several recent studies have reported the presence of multiple independent SNPs and genetic heterogeneity in trait-associated loci. It is therefore reasonable to speculate that such a phenomenon could be common among loci known to be associated with a complex trait or disease. For testing this hypothesis, a total of 117 loci known to be associated with rheumatoid arthritis (RA), Crohn disease (CD), type 1 diabetes (T1D), or type 2 diabetes (T2D) were selected. The presence of multiple independent effects was assessed in the case-control samples genotyped by the Wellcome Trust Case Control Consortium study and imputed with SNP genotype information from the HapMap Project and the 1000 Genomes Project. Eleven loci with evidence of multiple independent effects were identified in the study, and the number was expected to increase at larger sample sizes and improved statistical power. The variance explained by the multiple effects in a locus was much higher than the variance explained by the single reported SNP effect. The results thus significantly improve our understanding of the allelic structure of these individual disease-associated loci, as well as our knowledge of the general genetic mechanisms of common complex traits and diseases. © 2012 The American Society of Human Genetics. Source


Schott J.M.,University College London
Neurobiology of Aging | Year: 2012

Defining cases and controls on the basis of biomarkers rather than clinical diagnosis may reduce sample sizes required for genetic studies. The aim of this study was to assess whether characterizing case/control status on the basis of cerebrospinal fluid (CSF) profile would increase power to replicate known genetic associations for Alzheimer's disease (AD). Independent of clinical diagnosis, Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with 2 CSF biomarkers for AD (Aβ1-42 < 192 pg/mL and tau phosphorylated at threonine 181 (p-tau) > 23 pg/mL, "CSF-positive") were compared with those without CSF evidence for AD (Aβ1-42 > 192 pg/mL and 181-phosphorylated tau < 23 pg/mL, "CSF-negative"). Minor allele frequency (MAF) and odds ratios (ORs) between these 2 groups were calculated for 7 single-nucleotide polymorphisms (SNPs) of interest. Two hundred thirty-two individuals were CSF-positive and 94 CSF-negative. There were no differences in age (74.7 ± 7.2 vs. 75.0 ± 6.5 years, p = 0.7), but significant differences in Mini Mental State Examination (MMSE) (25.9 ± 2.6 vs. 28.2 ± 1.7, p < 0.001) between the CSF-positive and CSF-negative groups. Significant differences in MAF (p < 0.05, uncorrected) were seen for CR1 (rs1408077; OR, 1.59; 95% confidence interval [CI], 1.01-2.49), PICALM (rs541458; OR, 0.68, 95% CI, 0.47-0.98), TOMM40 (rs2075650; OR, 4.30; 95% CI, 2.61-7.06); and possession of 1 or more APOE ε4 alleles (OR, 9.84; 95% CI, 5.48-17.67). These results suggest that using biomarkers of AD pathology to define case and control status may increase power in genetic association studies. © 2012 Elsevier Inc. Source


Cochat P.,University Claude Bernard Lyon 1 | Rumsby G.,University College London
New England Journal of Medicine | Year: 2013

Primary hyperoxaluria should be considered in any patient with a history of recurrent calcium oxalate stones, nephrocalcinosis, or both (Table 2). Once the diagnosis has been confirmed by genetic testing, aggressive supportive treatment is indicated, followed by an appropriate organ-transplantation strategy if renal function is declining. Future therapeutic developments are aimed at correcting the underlying defects without exposing patients to the lifelong risks associated with organ transplantation. Copyright © 2013 Massachusetts Medical Society. Source


De Strooper B.,Center for the Biology of Disease | De Strooper B.,Catholic University of Leuven | De Strooper B.,University College London
Cell | Year: 2014

γ-Secretase proteases have been associated with pathology in Alzheimer disease (AD), but we are just beginning to understand their basic mechanisms and physiological roles. A negative drug trial with a broad spectrum γ-secretase inhibitor in AD patients has severely dampened enthusiasm for the potential of pursuing γ-secretase research therapeutically. This pessimism is unwarranted: analysis of available information presented here demonstrates significant confounds for interpreting the outcome of the trial and argues that the major lessons pertain to broad knowledge gaps that are imperative to fill. ©2014 Elsevier Inc. Source


Barrios A.,University College London
Seminars in Cell and Developmental Biology | Year: 2014

The ability to generate behavioral plasticity according to ever-changing physiological demands and environmental conditions is a universal feature of decision-making circuits in all animals. Decision-making requires complex integration of internal states with sensory context. As a mate searching strategy, the Caenorhabditis elegans male modifies his exploratory behavior in relation to a source of food according to recent sensory experience with mates. Information about the reproductive and nutritional status of the male is also incorporated in his choice of exploratory behavior. The study of mate searching in the C. elegans male, a genetic model organism with a nervous system of only 383 neurons, provides the opportunity to elucidate the molecular and cellular mechanisms of state-dependent control of behavior and sensory integration. Here I review our progress in understanding the physiological and environmental regulation of the male's exploratory choices - to explore in search of mates or to exploit a source of food - and the neural circuits and neuromodulator pathways underlying this decision. © 2014 Elsevier Ltd. Source


Raimondi C.,University College London
Biochemical Society Transactions | Year: 2014

Neuropilin-1 (NRP1), together with neuropilin-2, belongs to the neuropilin family. Neuropilins are transmembrane proteins essential for vascular and neural development and act as co-receptors for secreted signalling molecules of the class 3 semaphorin and vascular endothelial growth factor A (VEGF-A) families. NRP1 promotes VEGF-A signal in blood vascular endothelium and semaphorin signal in lymphatic endothelium, by forming complexes with its co-receptors. Mouse mutant studies established that NRP1 expression is essential during development because mice lacking NRP1 expression die embryonically and show severe neuronal and cardiovascular defects. Even though the contribution of NRP1 to vascular development has been mainly ascribed to its function as a VEGF-A receptor, recent evidence suggests that NRP1 contributes to angiogenesis through VEGF-independent mechanisms. In the present paper, we provide an overview of NRP1 functions in the vasculature and discuss current knowledge of NRP1-dependent signalling in the endothelium. ©The Authors Journal compilation ©2014 Biochemical Society. Source


Dean M.C.,University College London
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

A chronology of dental development in Pan troglodytes is arguably the best available model with which to compare and contrast reconstructed dental chronologies of the earliest fossil hominins. Establishing a time scale for growth is a requirement for being able to make further comparative observations about timing and rate during both dento-skeletal growth and brain growth. The absolute timing of anterior tooth crown and root formation appears not to reflect the period of somatic growth. In contrast, the molar dentition best reflects changes to the total growth period. Earlier initiation of molar mineralization, shorter crown formation times, less root length formed at gingival emergence into functional occlusion are cumulatively expressed as earlier ages at molar eruption. Things that are similar in modern humans and Pan, such as the total length of time taken to form individual teeth, raise expectations that these would also have been the same in fossil hominins. The best evidence there is from the youngest fossil hominin specimens suggests a close resemblance to the model for Pan but also hints that Gorilla may be a better developmental model for some. A mosaic of great ape-like features currently best describes the timing of early hominin dental development. © 2010 The Royal Society. Source


Rahman S.,University College London
Journal of Inherited Metabolic Disease | Year: 2015

Mitochondrial diseases are clinically, biochemically and genetically heterogeneous disorders of two genomes, for which effective curative therapies are currently lacking. With the exception of a few rare vitamin/cofactor responsive conditions (including ACAD9 deficiency, disorders of coenzyme Q10 biosynthesis, and Leigh syndrome caused by mutations in the SLC19A3 transporter), the mainstay of treatment for the vast majority of patients involves supportive measures. The search for a cure for mitochondrial disease is the subject of intensive research efforts by many investigators across the globe, but the goal remains elusive. The clinical and genetic heterogeneity, multisystemic nature of many of these disorders, unpredictable natural course, relative inaccessibility of the mitochondrion and lack of validated, clinically meaningful outcome measures, have all presented great challenges to the design of rigorous clinical trials. This review discusses barriers to developing effective therapies for mitochondrial disease, models for evaluating the efficacy of novel treatments and summarises the most promising emerging therapies in six key areas: 1) antioxidant approaches; 2) stimulating mitochondrial biogenesis; 3) targeting mitochondrial membrane lipids, dynamics and mitophagy; 4) replacement therapy; 5) cell-based therapies; and 6) gene therapy approaches for both mtDNA and nuclear-encoded defects of mitochondrial metabolism. © 2015, SSIEM. Source


Sajic M.,University College London
Antioxidants and Redox Signaling | Year: 2014

Significance: Mitochondrial dynamics describes the continuous change in the position, size, and shape of mitochondria within cells. The morphological and functional complexity of neurons, the remarkable length of their processes, and the rapid changes in metabolic requirements arising from their intrinsic excitability render these cells particularly dependent on effective mitochondrial function and positioning. The rules that govern these changes and their functional significance are not fully understood, yet the dysfunction of mitochondrial dynamics has been implicated as a pathogenetic factor in a number of diseases, including disorders of the central and peripheral nervous systems. Recent Advances: In recent years, a number of mutations of genes encoding proteins that play important roles in mitochondrial dynamics and function have been discovered in patients with Charcot-Marie-Tooth (CMT) disease, a hereditary peripheral neuropathy. These findings have directly linked mitochondrial pathology to the pathology of peripheral nerve and have identified certain aspects of mitochondrial dynamics as potential early events in the pathogenesis of CMT. In addition, mitochondrial dysfunction has now been implicated in the pathogenesis of noninherited neuropathies, including diabetic and inflammatory neuropathies. Critical Issues: The role of mitochondria in peripheral nerve diseases has been mostly examined in vitro, and less so in animal models. Future Directions: This review examines available evidence for the role of mitochondrial dynamics in the pathogenesis of peripheral neuropathies, their relevance in human diseases, and future challenges for research in this field. © 2014 Mary Ann Liebert, Inc. Source


Barker P.F.,University College London
Physical Review Letters | Year: 2010

Doppler cooling the center-of-mass motion of an optically levitated microsphere via the velocity-dependent scattering force from narrow whispering gallery mode resonances is described. Light that is red detuned from the whispering gallery mode resonance can be used to damp the center-of-mass motion in a process analogous to the Doppler cooling of atoms. The scattering force is not limited by saturation but can be controlled by the incident power. Cooling times on the order of seconds are calculated for a 20 μm diameter silica microsphere trapped within optical tweezers. © 2010 The American Physical Society. Source


Partridge L.,University College London
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages. However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development. © 2010 The Royal Society. Source


Yu A.W.,University College London
Interactive cardiovascular and thoracic surgery | Year: 2013

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether vacuum-assisted closure therapy (VAC) is superior to conventional therapy for treating post-sternotomy mediastinitis. Altogether >261 papers were found using the reported search, of which 9 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Several studies indicate that VAC therapy is associated with shorter lengths of intensive care and in-hospital stay as well as faster rates of wound healing and fewer dressing changes. It has also been shown that VAC therapy is correlated with a statistically significant reduction in reinfection rates, particularly those that occur in the early postoperative period (at the 1-week follow-up). Patients can be discharged with the dressing in situ and managed in the community with a view to delayed closure or reconstruction. However, the studies comparing VAC with conventional therapy are all retrospective in nature and reinforce the need for randomized controlled trials in order to more accurately establish differences in outcomes between VAC and conventional therapy. Additionally, owing tło the variability of treatment protocols within the non-VAC arm, it is more challenging to draw definitive conclusions regarding the superiority of VAC therapy to every modality that is considered conventional treatment. We conclude that VAC therapy is a portable and an increasingly economical option for the treatment of post sternotomy mediastinitis. Although reductions in mortality rates were not reproduced in all studies, evidence suggests that VAC should still be considered as a first-line therapy for post-sternotomy mediastinitis and as a bridge therapy to musculocutaneous reconstruction or primary closure. Source


Muller D.P.R.,University College London
Molecular Nutrition and Food Research | Year: 2010

The clinical, neuropathological and electrophysiological evidence that vitamin E (α-tocopherol) is essential for normal neurological function will be reviewed. The possible reasons why neural tissues should be particularly affected by a deficiency of this fat-soluble vitamin and the mechanism(s) involved will be considered. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Fayad T.E.,University College London
The bone & joint journal | Year: 2013

Young adults with hip pain secondary to femoroacetabular impingement (FAI) are rapidly being recognised as an important cohort of orthopaedic patients. Interest in FAI has intensified over the last decade since its recognition as a precursor to arthritis of the hip and the number of publications related to the topic has increased exponentially in the last decade. Although not all patients with abnormal hip morphology develop osteoarthritis (OA), those with FAI-related joint damage rapidly develop premature OA. There are no explicit diagnostic criteria or definitive indications for surgical intervention in FAI. Surgery for symptomatic FAI appears to be most effective in younger individuals who have not yet developed irreversible OA. The difficulty in predicting prognosis in FAI means that avoiding unnecessary surgery in asymptomatic individuals, while undertaking intervention in those that are likely to develop premature OA poses a considerable dilemma. FAI treatment in the past has focused on open procedures that carry a potential risk of complications. Recent developments in hip arthroscopy have facilitated a minimally invasive approach to the management of FAI with few complications in expert hands. Acetabular labral preservation and repair appears to provide superior results when compared with debridement alone. Arthroscopic correction of structural abnormalities is increasingly becoming the standard treatment for FAI, however there is a paucity of high-level evidence comparing open and arthroscopic techniques in patients with similar FAI morphology and degree of associated articular cartilage damage. Further research is needed to develop an understanding of the natural course of FAI, the definitive indications for surgery and the long-term outcomes. Source


Zhaoping L.,University College London
Journal of Vision | Year: 2012

Where we look in visual tasks is determined by both bottom-up and top-down factors. One theory (Li, 1999a, 2002) suggests that visual area V1 creates a bottom-up saliency map, guiding gaze through extensive projections to the superior colliculus. V1 is the only visual cortical area that represents the eye of origin of an input and is also least associated with awareness; I therefore predicted that an ocular singleton (i.e., an item only shown to one eye among other items shown to the other eye) that is perceptually indistinct might nevertheless attract gaze. In visual searches for an orientation singleton target bar among uniformly oriented background bars, an ocular singleton non-target bar, at the same eccentricity as the target from the center of the search display, often captured the first search saccade. The chance of this capture was above 50% (e.g., 75%) when the eccentricity of the singletons was large and luminance did not vary between the bars, and it was below 50% when the eccentricity was smaller and luminance varied. After each search trial, observers reported whether an ocular singleton non-target (which was actually presented in half of the trials) had been shown. When different bars had similar luminance, misses numbered less than 50% and were independent of whether the gaze was captured by the ocular singleton. However, when luminance varied sufficiently between the bars, 50% were missed overall, albeit significantly less for those that captured gaze. The experiments in this work followed the guidelines in the Declaration of Helsinki. © ARVO. Source


Kumaran D.,University College London
Frontiers in Human Neuroscience | Year: 2012

Empirical research and theoretical accounts have traditionally emphasized the function of the hippocampus in episodic memory. Here we draw attention to the importance of the hippocampus to generalization, and focus on the neural representations and computations that might underpin its role in tasks such as the paired associate inference (PAI) paradigm. We make a principal distinction between two different mechanisms by which the hippocampus may support generalization: an encoding-based mechanism that creates overlapping representations which capture higher-order relationships between different items [e.g., Temporal Context Model (TCM): Howard et al., 2005]-and a retrieval-based model [Recurrence with Episodic Memory Results in Generalization (REMERGE): Kumaran and McClelland, in press] that effectively computes these relationships at the point of retrieval, through a recurrent mechanism that allows the dynamic interaction of multiple pattern separated episodic codes. We also discuss what we refer to as transfer effects-a more abstract example of generalization that has also been linked to the function of the hippocampus. We consider how this phenomenon poses inherent challenges for models such as TCM and REMERGE, and outline the potential applicability of a separate class of models-hierarchical Bayesian models (HBMs) in this context. Our hope is that this article will provide a basic framework within which to consider the theoretical mechanisms underlying the role of the hippocampus in generalization, and at a minimum serve as a stimulus for future work addressing issues that go to the heart of the function of the hippocampus. © 2012 Kumaran. Source


Schapira A.H.V.,University College London
Mount Sinai Journal of Medicine | Year: 2011

The last 25 years have witnessed remarkable advances in our understanding of the etiology and pathogenesis of Parkinson's disease. The ability to undertake detailed biochemical analyses of the Parkinson's disease postmortem brain enabled the identification of defects of mitochondrial and free-radical metabolism. The discovery of the first gene mutation for Parkinson's disease, in alpha-synuclein, ushered in the genetic era for the disease and the subsequent finding of several gene mutations causing parkinsonism, 15 at the time of writing. Technological advances both in sequencing technology and software analysis have allowed association studies of sufficiently large size accurately to describe genes conferring an increased risk for Parkinson's disease. What has been so surprising is the convergence of these 2 separate disciplines (biochemistry and genetics) in terms of reinforcing the importance of the same pathways (ie, mitochondrial dysfunction and free-radical metabolism). Other pathways are also important in pathogenesis, including protein turnover, inflammation, and post-translational modification, particularly protein phosphorylation and ubiquitination. However, even these additional pathways overlap with each other and with those of mitochondrial dysfunction and oxidative stress. This review explores these concepts with particular relevance to mitochondrial involvement. Mt Sinai J Med 78:872-881, 2011. © 2011 Mount Sinai School of Medicine. Source


Gilron I.,Queens University | Jensen T.S.,Aarhus University Hospital | Dickenson A.H.,University College London
The Lancet Neurology | Year: 2013

Chronic pain, a frequently neglected problem, is treated with different classes of drugs. Current agents are limited by incomplete efficacy and dose-limiting side-effects. Knowledge of pain processing implicates multiple concurrent mechanisms of nociceptive transmission and modulation. Thus, synergistic interactions of drug combinations might provide superior analgesia and fewer side-effects than monotherapy by targeting of multiple mechanisms. Several trials in neuropathic pain, fibromyalgia, arthritis, and other disorders have assessed various two-drug combinations containing antidepressants, anticonvulsants, non-steroidal anti-inflammatories, opioids, and other agents. In some trials, combined treatment showed superiority over monotherapy, but in others improved benefit or tolerability was not seen. Escalating efforts to develop novel analgesics that surpass the efficacy of current treatments have not yet been successful; therefore, combination therapy remains an important beneficial strategy. Methodological improvements in future translational research efforts are needed to maximise the potential of combination pharmacotherapy for pain. © 2013 Elsevier Ltd. Source


Hall A.M.,University College London
Pediatric Nephrology | Year: 2013

Tenofovir (TFV) is a widely used and effective treatment for HIV infection. Numerous studies have shown that TFV exposure is associated with small but significant declines in estimated glomerular filtration rate (eGFR). However, TFV toxicity is targeted mainly at the proximal tubule (PT), and in severe cases can cause the renal Fanconi syndrome or acute kidney injury. Severe toxicity occurs in a minority of patients, but milder PT dysfunction is more common; the long-term significance of this on kidney and bone health is uncertain. Recent work suggests that changes in eGFR on TFV therapy might be explained by inhibition of PT creatinine secretion rather than actual alterations in glomerular function. Risk factors for nephrotoxicity include pre-existing kidney disease, increased age, and low body mass. Mitochondria in the PT are the targets of TFV toxicity, but the exact mechanisms remain unclear. Substantial improvement of renal function occurs in many patients with TFV toxicity upon stopping therapy, but function does not always return to baseline. In recent years, TFV usage has been extended to new clinical spheres, including pediatrics, resource-poor settings and treatment of Hepatitis B infection; theoretical reasons exist as to why some of these patients might be at higher or lower risk of TFV toxicity. Finally, strategies have been proposed to prevent TFV toxicity or enhance recovery. © 2012 IPNA. Source


Cavanna A.E.,University of Birmingham | Cavanna A.E.,University College London | Rickards H.,University of Birmingham
Neuroscience and Biobehavioral Reviews | Year: 2013

Gilles de la Tourette syndrome (GTS) holds a unique status as quintessentially neuropsychiatric condition at the interface between neurology (movement disorder) and psychiatry (behavioural condition). This is a reflection of the common observation that the vast majority of patients present with behavioural problems in association with the motor and vocal tics which define GTS. The present article focuses on the relationship between GTS and obsessive-compulsive disorder (OCD), attention-deficit and hyperactivity disorder (ADHD), affective disorders (both major depression and bipolar affective disorder), and personality disorders. Over the last decade, converging lines of research have pointed towards the concept of a 'GTS spectrum', encompassing motor phenomena and behavioural symptoms, with important implications for the clinical management of patients. © 2012 Elsevier Ltd. Source


Rothman J.S.,University College London
Progress in molecular biology and translational science | Year: 2014

In this chapter, we describe how to create mathematical models of synaptic transmission and integration. We start with a brief synopsis of the experimental evidence underlying our current understanding of synaptic transmission. We then describe synaptic transmission at a particular glutamatergic synapse in the mammalian cerebellum, the mossy fiber to granule cell synapse, since data from this well-characterized synapse can provide a benchmark comparison for how well synaptic properties are captured by different mathematical models. This chapter is structured by first presenting the simplest mathematical description of an average synaptic conductance waveform and then introducing methods for incorporating more complex synaptic properties such as nonlinear voltage dependence of ionotropic receptors, short-term plasticity, and stochastic fluctuations. We restrict our focus to excitatory synaptic transmission, but most of the modeling approaches discussed here can be equally applied to inhibitory synapses. Our data-driven approach will be of interest to those wishing to model synaptic transmission and network behavior in health and disease. © 2014 Elsevier Inc. All rights reserved. Source


Bolton-Maggs P.H.B.,University of Manchester | Cohen H.,University College London
British Journal of Haematology | Year: 2013

The Serious Hazards of Transfusion (SHOT) UK confidential haemovigilance reporting scheme began in 1996. Over the 16 years of reporting, the evidence gathered has prompted changes in transfusion practice from the selection and management of donors to changes in hospital practice, particularly better education and training. However, half or more reports relate to errors in the transfusion process despite the introduction of several measures to improve practice. Transfusion in the UK is very safe: 2·9 million components were issued in 2012, and very few deaths are related to transfusion. The risk of death from transfusion as estimated from SHOT data in 2012 is 1 in 322 580 components issued and for major morbidity, 1 in 21 413 components issued; the risk of transfusion-transmitted infection is much lower. Acute transfusion reactions and transfusion-associated circulatory overload carry the highest risk for morbidity and death. The high rate of participation in SHOT by National Health Service organizations, 99·5%, is encouraging. Despite the very useful information gained about transfusion reactions, the main risks remain human factors. The recommendations on reduction of errors through a 'back to basics' approach from the first annual SHOT report remain absolutely relevant today. © 2013 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd. Source


Park H.-J.,Yonsei University | Friston K.,University College London
Science | Year: 2013

How rich functionality emerges from the invariant structural architecture of the brain remains a major mystery in neuroscience. Recent applications of network theory and theoretical neuroscience to large-scale brain networks have started to dissolve this mystery. Network analyses suggest that hierarchical modular brain networks are particularly suited to facilitate local (segregated) neuronal operations and the global integration of segregated functions. Although functional networks are constrained by structural connections, context-sensitive integration during cognition tasks necessarily entails a divergence between structural and functional networks. This degenerate (many-to-one) function-structure mapping is crucial for understanding the nature of brain networks. The emergence of dynamic functional networks from static structural connections calls for a formal (computational) approach to neuronal information processing that may resolve this dialectic between structure and function. Source


Rook G.A.W.,University College London
Clinical Reviews in Allergy and Immunology | Year: 2012

Throughout the twentieth century, there were striking increases in the incidences of many chronic inflammatory disorders in the rich developed countries. These included autoimmune disorders such as Type 1 diabetes and multiple sclerosis. Although genetics and specific triggering mechanisms such as molecular mimicry and viruses are likely to be involved, the increases have been so rapid that any explanation that omits environmental change is incomplete. This chapter suggests that a series of environmental factors, most of them microbial, have led to a decrease in the efficiency of our immunoregulatory mechanisms because we are in a state of evolved dependence on organisms with which we co-evolved (and that had to be tolerated) as inducers of immunoregulatory circuits. These organisms ("Old Friends") are depleted from the modern urban environment. Rather than considering fetal programming by maternal microbial exposures, neonatal programming, the hygiene hypothesis, gut microbiota, and diet as separate and competing hypotheses, I attempt here to integrate these ideas under a single umbrella concept that can provide the missing immunoregulatory environmental factor that is needed to explain the recent increases in autoimmune disease. © 2011 Springer Science+Business Media, LLC. Source


Patsalos P.N.,University College London | Patsalos P.N.,Chalfont Center for Epilepsy
Clinical Pharmacokinetics | Year: 2013

Since antiepileptic drugs (AEDs) are prescribed to treat various non-epilepsy-related disorders in addition to the fact that patients with epilepsy may develop concurrent disorders that will need treatment, the propensity for AEDs to interact with non-AEDs is considerable and indeed can present a difficult clinical problem. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs (eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide) and drugs used to treat non-epilepsy disorders. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. Pharmacokinetic interactions relate to hepatic enzyme induction or inhibition and involved a variety of drugs including psychoactive drugs, cardioactive drugs, oral contraceptives, antituberculous agents, analgesics and antineoplastic drugs. A total of 68 pharmacokinetic interactions have been described, with lamotrigine (n = 22), topiramate (n = 18) and oxcarbazepine (n = 7) being associated with most, whilst lacosamide, pregabalin, stiripentol and vigabatrin are associated with none. Overall, only three pharmacodynamic interactions have been described and occur with oxcarbazepine, perampanel and pregabalin. © 2013 Springer International Publishing Switzerland. Source


Seghier M.L.,University College London
Neuroscientist | Year: 2013

There is considerable interest in the structural and functional properties of the angular gyrus (AG). Located in the posterior part of the inferior parietal lobule, the AG has been shown in numerous meta-analysis reviews to be consistently activated in a variety of tasks. This review discusses the involvement of the AG in semantic processing, word reading and comprehension, number processing, default mode network, memory retrieval, attention and spatial cognition, reasoning, and social cognition. This large functional neuroimaging literature depicts a major role for the AG in processing concepts rather than percepts when interfacing perception-to-recognition-to-action. More specifically, the AG emerges as a cross-modal hub where converging multisensory information is combined and integrated to comprehend and give sense to events, manipulate mental representations, solve familiar problems, and reorient attention to relevant information. In addition, this review discusses recent findings that point to the existence of multiple subdivisions in the AG. This spatial parcellation can serve as a framework for reporting AG activations with greater definition. This review also acknowledges that the role of the AG cannot comprehensibly be identified in isolation but needs to be understood in parallel with the influence from other regions. Several interesting questions that warrant further investigations are finally emphasized. © The Author(s) 2013. Source


Zwijnenburg M.A.,University College London
Nanoscale | Year: 2011

We calculate the optical absorption spectra of low-energy uncapped zinc sulfide nanostructures found by global optimisation (basin-hopping/simulated annealing) using time-dependent density functional theory (TD-DFT) and compare the results with experimental spectra. We predict that for all nanostructures studied the lowest excited state found by TD-DFT corresponds to an exciton with an exciton binding energy that is much larger than that of excitons in bulk zinc sulfide. We further show that for the more symmetrical nanostructures some of the excitons are dark and that the absorption on-sets, the energy of the lowest exciton, for the different nanostructures show no clear evidence of quantum confinement. We propose that this apparent lack of quantum confinement finds its origin in the fact that the lowest exciton is not evenly spread over the whole nanostructure but shows large contributions for specific groups of atoms. Finally, we show that the predicted optical absorption spectra fit with those reported experimentally. © The Royal Society of Chemistry 2011. Source


Smart T.G.,University College London | Paoletti P.,French Institute of Health and Medical Research
Cold Spring Harbor Perspectives in Biology | Year: 2012

Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Hartley J.A.,University College London
Expert Opinion on Investigational Drugs | Year: 2011

Introduction: DNA interacting agents play a major role in cancer chemotherapy, either as single agents, in combination drug regimens, or as components of novel targeted therapies. The search for more selective and efficacious drugs that can deliver critical DNA damage with minimal side effects continues. Areas covered: The development of the pyrrolobenzodiazepines (PBDs) from their discovery as natural products in the 1960s, through synthetic PBD monomers, PBD hybrids and conjugates, and PBD dimers is described. The latter molecules are capable of forming sequence selective, non-distorting and potently cytotoxic DNA interstrand cross-links in the minor groove of DNA. In particular, the development of PBD dimer SJG-136 (SG2000), currently in Phase II clinical trials, is presented. Potential future cancer therapeutic applications of PBDs, including their use as components of targeting strategies, are also discussed. Expert opinion: The culmination of over four decades of study on structureâ€"activity relationships of PBDs has led to a detailed understanding of how to introduce structural modification to enhance biological activity and potency. The challenge for the next phase in the development of the PBDs is to harness this activity and potency in a new generation of cancer therapeutics. © 2011 Informa UK, Ltd. Source


Koudriachova M.V.,University College London
Journal of Power Sources | Year: 2011

With the aid of ab initio calculations, we compare the phase behavior upon lithiation of rutile particles of different sizes and morphologies. A rationale for the differences in their structural behavior is provided by combining concepts from Crystal Field Theory and semi-empirical concepts, such as bond length variation, minimal volume expansion, with accounts for the effects of diffusion and the anisotropy of the Li-distribution. It is shown that the phase behavior of spaghetti-like nano-particles differs from bulk rutile as a result of an extended single phase insertion domain and increased disorder of Li-ions. As Li-ions strive to minimize their repulsions by increasing their mutual separation a regular network of Li-ions is formed, being a precursor to the transformation of the rutile host lattice into spinel. © 2011 Elsevier B.V. All rights reserved. Source


Lorencatto F.,University College London
Journal of consulting and clinical psychology | Year: 2013

There is a difference between interventions as planned and as delivered in practice. Unless we know what was actually delivered, we cannot understand "what worked" in effective interventions. This study aimed to (a) assess whether an established taxonomy of 53 smoking cessation behavior change techniques (BCTs) may be applied or adapted as a method for reliably specifying the content of smoking cessation behavioral support consultations and (b) develop an effective method for training researchers and practitioners in the reliable application of the taxonomy. Fifteen transcripts of audio-recorded consultations delivered by England's Stop Smoking Services were coded into component BCTs using the taxonomy. Interrater reliability and potential adaptations to the taxonomy to improve coding were discussed following 3 coding waves. A coding training manual was developed through expert consensus and piloted on 10 trainees, assessing coding reliability and self-perceived competence before and after training. An average of 33 BCTs from the taxonomy were identified at least once across sessions and coding waves. Consultations contained on average 12 BCTs (range = 8-31). Average interrater reliability was high (88% agreement). The taxonomy was adapted to simplify coding by merging co-occurring BCTs and refining BCT definitions. Coding reliability and self-perceived competence significantly improved posttraining for all trainees. It is possible to apply a taxonomy to reliably identify and classify BCTs in smoking cessation behavioral support delivered in practice, and train inexperienced coders to do so reliably. This method can be used to investigate variability in provision of behavioral support across services, monitor fidelity of delivery, and identify training needs. Source


Scully M.,University College London | Goodship T.,Northumbria University
British Journal of Haematology | Year: 2014

Thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS) are acute, rare life-threatening thrombotic microangiopathies that require rapid diagnosis and treatment. They are defined by microangiopathic haemolytic anaemia and thrombocytopenia, with renal involvement primarily in aHUS and neurological and cardiological sequelae in TTP. Prompt treatment for most cases of both conditions is with plasma exchange initially and monoclonal therapy (rituximab in TTP and eculizumab in aHUS) as the mainstay of therapy. Here we discuss the diagnosis and therapy for both disorders. © 2014 The Authors. British Journal of Haematology Published by John Wiley & Sons Ltd. Source


Alic N.,University College London
Cell Metabolism | Year: 2016

Age-related cognitive decline is one of the most haunting aspects of human aging. In a recent publication, Coleen Murphy and colleagues (Kaletsky et al., 2016) describe the transcriptional program that maintains youthful function of aging neurons in the nematode worm. © 2016 Elsevier Inc. Source


Scanlon D.O.,University College London | Watson G.W.,Trinity College Dublin
Journal of Materials Chemistry | Year: 2012

SnO2 is an abundant, low cost, natively n-type, wide band gap oxide, which can achieve high conductivities due to facile donor doping. Realization of a p-type SnO2 would, however, open up many new avenues in device applications, and has become a major research goal. Previous experimental and theoretical studies have proved inconclusive, with the p-type ability of SnO2 being both supported and questioned in equal measure. In this study we use state of the art hybrid density functional theory to investigate the nature of intrinsic and extrinsic p-type defects in SnO 2. We demonstrate that all the p-type defects considered in SnO 2 produce localized hole polarons centered on anion sites. We calculate the thermodynamic ionization energies of these defects, and demonstrate that an efficient p-type SnO2 is not achievable. © 2012 The Royal Society of Chemistry. Source


In this study, we have examined the properties of synaptic transmission between dorsal root ganglion (DRG) and dorsal horn (DH) neurons, placed in co-culture. We also examined the effect of the anti-hyperalgesic gabapentinoid drug pregabalin (PGB) at this pharmacologically relevant synapse. The main method used was electrophysiological recording of excitatory post synaptic currents (EPSCs) in DH neurons. Synaptic transmission between DRG and DH neurons was stimulated by capsaicin, which activates transient receptor potential vanilloid-1 (TRPV1) receptors on small diameter DRG neurons. Capsaicin (1 μM) application increased the frequency of EPSCs recorded in DH neurons in DRG-DH co-cultures, by about 3-fold, but had no effect on other measured properties of the EPSCs. There was also no effect of capsaicin in the absence of co-cultured DRGs. Application of PGB (100 μM) for 40-48 h caused a reduction in the capsaicin-induced increase in EPSC frequency by 57%. In contrast, brief preincubation of PGB had no significant effect on the capsaicin-induced increase in EPSC frequency. In conclusion, this study shows that PGB applied for 40-48 h, but not acute application inhibits excitatory synaptic transmission at DRG-DH synapses, in response to nociceptive stimulation, most likely by a presynaptic effect on neurotransmitter release from DRG presynaptic terminals. Source


Williamson C.,Womens Health Academic Center | Geenes V.,University College London
Obstetrics and Gynecology | Year: 2014

Intrahepatic cholestasis of pregnancy is the most common pregnancy-specific liver disease that typically presents in the third trimester. The clinical features are maternal pruritus in the absence of a rash and deranged liver function tests, including raised serum bile acids. Intrahepatic cholestasis of pregnancy is associated with an increased risk of adverse perinatal outcomes, including spontaneous preterm delivery, meconium staining of the amniotic fluid, and stillbirth. It is commonly treated with ursodeoxycholic acid. There is accumulating evidence to suggest that intrahepatic cholestasis of pregnancy has a lasting influence on both maternal and fetal health. We review the etiology, diagnosis, and management of this intriguing condition. © 2014 by The American College of Obstetricians and Gynecologists. Source


Skipper J.I.,University College London
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

What do we hear when someone speaks and what does auditory cortex (AC) do with that sound? Given how meaningful speech is, it might be hypothesized that AC is most active when other people talk so that their productions get decoded. Here, neuroimaging meta-analyses show the opposite: AC is least active and sometimes deactivated when participants listened to meaningful speech compared to less meaningful sounds. Results are explained by an active hypothesis-and-test mechanism where speech production (SP) regions are neurally re-used to predict auditory objects associated with available context. By this model, more AC activity for less meaningful sounds occurs because predictions are less successful from context, requiring further hypotheses be tested. This also explains the large overlap of AC co-activity for less meaningful sounds with meta-analyses of SP. An experiment showed a similar pattern of results for non-verbal context. Specifically, words produced less activity in AC and SP regions when preceded by co-speech gestures that visually described those words compared to those words without gestures. Results collectively suggest that what we 'hear' during real-world speech perception may come more from the brain than our ears and that the function of AC is to confirm or deny internal predictions about the identity of sounds. Source


Chan S.L.,University College London
Genes & development | Year: 2014

AAUAAA is the most highly conserved motif in eukaryotic mRNA polyadenylation sites and, in mammals, is specifically recognized by the multisubunit CPSF (cleavage and polyadenylation specificity factor) complex. Despite its critical functions in mRNA 3' end formation, the molecular basis for CPSF-AAUAAA interaction remains poorly defined. The CPSF subunit CPSF160 has been implicated in AAUAAA recognition, but direct evidence has been lacking. Using in vitro and in vivo assays, we unexpectedly found that CPSF subunits CPSF30 and Wdr33 directly contact AAUAAA. Importantly, the CPSF30-RNA interaction is essential for mRNA 3' processing and is primarily mediated by its zinc fingers 2 and 3, which are specifically targeted by the influenza protein NS1A to suppress host mRNA 3' processing. Our data suggest that AAUAAA recognition in mammalian mRNA 3' processing is more complex than previously thought and involves multiple protein-RNA interactions. © 2014 Chan et al.; Published by Cold Spring Harbor Laboratory Press. Source


Hogan S.D.,University College London
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

Calculations of the photoexcitation spectra of ortho-positronium Rydberg states with principal quantum numbers between 10 and 30 are presented. The effects of Doppler broadening and saturation of the corresponding electric-dipole transitions are studied, together with the role of static and motionally induced electric fields. This is done in the context of recent measurements reported by Cassidy, and with regard to experiments involving the production of antihydrogen by charge-exchange between Rydberg positronium and cold antiprotons. © 2013 American Physical Society. Source


Mian O.S.,University College London
PloS one | Year: 2013

Vertigo is sometimes experienced in and around MRI scanners. Mechanisms involving stimulation of the vestibular system by movement in magnetic fields or magnetic field spatial gradients have been proposed. However, it was recently shown that vestibular-dependent ocular nystagmus is evoked when stationary in homogenous static magnetic fields. The proposed mechanism involves Lorentz forces acting on endolymph to deflect semicircular canal (SCC) cupulae. To investigate whether vertigo arises from a similar mechanism we recorded qualitative and quantitative aspects of vertigo and 2D eye movements from supine healthy adults (n = 25) deprived of vision while pushed into the 7T static field of an MRI scanner. Exposures were variable and included up to 135s stationary at 7T. Nystagmus was mainly horizontal, persisted during long-exposures with partial decline, and reversed upon withdrawal. The dominant vertiginous perception with the head facing up was rotation in the horizontal plane (85% incidence) with a consistent direction across participants. With the head turned 90 degrees in yaw the perception did not transform into equivalent vertical plane rotation, indicating a context-dependency of the perception. During long exposures, illusory rotation lasted on average 50 s, including 42 s whilst stationary at 7T. Upon withdrawal, perception re-emerged and reversed, lasting on average 30 s. Onset fields for nystagmus and perception were significantly correlated (p<.05). Although perception did not persist as long as nystagmus, this is a known feature of continuous SSC stimulation. These observations, and others in the paper, are compatible with magnetic-field evoked-vertigo and nystagmus sharing a common mechanism. With this interpretation, response decay and reversal upon withdrawal from the field, are due to adaptation to continuous vestibular input. Although the study does not entirely exclude the possibility of mechanisms involving transient vestibular stimulation during movement in and out of the bore, we argue these are less likely. Source


Duchen M.R.,University College London
Pflugers Archiv European Journal of Physiology | Year: 2012

Understanding the mechanisms of neuronal dysfunction and death represents a major frontier in contemporary medicine, involving the acute cell death in stroke, and the attrition of the major neurodegenerative diseases, including Parkinson's, Alzheimer's, Huntington's and Motoneuron diseases. A growing body of evidence implicates mitochondrial dysfunction as a key step in the pathogenesis of all these diseases, with the promise that mitochondrial processes represent valuable potential therapeutic targets. Each disease is characterised by the loss of a specific vulnerable population of cells-dopaminergic neurons in Parkinson's disease, spinal motoneurons in Motoneuron disease, for example. We discuss the possible roles of cell type-specific calcium signalling mechanisms in defining the pathological phenotype of each of these major diseases and review central mechanisms of calcium-dependent mitochondrial-mediated cell death. © 2012 The Author(s). Source


Cole T.J.,University College London
Annals of Human Biology | Year: 2012

Context: De Montbeillard produced the first growth chart in the late 18th century. Since then, growth assessment has developed to become an essential component of child health practice. Objective: To provide a brief history of (i) anthropometry, i.e. growth measurements; (ii) growth references, the statistical summary of anthropometry and (iii) growth charts, the visual representation of growth references for clinical use. Methods: The major contributors in the three categories over the past 200 years were identified and their historical contributionsput in context with more recent developments. Results: Anthropometry was originally collected for administrative or public health purposes, its medical role emerging at the end of the 19th century. Growth reference data were collected in earnest from the 19 th century, during which time the familiar statistical summary statisticsmean, SD, centileswere developed. More advanced statistical methods emerged much later. Growth charts first appeared in the late 19th century and Tanner and Whitehouse later popularized the concepts of velocity and conditional references for growth in puberty. An important recent reference is the WHO growth standard, which documents optimal growth and has been adopted by many countries including the UK. Arising from it, the UK-WHO charts have pioneered many design features to improve usability and accuracy. Conclusion: Growth charts have developed considerably in 200 years and they represent an impressive synthesis of anthropometry, statistical summary and chart design. © Informa UK, Ltd. Source


Swanton C.,University College London
Cancer Research | Year: 2012

Recent technologic advances have permitted higher resolution and more rapid analysis of individual cancer genomes at the single-nucleotide level. Such advances have shown bewildering intertumor heterogeneity with limited somatic alterations shared between tumors of the same histopathologic subtype. Exacerbating such complexity, increasing evidence of intratumor genetic heterogeneity (ITH) is emerging, both within individual tumor biopsies and spatially separated between biopsies of the same tumor. Sequential analysis of tumors has also revealed evidence that ITH temporally evolves during the disease course. ITH has implications for predictive or prognostic biomarker strategies, where the tumor subclone that may ultimately influence therapeutic outcome may evade detection because of its absence or presence at low frequency at diagnosis or because of its regional separation from the tumor biopsy site. In this review, the implications of "trunk and branch" tumor evolution for drug discovery approaches and emerging evidence that low-frequency somatic events may drive tumor growth through paracrine signaling fostering a tumor ecologic niche are discussed. The concept of an "actionable mutation" is considered within a model of clonal dominance and heterogeneous tumor cell dependencies. Evidence that cancer therapeutics may augment ITH and the need to track the tumor subclonal architecture through treatment are defined as key research areas. Finally, if combination therapeutic approaches to limit the consequences of ITH prove challenging, identification of drivers or suppressors of ITH may provide attractive therapeutic targets to limit tumor evolutionary rates and adaptation. ©2012 AACR. Source


Lane N.,University College London | Martin W.F.,Heinrich Heine University Dusseldorf
Cell | Year: 2012

Harnessing energy as ion gradients across membranes is as universal as the genetic code. We leverage new insights into anaerobe metabolism to propose geochemical origins that account for the ubiquity of chemiosmotic coupling, and Na+/H+ transporters in particular. Natural proton gradients acting across thin FeS walls within alkaline hydrothermal vents could drive carbon assimilation, leading to the emergence of protocells within vent pores. Protocell membranes that were initially leaky would eventually become less permeable, forcing cells dependent on natural H+ gradients to pump Na+ ions. Our hypothesis accounts for the Na+/H + promiscuity of bioenergetic proteins, as well as the deep divergence between bacteria and archaea. © 2012 Elsevier Inc. Source


Newton J.M.,University College London
International Journal of Pharmaceutics | Year: 2010

The evidence in the literature for the concept that multi-particulate dosage forms below a specific size empty from the stomach as if they were liquids and hence have the potential to provide the best solution to the formulation of controlled release oral dosage forms, has been considered. There is some evidence that particles less than 1.0. mm provide a more rapid response than larger size particles but there is also evidence that this is not always the case and that rapid and reproducible gastric emptying of small particles does not always occur when they are administered. There is strong evidence that food can delay the gastric emptying of multi-particulate systems. Some of the misconception for gastric emptying performance of multi-particulate system is shown to be related to the limitation of the study design and limitation of the way the data is processed. Nevertheless, there is clear evidence that multi-particulate systems can provide effective oral controlled release dosage forms. There is still some way to go with experimental techniques which would allow a definitive answer to the issue of how the variability of the gastric emptying of multi-particulate systems of less than 2.0. mm arises. © 2010 Elsevier B.V. Source


Mallik S.,University College London
Journal of neurology, neurosurgery, and psychiatry | Year: 2014

Trials of potential neuroreparative agents are becoming more important in the spectrum of multiple sclerosis research. Appropriate imaging outcomes are required that are feasible from a time and practicality point of view, as well as being sensitive and specific to myelin, while also being reproducible and clinically meaningful. Conventional MRI sequences have limited specificity for myelination. We evaluate the imaging modalities which are potentially more specific to myelin content in vivo, such as magnetisation transfer ratio (MTR), restricted proton fraction f (from quantitative magnetisation transfer measurements), myelin water fraction and diffusion tensor imaging (DTI) metrics, in addition to positron emission tomography (PET) imaging. Although most imaging applications to date have focused on the brain, we also consider measures with the potential to detect remyelination in the spinal cord and in the optic nerve. At present, MTR and DTI measures probably offer the most realistic and feasible outcome measures for such trials, especially in the brain. However, no one measure currently demonstrates sufficiently high sensitivity or specificity to myelin, or correlation with clinical features, and it should be useful to employ more than one outcome to maximise understanding and interpretation of findings with these sequences. PET may be less feasible for current and near-future trials, but is a promising technique because of its specificity. In the optic nerve, visual evoked potentials can indicate demyelination and should be correlated with an imaging outcome (such as optic nerve MTR), as well as clinical measures. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. Source


Steptoe A.,University College London | Deaton A.,Princeton University | Stone A.A.,State University of New York at Stony Brook | Stone A.A.,University of Southern California
The Lancet | Year: 2015

Subjective wellbeing and health are closely linked to age. Three aspects of subjective wellbeing can be distinguished - evaluative wellbeing (or life satisfaction), hedonic wellbeing (feelings of happiness, sadness, anger, stress, and pain), and eudemonic wellbeing (sense of purpose and meaning in life). We review recent advances in the specialty of psychological wellbeing, and present new analyses about the pattern of wellbeing across ages and the association between wellbeing and survival at older ages. The Gallup World Poll, a continuing survey in more than 160 countries, shows a U-shaped relation between evaluative wellbeing and age in high-income, English speaking countries, with the lowest levels of wellbeing in ages 45-54 years. But this pattern is not universal. For example, respondents from the former Soviet Union and eastern Europe show a large progressive reduction in wellbeing with age, respondents from Latin America also shows decreased wellbeing with age, whereas wellbeing in sub-Saharan Africa shows little change with age. The relation between physical health and subjective wellbeing is bidirectional. Older people with illnesses such as coronary heart disease, arthritis, and chronic lung disease show both increased levels of depressed mood and impaired hedonic and eudemonic wellbeing. Wellbeing might also have a protective role in health maintenance. In an analysis of the English Longitudinal Study of Ageing, we identify that eudemonic wellbeing is associated with increased survival; 29·3% of people in the lowest wellbeing quartile died during the average follow-up period of 8·5 years compared with 9·3% of those in the highest quartile. Associations were independent of age, sex, demographic factors, and baseline mental and physical health. We conclude that the wellbeing of elderly people is an important objective for both economic and health policy. Present psychological and economic theories do not adequately account for the variations in patterns of wellbeing with age across different parts of the world. The apparent association between wellbeing and survival is consistent with a protective role of high wellbeing, but alternative explanations cannot be ruled out at this stage. © 2015 Elsevier Ltd. Source


CASSCF calculated wavefunctions are presented for three f-element metallocenes, MCOT2 (M = Ce, Th, Pu; COT = η8-C 8H8). The configurational admixture of these systems is investigated and, where the ThCOT2 ground state is well-defined as a monodeterminantal Th(iv) state, the cerocene ground state is found to be strong multiconfigurational and to bear strong similarities to that of plutonocene. Associated electronic densities are studied using QTAIM topological analysis and compared to CASSCF-derived densities of the aromatic systems benzene and the COT dianion. This analysis provides evidence of enhanced covalent character in plutonocene, supporting structural data calculated previously. Evidence of charge localisation in found in cerocene, this being most pronounced in its excited state of Ag symmetry. QTAIM analysis reveals that the ligand electronic structure is very similar in all metallocenes, and density differences show little variation in the ligand between the cerocene ground and excited state. Orbital contributions to integrated QTAIM properties are considered, and excellent agreement with experimentally determined f-orbital occupation is obtained. All methods of analysis support a Ce(iv) or mixed valence assignment of the cerocene ground state, whereas the Ag excited state is best described as a Ce(iii) state. © 2013 The Royal Society of Chemistry. Source


Lane N.,University College London
Cell | Year: 2012

Mixing of mitochondrial DNAs (heteroplasmy) is unfavorable for reasons unknown. Sharpley et al. show that heteroplasmy has surprising genetic and behavioral effects in mice, even when each haplotype alone produces a normal phenotype. This interference is bioenergetic and may have contributed to the evolution of sexes. © 2012 Elsevier Inc. Source


Medda F.,University College London
Journal of Transport Geography | Year: 2012

Cities worldwide have been experiencing escalating problems in obtaining financial resources for transport investment. Investments in transport thus need to seek new paradigms to solve these problems. Accessibility is a pivotal element in this context because it may induce increases in land value whereby some or all of these increments in land value resultant from the increase in accessibility can be captured to recover the capital costs of a transport investment. From this perspective the present paper reviews the main land value capture finance (LVC) mechanisms (betterment tax, accessibility increment contribution, and joint development) in relation to increased transport accessibility. The three financing instruments retain common features such as the ability to achieve wider public goals and private objectives, and they are flexible and can be implemented through different forms of financial instruments. We conclude that, for the successful implementation of a land value capture finance programme to take place, we must always consider the context (the urban area and the transport mode) in addition to the economic relationship between the life cycle of the transport system, its profitability and the property market. © 2012 Elsevier Ltd. Source


Patsalos P.N.,University College London | Patsalos P.N.,Chalfont Center for Epilepsy
Clinical Pharmacokinetics | Year: 2013

Since 1989 there has been an exponential introduction of new antiepileptic drugs (AEDs) into clinical practice and these include eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide; 16 in total. Because often the treatment of epilepsy is lifelong, and because patients are commonly prescribed polytherapy with other AEDs, AED interactions are an important consideration in the treatment of epilepsy and indeed can be a major therapeutic challenge. For new AEDs, their propensity to interact is particularly important because inevitably they can only be prescribed, at least in the first instance, as adjunctive polytherapy. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. The principal pharmacokinetic interaction relates to hepatic enzyme induction or inhibition whilst pharmacodynamic interactions principally entail adverse effect synergism, although examples of anticonvulsant synergism also exist. Overall, the new AEDs are less interacting primarily because many are renally excreted or not hepatically metabolised (e.g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin) and most do not (or minimally) induce or inhibit hepatic metabolism. A total of 139 pharmacokinetic interactions between concurrent AEDs have been described. The least pharmacokinetic interactions (n ≤ 5) are associated with gabapentin, lacosamide, tiagabine, vigabatrin and zonisamide, whilst lamotrigine (n = 17), felbamate (n = 15), oxcarbazepine (n = 14) and rufinamide (n = 13) are associated with the most. To date, felbamate, gabapentin, oxcarbazepine, perampanel, pregabalin, retigabine, rufinamide, stiripentol and zonisamide have not been associated with any pharmacodynamic interactions. © 2013 Springer International Publishing Switzerland. Source


Up to 40% of patients with temporal lobe epilepsy (TLE) are refractory to medication. Surgery is an effective treatment but may cause new neurologic deficits including visual field deficits (VFDs). The ability to drive after surgery is a key goal, but a postoperative VFD precludes driving in 4-50% of patients even if seizure-free. VFDs are a consequence of damage to the most anterior portion of the optic radiation, Meyer's loop. Anatomic dissection reveals that the anterior extent of Meyer's loop is highly variable and may clothe the temporal horn, a key landmark entered during temporal lobe epilepsy surgery. Experience from surgery since the 1940s has shown that VFDs are common (48-100%) and that the degree of resection affects the frequency or severity of the deficit. The pseudowedge shape of the deficit has led to a revised retinotopic model of the organization of the optic radiation. Evidence suggests that the left optic radiation is more anterior and thus at greater risk. Alternative surgical approaches, such as selective amygdalo-hippocampectomy, may reduce this risk, but evidence is conflicting or lacking. The optic radiation can be delineated in vivo using diffusion tensor imaging tractography, which has been shown to be useful in predicting the postoperative VFDs and in surgical planning. These data are now being used for surgical guidance with the aim of reducing the severity of VFDs. Compensation for brain shift occurring during surgery can be performed using intraoperative magnetic resonance imaging (MRI), but the additional utility of this expensive technique remains unproven. © 2013 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of the International League Against Epilepsy. Source


Walker S.M.,University College London
Clinics in Perinatology | Year: 2013

Nociceptive pathways are functional following birth. In addition to physiological and behavioral responses, neurophysiological measures and neuroimaging evaluate nociceptive pathway function and quantify responses to noxious stimuli in preterm and term neonates. Intensive care and surgery can expose neonates to painful stimuli when the developing nervous system is sensitive to changing input, resulting in persistent impacts into later childhood. Early pain experience has been correlated with increased sensitivity to subsequent painful stimuli, impaired neurodevelopmental outcomes, and structural changes in brain development. Parallel preclinical studies have elucidated underlying mechanisms and evaluate preventive strategies to inform future clinical trials. © 2013 Elsevier Inc. Source


Brewin C.R.,University College London
Psychological Bulletin | Year: 2014

The study of flashbacks is becoming increasingly important, as new proposals for the 11th edition of the World Health Organization's International Classification of Diseases give them an increasingly prominent role in the diagnosis of posttraumatic stress disorder. Amplifying the commentary of Kvavilashvili (2014), I contend that further progress is likely to depend on improved definition, distinguishing them from other forms of involuntary memory, and on more precise measurement. Improved measurement requires systematic testing of questionnaire and interview items as well as the use of experimental designs that contrast flashbacks directly with voluntary memory. Future research can now build on a solid base of theory and empirical findings, but it is always likely to be limited by the fact that it is difficult to bring involuntary memory under complete experimental control. © 2014 American Psychological Association. Source


Hergovich A.,University College London | Hemmings B.A.,Friedrich Miescher Institute for Biomedical Research
Seminars in Cell and Developmental Biology | Year: 2012

Over the past decade Hippo kinase signalling has been established as an essential tumour suppressor pathway controlling tissue growth in flies and mammals. All members of the Hippo core signalling cassette are conserved from yeast to humans, whereby the yeast analogues of Hippo, Mats and Lats are central components of the mitotic exit network and septation initiation network in budding and fission yeast, respectively. Here, we discuss how far core Hippo signalling components in Drosophila melanogaster and mammals have reported similar mitotic functions as already established for their highly conserved yeast counterparts. © 2012. Source


Manzoni C.,University College London
Biochemical Society Transactions | Year: 2012

LRRK2 (leucine-rich repeat kinase 2) is an enzyme implicated in human disease, containing kinase and GTPase functions within the same multidomain open reading frame. Dominant mutations in the LRRK2 gene are the most common cause of familial PD (Parkinson's disease). Additionally, in genome-wide association studies, the LRRK2 locus has been linked to risk of PD, Crohn's disease and leprosy, and LRRK2 has also been linked with cancer. Despite its associationwith human disease, very little is known about its pathophysiology. Recent reports suggest a functional association between LRRK2 and autophagy. Implications of this set of data for our understanding of LRRK2's role in physiology and disease are discussed in the present paper. ©The Authors Journal compilation ©2012 Biochemical Society. Source


Waldmann I.P.,University College London
Astrophysical Journal | Year: 2012

The characterization of ever smaller and fainter extrasolar planets requires an intricate understanding of one's data and the analysis techniques used. Correcting the raw data at the 10-4 level of accuracy in flux is one of the central challenges. This can be difficult for instruments that do not feature a calibration plan for such high precision measurements. Here, it is not always obvious how to de-correlate the data using auxiliary information of the instrument and it becomes paramount to know how well one can disentangle instrument systematics from one's data, given nothing but the data themselves. We propose a non-parametric machine learning algorithm, based on the concept of independent component analysis, to de-convolve the systematic noise and all non-Gaussian signals from the desired astrophysical signal. Such a "blind" signal de-mixing is commonly known as the "Cocktail Party problem" in signal processing. Given multiple simultaneous observations of the same exoplanetary eclipse, as in the case of spectrophotometry, we show that we can often disentangle systematic noise from the original light-curve signal without the use of any complementary information of the instrument. In this paper, we explore these signal extraction techniques using simulated data and two data sets observed with the Hubble Space Telescope NICMOS instrument. Another important application is the de-correlation of the exoplanetary signal from time-correlated stellar variability. Using data obtained by the Kepler mission we show that the desired signal can be de-convolved from the stellar noise using a single time series spanning several eclipse events. Such non-parametric techniques can provide important confirmations of the existent parametric corrections reported in the literature, and their associated results. Additionally they can substantially improve the precision exoplanetary light-curve analysis in the future. © 2012 The American Astronomical Society. All rights reserved. Source


Bockenhauer D.,University College London | Bichet D.G.,University of Montreal
Nature Reviews Nephrology | Year: 2015

Healthy kidneys maintain fluid and electrolyte homoeostasis by adjusting urine volume and composition according to physiological needs. The final urine composition is determined in the last tubular segment: the collecting duct. Water permeability in the collecting duct is regulated by arginine vasopressin (AVP). Secretion of AVP from the neurohypophysis is regulated by a complex signalling network that involves osmosensors, barosensors and volume sensors. AVP facilitates aquaporin (AQP)-mediated water reabsorption via activation of the vasopressin V2 receptor (AVPR2) in the collecting duct, thus enabling concentration of urine. In nephrogenic diabetes insipidus (NDI), inability of the kidneys to respond to AVP results in functional AQP deficiency. Consequently, affected patients have constant diuresis, resulting in large volumes of dilute urine. Primary forms of NDI result from mutations in the genes that encode the key proteins AVPR2 and AQP2, whereas secondary forms are associated with biochemical abnormalities, obstructive uropathy or the use of certain medications, particularly lithium. Treatment of the disease is informed by identification of the underlying cause. Here we review the clinical aspects and diagnosis of NDI, the various aetiologies, current treatment options and potential future developments. © 2015 Macmillan Publishers Limited. Source


A number of autobiographical memory theories and clinical theories of posttraumatic stress disorder (PTSD) make claims that are different from standard views of memory and have been the subject of controversy. These claims include the existence of a long-term perceptual memory system supporting conscious experience separate to episodic memory; greater involvement of perceptual memory in the response to emotion-laden and personally meaningful events; increased perceptual memory intrusions accompanied by impaired episodic memory for the traumatic event among PTSD patients; and a lack of association, or inverse association, between indices of voluntary recall and involuntary images relating to the same traumatic materials. In this article I review current research on perceptual memory, which supports the presence of long-term representations that are selective or incomplete reflections of sensory input. The functional independence of perceptual and episodic memory is illustrated by research on verbal overshadowing but is most clearly exemplified by the strong evidence in favor of enhanced perceptual memory and impaired episodic memory in PTSD. Theoretical predictions concerning the relation between perceptual priming and the development of intrusive images, the effect of verbal versus visuospatial secondary tasks on intrusive trauma images, and the independence of voluntary and involuntary memory for the same materials have garnered widespread support. Reasons for the continuing controversy over traumatic memory are discussed, and some implications of the review for general theories of recall and recognition, clinical theories of PTSD, and "special mechanism" views of memory are set out. © 2014 American Psychological Association. Source


Holton J.L.,University College London
Acta neuropathologica communications | Year: 2014

We report the case of a 75-year-old ex-professional boxer who developed diplopia and eye movement abnormalities in his 60's followed by memory impairment, low mood and recurrent falls. Examination shortly before death revealed hypomimia, dysarthria, vertical supranuclear gaze palsy and impaired postural reflexes. Pathological examination demonstrated 4-repeat tau neuronal and glial lesions, including tufted astrocytes, consistent with a diagnosis of progressive supranuclear palsy. In addition, neurofibrillary tangles composed of mixed 3-repeat and 4-repeat tau and astrocytic tangles in a distribution highly suggestive of chronic traumatic encephalopathy were observed together with limbic TDP-43 pathology. Possible mechanisms for the co-occurrence of these two tau pathologies are discussed. Source


Chang C.-Y.,University College London
Journal of Construction Engineering and Management | Year: 2014

Incentives are widely used in construction procurement to motivate the contractor to make cost-reduction efforts. How to choose the right incentive intensity is a critical decision in construction procurement. In this regard, the principal-agent theory has been highly influential in theory and practice alike. However, this research argues that this theoretical model may lead to a biased decision. To demonstrate this point, this research draws on its modeling technique to analyze a standard pain-gain sharing arrangement in construction contracts, finding that taking no account of contract breakup hazards will result in underuse of incentives. When the outturn cost also depends on the contractor's effort, high-powered incentives can better tap into the contractor's efficiency improvement potential. The additional profit resulting from efficiency savings can serve as a buffer for downside cost shocks with the effect of reducing the likelihood of contract breakup. This benefit will make it desirable to use incentives more intensively than what is suggested by the principal-agent theory. © 2014 American Society of Civil Engineers. Source


Brandao F.G.S.L.,University College London | Horodecki M.,University of Gdansk
Nature Physics | Year: 2013

Area laws for entanglement in quantum many-body systems give useful information about their lowerature behaviour and are tightly connected to the possibility of good numerical simulations. An intuition from quantum many-body physics suggests that an area law should hold whenever there is exponential decay of correlations in the system, a property found, for instance, in non-critical phases of matter. However, the existence of quantum data-hiding states - that is, states having very small correlations, yet a volume scaling of entanglement - was believed to be a serious obstruction to such an implication. Here we prove that notwithstanding the phenomenon of data hiding, one-dimensional quantum many-body states satisfying exponential decay of correlations always fulfil an area law. To obtain this result we combine several recent advances in quantum information theory, thus showing the usefulness of the field for addressing problems in other areas of physics. © 2013 Macmillan Publishers Limited. Source


Liu M.,University College London
Construction and Building Materials | Year: 2011

This research investigated the feasibility of using ground glass in self-compacting concrete (SCC). The ground glass was used as a partial replacement for both the cement and fine aggregate. The results show that to keep the filling ability constant, the inclusion of ground glass would require an increase in water/powder ratio and a reduction in superplasticizer dosage. These did not change the passing ability, but degraded the consistence retention and hardened properties such as strength but not to a prohibitive extent. This research concludes that SCC with satisfactory fresh properties can be produced by incorporating up to 104 kg/m3 ground glass, replacing about 10% cement and 10% sand, without the need for viscosity modifying agent (VMA). The successful completion of this study can lead to the application of ground glass in SCC, thus widening the types of additions available for SCC, saving landfill and reducing CO2 emissions by the use of less cement and sand. © 2010 Elsevier Ltd. All rights reserved. Source


Wheeler D.C.,University College London | Becker G.J.,Royal Melbourne Hospital
Kidney International | Year: 2013

The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for management of blood pressure (BP) in chronic kidney disease (CKD) supersedes the 2004 Kidney Disease Quality Outcomes Initiative document on this topic. The new guideline has been designed to assist clinical decision making in patients with CKD who are not receiving dialysis. The recommendations in the guideline acknowledge that no single BP target is optimal for all CKD patients and encourage individualization of treatment depending on age, the severity of albuminuria, and comorbidities. In general, the available evidence indicates that in CKD patients without albuminuria the target BP should be ≤140 mm Hg systolic and ≤90 mm Hg diastolic. However, in most patients with an albumin excretion rate of ≥30 mg/24 h (i.e., those with both micro- and macroalbuminuria), a lower target of ≤130 mm Hg systolic and ≤80 mm Hg diastolic is suggested. In achieving BP control, the value of lifestyle changes and the need for multiple pharmacological agents is acknowledged. Use of agents that block the renin-angiotensin-aldosterone system is recommended or suggested in all patients with an albumin excretion rate of ≥30 mg/24 h. Recommendations are almost identical in CKD patients with and without diabetes. Special considerations relevant to children and those of older age and those who have received a kidney transplant are included. Ongoing controversies in BP management in the context of CKD are highlighted along with key areas for future research. © 2012 International Society of Nephrology. Source


Factors affecting transcriptional elongation have been characterized extensively in in vitro, single cell (yeast) and cell culture systems; however, data from the context of multicellular organisms has been relatively scarce. While studies in homogeneous cell populations have been highly informative about the underlying molecular mechanisms and prevalence of polymerase pausing, they do not reveal the biological impact of perturbing this regulation in an animal. The core components regulating pausing are expressed in all animal cells and are recruited to the majority of genes, however, disrupting their function often results in discrete phenotypic effects. Mutations in genes encoding key regulators of transcriptional pausing have been recovered from several genetic screens for specific phenotypes or interactions with specific factors in mice, zebrafish and flies. Analysis of these mutations has revealed that control of transcriptional pausing is critical for a diverse range of biological pathways essential for animal development and survival. © 2013 WILEY Periodicals, Inc. Source


Orrell R.W.,University College London
British Medical Bulletin | Year: 2010

Introduction: There is no curative treatment for the common motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy. Nevertheless, there is an increasing volume of published studies. This review assesses the current evidence for treatment of these conditions. Sources of data: Primarily, the systematic reviews of the Cochrane Collaboration, with additional reference to other systematic reviews and online sites. Areas of agreement: Riluzole remains the only medication with demonstrated efficacy and regulatory approval for the treatment of ALS. Areas of controversy, growing points and areas timely for developing research: The design of clinical trials and the publication of unsatisfactory studies, in both human and animal models, continue to cause confusion in advising on patient management. Improvements in trial design, critical assessment of studies for publication and avoidance of bias towards publication of positive results are needed. A better understanding of pathogenesis should lead to more potent interventions. © The Author 2009. Published by Oxford University Press. All rights reserved. Source


Valerio M.,University College London
Prostate Cancer and Prostatic Diseases | Year: 2014

Background:To evaluate the safety and clinical feasibility of focal irreversible electroporation (IRE) of the prostate.Methods:We assessed the toxicity profile and functional outcomes of consecutive patients undergoing focal IRE for localised prostate cancer in two centres. Eligibility was assessed by multi-parametric magnetic resonance imaging (mpMRI) and targeted and/or template biopsy. IRE was delivered under transrectal ultrasound guidance with two to six electrodes positioned transperineally within the cancer lesion. Complications were recorded and scored accordingly to the NCI Common Terminology Criteria for Adverse Events; the functional outcome was physician reported in all patients with at least 6 months follow-up. A contrast-enhanced MRI 1 week after the procedure was carried out to assess treatment effect with a further mpMRI at 6 months to rule out evidence of residual visible cancer.Results:Overall, 34 patients with a mean age of 65 years (s.d.=±6) and a median PSA of 6.1 ng ml-1 (interquartile range (IQR)= 4.3-7.7) were included. Nine (26%), 24 (71%) and 1 (3%) men had low, intermediate and high risk disease, respectively (D'Amico criteria). After a median follow-up of 6 months (range 1-24), 12 grade 1 and 10 grade 2 complications occurred. No patient had grade >/= 3 complication. From a functional point of view, 100% (24/24) patients were continent and potency was preserved in 95% (19/20) men potent before treatment. The volume of ablation was a median 12 ml (IQR=5.6-14.5 ml) with the median PSA after 6 months of 3.4 ng ml-1 (IQR=1.9-4.8 ng ml-1). MpMRI showed suspicious residual disease in six patients, of whom four (17%) underwent another form of local treatment.Conclusions:Focal IRE has a low toxicity profile with encouraging genito-urinary functional outcomes. Further prospective development studies are needed to confirm the functional outcomes and to explore the oncological potential.Prostate Cancer and Prostatic Disease advance online publication, 2 September 2014; doi:10.1038/pcan.2014.33. Source


Burnstock G.,University College London | Burnstock G.,University of Melbourne | Ralevic V.,Queens Medical Center
Pharmacological Reviews | Year: 2014

Purinergic signaling plays important roles in control of vascular tone and remodeling. There is dual control of vascular tone by ATP released as a cotransmitter with noradrenaline from perivascular sympathetic nerves to cause vasoconstriction via P2X1 receptors, whereas ATP released from endothelial cells in response to changes in blood flow (producing shear stress) or hypoxia acts on P2X and P2Y receptors on endothelial cells to produce nitric oxide and endothelium-derived hyperpolarizing factor, which dilates vessels. ATP is also released from sensory-motor nerves during antidromic reflex activity to produce relaxation of some blood vessels. In this review, we stress the differences in neural and endothelial factors in purinergic control of different blood vessels. The long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides in promoting migration and proliferation of both vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis and vessel remodeling during restenosis after angioplasty are described. The pathophysiology of blood vessels and therapeutic potential of purinergic agents in diseases, including hypertension, atherosclerosis, ischemia, thrombosis and stroke, diabetes, and migraine, is discussed. © 2013 by The American Society for Pharmacology and Experimental Therapeutics. Source


Howorka S.,University College London
Current Opinion in Biotechnology | Year: 2011

Multimeric protein assemblies are essential components in viruses, bacteria, eukaryotic cells, and organisms where they act as cytoskeletal scaffold, storage containers, or for directional transport. The bottom-up structures can be exploited in nanobiotechnology by harnessing their built-in properties and combining them with new functional modules. This review summarizes the design principles of natural protein assemblies, highlights recent progress in their structural elucidation, and shows how rational engineering can create new biomaterials for applications in vaccine development, biocatalysis, materials science, and synthetic biology. © 2011 Elsevier Ltd. Source


Hunter A.,University College London
International Journal of Approximate Reasoning | Year: 2014

An argument graph is a graph where each node denotes an argument, and each arc denotes an attack by one argument on another. It offers a valuable starting point for theoretical analysis of argumentation following the proposals by Dung. However, the definition of an argument graph does not take into account the belief in the attacks. In particular, when constructing an argument graph from informal arguments, where each argument is described in free text, it is often evident that there is uncertainty about whether some of the attacks hold. This might be because there is some expressed doubt that an attack holds or because there is some imprecision in the language used in the arguments. In this paper, we use the set of spanning subgraphs of an argument graph as a sample space. A spanning subgraph contains all the arguments, and a subset of the attacks, of the argument graph. We assign a probability value to each spanning subgraph such that the sum of the assignments is 1. This means we can reflect the uncertainty over which is the actual subgraph using this probability distribution. Using the probability distribution over subgraphs, we can then determine the probability that a set of arguments is admissible or an extension. We can also obtain the probability of an attack relationship in the original argument graph as a marginal distribution (i.e. it is the sum of the probability assigned to each subgraph containing that attack relationship). We investigate some of the features of this proposal, and we consider the utility of our framework for capturing some practical argumentation scenarios. © 2013 Elsevier Inc. All rights reserved. Source


Cazorla C.,University College London
Thin Solid Films | Year: 2010

We present a theoretical study of the binding of collagen amino acids (AA, namely glycine, Gly; proline, Pro; and hydroxyproline, Hyp) to graphene (Gr), Ca-doped graphene and graphane (Gra) using density AR functional theory calculations and ab initio molecular dynamics (AIMD) simulations. It is found that binding of Gly, Pro and Hyp to Gr and Gra is thermodynamically favorable yet dependent on the amino acid orientation and always very weak (adsorption energies Eads range from -90 to -20 meV). AIMD simulations reveal that room-temperature thermal excitations are enough to induce detachment of Gly and Pro from Gr and of all three amino acids from Gra. Interestingly, we show that collagen AA binding to Gr is enhanced dramatically by doping the carbon surface with calcium atoms (corresponding Eads values decrease by practically two orders of magnitude with respect to the non-doped case). This effect is result of electronic charge transfers from the Ca impurity AR (donor) to Gr (acceptor) and the carboxyl group (COOH) of the amino acid (acceptor). The possibility AR of using Gr and Gra as nanoframes for sensing of collagen amino acids has also been investigated by performing electronic density AR of states analysis. It is found that, whether Gr is hardly sensitive, the electronic band gap of Gra can be modulated by attaching different number and species of AAs onto it. The results presented in this work provide fundamental insights on the quantum interactions of collagen protein components with carbon-based nanostructures and can be useful for developments in bio and nanotechnology fields. © 2010 Elsevier B.V. Source


Ruhrberg C.,University College London | Bautch V.L.,University of North Carolina at Chapel Hill
Cellular and Molecular Life Sciences | Year: 2013

The developing central nervous system (CNS) is vascularized via ingression of blood vessels from the outside as the neural tissue expands. This angiogenic process occurs without perturbing CNS architecture due to exquisite cross-talk between the neural compartment and invading blood vessels. Subsequently, this intimate relationship also promotes the formation of the neurovascular unit that underlies the blood-brain barrier and regulates blood flow to match brain activity. This review provides a historical perspective on research into CNS blood vessel growth and patterning, discusses current models used to study CNS angiogenesis, and provides an overview of the cellular and molecular mechanisms that promote blood vessel growth and maturation. Finally, we highlight the significance of these mechanisms for two different types of neurovascular CNS disease. © 2013 The Author(s). Source


Raihani N.J.,University College London
Proceedings. Biological sciences / The Royal Society | Year: 2012

Joint group membership is of major importance for cooperation in humans, and close ties or familiarity with a partner are also thought to promote cooperation in other animals. Here, we present the opposite pattern: female cleaner fish, Labroides dimidiatus, behave more cooperatively (by feeding more against their preference) when paired with an unfamiliar male rather than with their social partner. We propose that cooperation based on asymmetric punishment causes this reversed pattern. Males are larger than and dominant to female partners and are more aggressive to unfamiliar than to familiar female partners. In response, females behave more cooperatively with unfamiliar male partners. Our data suggest that in asymmetric interactions, weaker players might behave more cooperatively with out-group members than with in-group members to avoid harsher punishment. Source


Friston K.,University College London
Behavioral and Brain Sciences | Year: 2013

Why do brains have so many connections? The principles exposed by Andy Clark provide answers to questions like this by appealing to the notion that brains distil causal regularities in the sensorium and embody them in models of their world. For example, connections embody the fact that causes have particular consequences. This commentary considers the imperatives for this form of embodiment. © 2013 Cambridge University Press. Source


Fielding A.K.,University College London
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

The author discusses both the standards of care and more controversial areas in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Source


Okusa M.D.,University of Virginia | Davenport A.,University College London
Kidney International | Year: 2014

The KDIGO guidelines for acute kidney injury (AKI) are designed to assist health-care providers around the world in managing patients with AKI. Clinical guidelines are intended to help the clinician make an informed decision based on review of the currently available evidence. Due to the generic nature of guidelines, it is sometimes difficult to translate a guideline for a particular individual patient who may have specific clinical circumstances. To illustrate this point, we have discussed the interpretation of the KDIGO guideline in patients who have subtleties in their clinical presentation, which may make treatment decisions less than straightforward © 2013 International Society of Nephrology. Source


Hagura N.,University College London
Proceedings. Biological sciences / The Royal Society | Year: 2013

Szechuan pepper, a widely used ingredient in the cuisine of many Asian countries, is known for the tingling sensation it induces on the tongue and lips. While the molecular mechanism by which Szechuan pepper activates tactile afferent fibres has been clarified, the tingling sensation itself has been less studied, and it remains unclear which fibres are responsible. We investigated the somatosensory perception of tingling in humans to identify the characteristic temporal frequency and compare this to the established selectivity of tactile afferents. Szechuan pepper was applied to the lower lip of participants. Participants judged the frequency of the tingling sensation on the lips by comparing this with the frequencies of mechanical vibrations applied to their right index finger. The perceived frequency of the tingling was consistently at around 50 Hz, corresponding to the range of tactile RA1 afferent fibres. Furthermore, adaptation of the RA1 channel by prolonged mechanical vibration reliably reduced the tingling frequency induced by Szechuan pepper, confirming that the frequency-specific tactile channel is shared between Szechuan pepper and mechanical vibration. Combining information about molecular reactions at peripheral receptors with quantitative psychophysical measurement may provide a unique method for characterizing unusual experiences by decomposing them into identifiable minimal units of sensation. Source


Saiardi A.,University College London
Advances in Biological Regulation | Year: 2012

Phosphorus in his phosphate PO4 3- configuration is an essential constituent of all life forms. Phosphate diesters are at the core of nucleic acid structure, while phosphate monoester transmits information under the control of protein kinases and phosphatases. Due to these fundamental roles in biology it is not a surprise that phosphate cellular homeostasis is under tight control. Inositol pyrophosphates are organic molecules with the highest proportion of phosphate groups, and they are capable of regulating many biological processes, possibly by controlling energetic metabolism and adenosine triphosphate (ATP) production. Furthermore, inositol pyrophosphates influence inorganic polyphosphates (polyP) synthesis. The polymer polyP is solely constituted by phosphate groups and beside other known functions, it also plays a role in buffering cellular free phosphate [Pi] levels, an event that is ultimately necessary to generate ATP and inositol pyrophosphate. Although it is not yet clear how inositol pyrophosphates regulate cellular metabolism, understanding how inositol pyrophosphates influence phosphates homeostasis will help to clarify this important link. In this review I will describe the recent literature on this topic, with in the hope of inspiring further research in this fascinating area of biology. © 2012 Elsevier Ltd. Source


Kullmann D.M.,University College London
Journal of Physiology | Year: 2012

The early 1990s saw an intense debate over the locus of expression of NMDA receptor-dependent LTP. This provided an impetus for intense research into the mechanisms of modulation and trafficking of glutamate receptors and presynaptic vesicles. As new forms of LTP are discovered at different synapses, a simple resolution of the pre- versus postsynaptic debate seems increasingly remote. © 2012 The Physiological Society. Source


Schapira A.H.V.,University College London
Antioxidants and Redox Signaling | Year: 2012

Significance: Several genetic causes of familial Parkinson's disease (PD) have now been identified and include mutations of genes encoding mitochondrial proteins. Mitochondrial complex I toxins can induce dopaminergic cell death and produce a parkinsonian state. Importantly, defects of mitochondrial function have been identified in postmortem substantia nigra from pathologically proven cases of PD. Recent Advances: These observations provide compelling evidence to support the notion that mitochondria play an important role in the pathogenesis of PD. Thus, targeting mitochondrial function to delay or prevent neuronal cell death would represent a logical means to modify the course of this disease. Several attempts have already been made in this respect, and have been tested in clinical trial. Critical Issues: To date, there is no unequivocal evidence for an effective intervention to slow the disease. However, several novel mitochondrial targets are now emerging, including the potential to manipulate the mitochondrial pool to maintain function via biogenesis and mitophagy. Future Directions: This development in drug targets needs to be supported by a parallel improvement in clinical trial design to be able to detect a neuroprotective or disease-modifying effect over a reasonable time scale. © 2012, Mary Ann Liebert, Inc. Source


Habgood M.,University College London
Physical Chemistry Chemical Physics | Year: 2012

Solution and growth effects are in many cases critical in determining which crystal structure (polymorph) a molecule will adopt. Contemporary crystal structure prediction (CSP) rarely address formation and growth in a systematic way, relying instead on bulk thermodynamic stabilities. In this study, it is shown that analysis of simulated solutions of tetrolic acid in combination with calculation of stabilities for nanoscale clusters cut from bulk structures can distinguish between four computationally predicted crystal structures, including the two known forms and two speculative forms, rationalizing the formation of one structure rather than another on grounds other than bulk lattice energies. It is concluded that modelling of both solution-based supramolecular species and nanocrystal stabilities are necessary to explain the selection of one structure over another during crystal formation, and that they are sufficient for the specific case of tetrolic acid. © 2012 the Owner Societies. Source


Patsalos P.N.,University College London | Patsalos P.N.,Chalfont Center for Epilepsy
Epilepsia | Year: 2015

Summary The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5-2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co-ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2-12 mg); perampanel is 95% protein-bound to albumin and α1-acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half-life is ~105 h, whereas the calculated effective half-life is 48 h. These half-life values allow for once-daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half-life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4-inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use. © Wiley Periodicals, Inc. © 2014 International League Against Epilepsy. Source


Yang Z.,CAS Institute of Zoology | Yang Z.,University College London | Rannala B.,CAS Institute of Zoology | Rannala B.,University of California at Davis
Nature Reviews Genetics | Year: 2012

Phylogenies are important for addressing various biological questions such as relationships among species or genes, the origin and spread of viral infection and the demographic changes and migration patterns of species. The advancement of sequencing technologies has taken phylogenetic analysis to a new height. Phylogenies have permeated nearly every branch of biology, and the plethora of phylogenetic methods and software packages that are now available may seem daunting to an experimental biologist. Here, we review the major methods of phylogenetic analysis, including parsimony, distance, likelihood and Bayesian methods. We discuss their strengths and weaknesses and provide guidance for their use. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Orgeta V.,University College London
Journal of Anxiety Disorders | Year: 2011

Recent research has highlighted the important role of emotion dysregulation in the occurrence and maintenance of anxiety symptoms. The purpose of the present study was to investigate the relationship between anxiety symptoms and older adults' ability to regulate emotional experiences. A total of 167 community dwelling older adults completed self-report measures of affect and were asked to report how often they use specific emotion regulation strategies. Consistent with previous theories older adults experiencing increasing levels of anxiety reported greater difficulties in regulating emotional responses. Present results provide support for previous findings demonstrating that experiencing anxiety symptoms affects the ability to regulate emotional experiences. Current findings are likely to be informative in terms of understanding emotion dysregulation in older adults at risk of experiencing clinical symptoms of anxiety. © 2011 Elsevier Ltd. Source


Walker S.M.,University College London
Paediatric Anaesthesia | Year: 2014

Summary Effective management of procedural and postoperative pain in neonates is required to minimize acute physiological and behavioral distress and may also improve acute and long-term outcomes. Painful stimuli activate nociceptive pathways, from the periphery to the cortex, in neonates and behavioral responses form the basis for validated pain assessment tools. However, there is an increasing awareness of the need to not only reduce acute behavioral responses to pain in neonates, but also to protect the developing nervous system from persistent sensitization of pain pathways and potential damaging effects of altered neural activity on central nervous system development. Analgesic requirements are influenced by age-related changes in both pharmacokinetic and pharmacodynamic response, and increasing data are available to guide safe and effective dosing with opioids and paracetamol. Regional analgesic techniques provide effective perioperative analgesia, but higher complication rates in neonates emphasize the importance of monitoring and choice of the most appropriate drug and dose. There have been significant improvements in the understanding and management of neonatal pain, but additional research evidence will further reduce the need to extrapolate data from older age groups. Translation into improved clinical care will continue to depend on an integrated approach to implementation that encompasses assessment and titration against individual response, education and training, and audit and feedback. © 2013 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd. Source


Thom M.,University College London
Neuropathology and Applied Neurobiology | Year: 2014

Hippocampal sclerosis (HS) is a common pathology encountered in mesial temporal lobe epilepsy (MTLE) as well as other epilepsy syndromes and in both surgical and post-mortem practice. The 2013 International League Against Epilepsy (ILAE) classification segregates HS into typical (type 1) and atypical (type 2 and 3) groups, based on the histological patterns of subfield neuronal loss and gliosis. In addition, granule cell reorganization and alterations of interneuronal populations, neuropeptide fibre networks and mossy fibre sprouting are distinctive features of HS associated with epilepsies; they can be useful diagnostic aids to discriminate from other causes of HS, as well as highlighting potential mechanisms of hippocampal epileptogenesis. The cause of HS remains elusive and may be multifactorial; the contribution of febrile seizures, genetic susceptibility, inflammatory and neurodevelopmental factors are discussed. Post-mortem based research in HS, as an addition to studies on surgical samples, has the added advantage of enabling the study of the wider network changes associated with HS, the long-term effects of epilepsy on the pathology and associated comorbidities. It is likely that HS is heterogeneous in aspects of its cause, epileptogenetic mechanisms, network alterations and response to medical and surgical treatments. Future neuropathological studies will contribute to better recognition and understanding of these clinical and patho-aetiological subtypes of HS. © 2014 The Author. Source


Hardy T.A.,University of Sydney | Hardy T.A.,Brain and Mind Research Institute | Miller D.H.,University College London
The Lancet Neurology | Year: 2014

Baló's concentric sclerosis is often regarded as a rare variant of multiple sclerosis. Patients with this disorder present with acute or subacute neurological deterioration, with MRI showing one or more concentrically multilayered ring-like lesions usually in the cerebral white matter. Historically, Baló's concentric sclerosis was thought fatal in all cases. However, the availability of MRI has led to a better appreciation of the variable natural history of patients presenting with radiologically evident Baló lesions and the clinical association with multiple sclerosis and, less often, with other neurological disorders. Important advances have increased understanding of the immunopathogenic mechanisms associated with the formation of Baló lesions. However, how to treat an acute lesion and when or whether to start treatment are less well understood, although for patients with Baló lesions who also fulfil standard diagnostic criteria for multiple sclerosis, our opinion is that treatment with multiple sclerosis disease-modifying therapy would seem reasonable. © 2014 Elsevier Ltd. Source


Buchan D.W.,University College London
Nucleic acids research | Year: 2013

Here, we present the new UCL Bioinformatics Group's PSIPRED Protein Analysis Workbench. The Workbench unites all of our previously available analysis methods into a single web-based framework. The new web portal provides a greatly streamlined user interface with a number of new features to allow users to better explore their results. We offer a number of additional services to enable computationally scalable execution of our prediction methods; these include SOAP and XML-RPC web server access and new HADOOP packages. All software and services are available via the UCL Bioinformatics Group website at http://bioinf.cs.ucl.ac.uk/. Source


How do we decide whether to use external artifacts and reminders to remember delayed intentions, versus relying on unaided memory? Experiment 1 (N= 400) showed that participants' choice to forgo reminders in an experimental task was independently predicted by subjective confidence and objective ability, even when the two measures were themselves uncorrelated. Use of reminders improved performance, explaining significant variance in intention fulfilment even after controlling for unaided ability. Experiment 2 (N= 303) additionally investigated a pair of unrelated perceptual discrimination tasks, where the confidence and sensitivity of metacognitive judgments was decorrelated from objective performance using a staircase procedure. Participants with lower confidence in their perceptual judgments set more reminders in the delayed-intention task, even though confidence was unrelated to objective accuracy. However, memory confidence was a better predictor of reminder setting. Thus, propensity to set reminders was independently influenced by (a) domain-general metacognitive confidence; (b) task-specific confidence; and (c) objective ability. © 2015 Elsevier Inc. Source


de Vignemont F.,French National Center for Scientific Research | Iannetti G.D.,University College London
Neuropsychologia | Year: 2015

Several studies in humans and non-human primates have explored and characterised the features of the cortical representation of the portion of space immediately surrounding the body - the peripersonal space. In this paper we ask the following question: is it legitimate to assume that there is a single representation of peripersonal space? This issue has rarely been addressed in the literature, leading to much confusion, especially when one compares results reported in social psychology and in cognitive neuroscience. Indeed, studies in both fields explore and refer to more or less the same portion of space, but the terminology used to describe it differs greatly. Therefore, the definition of this portion of space immediately surrounding the body has remained quite vague, allowing for many variations. Here, we propose a dual model of peripersonal space, based on a clear functional distinction between bodily protection and goal-directed action. We argue that the two functions of peripersonal space require distinct sensory and motor processes that obey different principles. Furthermore, we highlight that the effects of anxiety and tool use on peripersonal space provide empirical support to our distinction. © 2014 Elsevier Ltd. Source


Towers M.,University of Sheffield | Wolpert L.,University College London | Tickle C.,University of Bath
Current Opinion in Cell Biology | Year: 2012

The developing limb is one of the first systems where it was proposed that a signalling gradient is involved in pattern formation. This gradient for specifying positional information across the antero-posterior axis is based on Sonic hedgehog signalling from the polarizing region. Recent evidence suggests that Sonic hedgehog signalling also specifies positional information across the antero-posterior axis by a timing mechanism acting in parallel with graded signalling. The progress zone model for specifying proximo-distal pattern, involving timing to provide cells with positional information, continues to be challenged, and there is further evidence that graded signalling by retinoic acid specifies the proximal part of the limb. Other recent papers present the first evidence that gradients of signalling by Wnt5a and FGFs govern cell behaviour involved in outgrowth and morphogenesis of the developing limb. © 2011 Elsevier Ltd. Source


Werner F.,University College London
Journal of Molecular Biology | Year: 2012

Evolutionary related multisubunit RNA polymerases (RNAPs) transcribe the genomes of all living organisms. Whereas the core subunits of RNAPs are universally conserved in all three domains of life-indicative of a common evolutionary descent-this only applies to one RNAP-associated transcription factor-Spt5, also known as NusG in bacteria. All other factors that aid RNAP during the transcription cycle are specific for the individual domain or only conserved between archaea and eukaryotes. Spt5 and its bacterial homologue NusG regulate gene expression in several ways by (i) modulating transcription processivity and promoter proximal pausing, (ii) coupling transcription and RNA processing or translation, and (iii) recruiting termination factors and thereby silencing laterally transferred DNA and protecting the genome against double-stranded DNA breaks. This review discusses recent discoveries that identify Spt5-like factors as evolutionary conserved nexus for the regulation and coordination of the machineries responsible for information processing in the cell. © 2012 Elsevier Ltd. Source


Rohrer J.D.,University College London
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2012

Frontotemporal dementia (FTD) is the second commonest young-onset neurodegenerative dementia. The canonical clinical syndromes are a behavioural variant (bvFTD) and two language variants (progressive nonfluent aphasia, PNFA, and semantic dementia, SD) although there is overlap with motor neurone disease and the atypical parkinsonian disorders corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Characteristic patterns of atrophy or hypometabolism are described in each of the variants but in reality imaging studies are rather heterogeneous. This review attempts to address four key questions in the neuroimaging of FTD: 1) what are the early imaging features of the different FTD syndromes (and how do these change as the disease progresses); 2) what do studies of presymptomatic genetic cases of FTD tell us about the very early stages of the disease; 3) can neuroimaging help to differentiate the different FTD syndromes; and 4) can neuroimaging help to differentiate FTD from other neurodegenerative diseases? This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease. © 2011 Elsevier B.V. Source


Burnstock G.,University College London
BioEssays | Year: 2012

Adenosine 5′-triphosphate (ATP) was identified in 1970 as the transmitter responsible for non-adrenergic, non-cholinergic neurotransmission in the gut and bladder and the term 'purinergic' was coined. Purinergic cotransmission was proposed in 1976 and ATP is now recognized as a cotransmitter in all nerves in the peripheral and central nervous systems. P1 (adenosine) and P2 (ATP) receptors were distinguished in 1978. Cloning of these receptors in the early 1990s was a turning point in the acceptance of the purinergic signalling hypothesis. There are both short-term purinergic signalling in neurotransmission, neuromodulation and secretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation and death in development and regeneration. Much is known about the mechanisms of ATP release and its breakdown by ectonucleotidases. Recently, there has been emphasis on purinergic pathophysiology, including neurodegenerative and neuropsychiatric disorders. Purinergic therapeutic strategies are being developed for treatment of gut, kidney, bladder, lung, skeletal and reproductive system disorders, pain and cancer. © 2012 WILEY Periodicals, Inc. Source


Hergovich A.,University College London
Biochemical Society Transactions | Year: 2012

The Hippo signal transduction cascade controls cell growth, proliferation and death, all of which are frequently deregulated in tumour cells. Since initial studies in Drosophila melanogaster were instrumental in defining Hippo signalling, the machinery was named after the central Ste20-like kinase Hippo. Moreover, given that loss of Hippo signalling components Hippo, Warts, and Mats resulted in uncontrolled tissue overgrowth, Hippo signalling was defined as a tumour-suppressor cascade. Significantly, all of the core factors of Hippo signalling have mammalian orthologues that functionally compensate for loss of their counterparts in Drosophila. Furthermore, studies in Drosophila and mammalian cell systems showed that Hippo signalling represents a kinase cascade that is tightly regulated by PPIs (protein-protein interactions). Several Hippo signalling molecules contain SARAH (Salvador/RASSF1A/Hippo) domains that mediate specific PPIs, thereby influencing the activities of MST1/2 (mammalian Ste20-like serine/threonine kinase 1/2) kinases, the human Hippo orthologues. Moreover, WW domains are present in several Hippo factors, and these domains also serve as interaction surfaces for regulatory PPIs in Hippo signalling. Finally, the kinase activities of LATS1/2 (large tumour-suppressor kinase 1/2), the human counterparts of Warts, are controlled by binding to hMOB1 (human Mps one binder protein 1), the human Mats. Therefore Hippo signalling is regulated by PPIs on several levels. In the present paper, I review the current understanding of how these regulatory PPIs are regulated and contribute to the functionality of Hippo signalling. ©The Authors Journal compilation ©2012 Biochemical Society. Source


Wray J.,University College London | Hartmann C.,Research Institute of Molecular Pathology
Trends in Cell Biology | Year: 2012

Embryonic stem cells (ESCs) - undifferentiated cells originating from preimplantation stage embryos - have prolonged self-renewal capacity and are pluripotent. Activation of the canonical Wnt pathway is implicated in maintenance of and exit from the pluripotent state. Recent findings demonstrate that the essential mediator of canonical Wnt signaling, β-catenin, is dispensable for ESC maintenance; however, its activation inhibits differentiation through derepression of T cell factor 3 (Tcf3)-bound genes. Wnt agonists are useful in deriving ESCs from recalcitrant mouse strains and the rat and in nuclear reprogramming of somatic stem cells. We discuss recent advances in our understanding of the role of canonical Wnt signaling in the regulation of ESC self-renewal and how its manipulation can improve pluripotent ESC derivation and maintenance. © 2011 Elsevier Ltd. Source


Newell B.R.,University of New South Wales | Shanks D.R.,University College London
Behavioral and Brain Sciences | Year: 2014

To what extent do we know our own minds when making decisions? Variants of this question have preoccupied researchers in a wide range of domains, from mainstream experimental psychology (cognition, perception, social behavior) to cognitive neuroscience and behavioral economics. A pervasive view places a heavy explanatory burden on an intelligent cognitive unconscious, with many theories assigning causally effective roles to unconscious influences. This article presents a novel framework for evaluating these claims and reviews evidence from three major bodies of research in which unconscious factors have been studied: multiple-cue judgment, deliberation without attention, and decisions under uncertainty. Studies of priming (subliminal and primes-to-behavior) and the role of awareness in movement and perception (e.g., timing of willed actions, blindsight) are also given brief consideration. The review highlights that inadequate procedures for assessing awareness, failures to consider artifactual explanations of landmark results, and a tendency to uncritically accept conclusions that fit with our intuitions have all contributed to unconscious influences being ascribed inflated and erroneous explanatory power in theories of decision making. The review concludes by recommending that future research should focus on tasks in which participants' attention is diverted away from the experimenter's hypothesis, rather than the highly reflective tasks that are currently often employed. Copyright © 2014 Cambridge University Press. Source


Minogue S.,University College London
Sub-cellular biochemistry | Year: 2012

Phosphatidylinositol 4-phosphate (PtdIns4P) is a quantitatively minor membrane phospholipid which is the precursor of PtdIns(4,5)P (2) in the classical agonist-regulated phospholipase C signalling pathway. However, PtdIns4P also governs the recruitment and function of numerous trafficking molecules, principally in the Golgi complex. The majority of phosphoinositides (PIs) phosphorylated at the D4 position of the inositol headgroup are derived from PtdIns4P and play roles in a diverse array of fundamental cellular processes including secretion, cell migration, apoptosis and mitogenesis; therefore, PtdIns4P biosynthesis can be regarded as key point of regulation in many PI-dependent processes.Two structurally distinct sequence families, the type II and type III PtdIns 4-kinases, are responsible for PtdIns4P synthesis in eukaryotic organisms. These important proteins are differentially expressed, localised and regulated by distinct mechanisms, indicating that the enzymes perform non-redundant roles in trafficking and signalling. In recent years, major advances have been made in our understanding of PtdIns4K biology and here we summarise current knowledge of PtdIns4K structure, function and regulation. Source


Gandhi S.,University College London
Oxidative medicine and cellular longevity | Year: 2012

Biological tissues require oxygen to meet their energetic demands. However, the consumption of oxygen also results in the generation of free radicals that may have damaging effects on cells. The brain is particularly vulnerable to the effects of reactive oxygen species due to its high demand for oxygen, and its abundance of highly peroxidisable substrates. Oxidative stress is caused by an imbalance in the redox state of the cell, either by overproduction of reactive oxygen species, or by dysfunction of the antioxidant systems. Oxidative stress has been detected in a range of neurodegenerative disease, and emerging evidence from in vitro and in vivo disease models suggests that oxidative stress may play a role in disease pathogenesis. However, the promise of antioxidants as novel therapies for neurodegenerative diseases has not been borne out in clinical studies. In this review, we critically assess the hypothesis that oxidative stress is a crucial player in common neurodegenerative disease and discuss the source of free radicals in such diseases. Furthermore, we examine the issues surrounding the failure to translate this hypothesis into an effective clinical treatment. Source


Pal K.,University College London
The Cochrane database of systematic reviews | Year: 2013

Diabetes is one of the commonest chronic medical conditions, affecting around 347 million adults worldwide. Structured patient education programmes reduce the risk of diabetes-related complications four-fold. Internet-based self-management programmes have been shown to be effective for a number of long-term conditions, but it is unclear what are the essential or effective components of such programmes. If computer-based self-management interventions improve outcomes in type 2 diabetes, they could potentially provide a cost-effective option for reducing the burdens placed on patients and healthcare systems by this long-term condition. To assess the effects on health status and health-related quality of life of computer-based diabetes self-management interventions for adults with type 2 diabetes mellitus. We searched six electronic bibliographic databases for published articles and conference proceedings and three online databases for theses (all up to November 2011). Reference lists of relevant reports and reviews were also screened. Randomised controlled trials of computer-based self-management interventions for adults with type 2 diabetes, i.e. computer-based software applications that respond to user input and aim to generate tailored content to improve one or more self-management domains through feedback, tailored advice, reinforcement and rewards, patient decision support, goal setting or reminders. Two review authors independently screened the abstracts and extracted data. A taxonomy for behaviour change techniques was used to describe the active ingredients of the intervention. We identified 16 randomised controlled trials with 3578 participants that fitted our inclusion criteria. These studies included a wide spectrum of interventions covering clinic-based brief interventions, Internet-based interventions that could be used from home and mobile phone-based interventions. The mean age of participants was between 46 to 67 years old and mean time since diagnosis was 6 to 13 years. The duration of the interventions varied between 1 to 12 months. There were three reported deaths out of 3578 participants.Computer-based diabetes self-management interventions currently have limited effectiveness. They appear to have small benefits on glycaemic control (pooled effect on glycosylated haemoglobin A1c (HbA1c): -2.3 mmol/mol or -0.2% (95% confidence interval (CI) -0.4 to -0.1; P = 0.009; 2637 participants; 11 trials). The effect size on HbA1c was larger in the mobile phone subgroup (subgroup analysis: mean difference in HbA1c -5.5 mmol/mol or -0.5% (95% CI -0.7 to -0.3); P < 0.00001; 280 participants; three trials). Current interventions do not show adequate evidence for improving depression, health-related quality of life or weight. Four (out of 10) interventions showed beneficial effects on lipid profile.One participant withdrew because of anxiety but there were no other documented adverse effects. Two studies provided limited cost-effectiveness data - with one study suggesting costs per patient of less than $140 (in 1997) or 105 EURO and another study showed no change in health behaviour and resource utilisation. Computer-based diabetes self-management interventions to manage type 2 diabetes appear to have a small beneficial effect on blood glucose control and the effect was larger in the mobile phone subgroup. There is no evidence to show benefits in other biological outcomes or any cognitive, behavioural or emotional outcomes. Source


Sampson E.L.,University College London
British Medical Bulletin | Year: 2010

The number of people with dementia will rise dramatically over the next 20 years. Currently, one in three people over the age of 65 will die with dementia. A PubMed search using MeSH headings for 'dementia' AND 'palliative care' and for specific areas, i.e. enteral feeding. National reports, UK guidelines and policies were also consulted. Advanced dementia is now being perceived as a 'terminal illness' with a similar symptom burden and prognosis to advanced cancer. People with dementia have poor access to good quality end-of-life care. Interventions such as antibiotics, fever management policies and enteral tube feeding remain in use despite little evidence that they improve quality of life or other outcomes. Research is required on the effectiveness of 'holistic' palliative care, outcome measures and the impact on carers and families. © 2010 The Author. Source


Khwaja A.,University College London
Current Topics in Microbiology and Immunology | Year: 2010

Although classical mutations in genes such as PIK3CA and PTEN occur at a relatively low frequency in haematological malignancies, activation of PI3K signalling is often detected in these tumours. In some conditions, for example acute myeloid leukaemia (AML), this is due to activating mutations of upstream regulators such as the FLT3 tyrosine kinase or RAS. Primary tumour cells taken from patients with AML, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia and multiple myeloma show varying levels of sensitivity to PI3K and mTOR inhibitors. The challenge now is to conduct high quality trials with novel agents that target these pathways to establish the level of clinical response and to identify those subsets of patients that are more likely to respond. © Springer-Verlag Berlin Heidelberg 2010. Source


Breuer J.,University College London
Current Topics in Microbiology and Immunology | Year: 2010

The molecular epidemiology of varicella zoster virus (VZV) has led to an understanding of virus evolution, spread, and pathogenesis. The availability of over 20 full length genomes has confirmed the existence of at least five virus clades and generated estimates of VZV evolution, with evidence of recombination both past and ongoing. Genotyping by restriction enzyme analysis (REA) and single nucleotide polymorphisms (SNP) has proven that the virus causing varicella is identical to that which later reactivates as zoster in an individual. Moreover, these methods have shown that reinfection, which is mostly asymptomatic, may also occur and the second virus may establish latency and reactivate. VZV is the only human herpesvirus that is spread by the respiratory route. Genotyping methods, together with epidemiological data and modeling, have provided insights into global differences in the transmission patterns of this ubiquitous virus. © Springer-Verlag Berlin Heidelberg 2010. Source


Perez de Oliveira L.,University College London
Marine Policy | Year: 2013

After years of facing problems such as overfishing, illegal fisheries and the consequences of the Prestige oil spill, the fishermen's association (c. ofradia) of Lira, a small town in the coast of Galicia (NW Spain), has pioneered a co-management initiative in the region by proposing the creation of a marine reserve. The proposal was designed and developed by the fishers in partnership with biologists and social scientists, environmentalists and members of the autonomous government of Galicia in a highly participatory process. The views of different stakeholders on the implementation process for the marine reserve were assessed through a programme of semi-structured interviews. These findings were also used to analyse issues related to the implementation process employing a governance analysis framework. It was observed that the inclusion of fishers in the decision-making and the use of their traditional ecological knowledge in the design of the reserve promoted a better understanding of its benefits and an improved compliance with the fishing regulations. The effectiveness of the marine reserve was very high during the first years but it has been recently undermined due to the reduction of financial state support for enforcement in the light of the current economic recession. Whilst this marine reserve was driven by the stakeholders, the prospects depend on an adequate state enforcement capacity. © 2013 Elsevier Ltd. Source


Habgood M.,University College London
Crystal Growth and Design | Year: 2011

Caffeine is a challenge in the study of organic crystallization, as the single crystal X-ray structures for both anhydrous phases are disordered. The symmetry-adapted ensemble approach is used in the form recently introduced for organic crystals to model the static disorder of form II (β) caffeine, giving structural motifs, energy, and entropy associated with the disorder. To explore whether it could be predicted that caffeine would form disordered structures, the analysis of the crystal energy landscape for caffeine is contrasted with that for isocaffeine. This demonstrates that near-symmetry in the intermolecular interactions of a molecule may be correlated with sets of nearly equienergetic crystal structures, to suggest disorder components. Symmetry-adapted ensemble calculations can then provide guidance as to whether disorder may be thermodynamically feasible. © 2011 American Chemical Society. Source


Gurusamy K.S.,University College London
The Cochrane database of systematic reviews | Year: 2013

Non surgical wounds include chronic ulcers (pressure or decubitus ulcers, venous ulcers, diabetic ulcers, ischaemic ulcers), burns and traumatic wounds. The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonisation (i.e. presence of MRSA in the absence of clinical features of infection such as redness or pus discharge) or infection in chronic ulcers varies between 7% and 30%. MRSA colonisation or infection of non surgical wounds can result in MRSA bacteraemia (infection of the blood) which is associated with a 30-day mortality of about 28% to 38% and a one-year mortality of about 55%. People with non surgical wounds colonised or infected with MRSA may be reservoirs of MRSA, so it is important to treat them, however, we do not know the optimal antibiotic regimen to use in these cases. To compare the benefits (such as decreased mortality and improved quality of life) and harms (such as adverse events related to antibiotic use) of all antibiotic treatments in people with non surgical wounds with established colonisation or infection caused by MRSA. We searched the following databases: The Cochrane Wounds Group Specialised Register (searched 13 March 2013); The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2); Database of Abstracts of Reviews of Effects (2013, Issue 2); NHS Economic Evaluation Database (2013, Issue 2); Ovid MEDLINE (1946 to February Week 4 2013); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, March 12, 2013); Ovid EMBASE (1974 to 2013 Week 10); EBSCO CINAHL (1982 to 8 March 2013). We included only randomised controlled trials (RCTs) comparing antibiotic treatment with no antibiotic treatment or with another antibiotic regimen for the treatment of MRSA-infected non surgical wounds. We included all relevant RCTs in the analysis, irrespective of language, publication status, publication year, or sample size. Two review authors independently identified the trials, and extracted data from the trial reports. We calculated the risk ratio (RR) with 95% confidence intervals (CI) for comparing the binary outcomes between the groups and planned to calculate the mean difference (MD) with 95% CI for comparing the continuous outcomes. We planned to perform the meta-analysis using both fixed-effect and random-effects models. We performed intention-to-treat analysis whenever possible. We identified three trials that met the inclusion criteria for this review. In these, a total of 47 people with MRSA-positive diabetic foot infections were randomised to six different antibiotic regimens. While these trials included 925 people with multiple pathogens, they reported the information on outcomes for people with MRSA infections separately (MRSA prevalence: 5.1%). The only outcome reported for people with MRSA infection in these trials was the eradication of MRSA. The three trials did not report the review's primary outcomes (death and quality of life) and secondary outcomes (length of hospital stay, use of healthcare resources and time to complete wound healing). Two trials reported serious adverse events in people with infection due to any type of bacteria (i.e. not just MRSA infections), so the proportion of patients with serious adverse events was not available for MRSA-infected wounds. Overall, MRSA was eradicated in 31/47 (66%) of the people included in the three trials, but there were no significant differences in the proportion of people in whom MRSA was eradicated in any of the comparisons, as shown below.1. Daptomycin compared with vancomycin or semisynthetic penicillin: RR of MRSA eradication 1.13; 95% CI 0.56 to 2.25 (14 people).2. Ertapenem compared with piperacillin/tazobactam: RR of MRSA eradication 0.71; 95% CI 0.06 to 9.10 (10 people).3. Moxifloxacin compared with piperacillin/tazobactam followed by amoxycillin/clavulanate: RR of MRSA eradication 0.87; 95% CI 0.56 to 1.36 (23 people). We found no trials comparing the use of antibiotics with no antibiotic for treating MRSA-colonised non-surgical wounds and therefore can draw no conclusions for this population. In the trials that compared different antibiotics for treating MRSA-infected non surgical wounds, there was no evidence that any one antibiotic was better than the others. Further well-designed RCTs are necessary. Source


Gurusamy K.S.,University College London
The Cochrane database of systematic reviews | Year: 2013

The management of people at high risk of perioperative death due to their general condition (high-risk surgical patients) with acute calculous cholecystitis is controversial, with no clear guidelines. In particular, the role of percutaneous cholecystostomy in these patients has not been defined. To compare the benefits (temporary or permanent relief of symptoms) and harms (recurrence of symptoms, procedure-related morbidity) of percutaneous cholecystostomy in the management of high-risk individuals with symptomatic gallstones. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded to December 2012 to identify the randomised clinical trials. We also handsearched the references lists of identified trials. We included only randomised clinical trials (irrespective of language, blinding, or publication status) addressing this issue. Two review authors collected data independently. For each outcome, we calculated the P values using Fisher's exact test or mean difference (MD) with 95% confidence intervals (CI). We included two trials with 156 participants for this review. The comparisons included in these two trials were percutaneous cholecystostomy followed by early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy (1 trial; 70 participants) and percutaneous cholecystostomy versus conservative treatment (1 trial; 86 participants). Both trials had high risk of bias. Percutaneous cholecystostomy with early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy: There was no significant difference in mortality between the two intervention groups (0/37 versus 1/33; Fisher's exact test: P value = 0.47). There was no significant difference in overall morbidity between the two intervention groups (1/31 versus 2/30; Fisher's exact test: P value = 0.61). This trial did not report on quality of life. There was no significant difference in the proportion of participants requiring conversion to open cholecystectomy between the two intervention groups (2/31 percutaneous cholecystostomy followed by early laparoscopic cholecystectomy versus 4/30 delayed laparoscopic cholecystectomy; Fisher's exact test: P value = 0.43). The mean total hospital stay was significantly lower in the percutaneous cholecystostomy followed by early laparoscopic cholecystectomy group compared with the delayed laparoscopic cholecystectomy group (1 trial; 61 participants; MD -9.90 days; 95% CI -12.31 to -7.49). The mean total costs were significantly lower in the percutaneous cholecystostomy followed by early laparoscopic cholecystectomy group compared with the delayed laparoscopic cholecystectomy group (1 trial; 61 participants; MD -1123.00 USD; 95% CI -1336.60 to -909.40). Percutaneous cholecystostomy versus conservative treatment: Nine of the 44 participants underwent delayed cholecystectomy in the percutaneous cholecystostomy group. Seven of the 42 participants underwent delayed cholecystectomy in the conservative treatment group. There was no significant difference in mortality between the two intervention groups (6/44 versus 7/42; Fisher's exact test: P value = 0.77). There was no significant difference in overall morbidity between the two intervention groups (6/44 versus 3/42; Fisher's exact test: P value = 0.49). The number of participants who underwent laparoscopic cholecystectomy was not reported in this trial. Therefore, we were unable to calculate the proportion of participants who underwent conversion to open cholecystectomy. The other outcomes, total hospital stay, quality of life, and total costs, were not reported in this trial. Based on the current available evidence from randomised clinical trials, we are unable to determine the role of percutaneous cholecystostomy in the clinical management of high-risk surgical patients with acute cholecystitis. There is a need for adequately powered randomised clinical trials of low risk of bias on this issue. Source


Gurusamy K.S.,University College London
The Cochrane database of systematic reviews | Year: 2013

Laparoscopic cholecystectomy (key-hole removal of the gallbladder) is now the most often used method for treatment of symptomatic gallstones. Several cardiopulmonary changes (decreased cardiac output, pulmonary compliance, and increased peak airway pressure) occur during pneumoperitoneum, which is now introduced to allow laparoscopic cholecystectomy. These cardiopulmonary changes may not be tolerated in individuals with poor cardiopulmonary reserve. To assess the benefits and harms of abdominal wall lift compared to pneumoperitoneum in patients undergoing laparoscopic cholecystectomy. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2013. We included all randomised clinical trials comparing abdominal wall lift (with or without pneumoperitoneum) versus pneumoperitoneum. We calculated the risk ratio (RR), rate ratio (RaR), or mean difference (MD) with 95% confidence intervals (CI) based on intention-to-treat analysis with both the fixed-effect and the random-effects models using the Review Manager (RevMan) software. For abdominal wall lift with pneumoperitoneum versus pneumoperitoneum, a total of 130 participants (all with low anaesthetic risk) scheduled for elective laparoscopic cholecystectomy were randomised in five trials to abdominal wall lift with pneumoperitoneum (n = 53) versus pneumoperitoneum only (n = 52). One trial which included 25 people did not state the number of participants in each group. All five trials had a high risk of bias. There was no mortality or conversion to open cholecystectomy in any of the participants in the trials that reported these outcomes. There was no significant difference in the rate of serious adverse events between the two groups (two trials; 2/29 events (0.069 events per person) versus 2/29 events (0.069 events per person); rate ratio 1.00; 95% CI 0.17 to 5.77). None of the trials reported quality of life, the proportion of people discharged as day-patient laparoscopic cholecystectomies, or pain between four and eight hours after the operation. There was no significant difference in the operating time between the two groups (four trials; 53 participants versus 54 participants; 13.39 minutes longer (95% CI 2.73 less to 29.51 minutes longer) in the abdominal wall lift with pneumoperitoneum group and 100 minutes in the pneumoperitoneum group).For abdominal wall lift versus pneumoperitoneum, a total of 774 participants (the majority with low anaesthetic risk) scheduled for elective laparoscopic cholecystectomy were randomised in 18 trials to abdominal wall lift without pneumoperitoneum (n = 332) versus pneumoperitoneum (n = 358). One trial which included 84 people did not state the number in each group. All the trials had a high risk of bias. There was no mortality in any of the trials that reported this outcome. There was no significant difference in the proportion of participants with serious adverse events (six trials; 5/172 (weighted proportion 2.4%) versus 2/171 (1.2%); RR 2.01; 95% CI 0.52 to 7.80). There was no significant difference in the rate of serious adverse events between the two groups (three trials; 5/99 events (weighted number of events per person = 0.346 events) versus 2/99 events (0.020 events per person); rate ratio 1.73; 95% CI 0.35 to 8.61). None of the trials reported quality of life or pain between four and eight hours after the operation. There was no significant difference in the proportion of people who underwent conversion to open cholecystectomy (11 trials; 5/225 (weighted proportion 2.3%) versus 7/235 (3.0%); RR 0.76; 95% CI 0.26 to 2.21). The operating time was significantly longer in the abdominal wall lift group than in the pneumoperitoneum group (16 trials; 6.87 minutes longer (95% CI 4.74 minutes to 9.00 minutes longer) in the abdominal wall lift group versus 75 minutes in the pneumoperitoneum group). There was no significant difference in the proportion of people discharged as laparoscopic cholecystectomy day-patients (two trials; 15/31 (weighted proportion 48.5%) versus 9/31 (29%); RR 1.67; 95% CI 0.85 to 3.26). Abdominal wall lift with or without pneumoperitoneum does not seem to offer an advantage over pneumoperitoneum in any of the patient-oriented outcomes for laparoscopic cholecystectomy in people with low anaesthetic risk. Hence it cannot be recommended routinely. The safety of abdominal wall lift is yet to be established. More research on the topic is needed because of the risk of bias in the included trials and because of the risk of type I and type II random errors due to the few participants included in the trials. Future trials should include people at higher anaesthetic risk. Furthermore, such trials should include blinded assessment of outcomes. Source


Gurusamy K.S.,University College London
The Cochrane database of systematic reviews | Year: 2013

T-tube drainage may prevent bile leak from the biliary tract following bile duct exploration and it offers post-operative access to the bile ducts for visualisation and exploration. Use of T-tube drainage after laparoscopic common bile duct (CBD) exploration is controversial. To assess the benefits and harms of T-tube drainage versus primary closure after laparoscopic common bile duct exploration. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until April 2013. We included all randomised clinical trials comparing T-tube drainage versus primary closure after laparoscopic common bile duct exploration. Two of four authors independently identified the studies for inclusion and extracted data. We analysed the data with both the fixed-effect and the random-effects model meta-analyses using Review Manager (RevMan) Analysis. For each outcome we calculated the risk ratio (RR), rate ratio (RaR), or mean difference (MD) with 95% confidence intervals (CI) based on intention-to-treat analysis. We included three trials randomising 295 participants: 147 to T-tube drainage versus 148 to primary closure. All trials had a high risk of bias. No one died during the follow-up period. There was no significant difference in the proportion of patients with serious morbidity (17/147 (weighted percentage 11.3%) in the T-tube drainage versus 9/148 (6.1%) in the primary closure group; RR 1.86; 95% CI 0.87 to 3.96; three trials), and no significant difference was found in the serious morbidity rates (weighted serious morbidity rate = 97 events per 1000 patients) in participants randomised to T-tube drainage versus serious morbidity rate = 61 events per 1000 patients in the primary closure group; RR 1.59; 95% CI 0.66 to 3.83; three trials). Quality of life was not reported in any of the trials. The operating time was significantly longer in the T-tube drainage group compared with the primary closure group (MD 21.22 minutes; 95% CI 12.44 minutes to 30.00 minutes; three trials). The hospital stay was significantly longer in the T-tube drainage group compared with the primary closure group (MD 3.26 days; 95% CI 2.49 days to 4.04 days; three trials). According to one trial, the participants randomised to T-tube drainage returned to work approximately eight days later than the participants randomised to the primary closure group (P < 0.005). T-tube drainage appears to result in significantly longer operating time and hospital stay as compared with primary closure without any evidence of benefit after laparoscopic common bile duct exploration. Based on currently available evidence, there is no justification for the routine use of T-tube drainage after laparoscopic common bile duct exploration in patients with common bile duct stones. More randomised trials comparing the effects of T-tube drainage versus primary closure after laparoscopic common bile duct exploration may be needed. Such trials should be conducted with low risk of bias, assessing the long-term beneficial and harmful effects including long-term complications such as bile stricture and recurrence of common bile duct stones. Source


Brown R.A.,University College London
Experimental Cell Research | Year: 2013

In the 40 years since Elsdale and Bard's analysis of fibroblast culture in collagen gels we have moved far beyond the concept that such 3D fibril network systems are better models than monolayer cultures. This review analyses key aspects of that progression of models, against a background of what exactly each model system tries to mimic. This story tracks our increasing understanding of fibroblast responses to soft collagen gels, in particularly their cytoskeletal contraction, migration and integrin attachment. The focus on fibroblast mechano-function has generated models designed to directly measure the overall force generated by fibroblast populations, their reaction to external loads and the role of the matrix structure. Key steps along this evolution of 3D collagen models have been designed to mimic normal skin, wound repair, tissue morphogenesis and remodelling, growth and contracture during scarring/fibrosis. As new models are developed to understand cell-mechanical function in connective tissues the collagen material has become progressively more important, now being engineered to mimic more complex aspects of native extracellular matrix structure. These have included collagen fibril density, alignment and hierarchical structure, controlling material stiffness and anisotropy. But of these, tissue-like collagen density is key in that it contributes to control of the others. It is concluded that across this 40 year window major progress has been made towards establishing a family of 3D experimental collagen tissue-models, suitable to investigate normal and pathological fibroblast mechano-functions. © 2013 Elsevier Inc. Source


Lloyd A.C.,University College London
Cell | Year: 2013

An adult animal consists of cells of vastly different size and activity, but the regulation of cell size remains poorly understood. Recent studies uncovering some of the signaling pathways important for size/growth control, together with the identification of diseases resulting from aberrations in these pathways, have renewed interest in this field. This Review will discuss our current understanding of how a cell sets its size, how it can adapt its size to a changing environment, and how these processes are relevant to human disease. © 2013 Elsevier Inc. Source


Brown R.P.,Liverpool John Moores University | Yang Z.,University College London
Systematic Biology | Year: 2010

Bayesian methods are increasingly being used to estimate divergence times without the restrictive assumption of a global clock. Little is known about their reliability for shallow phylogenies where DNA sequence divergence is low. We analyzed both simulated and real sequences to evaluate dating methods in phylogenies with mid-late Miocene roots. A large number of data sets (5000) with 10 taxa each were simulated under a rate-drift model for trees with 2 topologies (balanced or unbalanced) and with different sets of divergence times (characterized by long or short external branches). Data were analyzed using Bayesian Markov chain Monte Carlo methods in which the prior on divergence times was specified from a birth-death process with species sampling (BDS) or a Dirichlet distribution using the programs MCMCTREE and MULTIDIVTIME. The programs generally performed well on shallow phylogenies, but posterior mean node ages were biased and 95% posterior intervals included true ages in fewer than 95% of trees in some analyses. This typically occurred when the 95% prior interval did not include the true age and/or sequence lengths were ≤ 1 kbp. Widths of posterior intervals were also very dependent on the position of the calibrated node within the tree, particularly when sequences were short. Different divergence times priors within MCMCTREE, MULTIDIVTIME, and BEAST were used to analyze mitochondrial DNA data sets from a Bovid subfamily (the Caprinae) from Asian Laudakia and North African Chalcides lizards. Posterior divergence times were quite sensitive to different BDS priors but less sensitive to different Dirichlet priors. Our study demonstrates the impact of the prior on divergence times in shallow phylogenies and shows that 1) prior intervals on nodes should be assessed as a prerequisite to a dating analysis, 2) ≥ 1 kbp of quite rapidly evolving sequence may be required to obtain accurate posterior means and usefully narrow posterior intervals. Source


Mank J.E.,University College London
Trends in Genetics | Year: 2013

Sex chromosomes often entail gene dose differences between the sexes, which if not compensated for, lead to differences between males and females in the expression of sex-linked genes. Recent work has shown that different organisms respond to sex chromosome dose in a variety of ways, ranging from complete sex chromosome dosage compensation in some species to active compensation of only a minority genes in other organisms. Although we still do not understand the implications of the diversity in sex chromosome dosage compensation, its realization has created exciting new opportunities to study the evolution, mechanism, and consequences of gene regulation. However, confusion remains as to what sorts of genes are likely to be dosage compensated, how dosage compensation evolves, and why complete dosage compensation appears to be limited to male heterogametic species. In this review, I survey the status of dosage compensation to answer these questions and identify current controversies in this fast-moving field. © 2013 Elsevier Ltd. Source


Bockenhauer D.,University College London
Pediatric Nephrology | Year: 2013

Blessed were the days when it all made sense and the apparent mechanism for edema formation in nephrotic syndrome was straightforward: the kidneys lost protein in the urine, which lowered the plasma oncotic pressure. Thus, fluid leaked into the interstitium, depleting the intravascular volume with subsequent activation of renin/aldosterone and consequent avid renal sodium retention. As simple as that! Unfortunately, a number of clinical and laboratory observations have raised serious concerns about the accuracy of this "underfill" hypothesis. Instead, an "overfill" hypothesis was generated. Under this assumption, the nephrotic syndrome not only leads to urinary protein wasting, but also to primary sodium retention with consequent intravascular overfilling, with the excess fluid spilling into the flood plains of the interstitium, leading to edema. Recently, an attractive mechanism was proposed to explain this primary sodium retention: proteinuria includes plasma proteinases, such as plasmin, which activate the epithelial sodium channel in the collecting duct, ENaC. In this edition, further evidence for this hypothesis is being presented by confirming increased plasmin content in the urine of children with nephrotic syndrome and demonstrating ENaC activation. If correct, this hypothesis would provide a simple treatment for the edema: pharmacological blockade of ENaC, for instance, with amiloride. Yet, how come clinicians have not empirically discovered the presumed power of ENaC blockers in nephrotic syndrome? And why is it that some patients clearly show evidence of intravascular underfilling? The controversy of over- versus underfilling demonstrates how much we still have to learn about the pathophysiology of nephrotic syndrome. © 2013 IPNA. Source


Davenport A.,University College London
Nature Reviews Nephrology | Year: 2011

Prevention of clotting in the extracorporeal circuit was one of the major hurdles that had to be overcome to enable the expansion of routine outpatient hemodialysis to free-standing satellite centers and the home. Unfractionated heparin, the anticoagulant of choice for many years, is now being replaced by low-molecular-weight heparins (LMWHs) in an expanding number of countries. This trend is attributable to the ease and convenience of the administration of LMWHs coupled with their reliability and predictability of dosing. However, the choice of which LMWH to use depends on the duration and frequency of the dialysis sessions. For patients who are allergic to heparin or have heparin-induced thrombocytopenia, alternative anticoagulants - the direct thrombin inhibitors and heparinoids - are now available. These agents either have short half-lives (and therefore need to be delivered by infusions), or prolonged half-lives, which allows simple bolus administration, but increases the risk of drug accumulation, overdosage and hemorrhage. In patients at risk of bleeding, regional anticoagulants enable anticoagulation to be limited to the extracorporeal circuit. Prostanoids and nafamostat mesilate are expensive regional anticoagulants, and citrate infusions add complexity to the procedure. A citrate-based dialyzate has now been introduced that might enable heparin-free dialysis or reduce systemic anticoagulant requirements. © 2011 Macmillan Publishers Limited. All rights reserved. Source


Lachmann H.J.,University College London
Clinical and Experimental Immunology | Year: 2011

ARTICLES PUBLISHED IN THIS CLINICAL IMMUNOLOGY REVIEW SERIES allergy in childhood, allergy diagnosis by use of the clinical immunology laboratory, anaphylaxis, angioedema, management of pulmonary diseases in primary antibody deficiency, periodic fever syndrome, recurrent infections in childhood, recurrent oro-genital ulceration, recurrent superficial abcesses, SLE and Sjögren's syndrome, urticaria, vasculitis/CTD The periodic fever syndromes are disorders of innate immunity. They may be inherited or acquired and present as recurrent attacks of apparently spontaneous self-limiting inflammation without evidence of autoantibodies or infection. Over the past decade-and-a-half there has been significant progress in their understanding and treatment. © 2011 The Author. Clinical and Experimental Immunology © 2011 British Society for Immunology. Source


Snowling M.J.,University of York | Hulme C.,University College London
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2012

This article reviews our understanding of reading disorders in children and relates it to current proposals for their classification in DSM-5. There are two different, commonly occurring, forms of reading disorder in children which arise from different underlying language difficulties. Dyslexia (as defined in DSM-5), or decoding difficulty, refers to children who have difficulty in mastering the relationships between the spelling patterns of words and their pronunciations. These children typically read aloud inaccurately and slowly, and experience additional problems with spelling. Dyslexia appears to arise principally from a weakness in phonological (speech sound) skills, and there is good evidence that it can be ameliorated by systematic phonic teaching combined with phonological awareness training. The other major form of reading difficulty is reading comprehension impairment. These children read aloud accurately and fluently, but have difficulty understanding what they have read. Reading comprehension impairment appears to arise from weaknesses in a range of oral language skills including poor vocabulary knowledge, weak grammatical skills and difficulties in oral language comprehension. We suggest that the omission of reading comprehension impairment from DSM-5 is a serious one that should be remedied. Both dyslexia and reading comprehension impairment are dimensional in nature, and show strong continuities with other disorders of language. We argue that recognizing the continuities between reading and language disorders has important implications for assessment and treatment, and we note that the high rates of comorbidity between reading disorders and other seemingly disparate disorders (including ADHD and motor disorders) raises important challenges for understanding these disorders. © 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health. Source


Castan Broto V.,University College London | Bulkeley H.,Durham University
Global Environmental Change | Year: 2013

Cities are key sites where climate change is being addressed. Previous research has largely overlooked the multiplicity of climate change responses emerging outside formal contexts of decision-making and led by actors other than municipal governments. Moreover, existing research has largely focused on case studies of climate change mitigation in developed economies. The objective of this paper is to uncover the heterogeneous mix of actors, settings, governance arrangements and technologies involved in the governance of climate change in cities in different parts of the world. The paper focuses on urban climate change governance as a process of experimentation. Climate change experiments are presented here as interventions to try out new ideas and methods in the context of future uncertainties. They serve to understand how interventions work in practice, in new contexts where they are thought of as innovative. To study experimentation, the paper presents evidence from the analysis of a database of 627 urban climate change experiments in a sample of 100 global cities. The analysis suggests that, since 2005, experimentation is a feature of urban responses to climate change across different world regions and multiple sectors. Although experimentation does not appear to be related to particular kinds of urban economic and social conditions, some of its core features are visible. For example, experimentation tends to focus on energy. Also, both social and technical forms of experimentation are visible, but technical experimentation is more common in urban infrastructure systems. While municipal governments have a critical role in climate change experimentation, they often act alongside other actors and in a variety of forms of partnership. These findings point at experimentation as a key tool to open up new political spaces for governing climate change in the city. © 2012 Elsevier Ltd. Source


Pickard C.J.,University College London | Needs R.J.,Theory of Condensed Matter Group
Physical Review Letters | Year: 2011

First-principles density-functional-theory calculations show that compression of alkali metals stabilizes open structures with localized interstitial electrons which may exhibit a Stoner-type instability towards ferromagnetism. We find ferromagnetic phases of the lithium-IV-type, simple cubic, and simple hexagonal structures in the heavier alkali metals, which may be described as s-band ferromagnets. We predict that the most stable phases of potassium at low temperatures and pressures around 20 GPa are ferromagnets. © 2011 American Physical Society. Source


Burnstock G.,University College London | Burnstock G.,University of Melbourne
Purinergic Signalling | Year: 2014

Purinergic signalling plays major roles in the physiology and pathophysiology of digestive organs. Adenosine 5′-triphosphate (ATP), together with nitric oxide and vasoactive intestinal peptide, is a cotransmitter in non-adrenergic, non-cholinergic inhibitory neuromuscular transmission. P2X and P2Y receptors are widely expressed in myenteric and submucous enteric plexuses and participate in sympathetic transmission and neuromodulation involved in enteric reflex activities, as well as influencing gastric and intestinal epithelial secretion and vascular activities. Involvement of purinergic signalling has been identified in a variety of diseases, including inflammatory bowel disease, ischaemia, diabetes and cancer. Purinergic mechanosensory transduction forms the basis of enteric nociception, where ATP released from mucosal epithelial cells by distension activates nociceptive subepithelial primary afferent sensory fibres expressing P2X3 receptors to send messages to the pain centres in the central nervous system via interneurons in the spinal cord. Purinergic signalling is also involved in salivary gland and bile duct secretion. © 2013 Springer Science+Business Media Dordrecht. Source


Rook G.A.W.,University College London
Digestive Diseases | Year: 2011

The current 'Darwinian' synthesis of the hygiene (or 'Old Friends') hypothesis suggests that the increase in chronic inflammatory disorders that started in Europe in the mid-19th century and progressed until the late 20th century is at least partly attributable to immunodysregulation resulting from lack of exposure to microorganisms that were tasked by co-evolutionary processes with establishing the 'normal' background levels of immunoregulation, a role that they perform in concert with the normal microbiota. This is an example of 'evolved dependence'. The relevant organisms co-evolved with mammals, already accompanied early hominids in the Paleolithic era and are associated with animals, mud and faeces. These organisms often establish stable carrier states, or are encountered continuously in primitive environments as 'pseudocommensals' from mud and water. These organisms were not lost during the first epidemiological transition, which might even have resulted in increased exposure to them. However, the crucial organisms are lost progressively as populations undergo the second epidemiological transition (modern urban environment). Recently evolved sporadic 'childhood infections' are not likely to have evolved immunoregulatory roles, and epidemiology supports this contention. The consequences of the loss of the Old Friends and distortion of the microbiota are aggravated by other modern environmental changes that also lead to enhanced inflammatory responses (obesity, vitamin D deficiency, pollution (dioxins), etc.). The range of chronic inflammatory disorders affected may be larger than had been assumed (allergies, autoimmunity, inflammatory bowel disease, but also coeliac disease, food allergy, vascular disease, some cancers, and depression/anxiety when accompanied by raised inflammatory cytokines). Copyright © 2011 S. Karger AG, Basel. Source


Sidebottom A.,University College London
British Journal of Criminology | Year: 2015

It is well known that many victims of crime do not notify the police. Research suggests that factors related to the victim, crime event and wider community are all implicated in the decision to report victimization. Few studies have investigated the correlates of victim reporting in developing countries, mainly owing to a lack of relevant data. It is therefore unclear whether the determinants of victim reporting in Western industrialized countries are generalizable to low-income developing settings. This paper explores the factors associated with victims reporting assault to the police in the African context of Malawi, using data from a nationally representative household survey. Results of a multilevel logistic regression indicate some similarities with the Western criminological literature, such as age of the victim and crime seriousness positively correlating with crime reporting. Other results seem to reflect the distinctive characteristics of Malawi, with victims more likely to report being assaulted if they are male, have access to a working phone or live in urban areas. The results illustrate the importance of studying criminological phenomena across a diverse range of settings. Implications of the findings for future research and crime prevention are discussed. © 2014 The Author. Source


Romero-Gomez M.,University of Seville | Montagnese S.,University of Padua | Jalan R.,University College London
Journal of Hepatology | Year: 2015

Hepatic encephalopathy in a hospitalized cirrhotic patient is associated with a high mortality rate and its presence adds further to the mortality of patients with acute-on-chronic liver failure (ACLF). The exact pathophysiological mechanisms of HE in this group of patients are unclear but hyperammonemia, systemic inflammation (including sepsis, bacterial translocation, and insulin resistance) and oxidative stress, modulated by glutaminase gene alteration, remain as key factors. Moreover, alcohol misuse, hyponatremia, renal insufficiency, and microbiota are actively explored. HE diagnosis requires exclusion of other causes of neurological, metabolic and psychiatric dysfunction. Hospitalization in the ICU should be considered in every patient with overt HE, but particularly if this is associated with ACLF. Precipitating factors should be identified and treated as required. Evidence-based specific management options are limited to bowel cleansing and non-absorbable antibiotics. Ammonia lowering drugs, such as glycerol phenylbutyrate and ornithine phenylacetate show promise but are still in clinical trials. Albumin dialysis may be useful in refractory cases. Antibiotics, prebiotics, and treatment of diabetes reduce systemic inflammation. Where possible and not contraindicated, large portalsystemic shunts may be embolized but liver transplantation is the most definitive step in the management of HE in this setting. HE in patients with ACLF appears to be clinically and pathophysiologically distinct from that of acute decompensation and requires further studies and characterization. © 2014 European Association for the Study of the Liver. Source


Geraci M.,University College London
Journal of Statistical Software | Year: 2014

Inference in quantile analysis has received considerable attention in the recent years. Linear quantile mixed models (Geraci and Bottai 2014) represent a flexible statistical tool to analyze data from sampling designs such as multilevel, spatial, panel or longitudinal, which induce some form of clustering. In this paper, I will show how to estimate conditional quantile functions with random effects using the R package lqmm. Modeling, estimation and inference are discussed in detail using a real data example. A thorough description of the optimization algorithms is also provided. Source


Haines T.S.F.,University College London | Xiang T.,Queen Mary, University of London
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2014

Video analysis often begins with background subtraction. This problem is often approached in two steps-a background model followed by a regularisation scheme. A model of the background allows it to be distinguished on a per-pixel basis from the foreground, whilst the regularisation combines information from adjacent pixels. We present a new method based on Dirichlet process Gaussian mixture models, which are used to estimate per-pixel background distributions. It is followed by probabilistic regularisation. Using a non-parametric Bayesian method allows per-pixel mode counts to be automatically inferred, avoiding over-/under-fitting. We also develop novel model learning algorithms for continuous update of the model in a principled fashion as the scene changes. These key advantages enable us to outperform the state-of-the-art alternatives on four benchmarks. © 2014 IEEE. Source


Qiu W.,University College London
Marine Policy | Year: 2013

This paper examines the governance of the Sanya Coral Reef National Marine Nature Reserve (SCR-NMNR) in China in the context of a rapidly growing local economy, driven mainly by recent growth in the tourism sector. The governance approach adopted in the SCR-NMNR is characterised by significant decentralisation, i.e. many roles have been devolved to the local government. However, this has led to the undermining of strategic conservation objectives by local economic development priorities, through the rapid development of mass tourism involving both the private sector and the local government. This reliance on economic incentives has provided alternative livelihoods and resources for the management of the MPA, but has also incurred environmental and social costs. Overall, it can be argued that the current governance approach cannot effectively address the full spectrum of challenges encountered, in that these costs appear to outweigh the benefits. In order to improve the governance of the SCR-NMNR towards more effective and equitable outcomes, strengthened leadership from the central state will be needed, as well as a sense of community stewardship towards the MPA. © 2013. Source


Singleton A.,U.S. National Institute on Aging | Hardy J.,University College London
Human Molecular Genetics | Year: 2011

The dominant and sometimes competing theories for the aetiology of complex human disease have been the common disease, common variant (CDCV) hypothesis, and the multiple rare variant (MRV) hypothesis. With the advent of genome wide association studies and of second-generation sequencing, we are fortunate in being able to test these ideas. The results to date suggest that these hypotheses are not mutually exclusive. Further, initial evidence suggests that both MRV and CDCV can be true at the same loci, and that other disease-related genetic mechanisms also exist at some of these loci. We propose calling these, pleomorphic risk loci, and discuss here how such loci not only offer understanding of the genetic basis of disease, but also provide mechanistic biological insight into disease processes. Source


Landslides are a common hazard in the highly urbanized hilly areas in Chittagong Metropolitan Area (CMA), Bangladesh. The main cause of the landslides is torrential rain in short period of time. This area experiences several landslides each year, resulting in casualties, property damage, and economic loss. Therefore, the primary objective of this research is to produce the Landslide Susceptibility Maps for CMA so that appropriate landslide disaster risk reduction strategies can be developed. In this research, three different Geographic Information System-based Multi-Criteria Decision Analysis methods—the Artificial Hierarchy Process (AHP), Weighted Linear Combination (WLC), and Ordered Weighted Average (OWA)—were applied to scientifically assess the landslide susceptible areas in CMA. Nine different thematic layers or landslide causative factors were considered. Then, seven different landslide susceptible scenarios were generated based on the three weighted overlay techniques. Later, the performances of the methods were validated using the area under the relative operating characteristic curves. The accuracies of the landslide susceptibility maps produced by the AHP, WLC_1, WLC_2, WLC_3, OWA_1, OWA_2, and OWA_3 methods were found as 89.80, 83.90, 91.10, 88.50, 90.40, 95.10, and 87.10 %, respectively. The verification results showed satisfactory agreement between the susceptibility maps produced and the existing data on the 20 historical landslide locations. © 2014, The Author(s). Source


Walker M.C.,University College London
Epilepsia | Year: 2011

There is a long history of the use of brain stimulation in the treatment of epilepsy but relatively little experience for its use in status epilepticus. Electroconvulsive therapy, transcranial magnetic stimulation, subcortical and cortical stimulation have all been tried with varying degrees of success in single cases or small case series. It remains unclear, however, which brain areas should be stimulated and the parameters that should be used. Moreover, the aim (stopping status epilepticus) is different from preventing seizures and so the brain areas and parameters that are useful in epilepsy may not directly translate to the treatment of status epilepticus. © Wiley Periodicals, Inc. © 2011 International League Against Epilepsy. Source


Smith M.,University College London
Epilepsia | Year: 2011

There is little evidence to guide the choice of intravenous anesthetic agent to treat refractory status epilepticus but midazolam, propofol, and barbiturates are widely used. It is impractical to use inhalational anesthetic agents in most circumstances and there is little experience with non-GABA-ergic agents such as ketamine. A more aggressive treatment approach, aiming for EEG suppression, is most likely to result in sustained cessation of seizure activity but this is associated with increased treatment-related complications. Side effects of treatment, including hypotension, gastric paresis, and pneumonia, are common and contribute independently to poor outcome and death. © Wiley Periodicals, Inc. © 2011 International League Against Epilepsy. Source


Super-refractory status epilepticus (SE) is a stage of refractory SE characterized by unresponsiveness to initial anesthetic therapy. It is a new concept that has been the focus of recent basic and therapeutic work, and is defined as "SE that continues or recurs 24 hours or more after the onset of anesthesia, including those cases in which SE recurs on the reduction or withdrawl of anesthesia." It is encountered typically, but not exclusively, in two quite distinctive clinical situations: (1) in patients with severe acute brain injury, and (2) in patients with no history of epilepsy in whom status epilepticus develops out of the blue with no overt cause. There are a variety of treatments used, almost entirely based on open observational studies or case reports. Therapy includes anesthesia, antiepileptic drug therapy, hypothermia and ICU therapy, other medical, immunological, and physical therapies. In this review, the range of possible therapies is outlined and an approach to therapy is discussed. © Wiley Periodicals, Inc. © 2011 International League Against Epilepsy. Source


Donoghue H.D.,University College London
Clinical Microbiology and Infection | Year: 2011

The direct detection of ancient Mycobacterium tuberculosis molecular biomarkers has profoundly changed our understanding of the disease in ancient and historical times. Initially, diagnosis was based on visual changes to skeletal human remains, supplemented by radiological examination. The introduction of biomolecular methods has enabled the specific identification of tuberculosis in human tissues, and has expanded our knowledge of the palaeopathological changes associated with the disease. We now realize that the incidence of past tuberculosis was greater than previously estimated, as M. tuberculosis biomarkers can be found in calcified and non-calcified tissues with non-specific or no visible pathological changes. Modern concepts of the origin and evolution of M. tuberculosis are informed by the detection of lineages of known location and date. © 2011 The Author. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases. Source


Johnson S.,University of Leicester | Marlow N.,University College London
Seminars in Fetal and Neonatal Medicine | Year: 2014

There is growing interest in the long-term mental health sequelae of extremely preterm birth. In this paper we review literature relating to mental health outcomes across the lifespan. Studies conducted in the preschool years, school age and adolescence, and adulthood show continuity in outcomes and point to an increased risk for inattention, socio-communicative problems and emotional difficulties in individuals born extremely preterm. Both behavioural and neuroimaging studies also provide evidence of a neurodevelopmental origin for mental health disorders in this population. Here we summarise contemporary evidence and highlight key methodological considerations for carrying out and interpreting studies in this field. © 2013 Elsevier Ltd. Source


Background/Aims: Both brain natriuretic peptide (BNP) and volume overload are reported to be powerful predictors of survival for peritoneal dialysis patients. The usefulness of single BNP determinations in helping determine volume status in peritoneal dialysis patients remains controversial, so we reviewed serial BNP and multifrequency bioimpedance measurements to determine whether changes in BNP reflected changes in volume status. Methods: Prospective measurements of fluid volume by multifrequency bioimpedance and serum N-terminal pro-BNP (NTproBNP) were conducted in stable adult peritoneal dialysis outpatients attending for routine assessments of peritoneal dialysis adequacy and transport status. Results: A total of 189 serial measurements were made in 92 patients, and NTproBNP increased from a median of 162.5 pmol/l (interquartile range 82-385.4) to 195 pmol/l (interquartile range 101.9-348.6; p < 0.05). Changes in NTproBNP correlated with changes in extracellular water (ECW), total body water (TBW) and ECW/TBW (r = 0.38, 0.31 and 0.45, respectively; all p < 0.0001). Patients were divided into quartiles depending upon NTproBNP changes; those with the greatest fall in NTproBNP had significant falls in ECW (p < 0.001), TBW (p = 0.001) and ECW/TBW (p < 0.001) compared to the quartile with the greatest increase in NTproBNP, who also had an increase in systolic blood pressure from 133.5 ± 22.7 to 142.7 ± 28.8 mm Hg (p = 0.0078), whereas it fell in the quartile with the greatest fall in NTproBNP (143.8 ± 24.6 vs. 136.5 ± 18.7 mm Hg). Conclusions: Serial measurements of NTproBNP correlated with changes in volume assessments made by multifrequency bioimpedance in peritoneal dialysis outpatients. As multifrequency bioimpedance measures total ECW, rather than effective plasma volume, serial NTproBNP determinations may prove an adjunct to the clinical assessment of volume status in peritoneal dialysis patients. © 2012 S. Karger AG, Basel. Source


Wolpert M.,University College London
Administration and Policy in Mental Health and Mental Health Services Research | Year: 2014

Having been a national advocate for the use of patient reported outcome measures (PROMs) in Child and Adolescent Mental Health Services (CAMHS) in the UK for the last decade, I have become increasingly concerned that unless the potential iatrogenic impact of widespread policy requirement for use of PROMs (Department of Health, Children and Young People's Health Outcomes Strategy, 2012) is recognised and addressed their real potential benefits (Sapyta et al.; J Clin Psychol 61(2):145-153, 2005) may never be realized. Drawing on examples from PROMs implementation in CAMHS in the UK (Wolpert et al.; J Ment Health 21(2):165-173, 2012a; Child Adolesc Mental Health 17(3):129-130, 2012b). I suggest key ways forward if PROMs are to support best clinical practice rather than undermine it. © 2013 The Author(s). Source


Gurusamy K.S.,University College London
The Cochrane database of systematic reviews | Year: 2013

Methicillin-resistant Staphylococcus aureus (MRSA) infection after surgery is usually rare, but incidence can be up to 33% in certain types of surgery. Postoperative MRSA infection can occur as surgical site infections (SSI), chest infections, or bloodstream infections (bacteraemia). The incidence of MRSA SSIs varies from 1% to 33% depending upon the type of surgery performed and the carrier status of the individuals concerned. The optimal antibiotic regimen for the treatment of MRSA in surgical wounds is not known. To compare the benefits and harms of various antibiotic treatments in people with established surgical site infections (SSIs) caused by MRSA . In February 2013 we searched the following databases: The Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL); Database of Abstracts of Reviews of Effects (DARE); NHS Economic Evaluation Database; Health Technology Assessment (HTA) Database; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. We included only randomised controlled trials (RCTs) comparing one antibiotic regimen with another antibiotic regimen for the treatment of SSIs due to MRSA. All RCTs irrespective of language, publication status, publication year, or sample size were included in the analysis. Two review authors independently decided on inclusion and exclusion of trials, and extracted data. We planned to calculate the risk ratio (RR) with 95% confidence intervals (CI) for comparing the binary outcomes between the groups and mean difference (MD) with 95% CI for comparing the continuous outcomes. We planned to perform the meta-analysis using both a fixed-effect and a random-effects model. We performed intention-to-treat analysis whenever possible. We included one trial involving 59 people hospitalised because of MRSA SSIs. Thirty participants were randomised to linezolid (600 mg either intravenously or orally every 12 hours for seven to 14 days) and 29 to vancomycin (1 g intravenously every 12 hours for seven to 14 days). The type of surgical procedures that were performed were not reported. The trial reported one outcome, which was the eradication of MRSA. The proportion of people in whom MRSA was eradicated was statistically significantly higher in the linezolid group than in the vancomycin group (RR 1.80; 95% CI 1.20 to 2.68). There is currently no evidence to recommend any specific antibiotic in the treatment of MRSA SSIs. Linezolid is superior to vancomycin in the eradication of MRSA SSIs on the basis of evidence from one small trial that was at high risk of bias, but the overall clinical implications of using linezolid instead of vancomycin are not known. Further well-designed randomised clinical trials are necessary in this area. Source


Surgical resection is the only potentially curative treatment for pancreatic and periampullary cancer. A considerable proportion of patients undergo unnecessary laparotomy because of underestimation of the extent of the cancer on computed tomography (CT) scanning. Laparoscopy can detect metastases not visualised on CT scanning, enabling better assessment of the spread of cancer (staging of cancer). There has been no systematic review or meta-analysis assessing the role of diagnostic laparoscopy in assessing the resectability with curative intent in patients with pancreatic and periampullary cancer. To determine the diagnostic accuracy of diagnostic laparoscopy performed as an add-on test to CT scanning in the assessment of curative resectability in pancreatic and periampullary cancer. We searched the Cochrane Register of Diagnostic Test Accuracy Studies, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, EMBASE via OvidSP (from inception to 13 September 2012), and Science Citation Index Expanded (from 1980 to 13 September 2012). We included diagnostic accuracy studies of diagnostic laparoscopy in patients with potentially resectable pancreatic and periampullary cancer on CT scan, where confirmation of liver or peritoneal involvement was by histopathological examination of suspicious (liver or peritoneal) lesions obtained at diagnostic laparoscopy or laparotomy. We accepted any criteria of resectability used in the studies. We included studies irrespective of language, publication status, or study design (prospective or retrospective). We excluded case-control studies. Two authors independently performed data extraction and quality assessment using the QUADAS-2 tool. The specificity of diagnostic laparoscopy in all studies was 1 because there were no false positives since laparoscopy and the reference standard are one and the same if histological examination after diagnostic laparoscopy is positive. Therefore, the sensitivities were meta-analysed using a univariate random-effects logistic regression model. The probability of unresectability in patients who had a negative laparoscopy (post-test probability for patients with a negative test result) was calculated using the median probability of unresectability (pre-test probability) from the included studies and the negative likelihood ratio derived from the model (specificity of 1 assumed). The difference between the pre-test and post-test probabilities gave the overall added value of diagnostic laparoscopy compared to the standard practice of CT scan staging alone. Fifteen studies with a total of 1015 patients were included in the meta-analysis. Only one study including 52 patients had a low risk of bias and low applicability concern in the patient selection domain. The median pre-test probability of unresectable disease after CT scanning across studies was 40.3% (that is 40 out of 100 patients who had resectable cancer after CT scan were found to have unresectable disease on laparotomy). The summary sensitivity of diagnostic laparoscopy was 68.7% (95% CI 54.3% to 80.2%). Assuming a pre-test probability of 40.3%, the post-test probability of unresectable disease for patients with a negative test result was 0.17 (95% CI 0.12 to 0.24). This indicates that if a patient is said to have resectable disease after diagnostic laparoscopy and CT scan, there is a 17% probability that their cancer will be unresectable compared to a 40% probability for those receiving CT alone.A subgroup analysis of patients with pancreatic cancer gave a summary sensitivity of 67.9% (95% CI 41.1% to 86.5%). The post-test probability of unresectable disease after being considered resectable on both CT and diagnostic laparoscopy was 18% compared to 40% for those receiving CT alone. Diagnostic laparoscopy may decrease the rate of unnecessary laparotomy in patients with pancreatic and periampullary cancer found to have resectable disease on CT scan. On average, using diagnostic laparoscopy with biopsy and histopathological confirmation of suspicious lesions prior to laparotomy would avoid 23 unnecessary laparotomies in 100 patients in whom resection of cancer with curative intent is planned. Source


Sanders R.D.,University College London
The Cochrane database of systematic reviews | Year: 2013

Patients undergoing vascular surgery are a high-risk population with widespread atherosclerosis, an adverse cardiovascular risk profile and often multiple co-morbidities. Postoperative cardiovascular separate analyses for the comparisons of statin with placebo/no treatment and between different doses of statin. We presented results as pooled risk ratios (RRs) with 95% confidence intervals (CIs) based on random-effects models (inverse variance method). We employed the Chi(2) test and calculated the I(2) statistic to investigate study heterogeneity. We identified six eligible studies in total. The six Included studies were generally of high quality, but the largest eligible study was excluded because of concerns about its validity. Study populations were statin naive, which led to a considerable loss of eligible participants.Five RCTs compared statin use with placebo or standard care. We pooled results from three studies, with a total of 178 participants, for mortality and non-fatal event outcomes. In the statin group, 7/105 (6.7%) participants died within 30 days of surgery, as did 10/73 (13.7%) participants in the control group. Only one death in each group was from cardiovascular causes, with an incidence of 0.95% in statin participants and 1.4% in control participants, respectively. All deaths occurred in a single study population, and so effect estimates were derived from one study only. The risk ratio (RR) of all-cause mortality in statin users showed a non-significant decrease in risk (RR 0.73, 95% CI 0.31 to 1.75). For cardiovascular death, the risk ratio was 1.05 (95% CI 0.07 to 16.20). Non-fatal MI within 30 days of surgery was reported in three studies and occurred in 4/105 (3.8%) participants in the statin group and 8/73 (11.0%) participants receiving placebo, for a non-significant decrease in risk (RR 0.47, 95% CI 0.15 to 1.52). Several studies reported muscle enzyme levels as safety measures, but only three (with a total of 188 participants) reported explicitly on clinical muscle syndromes, with seven events reported and no significant difference found between statin users and controls (RR 0.94, 95% CI 0.24 to 3.63). The only participant-reported outcome was nausea in one small study,with no significant difference in risk between groups.Two studies compared different doses of atorvastatin, with a total of 145 participants, but reported data were not sufficient to allow us to determine the effect of higher doses on any outcome. Evidence was insufficient to allow review authors to conclude that statin use resulted in either a reduction or an increase in any of the outcomes examined. The existing body of evidence leaves questions about the benefits of perioperative use of statins for vascular surgery unanswered. Widespread use of statins in the target population means that it may now be difficult for researchers to undertake the large RCTs needed to demonstrate any effect on the incidence of postoperative cardiovascular events. However, participant-reported outcomes have been neglected and warrant further study. Source


Mayo-Wilson E.,University College London
The Cochrane database of systematic reviews | Year: 2013

Anxiety disorders are the most common mental health problems. They are chronic and unremitting. Effective treatments are available, but access to services is limited. Media-delivered behavioural and cognitive behavioural interventions (self-help) aim to deliver treatment with less input from professionals compared with traditional therapies. To assess the effects of media-delivered behavioural and cognitive behavioural therapies for anxiety disorders in adults. Published and unpublished studies were considered without restriction by language or date. The Cochrane Depression, Anxiety and Neurosis Review Group's Specialized Register (CCDANCTR) was searched all years to 1 January 2013. The CCDANCTR includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). Complementary searches were carried out on Ovid MEDLINE (1950 to 23 February 2013) and PsycINFO (1987 to February, Week 2, 2013), together with International trial registries (the trials portal of the World Health Organization (ICTRP) and ClinicalTrials.gov). Reference lists from previous meta-analyses and reports of randomised controlled trials were checked, and authors were contacted for unpublished data. Randomised controlled trials of media-delivered behavioural or cognitive behavioural therapy in adults with anxiety disorders (other than post-traumatic stress disorder) compared with no intervention (including attention/relaxation controls) or compared with face-to-face therapy. Both review authors independently screened titles and abstracts. Study characteristics and outcomes were extracted in duplicate. Outcomes were combined using random-effects models, and tests for heterogeneity and for small study bias were conducted. We examined subgroup differences by type of disorder, type of intervention provided, type of media, and recruitment methods used. One hundred and one studies with 8403 participants were included; 92 studies were included in the quantitative synthesis. These trials compared several types of media-delivered interventions (with varying levels of support) with no treatment and with face-to-face interventions. Inconsistency and risk of bias reduced our confidence in the overall results. For the primary outcome of symptoms of anxiety, moderate-quality evidence showed medium effects compared with no intervention (standardised mean difference (SMD) 0.67, 95% confidence interval (CI) 0.55 to 0.80; 72 studies, 4537 participants), and low-quality evidence of small effects favoured face-to-face therapy (SMD -0.23, 95% CI -0.36 to -0.09; 24 studies, 1360 participants). The intervention was associated with greater response than was seen with no treatment (risk ratio (RR) 2.34, 95% CI 1.81 to 3.03; 21 studies, 1547 participants) and was not significantly inferior to face-to-face therapy in these studies (RR 0.78, 95 % CI 0.56 to 1.09; 10 studies, 575 participants), but the latter comparison included versions of therapies that were not as comprehensive as those provided in routine clinical practice. Evidence suggested benefit for secondary outcome measures (depression, mental-health related disability, quality of life and dropout), but this evidence was of low to moderate quality. Evidence regarding harm was lacking. Self-help may be useful for people who are not able or are not willing to use other services for people with anxiety disorders; for people who can access it, face-to-face cognitive behavioural therapy is probably clinically superior. Economic analyses were beyond the scope of this review.Important heterogeneity was noted across trials. Recent interventions for specific problems that incorporate clinician support may be more effective than transdiagnostic interventions (i.e. interventions for multiple disorders) provided with no guidance, but these issues are confounded in the available trials.Although many small trials have been conducted, the generalisability of their findings is limited. Most interventions tested are not available to consumers. Self-help has been recommended as the first step in the treatment of some anxiety disorders, but the short-term and long-term effectiveness of media-delivered interventions has not been established. Large, pragmatic trials are needed to evaluate and to maximise the benefits of self-help interventions. Source


Gurusamy K.S.,University College London
The Cochrane database of systematic reviews | Year: 2013

Gallstones and alcohol account for more than 80% of acute pancreatitis. Cholecystectomy is the definitive treatment for gallstones. Laparoscopic cholecystectomy is the preferred route for performing cholecystectomy. The timing of laparoscopic cholecystectomy after an attack of acute biliary pancreatitis is controversial. To compare the benefits and harms of early versus delayed laparoscopic cholecystectomy in people with acute biliary pancreatitis. For mild acute pancreatitis, we considered 'early' laparoscopic cholecystectomy to be laparoscopic cholecystectomy performed within three days of onset of symptoms. We considered all laparoscopic cholecystectomies performed beyond three days of onset of symptoms as 'delayed'. For severe acute pancreatitis, we considered 'early' laparoscopic cholecystectomy as laparoscopic cholecystectomy performed within the index admission. We considered all laparoscopic cholecystectomies performed in a later admission as 'delayed'. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, issue 12), MEDLINE, EMBASE, Science Citation Index Expanded, and trial registers until January 2013. We included randomised controlled trials, irrespective of language or publication status, comparing early versus delayed laparoscopic cholecystectomy for people with acute biliary pancreatitis. Two authors independently assessed trials for inclusion and independently extracted data. We planned to analyse data with both the fixed-effect and the random-effects models using Review Manager 5 (RevMan 2011). We calculated the risk ratio (RR), or mean difference (MD) with 95% confidence intervals (CI) based on an intention-to-treat analysis. We identified one trial comparing early versus delayed laparoscopic cholecystectomy for people with mild acute pancreatitis. Fifty participants with mild acute gallstone pancreatitis were randomised either to early laparoscopic cholecystectomy (within 48 hours of admission irrespective of whether the abdominal symptoms were resolved or the laboratory values had returned to normal) (n = 25), or to delayed laparoscopic cholecystectomy (surgery after resolution of abdominal pain and after the laboratory values had returned to normal) (n = 25). This trial is at high risk of bias. There was no short-term mortality in either group. There was no significant difference between the groups in the proportion of participants who developed serious adverse events (RR 0.33; 95% CI 0.01 to 7.81). Health-related quality of life was not reported in this trial. There were no conversions to open cholecystectomy in either group. The total hospital stay was significantly shorter in the early laparoscopic cholecystectomy group than in the delayed laparoscopic cholecystectomy group (MD -2.30 days; 95% CI -4.40 to -0.20). This trial reported neither the number of work-days lost nor the costs. We did not identify any trials comparing early versus delayed laparoscopic cholecystectomy after severe acute pancreatitis. There is no evidence of increased risk of complications after early laparoscopic cholecystectomy. Early laparoscopic cholecystectomy may shorten the total hospital stay in people with mild acute pancreatitis. If appropriate facilities and expertise are available, early laparoscopic cholecystectomy appears preferable to delayed laparoscopic cholecystectomy in those with mild acute pancreatitis. There is currently no evidence to support or refute early laparoscopic cholecystectomy for people with severe acute pancreatitis. Further randomised controlled trials at low risk of bias are necessary in people with mild acute pancreatitis and severe acute pancreatitis. Source


Though many people around the world now spend much of their time surrounded by bodies of controlled ambient air indoors, we still know relatively little about the subjectivities involved. Some have deployed the idea of air-conditioning addiction. Others emphasise the enjoyable sensations associated with temporary escape. The research described in this paper sought to add some empirical depth to these discussions by combining theories of social practice with a programme of serial interviews to examine how a sample of city professionals felt about the long periods they spent inside air-conditioned offices. The rationale was that, through these means, it should be possible to identify ways of disrupting otherwise habitual indoor existences and thereby discourage people from becom- ing increasingly reliant upon ambient conditions that are environmentally costly to supply. Describing their passage through a typical working day, this paper focuses on the moments when it might have occurred to them to spend time outside and how certain mental and material elements combined to impede the arrival of this decision. This exercise is used to draw out suggestions about how a better relationship between professional office workers and the everyday outdoors could be encouraged. The broader conclusion is that contextual studies which examine how places and practices produce decisions, instead of assuming individual people merely make them, have their part to play in fostering positive social futures. © 2011 Pion Ltd. Source


de la Torre I.,University College London
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

The emergence of the Acheulean from the earlier Oldowan constitutes a major transition in human evolution, the theme of this special issue. This paper discusses the evidence for the origins of the Acheulean, a cornerstone in the history of human technology, from two perspectives; firstly, a review of the history of investigations on Acheulean research is presented. This approach introduces the evolution of theories throughout the development of the discipline, and reviews the way in which cumulative knowledge led to the prevalent explanatory framework for the emergence of the Acheulean. The second part presents the current state of the art in Acheulean origins research, and reviews the hard evidence for the appearance of this technology in Africa around 1.7 Ma, and its significance for the evolutionary history of Homo erectus. © 2016 The Author(s) Published by the Royal Society. All rights reserved. Source


Dean M.C.,University College London
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

An important question in palaeoanthropology is whether, among the australopiths and the first fossil hominins attributed to early Homo, there was a shift towards a more prolonged period of growth that can be distinguished from that of the living great apes and whether between the end of weaning and the beginning of puberty there was a slow period of growth as there is in modern humans. Evidence for the pace of growth in early fossil hominins comes from preserved tooth microstructure. A record of incremental growth in enamel and dentine persists, which allows us to reconstruct tooth growth and compare key measures of dental maturation with modern humans and living great apes. Despite their diverse diets and way of life, it is currently difficult to identify any clear differences in the timing of dental development among living great apes, australopiths and the earliest hominins attributed to the genus Homo. There is, however, limited evidence that some early hominins may have attained a greater proportion of their body mass and stature relatively earlier in the growth period than is typical of modern humans today. © 2016 The Author(s) Published by the Royal Society. All rights reserved. Source


Rossouw T.I.,North East London National Health Service NHS Foundation Trust NELFT | Fonagy P.,University College London
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2012

Objective: We examined whether mentalization-based treatment for adolescents (MBT-A) is more effective than treatment as usual (TAU) for adolescents who self-harm. Method: A total of 80 adolescents (85 female) consecutively presenting to mental health services with self-harm and comorbid depression were randomly allocated to either MBT-A or TAU. Adolescents were assessed for self-harm, risk-taking and mood at baseline and at 3-monthly intervals until 12 months. Their attachment style, mentalization ability and borderline personality disorder (BPD) features were also assessed at baseline and at the end of the 12-month treatment. Results: MBT-A was more effective than TAU in reducing self-harm and depression. This superiority was explained by improved mentalization and reduced attachment avoidance and reflected improvement in emergent BPD symptoms and traits. Conclusions: MBT-A may be an effective intervention to reduce self-harm in adolescents. Clinical trial registration information: - The emergence of personality disorder traits in adolescents who deliberately self harm and the potential for using a mentalisation based treatment approach as an early intervention for such individuals: a randomised controlled trial; http://www.controlled-trials.com; ISRCTN95266816. © 2012 American Academy of Child and Adolescent Psychiatry. Source


Scully M.,University College London
Blood Reviews | Year: 2010

Thrombotic thrombocytopenic purpura is an acute life threatening disorder, characterised by thrombocytopenia, microangiopathic haemolytic anaemia and multi organ microvascular thrombi that results in variable clinical symptoms. Just over a decade ago, the missing enzyme required for von Willebrand cleavage was recognised in TTP patients, subsequently identified as ADAMTS 13. Assays have confirmed that the majority of TTP cases are idiopathic and are associated with inhibitors and or IgG antibodies to ADAMTS 13. Such cases take longer to treat and are more likely to relapse. Evidence to date suggests the majority of antibodies block the spacer domain of ADAMTS 13. There may be other antibodies binding to ADAMTS 13 domains but their overall clinical involvement remains to be determined. Immunosuppressive treatments have until now been unsatisfactory. However, monoclonal anti-CD 20 therapy, acting on B-lymphocytes involved in antibody production results in remission in most patients and prevention of recurrent relapse. Further investigation into the antibodies produced in TTP and other aspects of immune dysfunction, such as T cells will further our understanding of this devastating disorder. © 2009 Elsevier Ltd. All rights reserved. Source


Foley A.R.,University College London
Brain : a journal of neurology | Year: 2013

The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed 'collagen VI-related myopathies' and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with Bethlem myopathy was not significant (P = 0.1432). Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years (±4.0) and in patients with intermediate collagen VI-related myopathy by 20.7 years (±1.5). The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials. Source


Vugler A.A.,University College London
Retina | Year: 2010

Background: Retinal diseases such as age-related macular degeneration and retinitis pigmentosa remain major causes of severe vision loss in humans. Clinical trials for treatment of retinal degenerations are underway and advancements in our understanding of retinal biology in health/disease have implications for novel therapies. Methods: A review of retinal biology is used to inform a discussion of current strategies to maintain/repair neural circuitry in age-related macular degeneration, retinitis pigmentosa, and Type 2 Leber congenital amaurosis. Results: In age-related macular degeneration/retinitis pigmentosa, a progressive loss of rods/cones results in corruption of bipolar cell circuitry, although retinal output neurons/photoreceptive melanopsin cells survive. Visual function can be stabilized/enhanced after treatment in age-related macular degeneration, but in advanced degenerations, reorganization of retinal circuitry may preclude attempts to restore cone function. In Type 2 Leber congenital amaurosis, useful vision can be restored by gene therapy where central cones survive. Remarkable progress has been made in restoring vision to rodents using light-responsive ion channels inserted into bipolar cells/retinal ganglion cells. Conclusion: Advances in genetic, cellular, and prosthetic therapies show varying degrees of promise for treating retinal degenerations. While functional benefits can be obtained after early therapeutic interventions, efforts should be made to minimize circuitry changes as soon as possible after rod/cone loss. Advances in retinal anatomy/physiology and genetic technologies should allow refinement of future reparative strategies. © The Ophthalmic Communications Society, Inc. Source


Shortt A.J.,University College London
Cochrane database of systematic reviews (Online) | Year: 2013

Myopia (also known as short-sightedness or near-sightedness) is an ocular condition in which the refractive power of the eye is greater than is required, resulting in light from distant objects being focused in front of the retina instead of directly on it. The two most commonly used surgical techniques to permanently correct myopia are photorefractive keratectomy (PRK) and laser-assisted in-situ keratomileusis (LASIK). To compare the effectiveness and safety of LASIK and PRK for correction of myopia by examining post-treatment uncorrected visual acuity, refractive outcome, loss of best spectacle-corrected visual acuity, pain scores, flap complications in LASIK, subepithelial haze, adverse events, quality of life indices and higher order aberrations. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 11), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2012), EMBASE (January 1980 to November 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 November 2012. We also searched the reference lists of the studies and the Science Citation Index. We included randomised controlled trials comparing LASIK and PRK for the correction of any degree of myopia. Two authors independently assessed trial quality and extracted data. We summarised data using the odds ratio and mean difference. We combined odds ratios using a random-effects model after testing for heterogeneity. We included 13 trials (1135 participants, 1923 eyes) in this review. Nine of these trials randomised eyes to treatment, two trials randomised people to treatment and treated both eyes, and two trials randomised people to treatment and treated one eye. None of the paired trials reported an appropriate paired analysis. We considered the overall quality of evidence to be low for most outcomes because of the risk of bias in the included trials. There was evidence that LASIK gives a faster visual recovery than PRK and is a less painful technique. Results at one year after surgery were comparable: most analyses favoured LASIK but they were not statistically significant. LASIK gives a faster visual recovery and is a less painful technique than PRK. The two techniques appear to give similar outcomes one year after surgery. Further trials using contemporary techniques are required to determine whether LASIK and PRK as currently practised are equally safe. Randomising eyes to treatment is an efficient design, but only if analysed properly. In future trials, more efforts could be made to mask the assessment of outcome. Source


Brocklehurst P.,University College London
Cochrane database of systematic reviews (Online) | Year: 2013

Bacterial vaginosis is an imbalance of the normal vaginal flora with an overgrowth of anaerobic bacteria and a lack of the normal lactobacillary flora. Women may have symptoms of a characteristic vaginal discharge but are often asymptomatic. Bacterial vaginosis during pregnancy has been associated with poor perinatal outcomes and, in particular, preterm birth (PTB). Identification and treatment may reduce the risk of PTB and its consequences. To assess the effects of antibiotic treatment of bacterial vaginosis in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2012), searched cited references from retrieved articles and reviewed abstracts, letters to the editor and editorials. Randomised trials comparing antibiotic treatment with placebo or no treatment, or comparing two or more antibiotic regimens in pregnant women with bacterial vaginosis or intermediate vaginal flora whether symptomatic or asymptomatic and detected through screening. Two review authors independently assessed trials for inclusion, trial quality and extracted data. We contacted study authors for additional information. We included 21 trials of good quality, involving 7847 women diagnosed with bacterial vaginosis or intermediate vaginal flora.Antibiotic therapy was shown to be effective at eradicating bacterial vaginosis during pregnancy (average risk ratio (RR) 0.42; 95% confidence interval (CI) 0.31 to 0.56; 10 trials, 4403 women; random-effects, T2 = 0.19, I2 = 91%). Antibiotic treatment also reduced the risk of late miscarriage (RR 0.20; 95% CI 0.05 to 0.76; two trials, 1270 women, fixed-effect, I2 = 0%).Treatment did not reduce the risk of PTB before 37 weeks (average RR 0.88; 95% CI 0.71 to 1.09; 13 trials, 6491 women; random-effects, T2 = 0.06, I2 = 48%), or the risk of preterm prelabour rupture of membranes (RR 0.74; 95% CI 0.30 to 1.84; two trials, 493 women). It did increase the risk of side-effects sufficient to stop or change treatment (RR 1.66; 95% CI 1.02 to 2.68; four trials, 2323 women, fixed-effect, I2 = 0%).In this updated review, treatment before 20 weeks' gestation did not reduce the risk of PTB less than 37 weeks (average RR 0.85; 95% CI 0.62 to 1.17; five trials, 4088 women; random-effects, T2 = 0.06, I2 = 49%).In women with a previous PTB, treatment did not affect the risk of subsequent PTB (average RR 0.78; 95% CI 0.42 to 1.48; three trials, 421 women; random-effects, T2 = 0.19, I2 = 72%).In women with abnormal vaginal flora (intermediate flora or bacterial vaginosis), treatment may reduce the risk of PTB before 37 weeks (RR 0.53; 95% CI 0.34 to 0.84; two trials, 894 women).One small trial of 156 women compared metronidazole and clindamycin, both oral and vaginal, with no significant differences seen for any of the pre-specified primary outcomes. Statistically significant differences were seen for the outcomes of prolongation of gestational age (days) (mean difference (MD) 1.00; 95% CI 0.26 to 1.74) and birthweight (grams) (MD 75.18; 95% CI 25.37 to 124.99) however these represent relatively small differences in the clinical setting.Oral antibiotics versus vaginal antibiotics did not reduce the risk of PTB (RR 1.09; 95% CI 0.78 to 1.52; two trials, 264 women). Oral antibiotics had some advantage over vaginal antibiotics (whether metronidazole or clindamycin) with respect to admission to neonatal unit (RR 0.63; 95% CI 0.42 to 0.92, one trial, 156 women), prolongation of gestational age (days) (MD 9.00; 95% CI 8.20 to 9.80; one trial, 156 women) and birthweight (grams) (MD 342.13; 95% CI 293.04 to 391.22; one trial, 156 women).Different frequency of dosing of antibiotics was assessed in one small trial and showed no significant difference for any outcome assessed. Antibiotic treatment can eradicate bacterial vaginosis in pregnancy. The overall risk of PTB was not significantly reduced. This review provides little evidence that screening and treating all pregnant women with bacterial vaginosis will prevent PTB and its consequences. When screening criteria were broadened to include women with abnormal flora there was a 47% reduction in preterm birth, however this is limited to two included studies. Source


Vizard E.,University College London
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2013

Background: The assessment of victims of child sexual abuse (CSA) is now a recognized aspect of clinical work for both CAMH and adult services. As juvenile perpetrators of CSA are responsible for a significant minority of the sexual assaults on other children, CAMH services are increasingly approached to assess these oversexualized younger children or sexually abusive adolescents. A developmental approach to assessment and treatment intervention is essential in all these cases. Method: This review examines research on the characteristics of child victims and perpetrators of CSA. It describes evidence-based approaches to assessment and treatment of both groups of children. A selective review of MEDLINE, Psycinfo, Cochrane Library, and other databases was undertaken. Recommendations are made for clinical practice and future research. Findings: The characteristics of CSA victims are well known and those of juvenile perpetrators of sexual abuse are becoming recognized. Assessment approaches for both groups of children should be delivered within a safeguarding context where risk to victims is minimized. Risk assessment instruments should be used only as adjuncts to a full clinical assessment. Given high levels of psychiatric comorbidity, assessment, treatment, and other interventions should be undertaken by mental health trained staff. Conclusions: Victims and perpetrators of CSA present challenges and opportunities for professional intervention. Their complex presentations mean that their needs should be met by highly trained staff. However, their youth and developmental immaturity also give an opportunity to nip problem symptoms and behaviors in the bud. The key is in the earliest possible intervention with both groups. Future research should focus on long-term adult outcomes for both child victims and children who perpetrate CSA. Adult outcomes of treated children could identify problems and/or strengths in parenting the next generation and also the persistence and/or desistence of sexualized or abusive behavior. © 2013 Association for Child and Adolescent Mental Health. Source


Gurusamy K.S.,University College London
The Cochrane database of systematic reviews | Year: 2013

Pancreatic resections are associated with high morbidity (30% to 60%) and mortality (5%). Synthetic analogues of somatostatin are advocated by some surgeons to reduce complications following pancreatic surgery; however, their use is controversial. To determine whether prophylactic somatostatin analogues should be used routinely in pancreatic surgery. We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 1), MEDLINE, EMBASE and Science Citation Index Expanded to February 2013. We included randomised controlled trials comparing prophylactic somatostatin or one of its analogues versus no drug or placebo during pancreatic surgery (irrespective of language or publication status). Two review authors independently assessed trials for inclusion and independently extracted data. We analysed data with both the fixed-effect and random-effects models using Review Manager (RevMan). We calculated the risk ratio (RR), mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) based on an intention-to-treat or available case analysis. When it was not possible to perform either of the above, we performed a per protocol analysis. We identified 21 trials (19 trials of high risk of bias) involving 2348 people. There was no significant difference in the perioperative mortality (RR 0.80; 95% CI 0.56 to 1.16; n = 2210) or the number of people with drug-related adverse effects between the two groups (RR 2.09; 95% CI 0.83 to 5.24; n = 1199). Quality of life was not reported in any of the trials. The overall number of participants with postoperative complications was significantly lower in the somatostatin analogue group (RR 0.70; 95% CI 0.61 to 0.80; n = 1903) but there was no significant difference in the re-operation rate (RR 1.26; 95% CI 0.58 to 2.70; n = 687) or hospital stay (MD -1.29 days; 95% CI -2.60 to 0.03; n = 1314) between the groups. The incidence of pancreatic fistula was lower in the somatostatin analogue group (RR 0.66; 95% CI 0.55 to 0.79; n = 2206). The proportion of these fistulas that were clinically significant was not mentioned in most trials. On inclusion of trials that clearly distinguished clinically significant fistulas, there was no significant difference between the two groups (RR 0.69; 95% CI 0.38 to 1.28; n = 292). Somatostatin analogues may reduce perioperative complications but do not reduce perioperative mortality. Further adequately powered trials with low risk of bias are necessary. Based on the current available evidence, somatostatin and its analogues are recommended for routine use in people undergoing pancreatic resection. Source


Jones P.J.S.,University College London
Marine Policy | Year: 2013

The Galápagos Marine Reserve (GMR) has faced major governance challenges since its designation in 1998, largely due to the driving forces of immigration from the mainland; a heterogeneous population that has a mainland rather than an island identity; increasing demand for marine resources from global seafood markets; and the rapid growth of tourism. Until recently, the pressures related to these driving forces had challenged measures to promote the effectiveness of the GMR. Decisions taken through the participatory management structure were often undermined by a combination of civil unrest, illegal activities and lack of enforcement. A recent period of relative political stability, coupled with several new measures to address these driving forces, has improved the potential effectiveness of the governance framework. These measures include controls on immigration, the use of remote surveillance technologies to enforce fishing restrictions and a system for the improved management of tourism vessels. Whilst participative and economic incentives will continue to be important, increasing political will to promote long-term sustainability and related improvements in the use of legal incentives, including enforcement technologies and effective prosecutions for those who breach restrictions, are likely to be key elements of the governance framework. It is argued that these measures, coupled with the emergence of a more marine-aware generation of Galápagos citizens, should pave the way for major improvements in the effectiveness of the GMR, hopefully sufficiently strengthening the governance framework to withstand the major driving forces that could otherwise perturb it. © 2013 Elsevier Ltd. Source


Arachchillage D.J.,University College London
Current rheumatology reports | Year: 2013

The current mainstay of treatment of thrombotic APS is long-term anticoagulation with oral vitamin K antagonists (VKA) such as warfarin. However, the use of warfarin is problematic, particularly in patients with antiphospholipid syndrome (APS). The new oral anticoagulants (NOAC) include dabigatran etexilate (Pradaxa®), a direct thrombin inhibitor, and rivaroxaban (Xarelto®), Apixaban (Eliquis) and Edoxaban (Lixiana®), which are direct anti-Xa inhibitors. Unlike warfarin, these agents do not interact with dietary constituents and alcohol, have few reported drug interactions, and monitoring of their anticoagulant intensity is not routinely required due to their predictable anticoagulant effects. In this chapter, we discuss clinical and laboratory aspects of NOAC. These agents have been approved for several therapeutic indications based on phase III prospective randomised controlled clinical trials using warfarin at a target INR of 2.5 (i.e. range 2.0-3.0) as the comparator. However these trials may not be directly applicable to patients with antiphospholipid syndrome (APS) where prospective clinical studies of NOAC are the way forward. Source


Lanceley A.,University College London
The Cochrane database of systematic reviews | Year: 2013

Cervical cancer is the second most common cancer among women up to 65 years of age and is the most frequent cause of death from gynaecological cancers worldwide. Although surveillance of women after completion of primary treatment for cervical cancer is purported to have an impact on their overall survival (OS), no strictly defined follow-up protocols are available for these women. Wide diversity in management has been noted in the follow-up of women who have completed primary treatment for cervical cancer. Traditionally, women treated for cervical cancer undergo routine long-term, even life-long, follow-up. The primary objective of this practice has been to detect and treat recurrence early. This review sets out to systematically evaluate available evidence for the role of different models of follow-up after cervical cancer and the optimal use of investigations. To evaluate the benefits, harms and costs of different follow-up protocols for women who have completed primary treatment for cervical cancer. We searched CENTRAL (The Cochrane Library 2013, Issue 1), the Cochrane Gynaecological Cancer Group (CGCG) Trials Register, MEDLINE and EMBASE up to January 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of clinical guidelines and review articles and contacted experts in the field. We searched for randomised controlled trials (RCTs) that compared different follow-up protocols after primary treatment in women with cervical cancer. Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found, and therefore no data were analysed. The search strategy identified 1,377 unique references, of which all were excluded on the basis of title and abstract. We found no evidence to inform decisions about different follow-up protocols after primary treatment for women with cervical cancer. Ideally, a large RCT or, at the very least, well-designed non-randomised studies (NRSs) that use multi-variate analysis to adjust for baseline imbalances are needed to compare these follow-up protocols. Such studies could include prospective trials conducted to determine the benefits and harms of different follow-up protocols upon completion of primary treatment for cervical cancer, along with an RCT undertaken to compare predefined follow-up protocols versus participant-initiated follow-up versus no follow-up until a participant is referred to a gynaecological oncology service after signs or symptoms of recurrence have been identified in the primary care or community setting. Source


Tract-based spatial statistics (TBSS) is a popular method for the analysis of diffusion tensor imaging data. TBSS focuses on differences in white matter voxels with high fractional anisotropy (FA), representing the major fibre tracts, through registering all subjects to a common reference and the creation of a FA skeleton. This work considers the effect of choice of reference in the TBSS pipeline, which can be a standard template, an individual subject from the study, a study-specific template or a group-wise average. While TBSS attempts to overcome registration error by searching the neighbourhood perpendicular to the FA skeleton for the voxel with maximum FA, this projection step may not compensate for large registration errors that might occur in the presence of pathology such as atrophy in neurodegenerative diseases. This makes registration performance and choice of reference an important issue. Substantial work in the field of computational anatomy has shown the use of group-wise averages to reduce biases while avoiding the arbitrary selection of a single individual. Here, we demonstrate the impact of the choice of reference on: (a) specificity (b) sensitivity in a simulation study and (c) a real-world comparison of Alzheimer's disease patients to controls. In (a) and (b), simulated deformations and decreases in FA were applied to control subjects to simulate changes of shape and WM integrity similar to what would be seen in AD patients, in order to provide a "ground truth" for evaluating the various methods of TBSS reference. Using a group-wise average atlas as the reference outperformed other references in the TBSS pipeline in all evaluations. Source


Zachary I.C.,University College London
Biochemical Society Transactions | Year: 2011

Essential roles of NRP1 (neuropilin-1) in cardiovascular development and in neuronal axon targeting during embryogenesis are thought to be mediated primarily through binding of NRP1 to two unrelated types of ligands: the VEGF (vascular endothelial growth factor) family of angiogenic cytokines in the endothelium, and the class 3 semaphorins in neurons. A widely accepted mechanism for the role of NRP1 in the endothelium is VEGF binding to NRP1 and VEGFR2 (VEGF receptor 2) and VEGF-dependent formation of complexes or NRP1-VEGFR2 holoreceptors with enhanced signalling activity and biological function. However, although some basic features of this model are solidly based on biochemical and cellular data, others are open to question. Furthermore, a mechanistic account of NRP1 has to accommodate research which emphasizes the diversity of NRP1 functions in different cell types and particularly an emerging role in signalling by other growth factor ligands for RTKs (receptor tyrosine kinases) such as HGF (hepatocyte growth factor) and PDGF (platelet-derived growth factor). It is uncertain, however, whether the model of NRP1-RTK heterocomplex formation applies in all of these situations. In the light of these developments, the need to explain mechanistically the role of NRP1 in signalling is coming increasingly to the fore. The present article focuses on some of the most important unresolved questions concerning the mechanism(s) through which NRP1 acts, and highlights recent findings which are beginning to generate insights into these questions. ©The Authors Journal compilation ©2011 Biochemical Society. Source


Schapira A.H.V.,University College London
Journal of Neurology | Year: 2011

Parkinson's disease (PD) is characterised both clinically and pathologically by features that distinguish it from other parkinsonian disorders including, for instance, multiple system atrophy and progressive supranuclear palsy. The aetiologies of PD includes both genetic and environmental influences. Several single gene causes of autosomal dominant and recessive PD have been described. Recent genome-wide association (GWA) studies have identified a number of risk alleles for PD. No specific environmental cause has been defined but several factors have been described which influence the risk for PD. Mitochondrial dysfunction, free radical mediated damage, inflammatory change and proteasomal dysfunction have been thought to play a role in PD pathogenesis. Autophagy is now recognised as an important component of the cell's mechanism for protein turnover and has relevance for PD. There is some convergence and overlap of pathogenetic pathways between environmental and genetic factors. The importance of identifying the molecular and biochemical events that lead to PD lies in the prospect that novel drug targets will emerge and that new compounds will be developed that slow the progression of the disease. © Springer-Verlag 2011. Source


Grossniklaus U.,University of Zurich | Kelly B.,Emory University | Ferguson-Smith A.C.,University of Cambridge | Pembrey M.,University College London | And 2 more authors.
Nature Reviews Genetics | Year: 2013

Much attention has been given to the idea of transgenerational epigenetic inheritance, but fundamental questions remain regarding how much takes place and the impact that this might have on organisms. We asked five leading researchers in this area-working on a range of model organisms and in human disease-for their views on these topics. Their responses highlight the mixture of excitement and caution that surrounds transgenerational epigenetic inheritance and the wide gulf between species in terms of our knowledge of the mechanisms that may be involved. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Wolpert D.M.,University of Cambridge | Diedrichsen J.,University College London | Flanagan J.R.,Queens University
Nature Reviews Neuroscience | Year: 2011

The exploits of Martina Navratilova and Roger Federer represent the pinnacle of motor learning. However, when considering the range and complexity of the processes that are involved in motor learning, even the mere mortals among us exhibit abilities that are impressive. We exercise these abilities when taking up new activities-whether it is snowboarding or ballroom dancing-but also engage in substantial motor learning on a daily basis as we adapt to changes in our environment, manipulate new objects and refine existing skills. Here we review recent research in human motor learning with an emphasis on the computational mechanisms that are involved. © 2011 Macmillan Publishers Limited. All rights reserved. Source


Dolphin A.C.,University College London
Biochimica et Biophysica Acta - Biomembranes | Year: 2013

Voltage-gated calcium channels consist of the main pore-forming α1 subunit, together, except in the case of the T-type channels, with β and α2δ and sometimes γ subunits, which are collectively termed auxiliary or accessory subunits. This review will concentrate on the properties and role of the α 2δ subunits of these channels. These proteins are largely extracellular, membrane-associated proteins which influence the trafficking, localization, and biophysical properties of the channels. This article is part of a Special Issue entitled: Calcium channels. © 2012 Elsevier B.V. Source


Bhagani S.,University College London
Current Opinion in HIV and AIDS | Year: 2011

Purpose of review: Liver disease is an important cause of morbidity and mortality in the era of combination antiretroviral therapy in HIV/hepatitis C virus (HCV) co-infected patients. This review highlights the role of pegylated interferon-alpha (peg-IFN) and ribavirin (RBV) therapy and examines factors associated with response and strategies to maximize responses. Recent findings: HCV viral clearance is lower in HIV co-infected patients than in HCV mono-infected patients. However, in patients who attain sustained response there is clinical benefit in terms of liver disease associated morbidity and mortality and treatment is costeffective. Predictors of response appear similar, although there are a number of modifiable patient-associated and HIV-associated factors that could be addressed. Moreover, the use of weight-based RBV and treatment length guided by early viral responses improve response rate. Avoidance of drug-drug interactions and use of haematopoietic growth factors reduce adverse events and dose reductions and ultimately increase response rates. Very early prediction of treatment futility is promising. Induction dosing strategies have not yielded positive results, though twice weekly peg-IFN-alpha-2a induction therapy merits further investigation. Summary: Peg-IFN/RBV therapy plays an important role in the management of HCV in HIV-infected patients. Efforts to maximize response to current therapy need to continue while we await new therapies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Burnstock G.,University College London
Advances in Experimental Medicine and Biology | Year: 2013

ATP is a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the brain. There is a widespread presence of both adenosine (P1) and P2 nucleotide receptors in the brain on both neurons and glial cells. Adenosine receptors play a major role in presynaptic neuromodulation, while P2X ionotropic receptors are involved in fast synaptic transmission and synaptic plasticity. P2Y G protein-coupled receptors are largely involved in presynaptic activities, as well as mediating long-term (trophic) signalling in cell proliferation, differentiation and death during development and regeneration. Both P1 and P2 receptors participate in neuron-glial interactions. Purinergic signalling is involved in control of cerebral vascular tone and remodelling and has been implicated in learning and memory, locomotor and feeding behaviour and sleep. There is increasing interest in the involvement of purinergic signalling in the pathophysiology of the CNS, including trauma, ischaemia, epilepsy, neurodegenerative diseases, neuropsychiatric and mood disorders, and cancer, including gliomas. © 2013 Springer Science+Business Media Dordrecht. Source


Rook G.A.W.,University College London | Dalgleish A.,St Georges Healthcare NHS Trust
Immunological Reviews | Year: 2011

As man has moved rapidly from the hunter-gatherer environment to the living conditions of the industrialized countries, the incidences of some cancers have increased alarmingly. Recent increases are usually attributed to dietary changes or to altered exposures to putative carcinogens associated with the modern lifestyle. However, the changes in cancer incidence parallel similar increases in non-neoplastic chronic inflammatory disorders (inflammatory bowel disease, allergies, and autoimmunity), and the epidemiology is often strikingly similar. This parallel is worth exploring, because the increases in chronic inflammatory disorders are at least partly explained by immunoregulatory defects resulting from diminished exposure to microorganisms that co-evolved with mammals and developed a role in driving immunoregulatory circuits (the hygiene hypothesis). Dysregulated chronic inflammation can drive oncogenesis and also provides growth and angiogenic factors that enhance the subsequent proliferation and spread of tumor cells. Thus, a modern failure to downregulate inappropriate inflammation could underlie increases in some cancers in parallel with the increases in chronic inflammatory disorders. This possibility is supported by recent work showing that in some circumstances regulatory T cells protect against cancer, rather than aggravating it, as previously assumed. A greater understanding of these interactions might pave the way to improved microbe-based immunotherapies. © 2011 John Wiley & Sons A/S. Source


Glenn G.,University College London
Methods in Enzymology | Year: 2014

The preparation of protein samples for mass spectrometry and N-terminal sequencing is a key step in successfully identifying proteins. Mass spectrometry is a very sensitive technique, and as such, samples must be prepared carefully since they can be subject to contamination of the sample (e.g., due to incomplete subcellular fractionation or purification of a multiprotein complex), overwhelming of the sample by highly abundant proteins, and contamination from skin or hair (keratin can be a very common hit). One goal of sample preparation for mass spec is to reduce the complexity of the sample - in the example presented here, mitochondria are purified, solubilized, and fractionated by sucrose density gradient sedimentation prior to preparative 1D SDS-PAGE. It is important to verify the purity and integrity of the sample so that you can have confidence in the hits obtained. More protein is needed for N-terminal sequencing and ideally it should be purified to a single band when run on an SDS-polyacrylamide gel. The example presented here involves stably expressing a tagged protein in HEK293 cells and then isolating the protein by affinity purification and SDS-PAGE. © 2014 Elsevier Inc. All rights reserved. Source


Morello G.,University College London
Astrophysical Journal | Year: 2015

The study of the atmospheres of transiting exoplanets requires a photometric precision, and repeatability, of one part in ∼104. This is beyond the original calibration plans of current observatories, hence the necessity to disentangle the instrumental systematics from the astrophysical signals in raw data sets. Most methods used in the literature are based on an approximate instrument model. The choice of parameters of the model and their functional forms can sometimes be subjective, causing controversies in the literature. Recently, Morello et al. (2014, 2015) have developed a non-parametric detrending method that gave coherent and repeatable results when applied to Spitzer/IRAC data sets that were debated in the literature. Said method is based on independent component analysis (ICA) of individual pixel time-series, hereafter "pixel-ICA". The main purpose of this paper is to investigate the limits and advantages of pixel-ICA on a series of simulated data sets with different instrument properties, and a range of jitter timescales and shapes, non-stationarity, sudden change points, etc. The performances of pixel-ICA are compared against the ones of other methods, in particular polynomial centroid division, and pixel-level decorrelation method. We find that in simulated cases pixel-ICA performs as well or better than other methods, and it also guarantees a higher degree of objectivity, because of its purely statistical foundation with no prior information on the instrument systematics. The results of this paper, together with previous analyses of Spitzer/IRAC data sets, suggest that photometric precision and repeatability of one part in 104 can be achieved with current infrared space instruments. © 2015. The American Astronomical Society. All rights reserved.. Source


Serpente N.,University College London
Nature Reviews Molecular Cell Biology | Year: 2013

In 1983, a bulky and profusely illustrated textbook on molecular and cell biology began to inhabit the shelves of university libraries worldwide. The effect of capturing the eyes and souls of biologists was immediate as the book provided them with a new and invigorating outlook on what cells are and what they do. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Salomoni P.,University College London
Frontiers in Oncology | Year: 2013

The promyelocytic leukemia (PML) protein has been implicated in regulation of multiple key cellular functions, from transcription to calcium homeostasis. PML pleiotropic role is in part related to its ability to localize to both the nucleus and cytoplasm. In the nucleus, PML is known to regulate gene transcription, a role linked to its ability to associate with transcription factors as well as chromatin-remodelers. A new twist came from the discovery that the PML-interacting protein death-associated protein 6 (DAXX) acts as chaperone for the histone H3.3 variant. H3.3 is found enriched at active genes, centromeric heterochromatin, and telomeres, and has been proposed to act as important carrier of epigenetic information. Our recent work has implicated DAXX in regulation of H3.3 loading and transcription in the central nervous system (CNS). Remarkably, driver mutations in H3.3 and/or its loading machinery have been identified in brain cancer, thus suggesting a role for altered H3.3 function/deposition in CNS tumorigenesis. Aberrant H3.3 deposition may also play a role in leukemia pathogenesis, given DAXX role in PML-RARa-driven transformation and the identification of a DAXX missense mutation in acute myeloid leukemia. This review aims to critically discuss the existing literature and propose new avenues for investigation. © 2013 Salomoni. Source


Cramer L.P.,University College London
Current Opinion in Cell Biology | Year: 2013

For decades, ever growing data on myosin II provides strong evidence that interaction of myosin-II-motor-domain with actin filaments within cells retracts the cell rear during actin-based cell migration. Now it is clear myosin II motor-activity is not the sole force involved. Alternative force-generating mechanisms within cells clearly also exist to power cell rear retraction during actin-based cell migration. Given that nematode sperm cells migrate without actin and without cytoskeletal motor proteins it is perhaps not surprising other types of force power cell rear retraction in actin-based systems. Here, cell rear retraction driven by actin filament depolymerisation, actin filament crosslinking, cell front protrusion and possibly apparent membrane tension and their importance relative to myosin II-motor-based contractility are discussed. © 2013 Elsevier Ltd. Source


Paluch E.K.,University College London | Paluch E.K.,International Institute of Molecular Cell Biology | Raz E.,University of Munster
Current Opinion in Cell Biology | Year: 2013

Blebs are cellular protrusions that have been shown to be instrumental for cell migration in development and disease. Bleb expansion is driven by hydrostatic pressure generated in the cytoplasm by the contractile actomyosin cortex. The mechanisms of bleb formation thus fundamentally differ from the actin polymerization-based mechanisms responsible for lamellipodia expansion. In this review, we summarize recent findings relevant for the mechanics of bleb formation and the underlying molecular pathways. We then review the processes involved in determining the type of protrusion formed by migrating cells, in particular in vivo, in the context of embryonic development. Finally, we discuss how cells utilize blebs for their forward movement in the presence or absence of strong substrate attachment. © 2013 Elsevier Ltd. Source


Bhatia K.P.,University College London
Movement Disorders | Year: 2011

Paroxysmal movement disorders are a relatively rare and heterogenous group of conditions manifesting as episodic dyskinesia lasting a brief duration. Three forms are clearly recognized, namely, paroxysmal kinesigenic (PKD), nonkinisegenic (PNKD), and exercise induced (PED). There have been major advances in the understanding of the pathophysiological mechanisms and the genetics of these disorders, leading to better clinical definitions based on genotype-phenotype correlations in the familial idiopathic forms. PKD is genetically heterogenous, but there is linkage to chromosome 16 in a number of families. PNKD is due to mutations of the MR-1 gene. PED is genetically heterogenous, but a number of familial and sporadic cases may be due to GLUT-1 gene mutations. The GLUT1 gene-related form of PED may respond to a ketogenic diet. Potassium and calcium channel mutations underlie the 2 main forms of episodic ataxia (EA1 and EA2), whereas benign torticollis of infancy may also be a calcium channel disorder. © 2011 Movement Disorder Society. Source


Schapira A.H.,University College London | Jenner P.,Kings College London
Movement Disorders | Year: 2011

The past 25 years have seen a major expansion of knowledge concerning the cause of Parkinson's disease provided by an understanding of environmental and genetic factors that underlie the loss of nigral dopaminergic neurons. Based on the actions of toxins, postmortem investigations, and gene defects responsible for familial Parkinson's disease, there is now a general consensus about the mechanisms of cell death that contribute to neuronal loss in Parkinson's disease. Mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammatory change are considered to lead to cell dysfunction and death by apoptosis or autophagy. Ageing is the single most important risk factor for Parkinson's disease, and the biochemical changes that are a consequence of aging amplify these abnormalities in Parkinson's disease brain. What remains to be determined is the combination and sequence of events leading to cell death and whether this is identical in all brain regions where pathology occurs and in all individuals with Parkinson's disease. Focusing on those events that characterize Parkinson's disease, namely, mitochondrial dysfunction and Lewy body formation, may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection. © 2011 Movement Disorder Society. Source


Betteridge D.J.,University College London
Nature Reviews Cardiology | Year: 2011

Patients with diabetes mellitus are at increased risk of cardiovascular disease (CVD). Dyslipidemia, an important component of the insulin resistance syndrome and type 2 diabetes, is strongly related to CVD risk and is open to therapeutic intervention. Statins have proved to be safe, very-well tolerated, and highly effective in reducing the levels of LDL cholesterol and apolipoprotein B. Primary and secondary CVD prevention trials have shown that use of statins leads to highly significant reductions in the incidence of major CVD events. A wealth of data on the outcomes of statin therapy is now available to guide clinical practice in the population of patients with type 2 diabetes. Statin therapy in patients with type 1 diabetes seems to have a similar benefit to that seen in patients with type 2 diabetes. However, despite statin therapy, high CVD risk persists in these populations. More-intensive statin therapy produces greater reduction in the incidence of CVD events, but a more-global approach to lipid management is likely to result in further risk reduction. After reductions in the levels of LDL cholesterol and apolipoprotein B, the next target of lipid-lowering therapy is to increase HDL-cholesterol levels, which tend to be low in patients with type 2 diabetes. The most effective HDL-cholesterol-raising agent currently available for use in clinical practice is niacin. Trials with surrogate end points have pointed to the cardiovascular benefit of adding niacin to statin therapy. Large CVD end point trials, which include many patients with diabetes, are underway to test the combination of a statin and niacin versus a statin alone. © 2011 Macmillan Publishers Limited. All rights reserved. Source


Fielding A.K.,University College London
Hematology/Oncology Clinics of North America | Year: 2011

Approximately half of all adults with acute lymphoblastic leukemia now survive long term. This article summarizes the current approaches to treating acute lymphoblastic leukemia in adults, with a focus on a pragmatic approach to decision making. Coupled with a particularly punishing and often complex combination chemotherapy treatment regimen, treatment-related morbidity and mortality are frequent, and this article focuses on these situations. The field will change significantly over the next few years with many ongoing clinical studies and molecular insights which will be translated into providing prognostic information and novel therapeutic targets. © 2011 Elsevier Inc. Source


Hergovich A.,University College London
Cell and Bioscience | Year: 2013

The metazoan Hippo pathway is an essential tumour suppressor signalling cascade that ensures normal tissue growth by co-ordinating cell proliferation, cell death and cell differentiation. Over the past years, various genetic and biochemical studies in Drosophila and mammals have defined a conserved core Hippo signalling module, composed of members of the Ste20-like kinase, the MOB co-activator and the AGC kinase families. In Drosophila, stimulated Hippo kinase phosphorylates and thereby activates the Mats/Warts complex, which consequently phosphorylates and inactivates the transcriptional co-activator Yorkie. In mammals, the counterparts of the Hippo/Mats/Warts/Yorkie cascade, namely MST1/2, MOB1A/B, LATS1/2 and YAP/TAZ, function in a similar fashion. These canonical Hippo pathways are so highly conserved that human MST2, hMOB1A and LATS1 can compensate for the loss of Hippo, Mats and Warts in flies. However, recent reports have shown that Hippo signalling is more diverse and complex, in particular in mammals. In this review, we summarize our current understanding of mammalian LATS1/2 kinases together with their closest relatives, the NDR1/2 kinases. The regulation of the LATS/NDR family of kinases will be discussed, followed by a summary of all currently known LATS/NDR substrates. Last, but not least, the biological roles of LATS/NDR kinases will be reviewed with specific emphasis on recent discoveries of canonical and non-canonical LATS/NDR functions in the extended Hippo pathway. © 2013 Hergovich; licensee BioMed Central Ltd. Source


Williams K.,University College London
British journal of cancer | Year: 2013

A healthy lifestyle following a cancer diagnosis may improve long-term outcomes. No studies have examined health behaviour change among U.K. cancer survivors, or tracked behaviours over time in survivors and controls. We assessed smoking, alcohol and physical activity at three times (0-2 years before a cancer diagnosis, 0-2 years post-diagnosis and 2-4 years post-diagnosis) and at matched times in a comparison group. Data were from waves 1-5 of the English Longitudinal Study of Ageing; a cohort of older adults in England. Behavioural measures were taken at each wave. Generalised estimating equations were used to examine differences by group and time, and group-by-time interactions. Of the 5146 adults included in the analyses, 433 (8.4%) were diagnosed with cancer. Those with a cancer diagnosis were less likely to be physically active (P<0.01) and more likely to be sedentary (P<0.001). There were no group differences in alcohol or smoking. Smoking, alcohol and activity reduced over time in the whole group. Group-by-time interactions were not significant for smoking (P=0.17), alcohol (P=0.20), activity (P=0.17) or sedentary behaviour (P=0.86), although there were trends towards a transient improvement from pre-diagnosis to immediately post-diagnosis. We found little evidence that a cancer diagnosis motivates health-protective changes. Given the importance of healthy lifestyles, strategies for effective support for behaviour change in cancer survivors need to be identified. Source


Cabello A.,University of Seville | Severini S.,University College London | Winter A.,Autonomous University of Barcelona
Physical Review Letters | Year: 2014

Correlations in Bell and noncontextuality inequalities can be expressed as a positive linear combination of probabilities of events. Exclusive events can be represented as adjacent vertices of a graph, so correlations can be associated to a subgraph. We show that the maximum value of the correlations for classical, quantum, and more general theories is the independence number, the Lovász number, and the fractional packing number of this subgraph, respectively. We also show that, for any graph, there is always a correlation experiment such that the set of quantum probabilities is exactly the Grötschel-Lovász-Schrijver theta body. This identifies these combinatorial notions as fundamental physical objects and provides a method for singling out experiments with quantum correlations on demand. © 2014 American Physical Society. Source


Objectives: The aim of the study was to examine temporal and geographical patterns of mode of delivery in the European Collaborative Study (ECS), identify factors associated with elective caesarean section (CS) delivery in the highly active antiretroviral therapy (HAART) era and explore associations between mode of delivery and mother-to-child transmission (MTCT). Methods: The ECS is a cohort study in which HIV-infected pregnant women are enrolled and their infants prospectively followed. Data on 5238 mother-child pairs (MCPs) enrolled in Western European ECS sites between 1985 and 2007 were analysed. Results: The elective CS rate increased from 16% in 1985-1993 to 67% in 1999-2001, declining to 51% by 2005-2007. In 2002-2004, 10% of infants were delivered vaginally, increasing to 34% by 2005-2007. During the HAART era, women in Belgium, the United Kingdom and the Netherlands were less likely to deliver by elective CS than those in Italy and Spain [adjusted odds ratio (AOR) 0.07; 95% confidence interval (CI) 0.04-0.12]. The MTCT rate in 2005-2007 was 1%. Among MCPs with maternal HIV RNA<400 HIV-1 RNA copies/mL (n=960), elective CS was associated with 80% decreased MTCT risk (AOR 0.20; 95% CI 0.05-0.65) adjusting for HAART and prematurity. Two infants born to 559 women with viral loads <50 copies/mL were infected, one of whom was delivered by elective CS (MTCT rate 0.4%; 95% CI 0.04-1.29). Conclusions: Our findings suggest that elective CS prevents MTCT even at low maternal viral loads, but the study was insufficiently powered to enable a conclusion to be drawn as to whether this applies for viral loads <50 copies/mL. Diverging mode of delivery patterns in Europe reflect uncertainties regarding the risk-benefit balance of elective CS for women on successful HAART. © 2010 British HIV Association. Source


Shah M.M.,University College London
Journal of Physiology | Year: 2014

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated potassium ion channels. They are, however, activated by hyperpolarizing potentials and are permeable to cations. Four HCN subunits have been cloned, of which HCN1 and HCN2 subunits are predominantly expressed in the cortex. These subunits are principally located in pyramidal cell dendrites, although they are also found at lower concentrations in the somata of pyramidal neurons as well as other neuron subtypes. HCN channels are actively trafficked to dendrites by binding to the chaperone protein TRIP8b. Somato-dendritic HCN channels in pyramidal neurons modulate spike firing and synaptic potential integration by influencing the membrane resistance and resting membrane potential. Intriguingly, HCN channels are present in certain cortical axons and synaptic terminals too. Here, they regulate synaptic transmission but the underlying mechanisms appear to vary considerably amongst different synaptic terminals. In conclusion, HCN channels are expressed in multiple neuronal subcellular compartments in the cortex, where they have a diverse and complex effect on neuronal excitability. © 2014 The Physiological Society. Source


The term ‘habit’ is widely used to predict and explain behaviour. This paper examines use of the term in the context of health-related behaviour, and explores how the concept might be made more useful. A narrative review is presented, drawing on a scoping review of 136 empirical studies and 8 literature reviews undertaken to document usage of the term ‘habit’, and methods to measure it. A coherent definition of ‘habit’, and proposals for improved methods for studying it, were derived from findings. Definitions of ‘habit’ have varied in ways that are often implicit and not coherently linked with an underlying theory. A definition is proposed whereby habit is a process by which a stimulus generates an impulse to act as a result of a learned stimulus-response association. Habit-generated impulses may compete or combine with impulses and inhibitions arising from other sources, including conscious decision-making, to influence responses, and need not generate behaviour. Most research on habit is based on correlational studies using self-report measures. Adopting a coherent definition of ‘habit’, and a wider range of paradigms, designs and measures to study it, may accelerate progress in habit theory and application. © 2014 The Author(s). Published by Taylor & Francis. Source


Gems D.,University College London | Partridge L.,Max Planck Institute for Biology of Ageing
Annual Review of Physiology | Year: 2013

Discovering the biological basis of aging is one of the greatest remaining challenges for science. Work on the biology of aging has discovered a range of interventions and pathways that control aging rate. A picture is emerging of a signaling network that is sensitive to nutritional status and that controls growth, stress resistance, and aging. This network includes the insulin/IGF-1 and target of rapamycin (TOR) pathways and likely mediates the effects of dietary restriction on aging. Yet the biological processes upon which these pathways act to control life span remain unclear. A long-standing guiding assumption about aging is that it is caused by wear and tear, particularly damage at the molecular level. One view is that reactive oxygen species (ROS), including free radicals, generated as by-products of cellular metabolism, are a major contributor to this damage. Yet many recent tests of the oxidative damage theory have come up negative. Such tests have opened an exciting new phase in biogerontology in which fundamental assumptions about aging are being reexamined and revolutionary concepts are emerging. Among these concepts is the hyperfunction theory, which postulates that processes contributing to growth and reproduction run on in later life, leading to hypertrophic and hyperplastic pathologies. Here we reexamine central concepts about the nature of aging. Copyright © 2013 by Annual Reviews. All rights reserved. Source


Shorvon S.D.,University College London
Epilepsia | Year: 2011

The etiology of epilepsy is a major determinant of clinical course and prognosis, yet the current classifications of epilepsy do not list etiology in any detail. In this article, a classification (database) of the etiologies of epilepsy is proposed. In this scheme, the etiology of epilepsy is divided into four categories: idiopathic, symptomatic, provoked, and cryptogenic. These are defined and subcategories are proposed. A commentary addressing the following points is included: problems associated with assigning causation, symptomatic versus idiopathic epilepsy, focal versus generalized epilepsy, acquired epilepsy, acute symptomatic epilepsy, risk factor analysis, provoked epilepsy genetic and developmental epilepsy, and epilepsy as a disease not a symptom. © Wiley Periodicals, Inc. © 2011 International League Against Epilepsy. Source


Burnstock G.,University College London
Acta Physiologica | Year: 2013

The aim of this review is to describe the conceptual steps contributing to our current knowledge of purinergic signalling and to consider its involvement in the physiology and pathophysiology of the lower urinary tract. The voiding reflex involves ATP released as a cotransmitter with acetylcholine from parasympathetic nerves supplying the bladder and ATP released from urothelial cells during bladder distension to initiate the voiding reflex via P2X3 receptors on suburothelial low threshold sensory nerve fibres. This mechanosensory transduction pathway also participates, via high threshold sensory nerve fibres, in the initiation of pain in bladder and ureter. Treatment of prostate and bladder cancer with ATP is effective against the primary tumours in animal models and human cell lines, via P2X5 and P2X7 receptors, and also improves the systemic symptoms associated with advanced malignancy. Acupuncture is widely used for the treatment of urinary disorders, and a purinergic hypothesis is discussed for the underlying mechanism. © 2012 The Author Acta Physiologica © 2012 Scandinavian Physiological Society. Source


Schaette R.,University College London
Hearing Research | Year: 2014

The phantom auditory sensation of tinnitus is now studied in humans, animals, and computer models, and our understanding of how tinnitus is triggered and which neural mechanisms give rise to the phantom sensation in the brain has increased considerably. In most cases, tinnitus is associated with hearing loss, and even tinnitus patients with normal hearing thresholds might have cochlear damage that is not detected through conventional audiometry, as has been recently shown through auditory brainstem response measurements. Animals show behavioural signs of tinnitus after induction of hearing loss, indicating a causal relation. Moreover, surgical reduction of hearing loss in otosclerosis can reduce or even abolish tinnitus. However, hearing loss does not always lead to tinnitus. Psychophysical measurements have indicated that certain types of cochlear damage might be more closely linked to tinnitus than others. Recent animal studies have used behavioural testing to distinguish between animals with and without tinnitus after noise exposure. Comparisons between these groups of animals have helped identify neural correlates of tinnitus as well as factors that could represent a predisposition for tinnitus. Human neuroimaging studies have also begun to separate the neural signature of tinnitus from other consequences of hearing loss. The functional mechanisms that could underlie tinnitus development tinnitus have been analysed in computational modelling studies, which indicate that tinnitus could be a side-effect of the brain's attempt to compensate for hearing loss. Even though causal treatments for tinnitus are currently not available, hearing aids can provide considerable benefit when used in conjunction with counselling, tinnitus retraining therapy or cognitive behavioural therapy. Finally, animal studies demonstrate that the development of chronic noise-induced tinnitus might be prevented through timely interventions after noise exposure. © 2014 Elsevier B.V. Source


de Hamilton A.F.C.,University College London
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

Direct gaze is an engaging and important social cue, but the meaning of direct gaze depends heavily on the surrounding context. This paper reviews some recent studies of direct gaze, to understand more about what neural and cognitive systems are engaged by this social cue and why. The data show that gaze can act as an arousal cue and can modulate actions, and can activate brain regions linked to theory of mind and self-related processing. However, all these results are strongly modulated by the social meaning of a gaze cue and by whether participants believe that another person is really watching them. The implications of these contextual effects and audience effects for our theories of gaze are considered. © 2015 The Author(s) Published by the Royal Society. All rights reserved. Source


Wells J.C.K.,University College London
DMM Disease Models and Mechanisms | Year: 2012

Because obesity is associated with diverse chronic diseases, little attention has been directed to the multiple beneficial functions of adipose tissue. Adipose tissue not only provides energy for growth, reproduction and immune function, but also secretes and receives diverse signaling molecules that coordinate energy allocation between these functions in response to ecological conditions. Importantly, many relevant ecological cues act on growth and physique, with adiposity responding as a counterbalancing risk management strategy. The large number of individual alleles associated with adipose tissue illustrates its integration with diverse metabolic pathways. However, phenotypic variation in age, sex, ethnicity and social status is further associated with different strategies for storing and using energy. Adiposity therefore represents a key means of phenotypic flexibility within and across generations, enabling a coherent life-history strategy in the face of ecological stochasticity. The sensitivity of numerous metabolic pathways to ecological cues makes our species vulnerable to manipulative globalized economic forces. The aim of this article is to understand how human adipose tissue biology interacts with modern environmental pressures to generate excess weight gain and obesity. The disease component of obesity might lie not in adipose tissue itself, but in its perturbation by our modern industrialized niche. Efforts to combat obesity could be more effective if they prioritized 'external' environmental change rather than attempting to manipulate 'internal' biology through pharmaceutical or behavioral means. © 2012. Published by The Company of Biologists Ltd. Source


Pinney J.H.,University College London
Sub-cellular biochemistry | Year: 2012

Systemic AA amyloidosis is a rare complication of chronic inflammatory disorders. The amyloid fibrils are derived from serum amyloid A protein, an acute phase protein synthesized in the liver. Clinical presentation is most commonly due to the consequences of renal involvement, with proteinuria and progressive renal decline. Progression to end stage renal failure is common. Management is currently centred on reducing the supply of the precursor protein by treating the underlying inflammatory condition, whilst supporting the affected organs. Monitoring of the serum amyloid A protein is vital to assess whether there is adequate suppression of the underlying disease. The level of serum amyloid A protein is a powerful predictor of both patient survival and renal outcome. In patients with adequate suppression of the serum amyloid A protein amyloid deposits can be seen to regress and renal function can be stabilised and even improve. Source


Goate A.,University of Washington