TY - JOUR T1 - Influence of bearing pressure on liquefaction-induced settlement of shallow foundations A1 - Bertalot,D. A1 - Brennan,A. J. A1 - Villalobos,F. A. AU - Bertalot,D. AU - Brennan,A. J. AU - Villalobos,F. A. PY - 2013/11 Y1 - 2013/11 N2 - Earthquake-induced soil liquefaction continues to pose problems for structures on shallow foundations. One particular problem is the excessive settlement that such structures undergo as a consequence of earthquake shaking. For design and insurance purposes it is therefore necessary to be able to estimate the magnitude of these settlements. Current procedures relate the potential settlement to foundation size and liquefiable depth. However, the influence of foundation bearing pressure is also a significant factor. In particular, experimental results have indicated that large bearing pressures may inhibit liquefaction underneath a shallow foundation, resulting in lower induced settlement. By collecting new data from 23 buildings that suffered settlement and tilting as a consequence of soil liquefaction during the 27 February 2010 Maule earthquake in Chile, the existing method of estimating liquefaction-induced settlement is reassessed and shown to require bearing pressure information. Based on both the new and previously available data, a maximum potential settlement based on both foundation area and bearing pressure is proposed. AB - Earthquake-induced soil liquefaction continues to pose problems for structures on shallow foundations. One particular problem is the excessive settlement that such structures undergo as a consequence of earthquake shaking. For design and insurance purposes it is therefore necessary to be able to estimate the magnitude of these settlements. Current procedures relate the potential settlement to foundation size and liquefiable depth. However, the influence of foundation bearing pressure is also a significant factor. In particular, experimental results have indicated that large bearing pressures may inhibit liquefaction underneath a shallow foundation, resulting in lower induced settlement. By collecting new data from 23 buildings that suffered settlement and tilting as a consequence of soil liquefaction during the 27 February 2010 Maule earthquake in Chile, the existing method of estimating liquefaction-induced settlement is reassessed and shown to require bearing pressure information. Based on both the new and previously available data, a maximum potential settlement based on both foundation area and bearing pressure is proposed. KW - Site investigation KW - Liquefaction KW - Centrifuge modelling KW - Earthquakes KW - Footings/foundations UR - http://www.icevirtuallibrary.com/content/article/10.1680/geot.11.P.040 U2 - 10.1680/geot.11.P.040 DO - 10.1680/geot.11.P.040 M1 - Article JO - Géotechnique JF - Géotechnique SN - 0016-8505 IS - 5 VL - 63 SP - 391 EP - 399 ER - TY - JOUR T1 - River rehabilitation for the delivery of multiple ecosystem services at the river network scale A1 - Gilvear,David J A1 - Spray,Chris J A1 - Casas-Mulet,Roser AU - Gilvear,David J AU - Spray,Chris J AU - Casas-Mulet,Roser PY - 2013/9/15 Y1 - 2013/9/15 N2 - This paper presents a conceptual framework and methodology to assist with optimising the outcomes of river rehabilitation in terms of delivery of multiple ecosystem services and the benefits they represent for humans at the river network scale. The approach is applicable globally, but was initially devised in the context of a project critically examining opportunities and constraints on delivery of river rehabilitation in Scotland. The spatial-temporal approach highlighted is river rehabilitation measure, rehabilitation scale, location on the stream network, ecosystem service and timescale specific and could be used as initial scoping in the process of planning rehabilitation at the river network scale. The levels of service delivered are based on an expert-derived scoring system based on understanding how the rehabilitation measure assists in reinstating
important geomorphological, hydrological and ecological processes and hence
intermediate or primary ecosystem function. The framework permits a “total long-term (>25years) ecosystem service score” to be calculated which is the cumulative result of the combined effect of the number of and level of ecosystem services delivered over time. Trajectories over time for attaining the long-term ecosystem service score for each river rehabilitation measures are also given. Scores could also be weighted according to societal values and economic valuation. These scores could assist decision making in relation to river rehabilitation at the catchment scale in terms of directing resources towards alternative scenarios. A case study is presented of applying the methodology to the Eddleston Water in Scotland using proposed river rehabilitation options for the catchment to demonstrate the value of the approach. Our overall assertion is that unless sound conceptual frameworks are developed that permit the river network scale ecosystem services of river rehabilitation to be evaluated as part of the process of river basin planning and management, the total benefit of river
rehabilitation may well be reduced. River rehabilitation together with a ‘vision’ and framework within which it can be developed, is fundamental to future success in river basin management AB - This paper presents a conceptual framework and methodology to assist with optimising the outcomes of river rehabilitation in terms of delivery of multiple ecosystem services and the benefits they represent for humans at the river network scale. The approach is applicable globally, but was initially devised in the context of a project critically examining opportunities and constraints on delivery of river rehabilitation in Scotland. The spatial-temporal approach highlighted is river rehabilitation measure, rehabilitation scale, location on the stream network, ecosystem service and timescale specific and could be used as initial scoping in the process of planning rehabilitation at the river network scale. The levels of service delivered are based on an expert-derived scoring system based on understanding how the rehabilitation measure assists in reinstating
important geomorphological, hydrological and ecological processes and hence
intermediate or primary ecosystem function. The framework permits a “total long-term (>25years) ecosystem service score” to be calculated which is the cumulative result of the combined effect of the number of and level of ecosystem services delivered over time. Trajectories over time for attaining the long-term ecosystem service score for each river rehabilitation measures are also given. Scores could also be weighted according to societal values and economic valuation. These scores could assist decision making in relation to river rehabilitation at the catchment scale in terms of directing resources towards alternative scenarios. A case study is presented of applying the methodology to the Eddleston Water in Scotland using proposed river rehabilitation options for the catchment to demonstrate the value of the approach. Our overall assertion is that unless sound conceptual frameworks are developed that permit the river network scale ecosystem services of river rehabilitation to be evaluated as part of the process of river basin planning and management, the total benefit of river
rehabilitation may well be reduced. River rehabilitation together with a ‘vision’ and framework within which it can be developed, is fundamental to future success in river basin management KW - River network scale, river rehabilitation, ecosystem services, flood control, biodiversity, fisheries, water quality, physical habitat.. U2 - 10.1016/j.jenvman.2013.03.026 DO - 10.1016/j.jenvman.2013.03.026 M1 - Article JO - Journal of Environmental Management JF - Journal of Environmental Management SN - 0301-4797 VL - 126 SP - 30 EP - 43 ER - TY - JOUR T1 - Facial attractiveness is related to women’s cortisol and body fat, but not with immune responsiveness A1 - Rantala,Markus J. A1 - Coetzee,Vinet A1 - Moore,Fhionna R. A1 - Skrinda,Ilona A1 - Kecko,Sanita A1 - Krama,Tatjana A1 - Kivleniece,Inese A1 - Krams,Indrikis AU - Rantala,Markus J. AU - Coetzee,Vinet AU - Moore,Fhionna R. AU - Skrinda,Ilona AU - Kecko,Sanita AU - Krama,Tatjana AU - Kivleniece,Inese AU - Krams,Indrikis PY - 2013/8/23 Y1 - 2013/8/23 N2 - Recent studies suggest that facial attractiveness indicates immune responsiveness in men and that this relationship is moderated by stress hormones which interact with testosterone levels. However, studies testing whether facial attractiveness in women signals their immune responsiveness are lacking. Here, we photographed young Latvian women, vaccinated them against hepatitis B and measured the amount of specific antibodies produced, cortisol levels and percentage body fat. Latvian men rated the attractiveness of the women's faces. Interestingly, in women, immune responsiveness (amount of antibodies produced) did not predict facial attractiveness. Instead, plasma cortisol level was negatively associated with attractiveness, indicating that stressed women look less attractive. Fat percentage was curvilinearly associated with facial attractiveness, indicating that being too thin or too fat reduces attractiveness. Our study suggests that in contrast to men, facial attractiveness in women does not indicate immune responsiveness against hepatitis B, but is associated with two other aspects of long-term health and fertility: circulating levels of the stress hormone cortisol and percentage body fat. AB - Recent studies suggest that facial attractiveness indicates immune responsiveness in men and that this relationship is moderated by stress hormones which interact with testosterone levels. However, studies testing whether facial attractiveness in women signals their immune responsiveness are lacking. Here, we photographed young Latvian women, vaccinated them against hepatitis B and measured the amount of specific antibodies produced, cortisol levels and percentage body fat. Latvian men rated the attractiveness of the women's faces. Interestingly, in women, immune responsiveness (amount of antibodies produced) did not predict facial attractiveness. Instead, plasma cortisol level was negatively associated with attractiveness, indicating that stressed women look less attractive. Fat percentage was curvilinearly associated with facial attractiveness, indicating that being too thin or too fat reduces attractiveness. Our study suggests that in contrast to men, facial attractiveness in women does not indicate immune responsiveness against hepatitis B, but is associated with two other aspects of long-term health and fertility: circulating levels of the stress hormone cortisol and percentage body fat. KW - Beauty KW - Cortisol KW - Humans KW - Immune KW - Mate choice KW - Sexual selection U2 - 10.1098/rsbl.2013.0255 DO - 10.1098/rsbl.2013.0255 M1 - Article JO - Biology Letters JF - Biology Letters SN - 1744-9561 IS - 4 VL - 9 ER - TY - JOUR T1 - Mechanisms of immune dysfunction and bacterial persistence in non-cystic fibrosis bronchiectasis A1 - Chalmers,James D. A1 - Hill,Adam T. AU - Chalmers,James D. AU - Hill,Adam T. PY - 2013/8 Y1 - 2013/8 N2 - Bronchiectasis is a chronic inflammatory lung disease. The underlying cause is not identified in the majority of patients, but bronchiectasis is associated with a number of severe infections, immunodeficiencies and autoimmune disorders. Regardless of the underlying cause, the disease is characterised by a vicious cycle of bacterial colonisation, airway inflammation and airway structural damage. Inflammation in bronchiectasis is predominantly neutrophil driven. Neutrophils migrate to the airway under the action of pro-inflammatory cytokines such as interleukin-8, tumour necrosis factor-a and interleukin-1ß, all of which are increased in the airway of patients with bronchiectasis.Bacterial infection persists in the airway despite large numbers of neutrophils that would be expected to phagocytose and kill pathogens under normal circumstances. Evidence suggests that neutrophils are disabled by multiple mechanisms including cleavage of phagocytic receptors by neutrophil elastase and inhibition of phagocytosis by neutrophil peptides. Complement activation is impaired and neutrophil elastase may cleave activated complement from pathogens preventing effective opsonisation.Organisms also evade clearance by adapting to chronic infection. The formation of biofilms, reduced motility and the down-regulation of virulence factors are among the strategies used to subvert innate immune mechanisms.Greater understanding of the mechanisms underlying chronic colonisation in bronchiectasis will assist in the development of new treatments for this important disease. © 2012 Elsevier Ltd. AB - Bronchiectasis is a chronic inflammatory lung disease. The underlying cause is not identified in the majority of patients, but bronchiectasis is associated with a number of severe infections, immunodeficiencies and autoimmune disorders. Regardless of the underlying cause, the disease is characterised by a vicious cycle of bacterial colonisation, airway inflammation and airway structural damage. Inflammation in bronchiectasis is predominantly neutrophil driven. Neutrophils migrate to the airway under the action of pro-inflammatory cytokines such as interleukin-8, tumour necrosis factor-a and interleukin-1ß, all of which are increased in the airway of patients with bronchiectasis.Bacterial infection persists in the airway despite large numbers of neutrophils that would be expected to phagocytose and kill pathogens under normal circumstances. Evidence suggests that neutrophils are disabled by multiple mechanisms including cleavage of phagocytic receptors by neutrophil elastase and inhibition of phagocytosis by neutrophil peptides. Complement activation is impaired and neutrophil elastase may cleave activated complement from pathogens preventing effective opsonisation.Organisms also evade clearance by adapting to chronic infection. The formation of biofilms, reduced motility and the down-regulation of virulence factors are among the strategies used to subvert innate immune mechanisms.Greater understanding of the mechanisms underlying chronic colonisation in bronchiectasis will assist in the development of new treatments for this important disease. © 2012 Elsevier Ltd. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875625613&md5=68ee64997b334abf3ce6a281747b0b5a U2 - 10.1016/j.molimm.2012.09.011 DO - 10.1016/j.molimm.2012.09.011 M1 - Article JO - Molecular Immunology JF - Molecular Immunology SN - 0161-5890 IS - 1 VL - 55 SP - 27 EP - 34 ER - TY - JOUR T1 - Preface A1 - Linder,Patrick A1 - Fuller-Pace,Frances AU - Linder,Patrick AU - Fuller-Pace,Frances PY - 2013/8 Y1 - 2013/8 U2 - 10.1016/j.bbagrm.2013.04.008 DO - 10.1016/j.bbagrm.2013.04.008 M1 - Editorial JO - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms JF - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms SN - 1874-9399 IS - 8 VL - 1829 SP - 749 ER - TY - JOUR T1 - Retinal vessel segmentation using multiwavelet kernels and multiscale hierarchical decomposition A1 - Wang,Yangfan A1 - Ji,Guangrong A1 - Lin,Ping A1 - Trucco,Emanuele AU - Wang,Yangfan AU - Ji,Guangrong AU - Lin,Ping AU - Trucco,Emanuele PY - 2013/8 Y1 - 2013/8 N2 - We propose a comprehensive method for segmenting the retinal vasculature in fundus camera images. Our method does not require preprocessing and training and can therefore be used directly on different images sets. We enhance the vessels using matched filtering with multiwavelet kernels (MFMK), separating vessels from clutter and bright, localized features. Noise removal and vessel localization are achieved by a multiscale hierarchical decomposition of the normalized enhanced image. We show a necessary condition to achieve the optimal decomposition and derive the associated value of the scale parameter controlling the amount of details captured. Finally, we obtain a binary map of the vasculature by locally adaptive thresholding, generating a threshold surface based on the vessel edge information extracted by the previous processes. We report experimental results on two public retinal data sets, DRIVE and STARE, demonstrating an excellent performance in comparison with retinal vessel segmentation methods reported recently. © 2013 Elsevier Ltd. AB - We propose a comprehensive method for segmenting the retinal vasculature in fundus camera images. Our method does not require preprocessing and training and can therefore be used directly on different images sets. We enhance the vessels using matched filtering with multiwavelet kernels (MFMK), separating vessels from clutter and bright, localized features. Noise removal and vessel localization are achieved by a multiscale hierarchical decomposition of the normalized enhanced image. We show a necessary condition to achieve the optimal decomposition and derive the associated value of the scale parameter controlling the amount of details captured. Finally, we obtain a binary map of the vasculature by locally adaptive thresholding, generating a threshold surface based on the vessel edge information extracted by the previous processes. We report experimental results on two public retinal data sets, DRIVE and STARE, demonstrating an excellent performance in comparison with retinal vessel segmentation methods reported recently. © 2013 Elsevier Ltd. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875719608&md5=75254c48bf8dce237c83d856c77771b5 U2 - 10.1016/j.patcog.2012.12.014 DO - 10.1016/j.patcog.2012.12.014 M1 - Article JO - Pattern Recognition JF - Pattern Recognition SN - 0031-3203 IS - 8 VL - 46 SP - 2117 EP - 2133 ER - TY - JOUR T1 - The DEAD box proteins DDX5 (p68) and DDX17 (p72) T2 - Multi-tasking transcriptional regulators A1 - Fuller-Pace,Frances V AU - Fuller-Pace,Frances V PY - 2013/8 Y1 - 2013/8 N2 - Members of the DEAD box family of RNA helicases, which are characterised by the presence of twelve conserved motifs (including the signature D-E-A-D motif) within a structurally conserved 'helicase' core, are involved in all aspects of RNA metabolism. Apart from unwinding RNA duplexes, which established these proteins as RNA helicases, DEAD box proteins have been shown to also catalyse RNA annealing and to displace proteins from RNA. DEAD box proteins generally act as components of large multi-protein complexes and it is thought that interactions, via their divergent N- and C-terminal extensions, with other factors in the complexes may be responsible for the many different functions attributed to these proteins. In addition to their established crucial roles in the manipulation of RNA structure, it is becoming increasingly clear that several members of the DEAD box family act as regulators of transcription. In this review I shall focus on DDX5 (p68) and the highly related DDX17 (p72), two proteins for which there is a large body of evidence demonstrating that they function in transcriptional regulation. This article is part of a Special Issue entitled: The Biology of RNA helicases - Modulation for life. AB - Members of the DEAD box family of RNA helicases, which are characterised by the presence of twelve conserved motifs (including the signature D-E-A-D motif) within a structurally conserved 'helicase' core, are involved in all aspects of RNA metabolism. Apart from unwinding RNA duplexes, which established these proteins as RNA helicases, DEAD box proteins have been shown to also catalyse RNA annealing and to displace proteins from RNA. DEAD box proteins generally act as components of large multi-protein complexes and it is thought that interactions, via their divergent N- and C-terminal extensions, with other factors in the complexes may be responsible for the many different functions attributed to these proteins. In addition to their established crucial roles in the manipulation of RNA structure, it is becoming increasingly clear that several members of the DEAD box family act as regulators of transcription. In this review I shall focus on DDX5 (p68) and the highly related DDX17 (p72), two proteins for which there is a large body of evidence demonstrating that they function in transcriptional regulation. This article is part of a Special Issue entitled: The Biology of RNA helicases - Modulation for life. U2 - 10.1016/j.bbagrm.2013.03.004 DO - 10.1016/j.bbagrm.2013.03.004 M1 - Scientific review JO - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms JF - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms SN - 1874-9399 IS - 8 VL - 1829 SP - 756 EP - 763 ER - TY - JOUR T1 - Automatic fovea location in retinal images using anatomical priors and vessel density A1 - Chin,Khai Sing A1 - Trucco,Emanuele A1 - Tan,Lailing A1 - Wilson,Peter J. AU - Chin,Khai Sing AU - Trucco,Emanuele AU - Tan,Lailing AU - Wilson,Peter J. PY - 2013/7/15 Y1 - 2013/7/15 N2 - The aim of this paper is to devise an automatic algorithm locating the fovea center in retinal fundus images. We locate the fovea center as the region of minimum vessel density within a search region defined from anatomical priors, i.e., knowledge on the structure of the retina. Vessel density is computed from a binary vessel map, providing good invariance against image quality. Priors include the approximate distance from the optic disc, expressed in multiple of the disc diameter for generality. The disc is located automatically. We learn the distribution of disc-macula distances from clinical annotations on a sample of images independent of the test sample. We use the same sample of images to optimize the standard deviation of the Gaussian mask, which is used to weigh vessel density for cost estimation. We tested performance on a sample of 116 fundus images from the Tayside diabetic screening programme (TENOVUS) and 303 fundus images from MESSIDOR public data set. To test resilience to quality variations, TENOVUS images were divided into three quality groups and MESSIDOR images were divided into images with no risk of macula edema and with risk of macula edema. Algorithm result on TENOVUS images show good localization performance with all groups compared to manual ground truth annotations (92% estimates within 0.5 disc diameters of ground truth location with good quality, 70% with poor quality images). For MESSIDOR images, our algorithm recorded an accuracy of 80% for images with no risk of macula edema and 59% for images with risk of macula edema. © 2013 Elsevier B.V.All rights reserved. AB - The aim of this paper is to devise an automatic algorithm locating the fovea center in retinal fundus images. We locate the fovea center as the region of minimum vessel density within a search region defined from anatomical priors, i.e., knowledge on the structure of the retina. Vessel density is computed from a binary vessel map, providing good invariance against image quality. Priors include the approximate distance from the optic disc, expressed in multiple of the disc diameter for generality. The disc is located automatically. We learn the distribution of disc-macula distances from clinical annotations on a sample of images independent of the test sample. We use the same sample of images to optimize the standard deviation of the Gaussian mask, which is used to weigh vessel density for cost estimation. We tested performance on a sample of 116 fundus images from the Tayside diabetic screening programme (TENOVUS) and 303 fundus images from MESSIDOR public data set. To test resilience to quality variations, TENOVUS images were divided into three quality groups and MESSIDOR images were divided into images with no risk of macula edema and with risk of macula edema. Algorithm result on TENOVUS images show good localization performance with all groups compared to manual ground truth annotations (92% estimates within 0.5 disc diameters of ground truth location with good quality, 70% with poor quality images). For MESSIDOR images, our algorithm recorded an accuracy of 80% for images with no risk of macula edema and 59% for images with risk of macula edema. © 2013 Elsevier B.V.All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84876580532&md5=3b1aa123c48a4de8661f429b04f36087 U2 - 10.1016/j.patrec.2013.03.016 DO - 10.1016/j.patrec.2013.03.016 M1 - Article JO - Pattern Recognition Letters JF - Pattern Recognition Letters SN - 0167-8655 IS - 10 VL - 34 SP - 1152 EP - 1158 ER - TY - JOUR T1 - Comprehensive characterization and optimization of anti-LRRK2 (leucine-rich repeat kinase 2) monoclonal antibodies A1 - Davies,Paul A1 - Hinkle,Kelly M. A1 - Sukar,Nour N. A1 - Sepulveda,Bryan A1 - Mesias,Roxana A1 - Serrano,Geidy A1 - Alessi,Dario R. A1 - Beach,Thomas G. A1 - Benson,Deanna L. A1 - White,Charles L. A1 - Cowell,Rita M. A1 - Das,Sonal S. A1 - West,Andrew B. A1 - Melrose,Heather L. AU - Davies,Paul AU - Hinkle,Kelly M. AU - Sukar,Nour N. AU - Sepulveda,Bryan AU - Mesias,Roxana AU - Serrano,Geidy AU - Alessi,Dario R. AU - Beach,Thomas G. AU - Benson,Deanna L. AU - White,Charles L. AU - Cowell,Rita M. AU - Das,Sonal S. AU - West,Andrew B. AU - Melrose,Heather L. PY - 2013/7/1 Y1 - 2013/7/1 N2 - Missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a major cause of PD (Parkinson's disease). Several antibodies against LRRK2 have been developed, but results using these polyclonal antibodies have varied widely leading to conflicting conclusions. To address this challenge, the Michael J. Fox Foundation for Parkinson's Research generated a number of monoclonal antibodies targeting epitopes across the LRRK2 protein. In the present paper, we report optimized protocols and results for ten monoclonal antibodies for immunoblotting, immunohistochemistry, immunoprecipitation and kinase activity assays, in rat, mouse and human brain tissue. Several efficacious antibodies were identified, but results demonstrate that the mouse monoclonal N241A/34 is suitable for most applications, with the best overall rabbit monoclonal antibody being c41-2. These antibodies produced a dominant band of the expected size via immunoblotting and a lack of labelling in tissue derived from LRRK2-knockout animals under optimized conditions. A significant proportion of LRRK2 protein localizes to insoluble fractions and no evidence of truncated LRRK2 protein was detected in any fraction from rodent or human tissues. An assay was developed for the robust detection of LRRK2 kinase activity directly from frozen mouse and human brain tissue, but precipitous declines in activity were observed that corresponded to increasing post-mortem intervals and processing times. Finally, we demonstrate the highest levels of brain-localized LRRK2 in the striatum, but note differential expression patterns between rat and mouse in both striatum and cortex. Anti-LRRK2 monoclonal antibodies that are unlimited in availability together with the proposed standardized protocols should aid in the definition of LRRK2 function in both health and disease. AB - Missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a major cause of PD (Parkinson's disease). Several antibodies against LRRK2 have been developed, but results using these polyclonal antibodies have varied widely leading to conflicting conclusions. To address this challenge, the Michael J. Fox Foundation for Parkinson's Research generated a number of monoclonal antibodies targeting epitopes across the LRRK2 protein. In the present paper, we report optimized protocols and results for ten monoclonal antibodies for immunoblotting, immunohistochemistry, immunoprecipitation and kinase activity assays, in rat, mouse and human brain tissue. Several efficacious antibodies were identified, but results demonstrate that the mouse monoclonal N241A/34 is suitable for most applications, with the best overall rabbit monoclonal antibody being c41-2. These antibodies produced a dominant band of the expected size via immunoblotting and a lack of labelling in tissue derived from LRRK2-knockout animals under optimized conditions. A significant proportion of LRRK2 protein localizes to insoluble fractions and no evidence of truncated LRRK2 protein was detected in any fraction from rodent or human tissues. An assay was developed for the robust detection of LRRK2 kinase activity directly from frozen mouse and human brain tissue, but precipitous declines in activity were observed that corresponded to increasing post-mortem intervals and processing times. Finally, we demonstrate the highest levels of brain-localized LRRK2 in the striatum, but note differential expression patterns between rat and mouse in both striatum and cortex. Anti-LRRK2 monoclonal antibodies that are unlimited in availability together with the proposed standardized protocols should aid in the definition of LRRK2 function in both health and disease. U2 - 10.1042/BJ20121742 DO - 10.1042/BJ20121742 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 IS - 1 VL - 453 SP - 101 EP - 113 ER - TY - JOUR T1 - Ube2W conjugates ubiquitin to α-amino groups of protein N-termini A1 - Tatham,Michael H. A1 - Plechanovová,Anna A1 - Jaffray,Ellis G. A1 - Salmen,Helena A1 - Hay,Ronald T. AU - Tatham,Michael H. AU - Plechanovová,Anna AU - Jaffray,Ellis G. AU - Salmen,Helena AU - Hay,Ronald T. PY - 2013/7/1 Y1 - 2013/7/1 N2 - The covalent attachment of the protein ubiquitin to intracellular proteins by a process known as ubiquitylation regulates almost all major cellular systems, predominantly by regulating protein turnover. Ubiquitylation requires the co-ordinated action of three enzymes termed E1, E2 and E3, and typically results in the formation of an isopeptide bond between the C-terminal carboxy group of ubiquitin and the ?-amino group of a target lysine residue. However, ubiquitin is also known to conjugate to the thiol of cysteine residue side chains and the a-amino group of protein N-termini, although the enzymes responsible for discrimination between different chemical groups have not been defined. In the present study, we show that Ube2W (Ubc16) is an E2 ubiquitin-conjugating enzyme with specific protein N-terminal mono-ubiquitylation activity. Ube2W conjugates ubiquitin not only to its own N-terminus, but also to that of the small ubiquitin-like modifier SUMO (small ubiquitin-related modifier) in a manner dependent on the SUMO-targeted ubiquitin ligase RNF4 (RING finger protein 4). Furthermore, N-terminal mono-ubiquitylation of SUMO-2 primes it for poly-ubiquitylation by the Ubc13-UEV1 (ubiquitin-conjugating enzyme E2 variant 1) heterodimer, showing that N-terminal ubiquitylation regulates protein fate. The description in the present study is the first of an E2-conjugating enzyme with N-terminal ubiquitylation activity, and highlights the importance of E2 enzymes in the ultimate outcome of E3-mediated ubiquitylation. AB - The covalent attachment of the protein ubiquitin to intracellular proteins by a process known as ubiquitylation regulates almost all major cellular systems, predominantly by regulating protein turnover. Ubiquitylation requires the co-ordinated action of three enzymes termed E1, E2 and E3, and typically results in the formation of an isopeptide bond between the C-terminal carboxy group of ubiquitin and the ?-amino group of a target lysine residue. However, ubiquitin is also known to conjugate to the thiol of cysteine residue side chains and the a-amino group of protein N-termini, although the enzymes responsible for discrimination between different chemical groups have not been defined. In the present study, we show that Ube2W (Ubc16) is an E2 ubiquitin-conjugating enzyme with specific protein N-terminal mono-ubiquitylation activity. Ube2W conjugates ubiquitin not only to its own N-terminus, but also to that of the small ubiquitin-like modifier SUMO (small ubiquitin-related modifier) in a manner dependent on the SUMO-targeted ubiquitin ligase RNF4 (RING finger protein 4). Furthermore, N-terminal mono-ubiquitylation of SUMO-2 primes it for poly-ubiquitylation by the Ubc13-UEV1 (ubiquitin-conjugating enzyme E2 variant 1) heterodimer, showing that N-terminal ubiquitylation regulates protein fate. The description in the present study is the first of an E2-conjugating enzyme with N-terminal ubiquitylation activity, and highlights the importance of E2 enzymes in the ultimate outcome of E3-mediated ubiquitylation. U2 - 10.1042/BJ20130244 DO - 10.1042/BJ20130244 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 IS - 1 VL - 453 SP - 137 EP - 145 ER - TY - JOUR T1 - "Pattern Recognition" special issue T2 - Sparse representation for event recognition in videosurveillance A1 - Zhou,Huiyu A1 - Zhang,Jianguo A1 - Wang,Liang A1 - Zhang,Zhengyou A1 - Brown,Lisa M. AU - Zhou,Huiyu AU - Zhang,Jianguo AU - Wang,Liang AU - Zhang,Zhengyou AU - Brown,Lisa M. PY - 2013/7 Y1 - 2013/7 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875269101&md5=81b48e38bc9747923b004ed2cc6852e3 U2 - 10.1016/j.patcog.2013.01.026 DO - 10.1016/j.patcog.2013.01.026 M1 - Editorial JO - Pattern Recognition JF - Pattern Recognition SN - 0031-3203 IS - 7 VL - 46 SP - 1748 EP - 1749 ER - TY - JOUR T1 - An experimental test of the Westermarck effect T2 - sex differences in inbreeding avoidance A1 - Marcinkowska,Urszula M. A1 - Moore,Fhionna R. A1 - Rantala,Markus J. AU - Marcinkowska,Urszula M. AU - Moore,Fhionna R. AU - Rantala,Markus J. PY - 2013/7 Y1 - 2013/7 N2 - In order to avoid inbreeding, humans and other animals develop a strong sexual aversion to individuals with whom they have lived closely in infancy and early childhood (usually biological siblings), a phenomenon called the “Westermarck effect” or negative sexual imprinting. The mechanisms underlying this phenomenon, however, remain unclear. For example, it is not known whether negative imprinting is based only on actual sexual aversion to brothers and sisters or also on generalizing the traits of their siblings to nonkin. If imprinting is more general, one could predict that people would avoid mating with all individuals that resemble their other-sex siblings. In our study, women rated morphed other-sex faces that resemble their siblings as significantly lower in sexual attractiveness than morphed faces on average, and the opposite effect was found in men—similarity to sibling increased perceived attractiveness. Interestingly, self-similarity did not influence the preferences of either men or women. These sex differences are consistent with parental investment theory, as females bear greater costs associated with inbreeding depression, perhaps explaining their deeper aversion toward engagement in sexual activities with male individuals who bear cues to relatedness. Furthermore, they indicate that faces resembling siblings are valid stimuli for investigating facial similarity preference. AB - In order to avoid inbreeding, humans and other animals develop a strong sexual aversion to individuals with whom they have lived closely in infancy and early childhood (usually biological siblings), a phenomenon called the “Westermarck effect” or negative sexual imprinting. The mechanisms underlying this phenomenon, however, remain unclear. For example, it is not known whether negative imprinting is based only on actual sexual aversion to brothers and sisters or also on generalizing the traits of their siblings to nonkin. If imprinting is more general, one could predict that people would avoid mating with all individuals that resemble their other-sex siblings. In our study, women rated morphed other-sex faces that resemble their siblings as significantly lower in sexual attractiveness than morphed faces on average, and the opposite effect was found in men—similarity to sibling increased perceived attractiveness. Interestingly, self-similarity did not influence the preferences of either men or women. These sex differences are consistent with parental investment theory, as females bear greater costs associated with inbreeding depression, perhaps explaining their deeper aversion toward engagement in sexual activities with male individuals who bear cues to relatedness. Furthermore, they indicate that faces resembling siblings are valid stimuli for investigating facial similarity preference. KW - Facial preferences KW - Inbreeding avoidance KW - Incest avoidance KW - Sexual imprinting KW - Westermarck hypothesis U2 - 10.1093/beheco/art028 DO - 10.1093/beheco/art028 M1 - Article IS - 4 VL - 24 SP - 842 EP - 845 ER - TY - JOUR T1 - Comparison of a high-throughput high-content intracellular Leishmania donovani assay with an axenic amastigote assay. A1 - De Rycker,Manu A1 - Hallyburton,Irene A1 - Thomas,John A1 - Campbell,Lorna A1 - Wyllie,Susan A1 - Joshi,Dhananjay A1 - Cameron,Scott A1 - Gilbert,Ian H. A1 - Wyatt,Paul G. A1 - Frearson,Julie A. A1 - Fairlamb,Alan H. A1 - Gray,David W. AU - De Rycker,Manu AU - Hallyburton,Irene AU - Thomas,John AU - Campbell,Lorna AU - Wyllie,Susan AU - Joshi,Dhananjay AU - Cameron,Scott AU - Gilbert,Ian H. AU - Wyatt,Paul G. AU - Frearson,Julie A. AU - Fairlamb,Alan H. AU - Gray,David W. PY - 2013/7 Y1 - 2013/7 N2 - Visceral leishmaniasis is a neglected tropical disease with significant health impact. Current treatments are poor and there is an urgent need to develop new drugs. Primary screening assays used for drug discovery campaigns have typically used free-living forms of the Leishmania parasite to allow for high-throughput screening. Such screens do not necessarily reflect the physiological situation as the disease-causing stage of the parasite resides inside human host cells. Assessing drug sensitivity of intracellular parasites on scale has recently become feasible with the advent of high-content screening methods. Here we present a 384 well microscopy-based intramacrophage Leishmania donovani assay and compare it to an axenic amastigote system. A panel of eight reference compounds was tested in both systems as well as a human counterscreen cell line, and shows that for most clinically used compounds both axenic and intramacrophage assays report very similar results. A set of 15,659 diverse compounds was also screened in both systems. This resulted in the identification of seven new anti-leishmanial compounds and revealed a high false positive rate for the axenic assay. We conclude that the intramacrophage assay is more suited as a primary hit-discovery platform than the current form of the axenic assay and discuss how modifications to the axenic assay may render it more suitable for hit-discovery. AB - Visceral leishmaniasis is a neglected tropical disease with significant health impact. Current treatments are poor and there is an urgent need to develop new drugs. Primary screening assays used for drug discovery campaigns have typically used free-living forms of the Leishmania parasite to allow for high-throughput screening. Such screens do not necessarily reflect the physiological situation as the disease-causing stage of the parasite resides inside human host cells. Assessing drug sensitivity of intracellular parasites on scale has recently become feasible with the advent of high-content screening methods. Here we present a 384 well microscopy-based intramacrophage Leishmania donovani assay and compare it to an axenic amastigote system. A panel of eight reference compounds was tested in both systems as well as a human counterscreen cell line, and shows that for most clinically used compounds both axenic and intramacrophage assays report very similar results. A set of 15,659 diverse compounds was also screened in both systems. This resulted in the identification of seven new anti-leishmanial compounds and revealed a high false positive rate for the axenic assay. We conclude that the intramacrophage assay is more suited as a primary hit-discovery platform than the current form of the axenic assay and discuss how modifications to the axenic assay may render it more suitable for hit-discovery. UR - http://europepmc.org/abstract/MED/23571538 U2 - 10.1128/AAC.02398-12 DO - 10.1128/AAC.02398-12 M1 - Article JO - Antimicrobial Agents and Chemotherapy JF - Antimicrobial Agents and Chemotherapy SN - 0066-4804 IS - 7 VL - 57 SP - 2913 EP - 2922 ER - TY - JOUR T1 - Discrimination of Sri Lankan black teas using fluorescence spectroscopy and linear discriminant analysis A1 - Seetohul,L. Nitin A1 - Scott,Simon M. A1 - O'Hare,William T. A1 - Ali,Zulfiqur A1 - Islam,Meez AU - Seetohul,L. Nitin AU - Scott,Simon M. AU - O'Hare,William T. AU - Ali,Zulfiqur AU - Islam,Meez PY - 2013/7 Y1 - 2013/7 N2 - Background

The quality of teas is currently graded using trained tea tasters and their evaluation could be subjective. In this study the simple fluorescence based technique of total luminescence spectroscopy (TLS) in conjunction with data classification using principal component analysis (PCA) has been used to discriminate between teas from 11 different Sri Lankan plantations. Solvent extraction of the tea samples was followed by TLS to record excitation-emission matrices (EEM) in the excitation range 250 – 590 nm and emission range 300 – 700 nm.

Results

The application of PCA and linear discriminant analysis (LDA) allowed the successful classification of all 11 teas using only the first two principal components. LDA demonstrated how the technique was able to discriminate between all teas correctly with 100% classification.

Conclusion

Further development of this work could lead to a simple device which could be used by tea manufacturers instead or alongside trained tea tasters to grade teas.Copyright © 2012 Society of Chemical Industry AB - Background

The quality of teas is currently graded using trained tea tasters and their evaluation could be subjective. In this study the simple fluorescence based technique of total luminescence spectroscopy (TLS) in conjunction with data classification using principal component analysis (PCA) has been used to discriminate between teas from 11 different Sri Lankan plantations. Solvent extraction of the tea samples was followed by TLS to record excitation-emission matrices (EEM) in the excitation range 250 – 590 nm and emission range 300 – 700 nm.

Results

The application of PCA and linear discriminant analysis (LDA) allowed the successful classification of all 11 teas using only the first two principal components. LDA demonstrated how the technique was able to discriminate between all teas correctly with 100% classification.

Conclusion

Further development of this work could lead to a simple device which could be used by tea manufacturers instead or alongside trained tea tasters to grade teas.Copyright © 2012 Society of Chemical Industry U2 - 10.1002/jsfa.6044 DO - 10.1002/jsfa.6044 M1 - Article JO - Journal of the Science of Food and Agriculture JF - Journal of the Science of Food and Agriculture SN - 0022-5142 IS - 9 VL - 93 SP - 2308 EP - 2314 ER - TY - JOUR T1 - In Brief T2 - cell senescence A1 - Coates,Philip J. AU - Coates,Philip J. PY - 2013/7 Y1 - 2013/7 N2 - Cellular senescence is a key process that limits cancer development. The basics of our current understanding of the process are presented, including the genetic and epigenetic events that lead to the senescent phenotype. In addition to limiting replicative lifespan, senescence appears to act as a potent signal to activate immune clearance and alter the microenvironment. Finally, senescence induction is an area for anti-cancer therapeutic development, but will require the development of appropriate assays to identify the relevant target(s) in individual tumours. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. AB - Cellular senescence is a key process that limits cancer development. The basics of our current understanding of the process are presented, including the genetic and epigenetic events that lead to the senescent phenotype. In addition to limiting replicative lifespan, senescence appears to act as a potent signal to activate immune clearance and alter the microenvironment. Finally, senescence induction is an area for anti-cancer therapeutic development, but will require the development of appropriate assays to identify the relevant target(s) in individual tumours. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. U2 - 10.1002/path.4182 DO - 10.1002/path.4182 M1 - Article JO - Journal of Pathology JF - Journal of Pathology SN - 0022-3417 IS - 3 VL - 230 SP - 239 EP - 240 ER - TY - JOUR T1 - Infant feeding in Eastern Scotland T2 - a longitudinal mixed methods evaluation of antenatal intentions and postnatal satisfaction-the feeding your baby study A1 - Symon,Andrew G. A1 - Whitford,Heather A1 - Dalzell,Janet AU - Symon,Andrew G. AU - Whitford,Heather AU - Dalzell,Janet PY - 2013/7 Y1 - 2013/7 N2 - Background: breast-feeding initiation rates have improved in Scotland, but exclusive and partial breast-feeding rates fall rapidly for several reasons. We aimed to examine whether antenatal feeding intention was associated with satisfaction with infant feeding method; and to explore the similarities and differences in infant feeding experience of women with different antenatal feeding intention scores. Method(s): antenatal questionnaire assessment of infant feeding intentions, based on the theory of planned behaviour; two-weekly postnatal follow-up of infant feeding practice by text messaging; final telephone interview to determine reasons for and satisfaction with infant feeding practice. Results: 355 women in eastern Scotland were recruited antenatally; 292 completed postnatal follow up. Antenatal feeding intentions broadly predicted postnatal practice. The highest satisfaction scores were seen in mothers with no breast-feeding intention who formula fed from birth, and those with high breast-feeding intention who breastfed for more than 8 weeks. The lowest satisfaction scores were seen in those with high intention scores who only managed to breast feed for less than 3 weeks. This suggests that satisfaction with infant feeding is associated with achieving feeding goals, whether artificial milk or breast feeding. Reasons for stopping breast feeding were broadly similar over time (too demanding, pain, latching, perception of amount of milk, lack of professional support, sibling jealousy). Perseverance appeared to mark out those women who managed to breast feed for longer; this was seen across the socio-economic spectrum. Societal and professional pressure to breast feed was commonly experienced. Conclusions: satisfaction with actual infant feeding practice is associated with antenatal intention; levels are higher for those meeting their goals, whether formula feeding from birth or breast feeding for longer periods. Perceived pressure to breast feed raises questions about informed decision making. Identifying those who will benefit most from targeted infant feeding support is crucial. © 2012 Elsevier Ltd. All rights reserved. AB - Background: breast-feeding initiation rates have improved in Scotland, but exclusive and partial breast-feeding rates fall rapidly for several reasons. We aimed to examine whether antenatal feeding intention was associated with satisfaction with infant feeding method; and to explore the similarities and differences in infant feeding experience of women with different antenatal feeding intention scores. Method(s): antenatal questionnaire assessment of infant feeding intentions, based on the theory of planned behaviour; two-weekly postnatal follow-up of infant feeding practice by text messaging; final telephone interview to determine reasons for and satisfaction with infant feeding practice. Results: 355 women in eastern Scotland were recruited antenatally; 292 completed postnatal follow up. Antenatal feeding intentions broadly predicted postnatal practice. The highest satisfaction scores were seen in mothers with no breast-feeding intention who formula fed from birth, and those with high breast-feeding intention who breastfed for more than 8 weeks. The lowest satisfaction scores were seen in those with high intention scores who only managed to breast feed for less than 3 weeks. This suggests that satisfaction with infant feeding is associated with achieving feeding goals, whether artificial milk or breast feeding. Reasons for stopping breast feeding were broadly similar over time (too demanding, pain, latching, perception of amount of milk, lack of professional support, sibling jealousy). Perseverance appeared to mark out those women who managed to breast feed for longer; this was seen across the socio-economic spectrum. Societal and professional pressure to breast feed was commonly experienced. Conclusions: satisfaction with actual infant feeding practice is associated with antenatal intention; levels are higher for those meeting their goals, whether formula feeding from birth or breast feeding for longer periods. Perceived pressure to breast feed raises questions about informed decision making. Identifying those who will benefit most from targeted infant feeding support is crucial. © 2012 Elsevier Ltd. All rights reserved. U2 - 10.1016/j.midw.2012.06.017 DO - 10.1016/j.midw.2012.06.017 M1 - Article JO - Midwifery JF - Midwifery SN - 0266-6138 IS - 7 VL - 29 SP - e49-e56 ER - TY - JOUR T1 - Predictive validity of the Dundee multiple mini-interview A1 - Husbands,Adrian A1 - Dowell,Jonathan AU - Husbands,Adrian AU - Dowell,Jonathan PY - 2013/7 Y1 - 2013/7 N2 - The multiple mini-interview (MMI) is the primary admissions tool used to assess non-cognitive skills at Dundee Medical School. Although the MMI shows promise, more research is required to demonstrate its transferability and predictive validity, for instance, relative to other UK pre-admissions measures. AB - The multiple mini-interview (MMI) is the primary admissions tool used to assess non-cognitive skills at Dundee Medical School. Although the MMI shows promise, more research is required to demonstrate its transferability and predictive validity, for instance, relative to other UK pre-admissions measures. U2 - 10.1111/medu.12193 DO - 10.1111/medu.12193 M1 - Article JO - Medical Education JF - Medical Education SN - 0308-0110 IS - 7 VL - 47 SP - 717 EP - 725 ER - TY - JOUR T1 - Cross-cultural variation in women's preferences for cues to sex- and stress-hormones in the male face A1 - Moore,F.R. A1 - Coetzee,V. A1 - Contreras-Garduno,J. A1 - DeBruine,L.M. A1 - Kleisner,K. A1 - Krams,I. A1 - Marcinkowska,U. A1 - Nord,A. A1 - Perrett,D. I. A1 - Rantala,M. J. A1 - Schaum,N. A1 - Suzuki,T. N. AU - Moore,F.R. AU - Coetzee,V. AU - Contreras-Garduno,J. AU - DeBruine,L.M. AU - Kleisner,K. AU - Krams,I. AU - Marcinkowska,U. AU - Nord,A. AU - Perrett,D. I. AU - Rantala,M. J. AU - Schaum,N. AU - Suzuki,T. N. PY - 2013/6/23 Y1 - 2013/6/23 N2 - Women in the UK prefer the faces of men with low levels of the stress hormone cortisol, and the relationship is moderated by the sex hormone testosterone. In a Latvian sample, however, women's preferences were not affected by cortisol, and the interaction with testosterone differed from that of the UK. To further explore cross-cultural variation in preferences for facial cues to sex- and stress-hormones, we tested the preferences of women from 13 countries for facial composites constructed to differ in combinations of the hormones. We found significant relationships between a measure of societal development (the United Nations human development index 2011) and preferences for cues to testosterone in the face, and the interaction between preferences for cues to testosterone and cortisol. We also found a significant relationship between preferences for cues to testosterone and a societal-level measure of parasite stress. We conclude that societal-level ecological factors influence the relative value of traits revealed by combinations of sex- and stress-hormones. AB - Women in the UK prefer the faces of men with low levels of the stress hormone cortisol, and the relationship is moderated by the sex hormone testosterone. In a Latvian sample, however, women's preferences were not affected by cortisol, and the interaction with testosterone differed from that of the UK. To further explore cross-cultural variation in preferences for facial cues to sex- and stress-hormones, we tested the preferences of women from 13 countries for facial composites constructed to differ in combinations of the hormones. We found significant relationships between a measure of societal development (the United Nations human development index 2011) and preferences for cues to testosterone in the face, and the interaction between preferences for cues to testosterone and cortisol. We also found a significant relationship between preferences for cues to testosterone and a societal-level measure of parasite stress. We conclude that societal-level ecological factors influence the relative value of traits revealed by combinations of sex- and stress-hormones. KW - stress-linked immunocompetence handicap KW - Cortisol KW - TESTOSTERONE KW - FACE KW - attractiveness KW - MASCULINITY U2 - 10.1098/rsbl.2013.0050 DO - 10.1098/rsbl.2013.0050 M1 - Article JO - Biology Letters JF - Biology Letters IS - 3 VL - 9 ER - TY - JOUR T1 - Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors A1 - Sommer,Eeva M A1 - Dry,Hannah A1 - Cross,Darren A1 - Guichard,Sylvie A1 - Davies,Barry R. A1 - Alessi,Dario R. AU - Sommer,Eeva M AU - Dry,Hannah AU - Cross,Darren AU - Guichard,Sylvie AU - Davies,Barry R. AU - Alessi,Dario R. PY - 2013/6/15 Y1 - 2013/6/15 N2 - The majority of human cancers harbour mutations promoting activation of the Akt protein kinase, and Akt inhibitors are being evaluated in clinical trials. An important question concerns the understanding of the innate mechanisms that confer resistance of tumour cells to Akt inhibitors. SGK (serum- and glucocorticoid-regulated kinase) is closely related to Akt and controlled by identical upstream regulators {PI3K (phosphoinositide 3-kinase), PDK1 (phosphoinositide-dependent kinase 1) and mTORC2 [mTOR (mammalian target of rapamycin) complex 2]}. Mutations that trigger activation of Akt would also stimulate SGK. Moreover, Akt and SGK possess analogous substrate specificities and are likely to phosphorylate overlapping substrates to promote proliferation. To investigate whether cancers possessing high SGK activity could possess innate resistance to Akt-specific inhibitors (that do not target SGK), we analysed SGK levels and sensitivity of a panel of breast cancer cells towards two distinct Akt inhibitors currently in clinical trials (AZD5363 and MK-2206). This revealed a number of Akt-inhibitor-resistant lines displaying markedly elevated SGK1 that also exhibited significant phosphorylation of the SGK1 substrate NDRG1 [N-Myc (neuroblastoma-derived Myc) downstream-regulated gene 1]. In contrast, most Akt-inhibitor-sensitive cell lines displayed low/undetectable levels of SGK1. Intriguingly, despite low SGK1 levels, several Akt-inhibitor-sensitive cells showed marked NDRG1 phosphorylation that was, unlike in the resistant cells, suppressed by Akt inhibitors. SGK1 knockdown markedly reduced proliferation of Akt-inhibitor-resistant, but not -sensitive, cells. Furthermore, treatment of Akt-inhibitor-resistant cells with an mTOR inhibitor suppressed proliferation and led to inhibition of SGK1. The results of the present study suggest that monitoring SGK1 levels as well as responses of NDRG1 phosphorylation to Akt inhibitor administration could have a use in predicting the sensitivity of tumours to compounds that target Akt. Our findings highlight the therapeutic potential that SGK inhibitors or dual Akt/SGK inhibitors might have for treatment of cancers displaying elevated SGK activity. AB - The majority of human cancers harbour mutations promoting activation of the Akt protein kinase, and Akt inhibitors are being evaluated in clinical trials. An important question concerns the understanding of the innate mechanisms that confer resistance of tumour cells to Akt inhibitors. SGK (serum- and glucocorticoid-regulated kinase) is closely related to Akt and controlled by identical upstream regulators {PI3K (phosphoinositide 3-kinase), PDK1 (phosphoinositide-dependent kinase 1) and mTORC2 [mTOR (mammalian target of rapamycin) complex 2]}. Mutations that trigger activation of Akt would also stimulate SGK. Moreover, Akt and SGK possess analogous substrate specificities and are likely to phosphorylate overlapping substrates to promote proliferation. To investigate whether cancers possessing high SGK activity could possess innate resistance to Akt-specific inhibitors (that do not target SGK), we analysed SGK levels and sensitivity of a panel of breast cancer cells towards two distinct Akt inhibitors currently in clinical trials (AZD5363 and MK-2206). This revealed a number of Akt-inhibitor-resistant lines displaying markedly elevated SGK1 that also exhibited significant phosphorylation of the SGK1 substrate NDRG1 [N-Myc (neuroblastoma-derived Myc) downstream-regulated gene 1]. In contrast, most Akt-inhibitor-sensitive cell lines displayed low/undetectable levels of SGK1. Intriguingly, despite low SGK1 levels, several Akt-inhibitor-sensitive cells showed marked NDRG1 phosphorylation that was, unlike in the resistant cells, suppressed by Akt inhibitors. SGK1 knockdown markedly reduced proliferation of Akt-inhibitor-resistant, but not -sensitive, cells. Furthermore, treatment of Akt-inhibitor-resistant cells with an mTOR inhibitor suppressed proliferation and led to inhibition of SGK1. The results of the present study suggest that monitoring SGK1 levels as well as responses of NDRG1 phosphorylation to Akt inhibitor administration could have a use in predicting the sensitivity of tumours to compounds that target Akt. Our findings highlight the therapeutic potential that SGK inhibitors or dual Akt/SGK inhibitors might have for treatment of cancers displaying elevated SGK activity. KW - Mammalian target of rapamycin (mTOR) KW - n-myc downstream-regulated gene 1 (NDRG1) KW - protein kinase inhibitor KW - phosphoinositide 3-kinase (PI3K) KW - signal transduction inhibitor U2 - 10.1042/BJ20130342 DO - 10.1042/BJ20130342 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 IS - 3 VL - 452 SP - 499 EP - 508 ER - TY - JOUR T1 - A versatile platform for creating a comprehensive UAS-ORFeome library in Drosophila. A1 - Bischof,Johannes A1 - Bjorklund,Mikael A1 - Furger,Edy A1 - Schertel,Claus A1 - Taipale,Jussi A1 - Basler,Konrad AU - Bischof,Johannes AU - Bjorklund,Mikael AU - Furger,Edy AU - Schertel,Claus AU - Taipale,Jussi AU - Basler,Konrad PY - 2013/6/1 Y1 - 2013/6/1 N2 - Overexpression screens are used to explore gene functions in Drosophila, but this strategy suffers from the lack of comprehensive and systematic fly strain collections and efficient methods for generating such collections. Here, we present a strategy that could be used efficiently to generate large numbers of transgenic Drosophila strains, and a collection of 1149 UAS-ORF fly lines that were created with the site-specific ?C31 integrase method. For this collection, we used a set of 655 genes that were cloned as two variants, either as an open reading frame (ORF) with a native stop codon or with a C-terminal 3xHA tag. To streamline the procedure for transgenic fly generation, we demonstrate the utility of injecting pools of plasmids into embryos, each plasmid containing a randomised sequence (barcode) that serves as a unique identifier for plasmids and, subsequently, fly strains. We also developed a swapping technique that facilitates the rapid exchange of promoters and epitope tags in vivo, expanding the versatility of the ORF collection. The work described here serves as the basis of a systematic library of Gal4/UAS-regulated transgenes. AB - Overexpression screens are used to explore gene functions in Drosophila, but this strategy suffers from the lack of comprehensive and systematic fly strain collections and efficient methods for generating such collections. Here, we present a strategy that could be used efficiently to generate large numbers of transgenic Drosophila strains, and a collection of 1149 UAS-ORF fly lines that were created with the site-specific ?C31 integrase method. For this collection, we used a set of 655 genes that were cloned as two variants, either as an open reading frame (ORF) with a native stop codon or with a C-terminal 3xHA tag. To streamline the procedure for transgenic fly generation, we demonstrate the utility of injecting pools of plasmids into embryos, each plasmid containing a randomised sequence (barcode) that serves as a unique identifier for plasmids and, subsequently, fly strains. We also developed a swapping technique that facilitates the rapid exchange of promoters and epitope tags in vivo, expanding the versatility of the ORF collection. The work described here serves as the basis of a systematic library of Gal4/UAS-regulated transgenes. UR - http://europepmc.org/abstract/MED/23637332 U2 - 10.1242/dev.088757 DO - 10.1242/dev.088757 M1 - Article JO - Development JF - Development SN - 0950-1991 IS - 11 VL - 140 SP - 2434 EP - 2442 ER - TY - JOUR T1 - Achieving good oral health in children T2 - The importance of a current, relevant and unbiased evidence base in paediatric dentistry A1 - Clarkson,J. E. A1 - Bonetti,D. A1 - Worthington,H. AU - Clarkson,J. E. AU - Bonetti,D. AU - Worthington,H. PY - 2013/6 Y1 - 2013/6 N2 - The Cochrane Collaboration was founded in 1993 as an international, non-profit and independent organisation dedicated to making up-to-date, accurate and reliable information about healthcare readily available. This paper discusses how the Cochrane Oral Health Group reviews have contributed to the oral health evidence base used in the development of many international and UK dental guidance documents, particularly in the field of paediatric dentistry. AB - The Cochrane Collaboration was founded in 1993 as an international, non-profit and independent organisation dedicated to making up-to-date, accurate and reliable information about healthcare readily available. This paper discusses how the Cochrane Oral Health Group reviews have contributed to the oral health evidence base used in the development of many international and UK dental guidance documents, particularly in the field of paediatric dentistry. U2 - 10.1038/sj.bdj.2013.526 DO - 10.1038/sj.bdj.2013.526 M1 - Article JO - British Dental Journal JF - British Dental Journal SN - 0007-0610 IS - 11 VL - 214 SP - 583 EP - 585 ER - TY - JOUR T1 - AMPK modulates glucose-sensing in insulin-secreting cells by altered phosphotransfer to KATP channels A1 - Beall,Craig A1 - Watterson,Kenneth R. A1 - McCrimmon,Rory J. A1 - Ashford,Michael L.J. AU - Beall,Craig AU - Watterson,Kenneth R. AU - McCrimmon,Rory J. AU - Ashford,Michael L.J. PY - 2013/6 Y1 - 2013/6 N2 - Glucose-sensing (GS) behaviour in pancreatic ß-cells is dependent on ATP-sensitive K(+) channel (KATP) activity, which is controlled by the relative levels of the KATP ligands ATP and ADP, responsible for closing and opening KATP, respectively. However, the mechanism by which ß-cells transfer energy status from mitochondria to KATP, and hence to altered electrical excitability and insulin secretion, is presently unclear. Recent work has demonstrated a critical role for AMP-activated protein kinase (AMPK) in GS behaviour of cells. Electrophysiological recordings, coupled with measurements of gene and protein expression were made from rat insulinoma cells to investigate whether AMPK activity regulates this energy transfer process. Using the whole-cell recording configuration with sufficient intracellular ATP to keep KATP closed, raised AMPK activity induced GS electrical behaviour. This effect was prevented by the AMPK inhibitor, compound C and required a phosphotransfer process. Indeed, high levels of intracellular phosphocreatine or the presence of the adenylate kinase (AK) inhibitor AP5A blocked this action of AMPK. Using conditions that maximised AMPK-induced KATP opening, there was a significant increase in AK1, AK2 and UCP2 mRNA expression. Thus we propose that KATP opening in response to lowered glucose concentration requires AMPK activity, perhaps in concert with increased AK and UCP2 to enable mitochondrial-derived ADP signals to be transferred to plasma membrane KATP by phosphotransfer cascades. AB - Glucose-sensing (GS) behaviour in pancreatic ß-cells is dependent on ATP-sensitive K(+) channel (KATP) activity, which is controlled by the relative levels of the KATP ligands ATP and ADP, responsible for closing and opening KATP, respectively. However, the mechanism by which ß-cells transfer energy status from mitochondria to KATP, and hence to altered electrical excitability and insulin secretion, is presently unclear. Recent work has demonstrated a critical role for AMP-activated protein kinase (AMPK) in GS behaviour of cells. Electrophysiological recordings, coupled with measurements of gene and protein expression were made from rat insulinoma cells to investigate whether AMPK activity regulates this energy transfer process. Using the whole-cell recording configuration with sufficient intracellular ATP to keep KATP closed, raised AMPK activity induced GS electrical behaviour. This effect was prevented by the AMPK inhibitor, compound C and required a phosphotransfer process. Indeed, high levels of intracellular phosphocreatine or the presence of the adenylate kinase (AK) inhibitor AP5A blocked this action of AMPK. Using conditions that maximised AMPK-induced KATP opening, there was a significant increase in AK1, AK2 and UCP2 mRNA expression. Thus we propose that KATP opening in response to lowered glucose concentration requires AMPK activity, perhaps in concert with increased AK and UCP2 to enable mitochondrial-derived ADP signals to be transferred to plasma membrane KATP by phosphotransfer cascades. U2 - 10.1007/s10863-013-9509-9 DO - 10.1007/s10863-013-9509-9 M1 - Article JO - Journal of Bioenergetics and Biomembranes JF - Journal of Bioenergetics and Biomembranes SN - 0145-479X IS - 3 VL - 45 SP - 229 EP - 241 ER - TY - JOUR T1 - Clast shape analysis and clast transport paths in glacial environments T2 - A critical review of methods and the role of lithology A1 - Lukas,Sven A1 - Benn,Douglas I. A1 - Boston,Clare M. A1 - Brook,Martin A1 - Coray,Sandro A1 - Evans,David J.A. A1 - Graf,Andreas A1 - Kellerer-Pirklbauer,Andreas A1 - Kirkbride,Martin P. A1 - Krabbendam,Maarten A1 - Lovell,Harold A1 - Machiedo,Martin A1 - Mills,Stephanie C. A1 - Nye,Kate A1 - Reinardy,Benedict T.I. A1 - Ross,Fionna H. A1 - Signer,Michael AU - Lukas,Sven AU - Benn,Douglas I. AU - Boston,Clare M. AU - Brook,Martin AU - Coray,Sandro AU - Evans,David J.A. AU - Graf,Andreas AU - Kellerer-Pirklbauer,Andreas AU - Kirkbride,Martin P. AU - Krabbendam,Maarten AU - Lovell,Harold AU - Machiedo,Martin AU - Mills,Stephanie C. AU - Nye,Kate AU - Reinardy,Benedict T.I. AU - Ross,Fionna H. AU - Signer,Michael PY - 2013/6 Y1 - 2013/6 N2 - The reconstruction and tracing of transport paths in glaciated (and other) environments have a long tradition in the Earth Sciences. We here present a dataset of clast shape samples from a worldwide selection of glaciated mountain environments in order to assess the reliability of this approach overall and the role of lithology on the performance of clast shape measurements in particular. Our findings demonstrate that the widely-used RA-C co-variance approach is applicable to 63% of the 19 catchments investigated, while the alternative RWR-C approach is more widely applicable to 75% of these catchments. A systematic assessment of mixing of lithologies at the catchment scale demonstrates that such mixing leads to pronounced overlaps between different control envelopes that had previously been separated, thereby removing the discriminatory power of the method. Mixing of similar lithologies between different catchments shows an even more extreme loss of discriminatory power, which strongly suggests that lithology plays a primary role in determining clast shape, and that catchment-specific processes are superimposed. Systematic analysis of the dataset also shows that nearly all catchments (apart from two) can be grouped into two types. Type I relates to sites in lesser mountain ranges and is characterised by dominantly blocky forms in the subglacial realm, highlighting significant reworking processes. Type II sites are dominantly in high-mountain environments and characterised by a high similarity between subglacial and fluvial control envelopes. This indicates that, although reworking may be pronounced, it is not necessarily effective enough to remove the platy shape that most likely results from extraglacial and supraglacial inputs. Our study highlights the potential of clast shape analysis as a tool that allows generic processes to be identified between catchments, thereby enabling an understanding of debris cascades in glaciated mountain environments. We finish with recommendations for ensuring that future clast shape studies are robust, reproducible and comparable between different sites. © 2013 Elsevier B.V. AB - The reconstruction and tracing of transport paths in glaciated (and other) environments have a long tradition in the Earth Sciences. We here present a dataset of clast shape samples from a worldwide selection of glaciated mountain environments in order to assess the reliability of this approach overall and the role of lithology on the performance of clast shape measurements in particular. Our findings demonstrate that the widely-used RA-C co-variance approach is applicable to 63% of the 19 catchments investigated, while the alternative RWR-C approach is more widely applicable to 75% of these catchments. A systematic assessment of mixing of lithologies at the catchment scale demonstrates that such mixing leads to pronounced overlaps between different control envelopes that had previously been separated, thereby removing the discriminatory power of the method. Mixing of similar lithologies between different catchments shows an even more extreme loss of discriminatory power, which strongly suggests that lithology plays a primary role in determining clast shape, and that catchment-specific processes are superimposed. Systematic analysis of the dataset also shows that nearly all catchments (apart from two) can be grouped into two types. Type I relates to sites in lesser mountain ranges and is characterised by dominantly blocky forms in the subglacial realm, highlighting significant reworking processes. Type II sites are dominantly in high-mountain environments and characterised by a high similarity between subglacial and fluvial control envelopes. This indicates that, although reworking may be pronounced, it is not necessarily effective enough to remove the platy shape that most likely results from extraglacial and supraglacial inputs. Our study highlights the potential of clast shape analysis as a tool that allows generic processes to be identified between catchments, thereby enabling an understanding of debris cascades in glaciated mountain environments. We finish with recommendations for ensuring that future clast shape studies are robust, reproducible and comparable between different sites. © 2013 Elsevier B.V. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84876480382&md5=ca13770cc6e7b4a10da908ed7fbf6605 U2 - 10.1016/j.earscirev.2013.02.005 DO - 10.1016/j.earscirev.2013.02.005 M1 - Article VL - 121 SP - 96 EP - 116 ER - TY - JOUR T1 - Dynamic soil-structure interaction of monopile supported wind turbines in cohesive soil A1 - Lombardi,Domenico A1 - Bhattacharya,Subhamoy A1 - Muir Wood,David AU - Lombardi,Domenico AU - Bhattacharya,Subhamoy AU - Muir Wood,David PY - 2013/6 Y1 - 2013/6 N2 - Offshore wind turbines supported on monopile foundations are dynamically sensitive because the overall natural frequencies of these structures are close to the different forcing frequencies imposed upon them. The structures are designed for an intended life of 25 to 30 years, but little is known about their long term behaviour. To study their long term behaviour, a series of laboratory tests were conducted in which a scaled model wind turbine supported on a monopile in kaolin clay was subjected to between 32,000 and 172,000 cycles of horizontal loading and the changes in natural frequency and damping of the model were monitored. The experimental results are presented using a non-dimensional framework based on an interpretation of the governing mechanics. The change in natural frequency was found to be strongly dependent on the shear strain level in the soil next to the pile. Practical guidance for choosing the diameter of monopile is suggested based on element test results using the concept of volumetric threshold shear strain. © 2013. AB - Offshore wind turbines supported on monopile foundations are dynamically sensitive because the overall natural frequencies of these structures are close to the different forcing frequencies imposed upon them. The structures are designed for an intended life of 25 to 30 years, but little is known about their long term behaviour. To study their long term behaviour, a series of laboratory tests were conducted in which a scaled model wind turbine supported on a monopile in kaolin clay was subjected to between 32,000 and 172,000 cycles of horizontal loading and the changes in natural frequency and damping of the model were monitored. The experimental results are presented using a non-dimensional framework based on an interpretation of the governing mechanics. The change in natural frequency was found to be strongly dependent on the shear strain level in the soil next to the pile. Practical guidance for choosing the diameter of monopile is suggested based on element test results using the concept of volumetric threshold shear strain. © 2013. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875621439&md5=c4b12fa44414f7cb781d052c9ff0fe7b U2 - 10.1016/j.soildyn.2013.01.015 DO - 10.1016/j.soildyn.2013.01.015 M1 - Article JO - Soil Dynamics and Earthquake Engineering JF - Soil Dynamics and Earthquake Engineering SN - 0267-7261 VL - 49 SP - 165 EP - 180 ER - TY - JOUR T1 - Evidence that Cytochrome b5 and Cytochrome b5 Reductase Can Act as Sole Electron Donors to the Hepatic Cytochrome P450 System A1 - Henderson,Colin J A1 - McLaughlin,Lesley A A1 - Wolf,C Roland AU - Henderson,Colin J AU - McLaughlin,Lesley A AU - Wolf,C Roland PY - 2013/6 Y1 - 2013/6 N2 - We have previously described the development of genetic models to study the in vivo functions of the hepatic cytochrome P450 system, through the hepatic deletion of either cytochrome P450 oxidoreductase (POR; HRN line) or cytochrome b5 (Cyb5; HBN line). However, HRN mice still exhibit low levels of mono-oxygenase activity, in spite of the absence of detectable reductase protein. To investigate whether this is because cytochrome b5 and cytochrome b5 reductase can act as sole electron donors to the P450 system, we have crossed HRN with HBN mice to generate a line lacking hepatic expression of both electron donors (HBRN). HBRN mice exhibited exacerbation of the phenotypic characteristics of the HRN line - liver enlargement, hepatosteatosis and increased expression of certain cytochrome P450s. Also, drug metabolising activities in vitro were further reduced relative to the HRN model, in some cases to undetectable levels. Pharmacokinetic studies in vivo demonstrated that midazolam half-life, Cmax and area under the concentration-time curve (AUC) were increased, and clearance was decreased, to a greater extent in the HBRN line than in either the HBN or HRN model. Microsomal incubations using NADPH concentrations below the apparent Km of cytochrome b5 reductase, but well above that for POR, led to the virtual elimination of 7-benzyloxyquinoline turnover in HRN samples. These data provide strong evidence that cytochrome b5/cytochrome b5 reductase can act as a sole electron donors to the cytochrome P450 system in vitro and in vivo. AB - We have previously described the development of genetic models to study the in vivo functions of the hepatic cytochrome P450 system, through the hepatic deletion of either cytochrome P450 oxidoreductase (POR; HRN line) or cytochrome b5 (Cyb5; HBN line). However, HRN mice still exhibit low levels of mono-oxygenase activity, in spite of the absence of detectable reductase protein. To investigate whether this is because cytochrome b5 and cytochrome b5 reductase can act as sole electron donors to the P450 system, we have crossed HRN with HBN mice to generate a line lacking hepatic expression of both electron donors (HBRN). HBRN mice exhibited exacerbation of the phenotypic characteristics of the HRN line - liver enlargement, hepatosteatosis and increased expression of certain cytochrome P450s. Also, drug metabolising activities in vitro were further reduced relative to the HRN model, in some cases to undetectable levels. Pharmacokinetic studies in vivo demonstrated that midazolam half-life, Cmax and area under the concentration-time curve (AUC) were increased, and clearance was decreased, to a greater extent in the HBRN line than in either the HBN or HRN model. Microsomal incubations using NADPH concentrations below the apparent Km of cytochrome b5 reductase, but well above that for POR, led to the virtual elimination of 7-benzyloxyquinoline turnover in HRN samples. These data provide strong evidence that cytochrome b5/cytochrome b5 reductase can act as a sole electron donors to the cytochrome P450 system in vitro and in vivo. U2 - 10.1124/mol.112.084616 DO - 10.1124/mol.112.084616 M1 - Article JO - Molecular Pharmacology JF - Molecular Pharmacology SN - 0026-895X IS - 6 VL - 83 SP - 1209 EP - 1217 ER - TY - JOUR T1 - Modern approaches to caries management of the primary dentition A1 - Innes,N. P. T. A1 - Evans,D. J. P. AU - Innes,N. P. T. AU - Evans,D. J. P. PY - 2013/6 Y1 - 2013/6 N2 - When prevention of dental caries fails, and a child is exposed to the risk of pain and infection, the disease must be managed to reduce this risk. There is growing evidence supporting more 'biological' and fewer 'surgical' approaches to managing dental caries in primary teeth. These biological methods include partial and stepwise caries removal procedures, as well as techniques where no caries is removed. An overview of clinical trials comparing these biological methods to complete caries removal shows that they perform as well as traditional methods and have the advantage of reducing the incidence of iatrogenic pulpal exposures. The Hall Technique is one biological approach to managing caries in primary molars which involves sealing caries beneath preformed metal (stainless steel) crowns. The crown is cemented over the tooth without caries removal, tooth preparation or use of local anaesthesia. The clinical steps for the Hall Technique are straightforward but, as with all dental care provision, appropriate treatment planning for the procedure requires skill. The Hall Technique offers another method of managing early to moderately advanced, active carious lesions in primary molars, with good evidence of effectiveness and acceptability. This evidence aligns with the positive findings of other studies on biological strategies for managing caries in primary teeth. AB - When prevention of dental caries fails, and a child is exposed to the risk of pain and infection, the disease must be managed to reduce this risk. There is growing evidence supporting more 'biological' and fewer 'surgical' approaches to managing dental caries in primary teeth. These biological methods include partial and stepwise caries removal procedures, as well as techniques where no caries is removed. An overview of clinical trials comparing these biological methods to complete caries removal shows that they perform as well as traditional methods and have the advantage of reducing the incidence of iatrogenic pulpal exposures. The Hall Technique is one biological approach to managing caries in primary molars which involves sealing caries beneath preformed metal (stainless steel) crowns. The crown is cemented over the tooth without caries removal, tooth preparation or use of local anaesthesia. The clinical steps for the Hall Technique are straightforward but, as with all dental care provision, appropriate treatment planning for the procedure requires skill. The Hall Technique offers another method of managing early to moderately advanced, active carious lesions in primary molars, with good evidence of effectiveness and acceptability. This evidence aligns with the positive findings of other studies on biological strategies for managing caries in primary teeth. U2 - 10.1038/sj.bdj.2013.529 DO - 10.1038/sj.bdj.2013.529 M1 - Article JO - British Dental Journal JF - British Dental Journal SN - 0007-0610 IS - 11 VL - 214 SP - 559 EP - 566 ER - TY - JOUR T1 - Oesophageal bacterial biofilm changes in gastro-oesophageal reflux disease, Barrett's and oesophageal carcinoma T2 - association or causality? A1 - Blackett,K. L. A1 - Siddhi,S. S. A1 - Cleary,S. A1 - Steed,H. A1 - Miller,M. H. A1 - Macfarlane,S. A1 - Macfarlane,G. T. A1 - Dillon,J. F. AU - Blackett,K. L. AU - Siddhi,S. S. AU - Cleary,S. AU - Steed,H. AU - Miller,M. H. AU - Macfarlane,S. AU - Macfarlane,G. T. AU - Dillon,J. F. PY - 2013/6 Y1 - 2013/6 N2 - Barrett's oesophagus (BO) and gastro-oesophageal reflux disease (GERD) are precursors of oesophageal adenocarcinoma (OAC). There is an oesophageal biofilm, which changes in disease, but its role in aetiopathogenesis remains unclear. AB - Barrett's oesophagus (BO) and gastro-oesophageal reflux disease (GERD) are precursors of oesophageal adenocarcinoma (OAC). There is an oesophageal biofilm, which changes in disease, but its role in aetiopathogenesis remains unclear. U2 - 10.1111/apt.12317 DO - 10.1111/apt.12317 M1 - Article JO - Alimentary Pharmacology & Therapeutics JF - Alimentary Pharmacology & Therapeutics SN - 0269-2813 IS - 11 VL - 37 SP - 1084 EP - 1092 ER - TY - JOUR T1 - Phonological development in relation to native language and literacy T2 - Variations on a theme in six alphabetic orthographies A1 - Duncan,Lynne G. A1 - Castro,S.L. A1 - Defior,S. A1 - Seymour,Philip H.K. A1 - Baillie,Sheila A1 - Leybaert,J. A1 - Mousty,P. A1 - Genard,N. A1 - Sarris,M. A1 - Porpodas,C.D. A1 - Lund,R. A1 - Sigurdsson,B. A1 - Thráinsdóttir,A.S. A1 - Sucena,A. A1 - Serrano,F. AU - Duncan,Lynne G. AU - Castro,S.L. AU - Defior,S. AU - Seymour,Philip H.K. AU - Baillie,Sheila AU - Leybaert,J. AU - Mousty,P. AU - Genard,N. AU - Sarris,M. AU - Porpodas,C.D. AU - Lund,R. AU - Sigurdsson,B. AU - Thráinsdóttir,A.S. AU - Sucena,A. AU - Serrano,F. PY - 2013/6 Y1 - 2013/6 N2 - Phonological development was assessed in six alphabetic orthographies (English, French, Greek, Icelandic, Portuguese and Spanish) at the beginning and end of the first year of reading instruction. The aim was to explore contrasting theoretical views regarding: the question of the availability of phonology at the outset of learning to read (Study 1); the influence of orthographic depth on the pace of phonological development during the transition to literacy (Study 2); and the impact of literacy instruction (Study 3). Results from 242 children did not reveal a consistent sequence of development as performance varied according to task demands and language. Phonics instruction appeared more influential than orthographic depth in the emergence of an early meta-phonological capacity to manipulate phonemes, and preliminary indications were that cross-linguistic variation was associated with speech rhythm more than factors such as syllable complexity. The implications of the outcome for current models of phonological development are discussed. © 2013 Elsevier B.V. AB - Phonological development was assessed in six alphabetic orthographies (English, French, Greek, Icelandic, Portuguese and Spanish) at the beginning and end of the first year of reading instruction. The aim was to explore contrasting theoretical views regarding: the question of the availability of phonology at the outset of learning to read (Study 1); the influence of orthographic depth on the pace of phonological development during the transition to literacy (Study 2); and the impact of literacy instruction (Study 3). Results from 242 children did not reveal a consistent sequence of development as performance varied according to task demands and language. Phonics instruction appeared more influential than orthographic depth in the emergence of an early meta-phonological capacity to manipulate phonemes, and preliminary indications were that cross-linguistic variation was associated with speech rhythm more than factors such as syllable complexity. The implications of the outcome for current models of phonological development are discussed. © 2013 Elsevier B.V. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875789747&md5=a0e13626c9566600f637364bd7bb4eff U2 - 10.1016/j.cognition.2013.02.009 DO - 10.1016/j.cognition.2013.02.009 M1 - Article JO - Cognition JF - Cognition SN - 0010-0277 IS - 3 VL - 127 SP - 398 EP - 419 ER - TY - JOUR T1 - Preference for detail in medical illustrations amongst professionals and laypersons A1 - Strong,Jesse A1 - Erolin,Caroline AU - Strong,Jesse AU - Erolin,Caroline PY - 2013/6 Y1 - 2013/6 N2 - This study investigated the preferences of medical professionals and laypersons with respect to the level of detail shown in medical illustrations (i.e. graphic art shown in patient education materials) and the complexity of the subject being depicted (i.e. a visually simple versus a visually complex subject). Additionally, respondent's age, gender, and art background were recorded to yield further insight. The results showed that generally there was preference for high-detail (complex) illustrations between the two groups, though the professionals group was somewhat more diverse in their choices. The other variables had no impact on illustration preference. AB - This study investigated the preferences of medical professionals and laypersons with respect to the level of detail shown in medical illustrations (i.e. graphic art shown in patient education materials) and the complexity of the subject being depicted (i.e. a visually simple versus a visually complex subject). Additionally, respondent's age, gender, and art background were recorded to yield further insight. The results showed that generally there was preference for high-detail (complex) illustrations between the two groups, though the professionals group was somewhat more diverse in their choices. The other variables had no impact on illustration preference. UR - http://informahealthcare.com/doi/abs/10.3109/17453054.2013.790793 M1 - Article JO - Journal of Visual Communication in Medicine JF - Journal of Visual Communication in Medicine SN - 1745-3054 IS - 1-2 VL - 36 SP - 38 EP - 43 ER - TY - JOUR T1 - Role of endothelium-derived hyperpolarising factor in acetylcholine-mediated vasodilatation in skin A1 - Newton,D. J. A1 - Davies,J. A1 - Belch,J. J. F. A1 - Khan,F. AU - Newton,D. J. AU - Davies,J. AU - Belch,J. J. F. AU - Khan,F. PY - 2013/6 Y1 - 2013/6 N2 - Aim: Acetylcholine (ACh) is an endothelium-dependent vasodilator used to investigate endothelial function in the microcirculation. The mediators of its vasodilatory effects are not clear, but endothelium-derived hyperpolarising factor (EDHF) is thought to contribute, and appears to have particular importance in smaller peripheral vessels. The aim of this study was to investigate the role of EDHF in ACh-mediated vasodilator responses in human forearm skin. Methods: Laser Doppler imaging was used to measure forearm skin blood flow responses to iontophoretic administration of ACh in 7 healthy men. ACh in a 10-mg/mL solution was administered in accumulating doses using increasing delivery currents of 10, 15, 20, 50 and 100 µA. The measurements were repeated on subsequent visits when the effects of EDHF were blocked using intra-arterial sulphaphenazole at 2 mg/min (a cytochrome P-450 inhibitor), nitric oxide (NO) was blocked using intra-arterial administration of the NO synthetase inhibitor l-NG-monomethyl arginine (l-NMMA) at 4 µmol/min, and prostanoids were blocked with oral aspirin 1 g. Results: The microvascular response to ACh was significantly attenuated by sulphaphenazole alone (P=0.018), l-NMMA alone (P AB - Aim: Acetylcholine (ACh) is an endothelium-dependent vasodilator used to investigate endothelial function in the microcirculation. The mediators of its vasodilatory effects are not clear, but endothelium-derived hyperpolarising factor (EDHF) is thought to contribute, and appears to have particular importance in smaller peripheral vessels. The aim of this study was to investigate the role of EDHF in ACh-mediated vasodilator responses in human forearm skin. Methods: Laser Doppler imaging was used to measure forearm skin blood flow responses to iontophoretic administration of ACh in 7 healthy men. ACh in a 10-mg/mL solution was administered in accumulating doses using increasing delivery currents of 10, 15, 20, 50 and 100 µA. The measurements were repeated on subsequent visits when the effects of EDHF were blocked using intra-arterial sulphaphenazole at 2 mg/min (a cytochrome P-450 inhibitor), nitric oxide (NO) was blocked using intra-arterial administration of the NO synthetase inhibitor l-NG-monomethyl arginine (l-NMMA) at 4 µmol/min, and prostanoids were blocked with oral aspirin 1 g. Results: The microvascular response to ACh was significantly attenuated by sulphaphenazole alone (P=0.018), l-NMMA alone (P UR - http://www.minervamedica.it/en/journals/international-angiology/article.php?cod=R34Y2013N03A0312 M1 - Article JO - International Angiology JF - International Angiology SN - 0392-9590 IS - 3 VL - 32 SP - 312 EP - 318 ER - TY - JOUR T1 - Root–soil friction T2 - quantification provides evidence for measurable benefits for manipulation of root-tip traits A1 - McKenzie,Blair M. A1 - Mullins,Christopher E. A1 - Tisdall,Judith M. A1 - Bengough,A. Glyn AU - McKenzie,Blair M. AU - Mullins,Christopher E. AU - Tisdall,Judith M. AU - Bengough,A. Glyn PY - 2013/6 Y1 - 2013/6 N2 - To penetrate soil, a root requires pressure both to expand the cavity it is to occupy, sn, and to overcome root–soil friction, sf. Difficulties in estimating these two pressures independently have limited our ability to estimate the coefficient of soil–root friction, µsr. We used a rotated penetrometer probe, of similar dimensions to a root, and for the first time entering the soil at a similar rate to a root tip, to estimate sn. Separately we measured root penetration resistance (PR) Qr. Root PR was between two to four times sn. We estimated that the coefficient of root–soil friction (µsr) was 0.21–0.26, based on the geometry of the root tip. This is slightly larger than the 0.05–0.15 characteristic of boundary lubricants. Scanning electron microscopy showed that turgid border cells lined the root channel, supporting our hypothesis that the lubricant consisted of mucilage sandwiched between border cells and the surface of the root cap and epidermis. This cell–cell lubrication greatly decreased the friction that would otherwise be experienced had the surface of the root proper slid directly past unlubricated soil particles. Because root–soil friction can be a substantial component of root PR, successful manipulation of friction represents a promising opportunity for improving plant performance. AB - To penetrate soil, a root requires pressure both to expand the cavity it is to occupy, sn, and to overcome root–soil friction, sf. Difficulties in estimating these two pressures independently have limited our ability to estimate the coefficient of soil–root friction, µsr. We used a rotated penetrometer probe, of similar dimensions to a root, and for the first time entering the soil at a similar rate to a root tip, to estimate sn. Separately we measured root penetration resistance (PR) Qr. Root PR was between two to four times sn. We estimated that the coefficient of root–soil friction (µsr) was 0.21–0.26, based on the geometry of the root tip. This is slightly larger than the 0.05–0.15 characteristic of boundary lubricants. Scanning electron microscopy showed that turgid border cells lined the root channel, supporting our hypothesis that the lubricant consisted of mucilage sandwiched between border cells and the surface of the root cap and epidermis. This cell–cell lubrication greatly decreased the friction that would otherwise be experienced had the surface of the root proper slid directly past unlubricated soil particles. Because root–soil friction can be a substantial component of root PR, successful manipulation of friction represents a promising opportunity for improving plant performance. KW - bulk density KW - COMPACTION KW - Lubrication KW - MECHANICAL IMPEDANCE KW - rhizosphere KW - soil strength U2 - 10.1111/pce.12037 DO - 10.1111/pce.12037 M1 - Article IS - 6 VL - 36 SP - 1085 EP - 1092 ER - TY - JOUR T1 - Structure of diaminohydroxyphosphoribosylaminopyrimidine deaminase/5-amino-6-(5-phosphoribosylamino)uracil reductase from Acinetobacter baumannii A1 - Dawson,A. A1 - Trumper,P. A1 - Chrysostomou,G. A1 - Hunter,W. N. AU - Dawson,A. AU - Trumper,P. AU - Chrysostomou,G. AU - Hunter,W. N. PY - 2013/6 Y1 - 2013/6 N2 - The bifunctional diaminohydroxyphosphoribosylaminopyrimidine deaminase/5-amino-6-(5-phosphoribosylamino)uracil reductase (RibD) represents a potential antibacterial drug target. The structure of recombinant Acinetobacter baumannii RibD is reported in orthorhombic and tetragonal crystal forms at 2.2 and 2.0 Å resolution, respectively. Comparisons with orthologous structures in the Protein Data Bank indicated close similarities. The tetragonal crystal form was obtained in the presence of guanosine monophosphate, which surprisingly was observed to occupy the adenine-binding site of the reductase domain. AB - The bifunctional diaminohydroxyphosphoribosylaminopyrimidine deaminase/5-amino-6-(5-phosphoribosylamino)uracil reductase (RibD) represents a potential antibacterial drug target. The structure of recombinant Acinetobacter baumannii RibD is reported in orthorhombic and tetragonal crystal forms at 2.2 and 2.0 Å resolution, respectively. Comparisons with orthologous structures in the Protein Data Bank indicated close similarities. The tetragonal crystal form was obtained in the presence of guanosine monophosphate, which surprisingly was observed to occupy the adenine-binding site of the reductase domain. U2 - 10.1107/S174430911301292X DO - 10.1107/S174430911301292X M1 - Article JO - Acta Crystallographica F-Structural Biology and Crystallization Communications JF - Acta Crystallographica F-Structural Biology and Crystallization Communications IS - 6 VL - 69 SP - 611 EP - 617 ER - TY - JOUR T1 - Supporting 'work-related goals' rather than 'return to work' after cancer? T2 - a systematic review and meta-synthesis of 25 qualitative studies A1 - Wells,Mary A1 - Williams,Brian A1 - Firnigl,Danielle A1 - Lang,Heidi A1 - Coyle,Joanne A1 - Kroll,Thilo A1 - MacGillivray,Steve AU - Wells,Mary AU - Williams,Brian AU - Firnigl,Danielle AU - Lang,Heidi AU - Coyle,Joanne AU - Kroll,Thilo AU - MacGillivray,Steve PY - 2013/6 Y1 - 2013/6 N2 - Background: This study aimed to systematically review and synthesise qualitative studies of employment and cancer. Methods: A rigorous systematic review and meta-synthesis process was followed. A total of 13233 papers were retrieved from eight databases; 69 were deemed relevant following title and abstract appraisal. Four further publications were identified via contact with key authors. Screening of full texts resulted in the retention of 25 publications from six countries, which were included in the synthesis. Results: Studies consistently indicate that for people with cancer, 'work' forms a central basis for self-identity and self-esteem, provides financial security, forms and maintains social relationships, and represents an individual's abilities, talents and health. Work is therefore more than paid employment. Its importance to individuals rests on the relative value survivors place on these constituent functions. The desirability, importance and subsequent interpretation of individuals' experience of 'return to work' appears to be influenced by the ways in which cancer affects these functions or goals of 'work'. Our synthesis draws these complex elements into a heuristic model to help illustrate and communicate these inter-relationships. Conclusion: The concept of 'return to work' may be overly simplistic, and as a result, misleading. The proposed benefits previously ascribed to 'return to work' may only be achieved through consideration of the specific meaning and role of work to the individual. Interventions to address work-related issues need to be person-centred, acknowledging the work-related outcomes that are important to the individual. A conceptual and operational shift towards supporting survivors to identify and achieve their 'work-related goals' may be more appropriate. © 2012 John Wiley & Sons, Ltd. AB - Background: This study aimed to systematically review and synthesise qualitative studies of employment and cancer. Methods: A rigorous systematic review and meta-synthesis process was followed. A total of 13233 papers were retrieved from eight databases; 69 were deemed relevant following title and abstract appraisal. Four further publications were identified via contact with key authors. Screening of full texts resulted in the retention of 25 publications from six countries, which were included in the synthesis. Results: Studies consistently indicate that for people with cancer, 'work' forms a central basis for self-identity and self-esteem, provides financial security, forms and maintains social relationships, and represents an individual's abilities, talents and health. Work is therefore more than paid employment. Its importance to individuals rests on the relative value survivors place on these constituent functions. The desirability, importance and subsequent interpretation of individuals' experience of 'return to work' appears to be influenced by the ways in which cancer affects these functions or goals of 'work'. Our synthesis draws these complex elements into a heuristic model to help illustrate and communicate these inter-relationships. Conclusion: The concept of 'return to work' may be overly simplistic, and as a result, misleading. The proposed benefits previously ascribed to 'return to work' may only be achieved through consideration of the specific meaning and role of work to the individual. Interventions to address work-related issues need to be person-centred, acknowledging the work-related outcomes that are important to the individual. A conceptual and operational shift towards supporting survivors to identify and achieve their 'work-related goals' may be more appropriate. © 2012 John Wiley & Sons, Ltd. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84864808099&md5=9abe29ea45bd64a0f5386299cd9f3790 U2 - 10.1002/pon.3148 DO - 10.1002/pon.3148 M1 - Scientific review JO - Psycho-Oncology JF - Psycho-Oncology SN - 1057-9249 IS - 6 VL - 22 SP - 1208 EP - 1219 ER - TY - JOUR T1 - Understanding factors that impact on public and patient's risk perceptions and responses toward Clostridium difficile and other health care-associated infections T2 - A structured literature review A1 - Burnett,Emma A1 - Johnston,Bridget A1 - Kearney,Nora A1 - Corlett,Joanne A1 - MacGillivray,Stephen AU - Burnett,Emma AU - Johnston,Bridget AU - Kearney,Nora AU - Corlett,Joanne AU - MacGillivray,Stephen PY - 2013/6 Y1 - 2013/6 N2 - Clostridium difficile is the most common health care-associated infection and a major cause of death and increased morbidity. It is vital that patients and the public are provided with the right information and communication to assist them to understand their role in preventative measures. Successful implementation of communication and management strategies hinges on individuals' risk perceptions. AB - Clostridium difficile is the most common health care-associated infection and a major cause of death and increased morbidity. It is vital that patients and the public are provided with the right information and communication to assist them to understand their role in preventative measures. Successful implementation of communication and management strategies hinges on individuals' risk perceptions. KW - Infection prevention KW - Infection control KW - perceptions of risk KW - communication KW - management KW - Media U2 - 10.1016/j.ajic.2012.05.026 DO - 10.1016/j.ajic.2012.05.026 M1 - Article JO - American Journal of Infection Control JF - American Journal of Infection Control SN - 0196-6553 IS - 6 VL - 41 SP - 542 EP - 548 ER - TY - JOUR T1 - What lies beneath? T2 - Scanning probe tomography may have the answer A1 - Conneely,Michael J A1 - Campbell,Paul A AU - Conneely,Michael J AU - Campbell,Paul A PY - 2013/6 Y1 - 2013/6 N2 - Scanning probe microscopy facilitates high-resolution noninvasive imaging of surface topography on even the most delicate of biological structures. Moreover, the local probe nature of the instrument architecture lends itself to the measurement of many important physical properties. To date, biological investigations have largely been constrained to imaging surface (membrane)-borne phenomena; however, the advent of extremely high aspect-ratio 'needle' probe tips, as reported by Beard et al. (2013), suggests that the approach can now be extended to address the particular challenges associated with measuring subsurface microscopic targets, including the intracellular components of the stratum corneum. AB - Scanning probe microscopy facilitates high-resolution noninvasive imaging of surface topography on even the most delicate of biological structures. Moreover, the local probe nature of the instrument architecture lends itself to the measurement of many important physical properties. To date, biological investigations have largely been constrained to imaging surface (membrane)-borne phenomena; however, the advent of extremely high aspect-ratio 'needle' probe tips, as reported by Beard et al. (2013), suggests that the approach can now be extended to address the particular challenges associated with measuring subsurface microscopic targets, including the intracellular components of the stratum corneum. U2 - 10.1038/jid.2013.30 DO - 10.1038/jid.2013.30 M1 - Comment/debate JO - Journal of Investigative Dermatology JF - Journal of Investigative Dermatology SN - 0022-202X IS - 6 VL - 133 SP - 1458 EP - 1460 ER - TY - JOUR T1 - IFNβ autocrine feedback is required to sustain TLR induced production of MCP-1 in macrophages A1 - Pattison,Michael J. A1 - MacKenzie,Kirsty F. A1 - Elcombe,Suzanne E. A1 - Arthur,J. Simon C. AU - Pattison,Michael J. AU - MacKenzie,Kirsty F. AU - Elcombe,Suzanne E. AU - Arthur,J. Simon C. PY - 2013/5/21 Y1 - 2013/5/21 N2 - Chemokines, including MCP-1, are crucial to mounting an effective immune response due to their ability to recruit other immune cells. We show that sustained LPS or poly(I:C)-stimulated MCP-1 production requires an IFNß-mediated feedback loop. Consistent with this, exogenous IFNß was able to induce MCP-1 transcription in the absence of other stimuli. Blocking IFNß signaling with Ruxolitinib, a JAK inhibitor, inhibited MCP-1 transcription. The MCP-1 promoter contains potential STAT binding sites and we demonstrate that STAT1 is recruited upon IFNß stimulation. Furthermore we find that IL-10 knockout increases MCP-1 production in response to LPS, which may reflect an ability of IL-10 to repress IFNß production. Overall, these results show the importance of the balance between IFNß and IL-10 in the regulation of MCP-1. © 2013 Federation of European Biochemical Societies. AB - Chemokines, including MCP-1, are crucial to mounting an effective immune response due to their ability to recruit other immune cells. We show that sustained LPS or poly(I:C)-stimulated MCP-1 production requires an IFNß-mediated feedback loop. Consistent with this, exogenous IFNß was able to induce MCP-1 transcription in the absence of other stimuli. Blocking IFNß signaling with Ruxolitinib, a JAK inhibitor, inhibited MCP-1 transcription. The MCP-1 promoter contains potential STAT binding sites and we demonstrate that STAT1 is recruited upon IFNß stimulation. Furthermore we find that IL-10 knockout increases MCP-1 production in response to LPS, which may reflect an ability of IL-10 to repress IFNß production. Overall, these results show the importance of the balance between IFNß and IL-10 in the regulation of MCP-1. © 2013 Federation of European Biochemical Societies. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875925924&md5=561df5760f134c1a810c738158b5b0e1 U2 - 10.1016/j.febslet.2013.03.025 DO - 10.1016/j.febslet.2013.03.025 M1 - Article JO - FEBS Letters JF - FEBS Letters SN - 0014-5793 IS - 10 VL - 587 SP - 1496 EP - 1503 ER - TY - JOUR T1 - RXRα Inhibits the NRF2-ARE Signaling Pathway through a Direct Interaction with the Neh7 Domain of NRF2 A1 - Wang,Hongyan A1 - Liu,Kaihua A1 - Geng,Miao A1 - Gao,Peng A1 - Wu,Xiaoyuan A1 - Hai,Yan A1 - Li,Yangxia A1 - Li,Yulong A1 - Luo,Lin A1 - Hayes,John D. A1 - Wang,Xiu Jun A1 - Tang,Xiuwen AU - Wang,Hongyan AU - Liu,Kaihua AU - Geng,Miao AU - Gao,Peng AU - Wu,Xiaoyuan AU - Hai,Yan AU - Li,Yangxia AU - Li,Yulong AU - Luo,Lin AU - Hayes,John D. AU - Wang,Xiu Jun AU - Tang,Xiuwen PY - 2013/5/15 Y1 - 2013/5/15 N2 - The transcription factor NRF2 (NFE2L2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that limit the action of cytotoxic therapies in cancer. NRF2 acts by binding antioxidant response elements (ARE) in its target genes, but there is relatively limited knowledge about how it is negatively controlled. Here, we report that retinoic X receptor alpha (RXRa) is a hitherto unrecognized repressor of NRF2. RNAi-mediated knockdown of RXRa increased basal ARE-driven gene expression and induction of ARE-driven genes by the NRF2 activator tert-butylhydroquinone (tBHQ). Conversely, overexpression of RXRa decreased ARE-driven gene expression. Biochemical investigations showed that RXRa interacts physically with NRF2 in cancer cells and in murine small intestine and liver tissues. Furthermore, RXRa bound to ARE sequences in the promoters of NRF2-regulated genes. RXRa loading onto AREs was concomitant with the presence of NRF2, supporting the hypothesis that a direct interaction between the two proteins on gene promoters accounts for the antagonism of ARE-driven gene expression. Mutation analyses revealed that interaction between the two transcription factors involves the DNA-binding domain of RXRa and a region comprising amino acids 209-316 in human NRF2 that had not been defined functionally, but that we now designate as the NRF2-ECH homology (Neh) 7 domain. In non-small cell lung cancer cells where NRF2 levels are elevated, RXRa expression downregulated NRF2 and sensitized cells to the cytotoxic effects of therapeutic drugs. In summary, our findings show that RXRa diminishes cytoprotection by NRF2 by binding directly to the newly defined Neh7 domain in NRF2. Cancer Res; 73(10); 3097-108. ©2013 AACR. AB - The transcription factor NRF2 (NFE2L2) is a pivotal activator of genes encoding cytoprotective and detoxifying enzymes that limit the action of cytotoxic therapies in cancer. NRF2 acts by binding antioxidant response elements (ARE) in its target genes, but there is relatively limited knowledge about how it is negatively controlled. Here, we report that retinoic X receptor alpha (RXRa) is a hitherto unrecognized repressor of NRF2. RNAi-mediated knockdown of RXRa increased basal ARE-driven gene expression and induction of ARE-driven genes by the NRF2 activator tert-butylhydroquinone (tBHQ). Conversely, overexpression of RXRa decreased ARE-driven gene expression. Biochemical investigations showed that RXRa interacts physically with NRF2 in cancer cells and in murine small intestine and liver tissues. Furthermore, RXRa bound to ARE sequences in the promoters of NRF2-regulated genes. RXRa loading onto AREs was concomitant with the presence of NRF2, supporting the hypothesis that a direct interaction between the two proteins on gene promoters accounts for the antagonism of ARE-driven gene expression. Mutation analyses revealed that interaction between the two transcription factors involves the DNA-binding domain of RXRa and a region comprising amino acids 209-316 in human NRF2 that had not been defined functionally, but that we now designate as the NRF2-ECH homology (Neh) 7 domain. In non-small cell lung cancer cells where NRF2 levels are elevated, RXRa expression downregulated NRF2 and sensitized cells to the cytotoxic effects of therapeutic drugs. In summary, our findings show that RXRa diminishes cytoprotection by NRF2 by binding directly to the newly defined Neh7 domain in NRF2. Cancer Res; 73(10); 3097-108. ©2013 AACR. U2 - 10.1158/0008-5472.CAN-12-3386 DO - 10.1158/0008-5472.CAN-12-3386 M1 - Article JO - Cancer Research JF - Cancer Research SN - 0008-5472 IS - 10 VL - 73 SP - 3097 EP - 3108 ER - TY - JOUR T1 - Transient photocurrents as a spatially resolved probe of carrier transport and defect distributions in silicon thin films A1 - Reynolds,Steve A1 - Bruggemann,Rudi A1 - Grootoonk,Bjorn A1 - Smirnov,Vladimir AU - Reynolds,Steve AU - Bruggemann,Rudi AU - Grootoonk,Bjorn AU - Smirnov,Vladimir PY - 2013/5/15 Y1 - 2013/5/15 N2 - Transient photocurrent spectroscopy (TPC) yields the energetic distribution of localised states in disordered semiconductors from an analysis of the decay of photocurrent with time following a short laser pulse. By comparing results at different laser excitation wavelengths, and hence absorption depths, information
on spatial non-uniformities may also be inferred. Here we investigate the use of TPC as a spatial probe with reference to two thin-film silicon systems; amorphous silicon subjected to various light-induced degradation regimes, and microcrystalline silicon grown on a range of ‘seed’ layers. Computer simulation is used to support experimental findings, and to identify sensitivity and resolution limitations. AB - Transient photocurrent spectroscopy (TPC) yields the energetic distribution of localised states in disordered semiconductors from an analysis of the decay of photocurrent with time following a short laser pulse. By comparing results at different laser excitation wavelengths, and hence absorption depths, information
on spatial non-uniformities may also be inferred. Here we investigate the use of TPC as a spatial probe with reference to two thin-film silicon systems; amorphous silicon subjected to various light-induced degradation regimes, and microcrystalline silicon grown on a range of ‘seed’ layers. Computer simulation is used to support experimental findings, and to identify sensitivity and resolution limitations. U2 - 10.1016/j.mseb.2012.10.040 DO - 10.1016/j.mseb.2012.10.040 M1 - Article JO - Materials Science and Engineering B-Solid State Materials for Advanced Technology JF - Materials Science and Engineering B-Solid State Materials for Advanced Technology SN - 0921-5107 IS - 9 VL - 178 SP - 568 EP - 573 ER - TY - JOUR T1 - High-Power Wavelength Bistability and Tunability in a Passively Mode-Locked Quantum-Dot Laser A1 - Nikitichev,D. I. A1 - Cataluna,M. A1 - Fedorova,K. A. A1 - Ding,Y. A1 - Mikhrin,S. S. A1 - Krestnikov,I. L. A1 - Livshits,D. A. A1 - Rafailov,E. U. AU - Nikitichev,D. I. AU - Cataluna,M. AU - Fedorova,K. A. AU - Ding,Y. AU - Mikhrin,S. S. AU - Krestnikov,I. L. AU - Livshits,D. A. AU - Rafailov,E. U. PY - 2013/5/13 Y1 - 2013/5/13 N2 - Wavelength bistability and tunability are demonstrated in a two-section quantum-dot mode-locked laser with a non-identical capping layer structure. The continuous wave output power of 30 mW (25 mW) and mode-locked average power of 27 mW (20 mW) are achieved for 1245 nm (1295 nm) wavelengths respectively under the injection current of 300 mA. The largest switching range of more than 50 nm and wavelength tuning range with picosecond pulses and stable lasing wavelengths between 1245 nm and 1295 nm are demonstrated for gain current of 300 mA and 330 mA. AB - Wavelength bistability and tunability are demonstrated in a two-section quantum-dot mode-locked laser with a non-identical capping layer structure. The continuous wave output power of 30 mW (25 mW) and mode-locked average power of 27 mW (20 mW) are achieved for 1245 nm (1295 nm) wavelengths respectively under the injection current of 300 mA. The largest switching range of more than 50 nm and wavelength tuning range with picosecond pulses and stable lasing wavelengths between 1245 nm and 1295 nm are demonstrated for gain current of 300 mA and 330 mA. KW - quantum dot lasers KW - Mode-locked lasers KW - bistability KW - tunable laser UR - http://ieeexplore.ieee.org/stamp/stamp.jsp?tp=&arnumber=6409957 U2 - 10.1109/JSTQE.2013.2239610 DO - 10.1109/JSTQE.2013.2239610 M1 - Article JO - IEEE Journal of Selected Topics in Quantum Electronics JF - IEEE Journal of Selected Topics in Quantum Electronics SN - 1077-260X IS - 4 VL - 19 ER - TY - JOUR T1 - Novel regulation of cardiac Na pump via phospholemman A1 - Pavlovic,Davor A1 - Fuller,William A1 - Shattock,Michael J AU - Pavlovic,Davor AU - Fuller,William AU - Shattock,Michael J PY - 2013/5/11 Y1 - 2013/5/11 N2 - As the only quantitatively significant Na efflux pathway from cardiac cells, the Na/K ATPase (Na pump) is the primary regulator of intracellular Na. The transmembrane Na gradient it establishes is essential for normal electrical excitability, numerous coupled-transport processes and, as the driving force for Na/Ca exchange, thus seting cardiac Ca load and contractility. As Na influx varies with electrical excitation, heart rate and pathology, the dynamic regulation of Na efflux is essential. It is now widely recognized that phospholemman, a 72 amino acid accessory protein which forms part of the Na pump complex, is the key nexus linking cellular signaling to pump regulation. Phospholemman is the target of a variety of post-translational modifications (including phosphorylation, palmitoylation and glutathionation) and these can dynamically alter the activity of the Na pump. This review summarizes our current understanding of the multiple regulatory. AB - As the only quantitatively significant Na efflux pathway from cardiac cells, the Na/K ATPase (Na pump) is the primary regulator of intracellular Na. The transmembrane Na gradient it establishes is essential for normal electrical excitability, numerous coupled-transport processes and, as the driving force for Na/Ca exchange, thus seting cardiac Ca load and contractility. As Na influx varies with electrical excitation, heart rate and pathology, the dynamic regulation of Na efflux is essential. It is now widely recognized that phospholemman, a 72 amino acid accessory protein which forms part of the Na pump complex, is the key nexus linking cellular signaling to pump regulation. Phospholemman is the target of a variety of post-translational modifications (including phosphorylation, palmitoylation and glutathionation) and these can dynamically alter the activity of the Na pump. This review summarizes our current understanding of the multiple regulatory. U2 - 10.1016/j.yjmcc.2013.05.002 DO - 10.1016/j.yjmcc.2013.05.002 M1 - Article JO - Journal of Molecular and Cellular Cardiology JF - Journal of Molecular and Cellular Cardiology ER - TY - JOUR T1 - Global Quantitative SILAC Phosphoproteomics Reveals Differential Phosphorylation Is Widespread between the Procyclic and Bloodstream Form Lifecycle Stages of Trypanosoma brucei A1 - Urbaniak,Michael D. A1 - Martin,David M. A. A1 - Ferguson,Michael A. J. AU - Urbaniak,Michael D. AU - Martin,David M. A. AU - Ferguson,Michael A. J. PY - 2013/5/3 Y1 - 2013/5/3 N2 - We report a global quantitative phosphoproteomic study of bloodstream and procyclic form Trypanosoma brucei using SILAC labeling of each lifecycle stage. Phosphopeptide enrichment by SCX and TiO2 led to the identification of a total of 10096 phosphorylation sites on 2551 protein groups and quantified the ratios of 8275 phosphorylation sites between the two lifecycle stages. More than 9300 of these sites (92%) have not previously been reported. Model-based gene enrichment analysis identified over representation of Gene Ontology terms relating to the flagella, protein kinase activity, and the regulation of gene expression. The quantitative data reveal that differential protein phosphorylation is widespread between bloodstream and procyclic form trypanosomes, with significant intraprotein differential phosphorylation. Despite a lack of dedicated tyrosine kinases, 234 phosphotyrosine residues were identified, and these were 3-4 fold over-represented among site changing >10-fold between the two lifecycle stages. A significant proportion of the T. brucei kinome was phosphorylated, with evidence that MAPK pathways are functional in both lifecycle stages. Regulation of gene expression in T. brucei is exclusively post-transcriptional, and the extensive phosphorylation of RNA binding proteins observed may be relevant to the control of mRNA stability in this organism. AB - We report a global quantitative phosphoproteomic study of bloodstream and procyclic form Trypanosoma brucei using SILAC labeling of each lifecycle stage. Phosphopeptide enrichment by SCX and TiO2 led to the identification of a total of 10096 phosphorylation sites on 2551 protein groups and quantified the ratios of 8275 phosphorylation sites between the two lifecycle stages. More than 9300 of these sites (92%) have not previously been reported. Model-based gene enrichment analysis identified over representation of Gene Ontology terms relating to the flagella, protein kinase activity, and the regulation of gene expression. The quantitative data reveal that differential protein phosphorylation is widespread between bloodstream and procyclic form trypanosomes, with significant intraprotein differential phosphorylation. Despite a lack of dedicated tyrosine kinases, 234 phosphotyrosine residues were identified, and these were 3-4 fold over-represented among site changing >10-fold between the two lifecycle stages. A significant proportion of the T. brucei kinome was phosphorylated, with evidence that MAPK pathways are functional in both lifecycle stages. Regulation of gene expression in T. brucei is exclusively post-transcriptional, and the extensive phosphorylation of RNA binding proteins observed may be relevant to the control of mRNA stability in this organism. U2 - 10.1021/pr400086y DO - 10.1021/pr400086y M1 - Article JO - Journal of Proteome Research JF - Journal of Proteome Research SN - 1535-3893 IS - 5 VL - 12 SP - 2233 EP - 2244 ER - TY - JOUR T1 - Insights into Diphthamide, key Diphtheria Toxin effector A1 - Abdel-Fattah,Wael A1 - Scheidt,Viktor A1 - Uthman,Shanow A1 - Stark,Michael J. R. A1 - Schaffrath,Raffael AU - Abdel-Fattah,Wael AU - Scheidt,Viktor AU - Uthman,Shanow AU - Stark,Michael J. R. AU - Schaffrath,Raffael PY - 2013/5/3 Y1 - 2013/5/3 N2 - Diphtheria toxin (DT) inhibits eukaryotic translation elongation factor 2 (eEF2) by ADP-ribosylation in a fashion that requires diphthamide, a modified histidine residue on eEF2. In budding yeast, diphthamide formation involves seven genes, DPH1-DPH7. In an effort to further study diphthamide synthesis and interrelation among the Dph proteins, we found, by expression in E. coli and co-immune precipitation in yeast, that Dph1 and Dph2 interact and that they form a complex with Dph3. Protein-protein interaction mapping shows that Dph1-Dph3 complex formation can be dissected by progressive DPH1 gene truncations. This identifies N- and C-terminal domains on Dph1 that are crucial for diphthamide synthesis, DT action and cytotoxicity of sordarin, another microbial eEF2 inhibitor. Intriguingly, dph1 truncation mutants are sensitive to overexpression of DPH5, the gene necessary to synthesize diphthine from the first diphthamide pathway intermediate produced by Dph1-Dph3. This is in stark contrast to dph6 mutants, which also lack the ability to form diphthamide but are resistant to growth inhibition by excess Dph5 levels. As judged from site-specific mutagenesis, the amidation reaction itself relies on a conserved ATP binding domain in Dph6 that, when altered, blocks diphthamide formation and confers resistance to eEF2 inhibition by sordarin. AB - Diphtheria toxin (DT) inhibits eukaryotic translation elongation factor 2 (eEF2) by ADP-ribosylation in a fashion that requires diphthamide, a modified histidine residue on eEF2. In budding yeast, diphthamide formation involves seven genes, DPH1-DPH7. In an effort to further study diphthamide synthesis and interrelation among the Dph proteins, we found, by expression in E. coli and co-immune precipitation in yeast, that Dph1 and Dph2 interact and that they form a complex with Dph3. Protein-protein interaction mapping shows that Dph1-Dph3 complex formation can be dissected by progressive DPH1 gene truncations. This identifies N- and C-terminal domains on Dph1 that are crucial for diphthamide synthesis, DT action and cytotoxicity of sordarin, another microbial eEF2 inhibitor. Intriguingly, dph1 truncation mutants are sensitive to overexpression of DPH5, the gene necessary to synthesize diphthine from the first diphthamide pathway intermediate produced by Dph1-Dph3. This is in stark contrast to dph6 mutants, which also lack the ability to form diphthamide but are resistant to growth inhibition by excess Dph5 levels. As judged from site-specific mutagenesis, the amidation reaction itself relies on a conserved ATP binding domain in Dph6 that, when altered, blocks diphthamide formation and confers resistance to eEF2 inhibition by sordarin. KW - DIPHTHAMIDE BIOSYNTHESIS UR - http://www.mdpi.com/2072-6651/5/5/958 U2 - 10.3390/toxins5050958 DO - 10.3390/toxins5050958 M1 - Article IS - 5 VL - 5 SP - 958 EP - 968 ER - TY - JOUR T1 - Structural biology T2 - Security measures of a master regulator A1 - Alessi,Dario R. A1 - Kulathu,Yogesh AU - Alessi,Dario R. AU - Kulathu,Yogesh PY - 2013/5/1 Y1 - 2013/5/1 U2 - 10.1038/nature12101 DO - 10.1038/nature12101 M1 - Article JO - Nature JF - Nature ER - TY - JOUR T1 - The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system A1 - Strickson,Sam A1 - Campbell,David G A1 - Emmerich,Christoph H A1 - Knebel,Axel A1 - Plater,Lorna A1 - Ritorto,Maria Stella A1 - Shpiro,Natalia A1 - Cohen,Philip AU - Strickson,Sam AU - Campbell,David G AU - Emmerich,Christoph H AU - Knebel,Axel AU - Plater,Lorna AU - Ritorto,Maria Stella AU - Shpiro,Natalia AU - Cohen,Philip PY - 2013/5/1 Y1 - 2013/5/1 N2 - The compound BAY 11-7082 inhibits I?Ba [inhibitor of NF-?B (nuclear factor ?B)a] phosphorylation in cells and has been used to implicate the canonical IKKs (I?B kinases) and NF-?B in >350 publications. In the present study we report that BAY 11-7082 does not inhibit the IKKs, but suppresses their activation in LPS (lipopolysaccharide)-stimulated RAW macrophages and IL (interleukin)-1-stimulated IL-1R (IL-1 receptor) HEK (human embryonic kidney)-293 cells. BAY 11-7082 exerts these effects by inactivating the E2-conjugating enzymes Ubc (ubiquitin conjugating) 13 and UbcH7 and the E3 ligase LUBAC (linear ubiquitin assembly complex), thereby preventing the formation of Lys63-linked and linear polyubiquitin chains. BAY 11-7082 prevents ubiquitin conjugation to Ubc13 and UbcH7 by forming a covalent adduct with their reactive cysteine residues via Michael addition at the C3 atom of BAY 11-7082, followed by the release of 4-methylbenzene-sulfinic acid. BAY 11-7082 stimulated Lys48-linked polyubiquitin chain formation in cells and protected HIF1a (hypoxia-inducible factor 1a) from proteasomal degradation, suggesting that it inhibits the proteasome. The results of the present study indicate that the anti-inflammatory effects of BAY 11-7082, its ability to induce B-cell lymphoma and leukaemic T-cell death and to prevent the recruitment of proteins to sites of DNA damage are exerted via inhibition of components of the ubiquitin system and not by inhibiting NF-?B. AB - The compound BAY 11-7082 inhibits I?Ba [inhibitor of NF-?B (nuclear factor ?B)a] phosphorylation in cells and has been used to implicate the canonical IKKs (I?B kinases) and NF-?B in >350 publications. In the present study we report that BAY 11-7082 does not inhibit the IKKs, but suppresses their activation in LPS (lipopolysaccharide)-stimulated RAW macrophages and IL (interleukin)-1-stimulated IL-1R (IL-1 receptor) HEK (human embryonic kidney)-293 cells. BAY 11-7082 exerts these effects by inactivating the E2-conjugating enzymes Ubc (ubiquitin conjugating) 13 and UbcH7 and the E3 ligase LUBAC (linear ubiquitin assembly complex), thereby preventing the formation of Lys63-linked and linear polyubiquitin chains. BAY 11-7082 prevents ubiquitin conjugation to Ubc13 and UbcH7 by forming a covalent adduct with their reactive cysteine residues via Michael addition at the C3 atom of BAY 11-7082, followed by the release of 4-methylbenzene-sulfinic acid. BAY 11-7082 stimulated Lys48-linked polyubiquitin chain formation in cells and protected HIF1a (hypoxia-inducible factor 1a) from proteasomal degradation, suggesting that it inhibits the proteasome. The results of the present study indicate that the anti-inflammatory effects of BAY 11-7082, its ability to induce B-cell lymphoma and leukaemic T-cell death and to prevent the recruitment of proteins to sites of DNA damage are exerted via inhibition of components of the ubiquitin system and not by inhibiting NF-?B. U2 - 10.1042/BJ20121651 DO - 10.1042/BJ20121651 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 IS - 3 VL - 451 SP - 427 EP - 437 ER - TY - JOUR T1 - A systematic review of interventions for eating and drinking problems following treatment for head and neck cancer suggests a need to look beyond swallowing and trismus A1 - Cousins,Nadine A1 - MacAulay,Fiona A1 - Lang,Heidi A1 - MacGillivray,Steve A1 - Wells,Mary AU - Cousins,Nadine AU - MacAulay,Fiona AU - Lang,Heidi AU - MacGillivray,Steve AU - Wells,Mary PY - 2013/5 Y1 - 2013/5 N2 - PURPOSE: The incidence of head and neck cancer (HNC) is increasing, and treatment advances have contributed to improvements in survival. However, a growing number of HNC survivors now live with the long-term consequences of cancer treatment, in particular, problems with eating. The combined effects of HNC cancer, intensive chemotherapy, radiotherapy and surgery have a profound impact on functional, psychological, social and physical aspects of eating. Evidence is needed to underpin new rehabilitation approaches to address these complex problems. This review aimed to identify and summarise the evidence for rehabilitation interventions aimed at alleviating eating problems after HNC treatment. METHODS: A systematic review of studies indexed in Medline, CinAHL and PsycINFO using search terms relevant to a wide range of aspects of eating. Publications reporting empirical findings regarding physical, functional and/or psychosocial factors were included. RESULTS: Twenty-seven studies were identified. Fifteen focussed on swallowing exercises, eight on interventions to improve jaw mobility and four on swallowing and jaw exercises. None included interventions to address the complex combination of functional, physical and psychological problems associated with eating in this patient group. CONCLUSIONS: This review highlights that, whilst there is some evidence to support interventions aimed at improving swallowing and jaw mobility following treatment for HNC, studies are limited by their size and scope. Larger, high quality studies, which include patient-reported outcome measures, are required to underpin the development of patient-centred rehabilitation programmes. There is also a particular need to develop and evaluate interventions, which address the psychological and/or social aspects of eating. AB - PURPOSE: The incidence of head and neck cancer (HNC) is increasing, and treatment advances have contributed to improvements in survival. However, a growing number of HNC survivors now live with the long-term consequences of cancer treatment, in particular, problems with eating. The combined effects of HNC cancer, intensive chemotherapy, radiotherapy and surgery have a profound impact on functional, psychological, social and physical aspects of eating. Evidence is needed to underpin new rehabilitation approaches to address these complex problems. This review aimed to identify and summarise the evidence for rehabilitation interventions aimed at alleviating eating problems after HNC treatment. METHODS: A systematic review of studies indexed in Medline, CinAHL and PsycINFO using search terms relevant to a wide range of aspects of eating. Publications reporting empirical findings regarding physical, functional and/or psychosocial factors were included. RESULTS: Twenty-seven studies were identified. Fifteen focussed on swallowing exercises, eight on interventions to improve jaw mobility and four on swallowing and jaw exercises. None included interventions to address the complex combination of functional, physical and psychological problems associated with eating in this patient group. CONCLUSIONS: This review highlights that, whilst there is some evidence to support interventions aimed at improving swallowing and jaw mobility following treatment for HNC, studies are limited by their size and scope. Larger, high quality studies, which include patient-reported outcome measures, are required to underpin the development of patient-centred rehabilitation programmes. There is also a particular need to develop and evaluate interventions, which address the psychological and/or social aspects of eating. U2 - 10.1016/j.oraloncology.2012.12.002 DO - 10.1016/j.oraloncology.2012.12.002 M1 - Article JO - Oral Oncology JF - Oral Oncology IS - 5 VL - 49 SP - 387 EP - 400 ER - TY - JOUR T1 - Age estimation from radiographic images of the knee A1 - Hackman,Lucina A1 - Black,Sue AU - Hackman,Lucina AU - Black,Sue PY - 2013/5 Y1 - 2013/5 N2 -

This study examines the reliability of age estimation utilizing the Pyle and Hoerr atlas in relation to a modern Scottish population. The knee radiographs of 442 individuals (168 females, 274 males) were age assessed using the Pyle and Hoerr atlas. Analysis showed that there was a strong correlation between chronological age and estimated age (females R2 = 0.968, males R2 = 0.952). For females, the atlas method was most accurate between the ages of 9 and 15 years of age with an underage of 2.27 months and an overage of 2.38 months. For males, the atlas consistently overestimated age from the age of 9 years to the age of 16 years from between 0.14 and 8.81 months. The standard deviation for females was 9.86 months and for males was 10.75 months. This study showed that the Pyle and Hoerr atlas can be applied to a modern population with small modifications.

AB -

This study examines the reliability of age estimation utilizing the Pyle and Hoerr atlas in relation to a modern Scottish population. The knee radiographs of 442 individuals (168 females, 274 males) were age assessed using the Pyle and Hoerr atlas. Analysis showed that there was a strong correlation between chronological age and estimated age (females R2 = 0.968, males R2 = 0.952). For females, the atlas method was most accurate between the ages of 9 and 15 years of age with an underage of 2.27 months and an overage of 2.38 months. For males, the atlas consistently overestimated age from the age of 9 years to the age of 16 years from between 0.14 and 8.81 months. The standard deviation for females was 9.86 months and for males was 10.75 months. This study showed that the Pyle and Hoerr atlas can be applied to a modern population with small modifications.

UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84874449995&md5=f215723243fde567395faabcf2e9e97f U2 - 10.1111/1556-4029.12077 DO - 10.1111/1556-4029.12077 M1 - Article JO - Journal of Forensic Sciences JF - Journal of Forensic Sciences SN - 0022-1198 IS - 3 VL - 58 SP - 732 EP - 737 ER - TY - JOUR T1 - Anomalous pulmonary venous drainage T2 - chest radiography and cardiac imaging A1 - Athauda-Arachchi,Pandula A1 - Mordi,Ify A1 - Koch,Stephan A1 - Tzemos,Nikolaos AU - Athauda-Arachchi,Pandula AU - Mordi,Ify AU - Koch,Stephan AU - Tzemos,Nikolaos PY - 2013/5 Y1 - 2013/5 KW - SCIMITAR SYNDROME U2 - 10.1136/postgradmedj-2012-131469 DO - 10.1136/postgradmedj-2012-131469 M1 - Article JO - Postgraduate Medical Journal JF - Postgraduate Medical Journal SN - 0032-5473 IS - 1051 VL - 89 SP - 305 EP - 306 ER - TY - JOUR T1 - Assessment and feedback dialogue in online distance learning A1 - Ajjawi,Rola A1 - Schofield,Susie A1 - Mcaleer,Sean A1 - Walker,David AU - Ajjawi,Rola AU - Schofield,Susie AU - Mcaleer,Sean AU - Walker,David PY - 2013/5 Y1 - 2013/5 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84876326563&md5=2c9af55f3b91cad1c62741cef1bc4336 U2 - 10.1111/medu.12158 DO - 10.1111/medu.12158 M1 - Article JO - Medical Education JF - Medical Education SN - 0308-0110 IS - 5 VL - 47 SP - 527 EP - 528 ER - TY - JOUR T1 - Can pragmatic trials help us better understand chronic pain and improve treatment? A1 - Rowbotham,Michael C. A1 - Gilron,Ian A1 - Glazer,Clara A1 - Rice,Andrew S. C. A1 - Smith,Blair H. A1 - Stewart,Walter F. A1 - Wasan,Ajay D. AU - Rowbotham,Michael C. AU - Gilron,Ian AU - Glazer,Clara AU - Rice,Andrew S. C. AU - Smith,Blair H. AU - Stewart,Walter F. AU - Wasan,Ajay D. PY - 2013/5 Y1 - 2013/5 KW - DESIGN KW - ADHERENCE KW - ANTAGONISTS KW - VALIDITY KW - RANDOMIZED CONTROLLED-TRIALS KW - OPIOIDS KW - CLINICAL-TRIAL KW - STATEMENT KW - PRIMARY-CARE KW - 1ST-LINE UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875280039&md5=7053d1c253c492f8aac44204e6ec51c1 U2 - 10.1016/j.pain.2013.02.034 DO - 10.1016/j.pain.2013.02.034 M1 - Article JO - PAIN JF - PAIN SN - 0304-3959 IS - 5 VL - 154 SP - 643 EP - 646 ER - TY - CHAP T1 - Classical architecture in Renaissance Scotland A1 - McKean,Charles AU - McKean,Charles PB - Picard Publishing CY - Paris PY - 2013/5 Y1 - 2013/5 M1 - Chapter (peer-reviewed) SN - 9782708409545 BT - Le génie du lieu T2 - Le génie du lieu A2 - Chatenet,Monique ED - Chatenet,Monique ER - TY - JOUR T1 - Closure to "Evaluation of unsteady wall shear stress by Zielke's method" by Alan E. Vardy and Jim M. B. Brown A1 - Vardy,Alan E. A1 - Brown,Jim M. B. AU - Vardy,Alan E. AU - Brown,Jim M. B. PY - 2013/5 Y1 - 2013/5 U2 - 10.1061/(ASCE)HY.1943-7900.0000707 DO - 10.1061/(ASCE)HY.1943-7900.0000707 M1 - Comment/debate JO - Journal of Hydraulic Engineering JF - Journal of Hydraulic Engineering SN - 0733-9429 IS - 5 VL - 139 SP - 565 EP - 566 ER - TY - JOUR T1 - Commentary T2 - vancomycin or metronidazole in patients with primary sclerosing cholangitis? A1 - Paterson,J. C. M. A1 - Dillon,J. F. AU - Paterson,J. C. M. AU - Dillon,J. F. PY - 2013/5 Y1 - 2013/5 KW - microbiota KW - disease KW - liver KW - gut UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875869530&md5=2995fb3cc13b665fef9c25608b244ae8 U2 - 10.1111/apt.12282 DO - 10.1111/apt.12282 M1 - Comment/debate JO - Alimentary Pharmacology & Therapeutics JF - Alimentary Pharmacology & Therapeutics SN - 0269-2813 IS - 9 VL - 37 SP - 915 ER - TY - JOUR T1 - Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation A1 - Sinclair,Linda V A1 - Rolf,Julia A1 - Emslie,Elizabeth A1 - Shi,Yun-Bo A1 - Taylor,Peter M A1 - Cantrell,Doreen A AU - Sinclair,Linda V AU - Rolf,Julia AU - Emslie,Elizabeth AU - Shi,Yun-Bo AU - Taylor,Peter M AU - Cantrell,Doreen A PY - 2013/5 Y1 - 2013/5 N2 - T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells. AB - T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells. U2 - 10.1038/ni.2556 DO - 10.1038/ni.2556 M1 - Article JO - Nature Immunology JF - Nature Immunology SN - 1529-2908 IS - 5 VL - 14 SP - 500 EP - 508 ER - TY - JOUR T1 - Decrease in the rate of esotropia surgery in the United Kingdom from 2000 to 2010 A1 - Heng,S. Jacob A1 - MacEwen,Caroline J. AU - Heng,S. Jacob AU - MacEwen,Caroline J. PY - 2013/5 Y1 - 2013/5 N2 - A decrease in strabismus surgery in children has been previously documented in the UK. This study aims to examine whether the incidence of strabismus surgery in children is still decreasing and, if so, the possible reasons for this. AB - A decrease in strabismus surgery in children has been previously documented in the UK. This study aims to examine whether the incidence of strabismus surgery in children is still decreasing and, if so, the possible reasons for this. U2 - 10.1136/bjophthalmol-2012-302726 DO - 10.1136/bjophthalmol-2012-302726 M1 - Article JO - British Journal of Ophthalmology JF - British Journal of Ophthalmology SN - 0007-1161 IS - 5 VL - 97 SP - 598 EP - 600 ER - TY - JOUR T1 - Effects of antibiotics on bacterial species composition and metabolic activities in chemostats containing defined populations of human gut microorganisms A1 - Newton,Dorothy F A1 - Macfarlane,Sandra A1 - Macfarlane,George T AU - Newton,Dorothy F AU - Macfarlane,Sandra AU - Macfarlane,George T PY - 2013/5 Y1 - 2013/5 N2 - The composition and metabolic activities of the human colonic microbiota are modulated by a number of external factors, including diet and antibiotic therapy. Changes in the structure and metabolism of the gut microbiota may have long-term consequences for host health. The large intestine harbors a complex microbial ecosystem comprising several hundreds of different bacterial species, which complicates investigations on intestinal physiology and ecology. To facilitate such studies, a highly simplified microbiota consisting of 14 anaerobic and facultatively anaerobic organisms (Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium pseudolongum, Bifidobacterium adolescentis, Clostridium butyricum, C. perfringens, C. bifermentans, C. innocuum, Escherichia coli, Enterococcus faecalis, Enterococcus faecium, Lactobacillus acidophilus) was used in this investigation. Ampicillin [9.2 µg (ml culture)(-1)] was added to two chemostats operated at different dilution rates (D; 0.10 h(-1) and 0.21 h(-1)), and metronidazole [76.9 µg (ml culture)(-1)] was added to a third vessel (D = 0.21 h(-1)). Perturbations in bacterial physiology and metabolism were sampled over a 48-h period. Lactobacillus acidophilus and C. bifermentans populations did not establish in the fermentors under the imposed growth conditions. Ampicillin resulted in substantial reductions in bacteroides and C. perfringens populations at both dilution rates. Metronidazole strongly affected bacteroides communities but had no effect on bifidobacterial communities. The bacteriostatic effect of ampicillin on bifidobacterial species was growth rate dependent. Several metabolic activities were affected by antibiotic addition, including fermentation product formation and enzyme synthesis. The growth of antibiotic-resistant bifidobacteria in the large bowel may enable them to occupy ecological niches left vacant after antibiotic administration, preventing colonization by pathogenic species. AB - The composition and metabolic activities of the human colonic microbiota are modulated by a number of external factors, including diet and antibiotic therapy. Changes in the structure and metabolism of the gut microbiota may have long-term consequences for host health. The large intestine harbors a complex microbial ecosystem comprising several hundreds of different bacterial species, which complicates investigations on intestinal physiology and ecology. To facilitate such studies, a highly simplified microbiota consisting of 14 anaerobic and facultatively anaerobic organisms (Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium pseudolongum, Bifidobacterium adolescentis, Clostridium butyricum, C. perfringens, C. bifermentans, C. innocuum, Escherichia coli, Enterococcus faecalis, Enterococcus faecium, Lactobacillus acidophilus) was used in this investigation. Ampicillin [9.2 µg (ml culture)(-1)] was added to two chemostats operated at different dilution rates (D; 0.10 h(-1) and 0.21 h(-1)), and metronidazole [76.9 µg (ml culture)(-1)] was added to a third vessel (D = 0.21 h(-1)). Perturbations in bacterial physiology and metabolism were sampled over a 48-h period. Lactobacillus acidophilus and C. bifermentans populations did not establish in the fermentors under the imposed growth conditions. Ampicillin resulted in substantial reductions in bacteroides and C. perfringens populations at both dilution rates. Metronidazole strongly affected bacteroides communities but had no effect on bifidobacterial communities. The bacteriostatic effect of ampicillin on bifidobacterial species was growth rate dependent. Several metabolic activities were affected by antibiotic addition, including fermentation product formation and enzyme synthesis. The growth of antibiotic-resistant bifidobacteria in the large bowel may enable them to occupy ecological niches left vacant after antibiotic administration, preventing colonization by pathogenic species. U2 - 10.1128/AAC.00079-13 DO - 10.1128/AAC.00079-13 M1 - Article JO - Antimicrobial Agents and Chemotherapy JF - Antimicrobial Agents and Chemotherapy SN - 0066-4804 IS - 5 VL - 57 SP - 2016 EP - 2025 ER - TY - JOUR T1 - Exploitation of interspecific diversity for monocot crop improvement A1 - King,J. A1 - Armstead,I. A1 - Harper,J. A1 - Ramsey,L. A1 - Snape,J. A1 - Waugh,R. A1 - James,C. A1 - Thomas,A. A1 - Gasior,D. A1 - Kelly,R. A1 - Roberts,L. A1 - Gustafson,P. A1 - King,I. AU - King,J. AU - Armstead,I. AU - Harper,J. AU - Ramsey,L. AU - Snape,J. AU - Waugh,R. AU - James,C. AU - Thomas,A. AU - Gasior,D. AU - Kelly,R. AU - Roberts,L. AU - Gustafson,P. AU - King,I. PY - 2013/5 Y1 - 2013/5 N2 -

In many cultivated crop species there is limited genetic variation available for the development of new higher yielding varieties adapted to climate change and sustainable farming practises. The distant relatives of crop species provide a vast and largely untapped reservoir of genetic variation for a wide range of agronomically important traits that can be exploited by breeders for crop improvement. In this paper, in what we believe to be the largest introgression programme undertaken in the monocots, we describe the transfer of the entire genome of Festuca pratensis into Lolium perenne in overlapping chromosome segments. The L. perenne/F. pratensis introgressions were identified and characterised via 131 simple sequence repeats and 1612 SNPs anchored to the rice genome. Comparative analyses were undertaken to determine the syntenic relationship between L. perenne/F. pratensis and rice, wheat, barley, sorghum and Brachypodium distachyon. Analyses comparing recombination frequency and gene distribution indicated that a large proportion of the genes within the genome are located in the proximal regions of chromosomes which undergo low/very low frequencies of recombination. Thus, it is proposed that past breeding efforts to produce improved varieties have centred on the subset of genes located in the distal regions of chromosomes where recombination is highest. The use of alien introgression for crop improvement is important for meeting the challenges of global food supply and the monocots such as the forage grasses and cereals, together with recent technological advances in molecular biology, can help meet these challenges. Heredity (2013) 110, 475-483; doi:10.1038/hdy.2012.116; published online 16 January 2013

AB -

In many cultivated crop species there is limited genetic variation available for the development of new higher yielding varieties adapted to climate change and sustainable farming practises. The distant relatives of crop species provide a vast and largely untapped reservoir of genetic variation for a wide range of agronomically important traits that can be exploited by breeders for crop improvement. In this paper, in what we believe to be the largest introgression programme undertaken in the monocots, we describe the transfer of the entire genome of Festuca pratensis into Lolium perenne in overlapping chromosome segments. The L. perenne/F. pratensis introgressions were identified and characterised via 131 simple sequence repeats and 1612 SNPs anchored to the rice genome. Comparative analyses were undertaken to determine the syntenic relationship between L. perenne/F. pratensis and rice, wheat, barley, sorghum and Brachypodium distachyon. Analyses comparing recombination frequency and gene distribution indicated that a large proportion of the genes within the genome are located in the proximal regions of chromosomes which undergo low/very low frequencies of recombination. Thus, it is proposed that past breeding efforts to produce improved varieties have centred on the subset of genes located in the distal regions of chromosomes where recombination is highest. The use of alien introgression for crop improvement is important for meeting the challenges of global food supply and the monocots such as the forage grasses and cereals, together with recent technological advances in molecular biology, can help meet these challenges. Heredity (2013) 110, 475-483; doi:10.1038/hdy.2012.116; published online 16 January 2013

KW - SNP markers KW - comparative mapping KW - INTROGRESSION KW - interspecific diversity KW - LINKAGE MAP KW - recombination KW - CEREAL GENOME EVOLUTION KW - NUCLEAR-DNA AMOUNTS KW - MEADOW FESCUE KW - FESCUE FESTUCA-PRATENSIS KW - PERENNIAL RYEGRASS KW - Introgression mapping KW - RYEGRASS LOLIUM-MULTIFLORUM KW - monocots KW - PUCCINIA-CORONATA RESISTANCE KW - BARLEY GENOME U2 - 10.1038/hdy.2012.116 DO - 10.1038/hdy.2012.116 M1 - Article JO - Heredity JF - Heredity SN - 0018-067X IS - 5 VL - 110 SP - 475 EP - 483 ER - TY - JOUR T1 - Host microRNA molecular signatures associated with human H1N1 and H3N2 influenza A viruses reveal an unanticipated antiviral activity for miR-146a A1 - Terrier,Olivier A1 - Textoris,Julien A1 - Carron,Coralie A1 - Marcel,Virginie A1 - Bourdon,Jean-Christophe A1 - Rosa-Calatrava,Manuel AU - Terrier,Olivier AU - Textoris,Julien AU - Carron,Coralie AU - Marcel,Virginie AU - Bourdon,Jean-Christophe AU - Rosa-Calatrava,Manuel PY - 2013/5 Y1 - 2013/5 N2 - While post-transcriptional regulation of gene expression by microRNAs (miRNAs) has been shown to be involved in influenza virus replication cycle, only a few studies have further investigated this aspect in a human cellular model infected with human influenza viruses. In this study, we performed miRNA global profiling in human lung epithelial cells (A549) infected by two different subtypes of human influenza A viruses (H1N1 and H3N2). We identified a common miRNA signature in response to infection by the two different strains, highlighting a pool of five miRNAs commonly deregulated, which are known to be involved in the innate immune response or apoptosis. Among the five miRNA hits, the only upregulated miRNA in response to influenza infection corresponded to miR-146a. Based on a previously published gene expression dataset, we extracted inversely correlated miR-146a target genes and determined their first-level interactants. This functional analysis revealed eight distinct biological processes strongly associated with these interactants: Toll-like receptor pathway, innate immune response, cytokine production and apoptosis. To better understand the biological significance of miR-146a upregulation, using a reporter assay and a specific anti-miR-146a inhibitor, we confirmed that infection increased the endogenous miR-146a promoter activity and that inhibition of miR-146a significantly increased viral propagation. Altogether, our results suggest a functional role of miR-146a in the outcome of influenza infection, at the crossroads of several biological processes. AB - While post-transcriptional regulation of gene expression by microRNAs (miRNAs) has been shown to be involved in influenza virus replication cycle, only a few studies have further investigated this aspect in a human cellular model infected with human influenza viruses. In this study, we performed miRNA global profiling in human lung epithelial cells (A549) infected by two different subtypes of human influenza A viruses (H1N1 and H3N2). We identified a common miRNA signature in response to infection by the two different strains, highlighting a pool of five miRNAs commonly deregulated, which are known to be involved in the innate immune response or apoptosis. Among the five miRNA hits, the only upregulated miRNA in response to influenza infection corresponded to miR-146a. Based on a previously published gene expression dataset, we extracted inversely correlated miR-146a target genes and determined their first-level interactants. This functional analysis revealed eight distinct biological processes strongly associated with these interactants: Toll-like receptor pathway, innate immune response, cytokine production and apoptosis. To better understand the biological significance of miR-146a upregulation, using a reporter assay and a specific anti-miR-146a inhibitor, we confirmed that infection increased the endogenous miR-146a promoter activity and that inhibition of miR-146a significantly increased viral propagation. Altogether, our results suggest a functional role of miR-146a in the outcome of influenza infection, at the crossroads of several biological processes. U2 - 10.1099/vir.0.049528-0 DO - 10.1099/vir.0.049528-0 M1 - Article JO - Journal of General Virology JF - Journal of General Virology SN - 0022-1317 IS - 5 VL - 94 SP - 985 EP - 995 ER - TY - JOUR T1 - Identification of a cation transport pathway in Neisseria meningitidis PorB A1 - Kattner,C. A1 - Zaucha,J. A1 - Jaenecke,F. A1 - Zachariae,Ulrich A1 - Tanabe,M. AU - Kattner,C. AU - Zaucha,J. AU - Jaenecke,F. AU - Zachariae,Ulrich AU - Tanabe,M. PY - 2013/5 Y1 - 2013/5 N2 - Neisseria meningitidis is the main causative agent of bacterial meningitis. In its outer membrane, the trimeric Neisserial porin PorB is responsible for the diffusive transport of essential hydrophilic solutes across the bilayer. Previous molecular dynamics simulations based on the recent crystal structure of PorB have suggested the presence of distinct solute translocation pathways through this channel. Although PorB has been electrophysiologically characterized as anion-selective, cation translocation through nucleotide-bound PorB during pathogenesis is thought to be instrumental for host cell death. As a result, we were particularly interested in further characterizing cation transport through the pore. We combined a structural approach with additional computational analysis. Here, we present two crystal structures of PorB at 2.1 and 2.65 Å resolution. The new structures display additional electron densities around the protruding loop 3 (L3) inside the pore. We show that these electron densities can be identified as monovalent cations, in our case Cs, which are tightly bound to the inner channel. Molecular dynamics simulations reveal further ion interactions and the free energy landscape for ions inside PorB. Our results suggest that the crystallographically identified locations of Cs form a cation transport pathway inside the pore. This finding suggests how positively charged ions are translocated through PorB when the channel is inserted into mitochondrial membranes during Neisserial infection, a process which is considered to dissipate the mitochondrial transmembrane potential gradient and thereby induce apoptosis. © 2013 Wiley Periodicals, Inc. AB - Neisseria meningitidis is the main causative agent of bacterial meningitis. In its outer membrane, the trimeric Neisserial porin PorB is responsible for the diffusive transport of essential hydrophilic solutes across the bilayer. Previous molecular dynamics simulations based on the recent crystal structure of PorB have suggested the presence of distinct solute translocation pathways through this channel. Although PorB has been electrophysiologically characterized as anion-selective, cation translocation through nucleotide-bound PorB during pathogenesis is thought to be instrumental for host cell death. As a result, we were particularly interested in further characterizing cation transport through the pore. We combined a structural approach with additional computational analysis. Here, we present two crystal structures of PorB at 2.1 and 2.65 Å resolution. The new structures display additional electron densities around the protruding loop 3 (L3) inside the pore. We show that these electron densities can be identified as monovalent cations, in our case Cs, which are tightly bound to the inner channel. Molecular dynamics simulations reveal further ion interactions and the free energy landscape for ions inside PorB. Our results suggest that the crystallographically identified locations of Cs form a cation transport pathway inside the pore. This finding suggests how positively charged ions are translocated through PorB when the channel is inserted into mitochondrial membranes during Neisserial infection, a process which is considered to dissipate the mitochondrial transmembrane potential gradient and thereby induce apoptosis. © 2013 Wiley Periodicals, Inc. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875862947&md5=c0ca195a990632f18d383bb139ab9f08 U2 - 10.1002/prot.24241 DO - 10.1002/prot.24241 M1 - Article JO - Proteins: Structure, Function, and Bioinformatics JF - Proteins: Structure, Function, and Bioinformatics SN - 0887-3585 IS - 5 VL - 81 SP - 830 EP - 840 ER - TY - JOUR T1 - Iron acquisition and allocation in stramenopile algae A1 - Raven,John A AU - Raven,John A PY - 2013/5 Y1 - 2013/5 N2 - The essential element iron has a low biological availability in the surface ocean where photosynthetic organisms live. Recent advances in our understanding of iron acquisition mechanisms in brown algae and diatoms (stramenopile algae) show the importance of the reduction of ferric to ferrous iron prior to, or during, transport in the uptake process. The uses of iron in photosynthetic stramenopiles resembles that in other oxygenic organisms, although (with the exception of the diatom Thalassiosira oceanica from an iron-deficient part of the ocean) they lack plastocyanin, instead using cytochrome c 6, This same diatom further economizes genotypically on the use of iron in photosynthesis by decreasing the expression of photosystem I, cytochrome c 6, and the cytochrome b 6 f complex per cell and per photosystem II relative to the coastal Thalassiosira pseudonana; similar changes occur phenotypically in response to iron deficiency in other diatoms such as Phaeodactylum tricornutum. In some diatoms grown under iron-limiting conditions, essentially all of the iron in the cells can be accounted for by the iron occurring in catalytic proteins. However, stramenopiles can store iron. Genomic studies show that pennate, but not centric, diatoms have the iron storage protein ferritin. While Mössbauer and X-ray analysis of (57)Fe-labelled Ectocarpus siliculosus shows iron in an amorphous mineral phase resembling the core of ferritin, the genome shows no protein with significant sequence similarity to ferritin. AB - The essential element iron has a low biological availability in the surface ocean where photosynthetic organisms live. Recent advances in our understanding of iron acquisition mechanisms in brown algae and diatoms (stramenopile algae) show the importance of the reduction of ferric to ferrous iron prior to, or during, transport in the uptake process. The uses of iron in photosynthetic stramenopiles resembles that in other oxygenic organisms, although (with the exception of the diatom Thalassiosira oceanica from an iron-deficient part of the ocean) they lack plastocyanin, instead using cytochrome c 6, This same diatom further economizes genotypically on the use of iron in photosynthesis by decreasing the expression of photosystem I, cytochrome c 6, and the cytochrome b 6 f complex per cell and per photosystem II relative to the coastal Thalassiosira pseudonana; similar changes occur phenotypically in response to iron deficiency in other diatoms such as Phaeodactylum tricornutum. In some diatoms grown under iron-limiting conditions, essentially all of the iron in the cells can be accounted for by the iron occurring in catalytic proteins. However, stramenopiles can store iron. Genomic studies show that pennate, but not centric, diatoms have the iron storage protein ferritin. While Mössbauer and X-ray analysis of (57)Fe-labelled Ectocarpus siliculosus shows iron in an amorphous mineral phase resembling the core of ferritin, the genome shows no protein with significant sequence similarity to ferritin. U2 - 10.1093/jxb/ert121 DO - 10.1093/jxb/ert121 M1 - Comment/debate JO - Journal of Experimental Botany JF - Journal of Experimental Botany SN - 0022-0957 IS - 8 VL - 64 SP - 2119 EP - 2127 ER - TY - JOUR T1 - Laparoscopic Surgical Skills are Significantly Improved by the Use of a Portable Laparoscopic Simulator T2 - Results of a Randomized Controlled Trial A1 - Johnston,T J A1 - Tang,B A1 - Alijani,A A1 - Tait,I A1 - Steele,R J A1 - Ker,J A1 - Nabi,G A1 - Surgical Simulation Group at the University of Dundee AU - Johnston,T J AU - Tang,B AU - Alijani,A AU - Tait,I AU - Steele,R J AU - Ker,J AU - Nabi,G AU - Surgical Simulation Group at the University of Dundee PY - 2013/5 Y1 - 2013/5 N2 - There is growing evidence that training on virtual reality simulators leads to improved performance in the animate and human operating room. However, they are expensive, have a limited availability, and involve complex systems. Portable simulators are significantly cheaper, more user-friendly, and are flexible systems that are more suited to a surgical trainee's busy schedule. The use of portable surgical simulators to train skills and reduce errors has never been evaluated in prospective, randomized clinical settings. The objective of this study was to determine if training on the portable Integrated Laparoscopic Simulator leads to improved performance of core laparoscopic skills. AB - There is growing evidence that training on virtual reality simulators leads to improved performance in the animate and human operating room. However, they are expensive, have a limited availability, and involve complex systems. Portable simulators are significantly cheaper, more user-friendly, and are flexible systems that are more suited to a surgical trainee's busy schedule. The use of portable surgical simulators to train skills and reduce errors has never been evaluated in prospective, randomized clinical settings. The objective of this study was to determine if training on the portable Integrated Laparoscopic Simulator leads to improved performance of core laparoscopic skills. U2 - 10.1007/s00268-013-1945-5 DO - 10.1007/s00268-013-1945-5 M1 - Article JO - World Journal of Surgery JF - World Journal of Surgery IS - 5 VL - 37 SP - 957 EP - 964 ER - TY - JOUR T1 - Methylated tissue factor pathway inhibitor 2 (TFPI2) DNA in serum is a biomarker of metastatic melanoma A1 - Nigro,Cristiana Lo A1 - Wang,Hexiao A1 - McHugh,Angela A1 - Lattanzio,Laura A1 - Matin,Rubeta A1 - Harwood,Catherine A1 - Syed,Nelofer A1 - Hatzimichael,Eleftheria A1 - Briasoulis,Evangelos A1 - Merlano,Marco A1 - Evans,Alan A1 - Thompson,Alastair A1 - Leigh,Irene A1 - Fleming,Colin A1 - Inman,Gareth J. A1 - Proby,Charlotte A1 - Crook,Tim AU - Nigro,Cristiana Lo AU - Wang,Hexiao AU - McHugh,Angela AU - Lattanzio,Laura AU - Matin,Rubeta AU - Harwood,Catherine AU - Syed,Nelofer AU - Hatzimichael,Eleftheria AU - Briasoulis,Evangelos AU - Merlano,Marco AU - Evans,Alan AU - Thompson,Alastair AU - Leigh,Irene AU - Fleming,Colin AU - Inman,Gareth J. AU - Proby,Charlotte AU - Crook,Tim PY - 2013/5 Y1 - 2013/5 N2 - Transcriptional silencing of tissue factor pathway inhibitor 2 (TFPI2) occurs in several human tumors including melanoma. We investigated methylated TFPI2 as a biomarker of metastatic melanoma using qRT-PCR to assess TFPI2 expression and pyrosequencing to analyze CpG island methylation in malignant melanoma cell lines, in benign nevi, in 112 primary and metastatic melanomas, and in serum from 6 healthy individuals and 35 patients: 20 patients with primary and 15 patients with metastatic melanoma. The TFPI2 CpG island is unmethylated in nevi but methylation is associated with metastatic melanoma. Circulating methylated TFPI2 DNA is undetectable in sera from healthy individuals and detectable in sera from patients with primary and metastatic melanomas, but the presence of methylated TFPI2 DNA in serum is strongly associated with metastatic disease (P AB - Transcriptional silencing of tissue factor pathway inhibitor 2 (TFPI2) occurs in several human tumors including melanoma. We investigated methylated TFPI2 as a biomarker of metastatic melanoma using qRT-PCR to assess TFPI2 expression and pyrosequencing to analyze CpG island methylation in malignant melanoma cell lines, in benign nevi, in 112 primary and metastatic melanomas, and in serum from 6 healthy individuals and 35 patients: 20 patients with primary and 15 patients with metastatic melanoma. The TFPI2 CpG island is unmethylated in nevi but methylation is associated with metastatic melanoma. Circulating methylated TFPI2 DNA is undetectable in sera from healthy individuals and detectable in sera from patients with primary and metastatic melanomas, but the presence of methylated TFPI2 DNA in serum is strongly associated with metastatic disease (P UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84876670279&md5=b91b9587521249ac646680d64b3d47b1 U2 - 10.1038/jid.2012.493 DO - 10.1038/jid.2012.493 M1 - Article JO - Journal of Investigative Dermatology JF - Journal of Investigative Dermatology SN - 0022-202X IS - 5 VL - 133 SP - 1278 EP - 1285 ER - TY - JOUR T1 - Microbial responses to the erosional redistribution of soil organic carbon in arable fields. A1 - Dungait,Jennifer A.J. A1 - Ghee,Claire A1 - Rowan,John S. A1 - McKenzie,Blair M. A1 - Hawes,Cathy A1 - Dixon,Elisabeth R. A1 - Paterson,Eric A1 - Hopkins,David W. AU - Dungait,Jennifer A.J. AU - Ghee,Claire AU - Rowan,John S. AU - McKenzie,Blair M. AU - Hawes,Cathy AU - Dixon,Elisabeth R. AU - Paterson,Eric AU - Hopkins,David W. PY - 2013/5 Y1 - 2013/5 N2 - Quantifying the potential for eroding agricultural soils to act as sinks or sources of atmospheric carbon relies on accounting for the pools and fluxes of soil organic carbon (SOC) and nutrients, e.g. nitrogen (N), affected by erosion. Herein, we report the outcomes of an experiment where a C maize (Zea mays) crop (dC = -12.1‰) was cultivated and incorporated for 2 years to introduce a 'pulse' of C-enriched SOC to a C arable soil (dC = -27.4‰). Soils were sampled at eroding (top slope and upper slope) and depositional (lower slope and slope foot) positions of an accelerated erosion pathway that were confirmed using Cs measurements. The sand particle-sized fraction (63-2000 µm) was predominant and increased in the depositional slope positions due to selective loss of fine particles and preferential deposition of the coarsest fraction of transported sediment. There was a significant isometric relationship between the percentage SOC and total N: top slope > upper slope > lower slope, with similar values in the slope foot to the top slope. The dN values of the soils were enriched (7.3‰) at the slope foot, compared with the other slope positions (average 6.3‰), suggesting increased denitrification rates. The dC values of the soil microbial biomass C extracted from surface soils (0-5 cm) at each slope position showed that the proportion of maize C being incorporated into the soil microbial biomass declined in the downslope direction from 54% (top slope) to 43% (upper slope) to 18% (lower slope) in inverse proportion to the size of the soil microbial biomass, and increased to 41% at the slope foot. This suggests dynamic replacement of the SOC with crop C in the eroding slope positions and dilution of the transported C by C3-SOC in the depositional slope positions. This paper is evidence that erosional distribution of soil carbon leads to differential microbial utilisation of SOC between eroding and depositional sites. © 2013 Elsevier Ltd. AB - Quantifying the potential for eroding agricultural soils to act as sinks or sources of atmospheric carbon relies on accounting for the pools and fluxes of soil organic carbon (SOC) and nutrients, e.g. nitrogen (N), affected by erosion. Herein, we report the outcomes of an experiment where a C maize (Zea mays) crop (dC = -12.1‰) was cultivated and incorporated for 2 years to introduce a 'pulse' of C-enriched SOC to a C arable soil (dC = -27.4‰). Soils were sampled at eroding (top slope and upper slope) and depositional (lower slope and slope foot) positions of an accelerated erosion pathway that were confirmed using Cs measurements. The sand particle-sized fraction (63-2000 µm) was predominant and increased in the depositional slope positions due to selective loss of fine particles and preferential deposition of the coarsest fraction of transported sediment. There was a significant isometric relationship between the percentage SOC and total N: top slope > upper slope > lower slope, with similar values in the slope foot to the top slope. The dN values of the soils were enriched (7.3‰) at the slope foot, compared with the other slope positions (average 6.3‰), suggesting increased denitrification rates. The dC values of the soil microbial biomass C extracted from surface soils (0-5 cm) at each slope position showed that the proportion of maize C being incorporated into the soil microbial biomass declined in the downslope direction from 54% (top slope) to 43% (upper slope) to 18% (lower slope) in inverse proportion to the size of the soil microbial biomass, and increased to 41% at the slope foot. This suggests dynamic replacement of the SOC with crop C in the eroding slope positions and dilution of the transported C by C3-SOC in the depositional slope positions. This paper is evidence that erosional distribution of soil carbon leads to differential microbial utilisation of SOC between eroding and depositional sites. © 2013 Elsevier Ltd. KW - Soil erosion KW - Nitrogen cycling KW - Carbon cycling KW - Soil microbial biomass KW - Agriculture UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84874509032&md5=3bf45f59ce7679456e89eac809598008 U2 - 10.1016/j.soilbio.2013.01.027 DO - 10.1016/j.soilbio.2013.01.027 M1 - Article JO - Soil Biology & Biochemistry JF - Soil Biology & Biochemistry SN - 0038-0717 VL - 60 SP - 195 EP - 201 ER - TY - JOUR T1 - Neuropathic pain in the community T2 - more under-treated than refractory? A1 - Torrance,Nicola A1 - Ferguson,Janice A A1 - Afolabi,Ebenezer A1 - Bennett,Michael I. A1 - Serpell,Michael G A1 - Dunn,Kate M A1 - Smith,Blair H AU - Torrance,Nicola AU - Ferguson,Janice A AU - Afolabi,Ebenezer AU - Bennett,Michael I. AU - Serpell,Michael G AU - Dunn,Kate M AU - Smith,Blair H PY - 2013/5 Y1 - 2013/5 N2 - Best current estimates of neuropathic pain prevalence come from studies using screening tools detecting pain with probable neuropathic features; the proportion experiencing significant, long-term neuropathic pain, and the proportion not responding to standard treatment are unknown. These "refractory" cases are the most clinically important to detect, being the most severe, requiring specialist treatment. The aim of this study was to estimate the proportion of neuropathic pain in the population that is "refractory," and to quantify associated clinical and demographic features. We posted self-administered questionnaires to 10,000 adult patients randomly selected from 10 general practitioner practices in 5 UK locations. The questionnaire contained chronic pain identification and severity questions, cause of pain, SF-12, EQ-5D, S-LANSS (Self-administered Leeds Assessment of Neuropathic Signs and Symptoms), PSEQ (Pain Self-Efficacy Questionnaire), use of neuropathic pain medications, and health care utilisation. These data were combined to determine the presence and characteristics of "refractory" neuropathic pain according to the defining features identified by a Delphi survey of international experts. Graded categories of chronic pain with and without neuropathic characteristics were generated, incorporating the refractory criteria. Completed questionnaires were returned by 4451 individuals (response rate 47%); 399 had "chronic pain with neuropathic characteristics" (S-LANSS positive, 8.9% of the study sample); 215 (53.9%) also reported a positive relevant history ("Possible neuropathic pain"); and 98 (4.5% of all Chronic Pain) also reported an "adequate" trial of at least one neuropathic pain drug ("Treated possible neuropathic pain"). The most refractory cases were associated with dramatically poorer physical and mental health, lower pain self-efficacy, higher pain intensity and pain-related disability, and greater health care service use. © 2013 International Association for the Study of Pain. AB - Best current estimates of neuropathic pain prevalence come from studies using screening tools detecting pain with probable neuropathic features; the proportion experiencing significant, long-term neuropathic pain, and the proportion not responding to standard treatment are unknown. These "refractory" cases are the most clinically important to detect, being the most severe, requiring specialist treatment. The aim of this study was to estimate the proportion of neuropathic pain in the population that is "refractory," and to quantify associated clinical and demographic features. We posted self-administered questionnaires to 10,000 adult patients randomly selected from 10 general practitioner practices in 5 UK locations. The questionnaire contained chronic pain identification and severity questions, cause of pain, SF-12, EQ-5D, S-LANSS (Self-administered Leeds Assessment of Neuropathic Signs and Symptoms), PSEQ (Pain Self-Efficacy Questionnaire), use of neuropathic pain medications, and health care utilisation. These data were combined to determine the presence and characteristics of "refractory" neuropathic pain according to the defining features identified by a Delphi survey of international experts. Graded categories of chronic pain with and without neuropathic characteristics were generated, incorporating the refractory criteria. Completed questionnaires were returned by 4451 individuals (response rate 47%); 399 had "chronic pain with neuropathic characteristics" (S-LANSS positive, 8.9% of the study sample); 215 (53.9%) also reported a positive relevant history ("Possible neuropathic pain"); and 98 (4.5% of all Chronic Pain) also reported an "adequate" trial of at least one neuropathic pain drug ("Treated possible neuropathic pain"). The most refractory cases were associated with dramatically poorer physical and mental health, lower pain self-efficacy, higher pain intensity and pain-related disability, and greater health care service use. © 2013 International Association for the Study of Pain. KW - Neuropathic pain KW - Chronic pain KW - Epidemiology KW - S-LANSS KW - Refractory UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84874091699&md5=18f19726d5961e1370a2fa5189600933 U2 - 10.1016/j.pain.2012.12.022 DO - 10.1016/j.pain.2012.12.022 M1 - Article JO - PAIN JF - PAIN SN - 0304-3959 IS - 5 VL - 154 SP - 690 EP - 699 ER - TY - JOUR T1 - Neurovascular screening in hereditary haemorrhagic telangiectasia T2 - dilemmas for the paediatric neuroscience community A1 - Ganesan,Vijeya A1 - Robertson,Fergus A1 - Berg,Jonathan AU - Ganesan,Vijeya AU - Robertson,Fergus AU - Berg,Jonathan PY - 2013/5 Y1 - 2013/5 U2 - 10.1111/j.1469-8749.2012.04425.x DO - 10.1111/j.1469-8749.2012.04425.x M1 - Article JO - Developmental Medicine and Child Neurology JF - Developmental Medicine and Child Neurology SN - 0012-1622 IS - 5 VL - 55 SP - 405 EP - 407 ER - TY - JOUR T1 - Older people's views on what they need to successfully adjust to life with a hearing aid A1 - Kelly,Timothy B. A1 - Tolson,Debbie A1 - Day,Tracy A1 - McColgan,Gillian A1 - Kroll,Thilo A1 - Maclaren,William AU - Kelly,Timothy B. AU - Tolson,Debbie AU - Day,Tracy AU - McColgan,Gillian AU - Kroll,Thilo AU - Maclaren,William PY - 2013/5 Y1 - 2013/5 N2 - This article reports a study exploring what older people believe would enable them to adjust to and gain maximum benefit from wearing a hearing aid. A mixed methods approach was employed during 2006 involving interviews with key stakeholders, a survey across three Scottish health board areas and focus groups. Nine key stakeholders from six national and local organisations were interviewed about the needs of older people being fitted with hearing aids. In total, 240 older people belonging to three different types of hearing impaired older people were surveyed: long-term users of hearing aids, new hearing aid users, and those on a waiting list from urban and rural areas (response rate=24%). A series of eight follow-up focus groups with 31 audiology patients was held. Health professionals appeared to neglect appropriate provision of information and overly rely on technological interventions. Of 154 older people already fitted with hearing aids, only 52% of hearing aid users reported receiving enough practical help post fitting and only 41% reported receiving enough support. Approximately 40% reported not feeling confident in the use of their aids or their controls. Older people wanted more information than they received both before and after hearing aid fitting. Information provision and attention to the psychosocial aspects of care are key to enabling older people to adjust and optimise hearing aid benefit. © 2013 Blackwell Publishing Ltd. AB - This article reports a study exploring what older people believe would enable them to adjust to and gain maximum benefit from wearing a hearing aid. A mixed methods approach was employed during 2006 involving interviews with key stakeholders, a survey across three Scottish health board areas and focus groups. Nine key stakeholders from six national and local organisations were interviewed about the needs of older people being fitted with hearing aids. In total, 240 older people belonging to three different types of hearing impaired older people were surveyed: long-term users of hearing aids, new hearing aid users, and those on a waiting list from urban and rural areas (response rate=24%). A series of eight follow-up focus groups with 31 audiology patients was held. Health professionals appeared to neglect appropriate provision of information and overly rely on technological interventions. Of 154 older people already fitted with hearing aids, only 52% of hearing aid users reported receiving enough practical help post fitting and only 41% reported receiving enough support. Approximately 40% reported not feeling confident in the use of their aids or their controls. Older people wanted more information than they received both before and after hearing aid fitting. Information provision and attention to the psychosocial aspects of care are key to enabling older people to adjust and optimise hearing aid benefit. © 2013 Blackwell Publishing Ltd. KW - PROGRAM KW - IMPAIRMENT KW - QUALITY-OF-LIFE KW - service-user views KW - PERCEPTION KW - older people KW - hearing aid adjustment KW - audiological rehabilitation KW - INTERVENTION KW - REHABILITATION KW - ADULTS UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84873052751&md5=679fb2b752386d3fcc7b100b1e6d6499 U2 - 10.1111/hsc.12016 DO - 10.1111/hsc.12016 M1 - Article JO - Health and Social Care in the Community JF - Health and Social Care in the Community SN - 0966-0410 IS - 3 VL - 21 SP - 293 EP - 302 ER - TY - JOUR T1 - Post-transplant T cell chimerism predicts graft versus host disease but not disease relapse in patients undergoing an alemtuzumab based reduced intensity conditioned allogeneic transplant A1 - Nikolousis,E. A1 - Robinson,S. A1 - Nagra,S. A1 - Brookes,C. A1 - Kinsella,F. A1 - Tauro,S. A1 - Jeffries,S. A1 - Griffiths,M. A1 - Mahendra,P. A1 - Cook,M. A1 - Paneesha,S. A1 - Lovell,R. A1 - Kishore,B. A1 - Chaganti,S. A1 - Malladi,R. A1 - Raghavan,M. A1 - Moss,P. A1 - Milligan,D. A1 - Craddock,C. AU - Nikolousis,E. AU - Robinson,S. AU - Nagra,S. AU - Brookes,C. AU - Kinsella,F. AU - Tauro,S. AU - Jeffries,S. AU - Griffiths,M. AU - Mahendra,P. AU - Cook,M. AU - Paneesha,S. AU - Lovell,R. AU - Kishore,B. AU - Chaganti,S. AU - Malladi,R. AU - Raghavan,M. AU - Moss,P. AU - Milligan,D. AU - Craddock,C. PY - 2013/5 Y1 - 2013/5 N2 -

In this multicentre retrospective study we have studied the impact of T cell chimerism on the outcome of 133 patients undergoing an alemtuzumab based reduced intensity conditioning allograft (RIC). The median age of the patients was 50 years (range 42-55 years). 77 patients were transplanted using an HLA identical sibling donor while 56 patients received a fully matched volunteer unrelated donor graft. 64 patients had a lymphoid malignancy and 69 were transplanted for a myeloid malignancy. 38 patients (29%) relapsed with no significant difference in risk of relapse between patients developing full donor and mixed donor chimerism in the T-cell compartment on D + 90 and D + 180 post transplant. Day 90 full donor T cell chimerism correlated with an increased incidence of acute GVHD according to NIH criteria (p = 0.0004) and the subsequent development of chronic GVHD. Consistent with previous observations, our results confirmed a correlation between the establishment of T cell full donor chimerism and acute GVHD in T deplete RIC allografts. However our study failed to identify any correlation between T cell chimerism and relapse risk and challenge the use of pre-emptive donor lymphocyte infusions (DLI) in patients with mixed T cell chimerism transplanted using an alemtuzumab based RIC regimen. (C) 2013 Elsevier Ltd. All rights reserved.

AB -

In this multicentre retrospective study we have studied the impact of T cell chimerism on the outcome of 133 patients undergoing an alemtuzumab based reduced intensity conditioning allograft (RIC). The median age of the patients was 50 years (range 42-55 years). 77 patients were transplanted using an HLA identical sibling donor while 56 patients received a fully matched volunteer unrelated donor graft. 64 patients had a lymphoid malignancy and 69 were transplanted for a myeloid malignancy. 38 patients (29%) relapsed with no significant difference in risk of relapse between patients developing full donor and mixed donor chimerism in the T-cell compartment on D + 90 and D + 180 post transplant. Day 90 full donor T cell chimerism correlated with an increased incidence of acute GVHD according to NIH criteria (p = 0.0004) and the subsequent development of chronic GVHD. Consistent with previous observations, our results confirmed a correlation between the establishment of T cell full donor chimerism and acute GVHD in T deplete RIC allografts. However our study failed to identify any correlation between T cell chimerism and relapse risk and challenge the use of pre-emptive donor lymphocyte infusions (DLI) in patients with mixed T cell chimerism transplanted using an alemtuzumab based RIC regimen. (C) 2013 Elsevier Ltd. All rights reserved.

KW - KINETICS KW - MINIMAL RESIDUAL DISEASE KW - SURVIVAL KW - PATTERNS KW - T cell chimerism KW - IN-VIVO KW - ENGRAFTMENT KW - Reduced intensity transplant KW - Alemtuzumab KW - MIXED CHIMERISM KW - BONE-MARROW-TRANSPLANTATION KW - TOXICITY KW - HEMATOLOGIC MALIGNANCIES U2 - 10.1016/j.leukres.2013.01.010 DO - 10.1016/j.leukres.2013.01.010 M1 - Article IS - 5 VL - 37 SP - 561 EP - 565 ER - TY - JOUR T1 - Real-time RT-PCR threshold cycles value for Kir6.1 from the blood correlates with parameters of vascular function T2 - a potential for the vascular function biomarker? A1 - Khan,Faisel A1 - Choong,Wen Ling A1 - Du,Qingyou A1 - Jovanovic,Aleksandar AU - Khan,Faisel AU - Choong,Wen Ling AU - Du,Qingyou AU - Jovanovic,Aleksandar PY - 2013/5 Y1 - 2013/5 N2 - Abstract We examined the presence of KATP channel subunits, Kir6.1 and SUR2B, mRNAs in the blood and vascular function in healthy volunteers (41 males, 34 females). Real-time reverse transcriptase (RT)-PCR threshold cycles (Ct) was used as an indicator of mRNA levels. Baseline skin perfusion and the post-occlusion reactive hyperemia response exhibited a significant positive correlation with Ct for Kir6.1. There was no correlation between Kir6.1 Ct and brachial artery flow-mediated dilatation. Gender had no influence on relationships between blood Kir6.1 Ct and vascular function. We conclude that blood Kir6.1 mRNA levels could be potentially used as a biomarker of the vascular function. AB - Abstract We examined the presence of KATP channel subunits, Kir6.1 and SUR2B, mRNAs in the blood and vascular function in healthy volunteers (41 males, 34 females). Real-time reverse transcriptase (RT)-PCR threshold cycles (Ct) was used as an indicator of mRNA levels. Baseline skin perfusion and the post-occlusion reactive hyperemia response exhibited a significant positive correlation with Ct for Kir6.1. There was no correlation between Kir6.1 Ct and brachial artery flow-mediated dilatation. Gender had no influence on relationships between blood Kir6.1 Ct and vascular function. We conclude that blood Kir6.1 mRNA levels could be potentially used as a biomarker of the vascular function. U2 - 10.3109/1354750X.2013.770553 DO - 10.3109/1354750X.2013.770553 M1 - Article JO - Biomarkers JF - Biomarkers SN - 1354-750X IS - 3 VL - 18 SP - 221 EP - 229 ER - TY - JOUR T1 - Stuck in the middle with who? (Belatedly) engaging with Laughlin while becoming re-acquainted with Merton and middle range theorising A1 - Roslender,Robin AU - Roslender,Robin PY - 2013/5 Y1 - 2013/5 N2 - The paper engages with Laughlin's 1995 and 2004 contributions to the literature on accounting research methodology, seeking to critique and thereby extend his insights. It does so at a time when the discussion of methodological issues appears less important to many empirical accounting researchers than demonstrating a familiarity with the growing range of theoretical perspectives available to pursue such enquiries. The paper initially outlines Laughlin's original and revised frameworks, following which a number of the resultant attributions of specific schools of thought are questioned. The original categorisation exercise is concluded still to offer an insightful basis on which to compare and contrast empirical research approaches. For this reason, the same exercise is extended to locate three further, currently popular ways of seeing: institutional theory, actor network theory and practice theory. The focus then shifts to a more detailed exploration of the relationship that exists between Laughlin's idea of middle range thinking and Merton's characterisation of middle range theory and theorisation. Informed by the resultant insights, the middle range or substantive theory credentials of a range of schools of thought currently widely subscribed in interdisciplinary accounting research are then examined. AB - The paper engages with Laughlin's 1995 and 2004 contributions to the literature on accounting research methodology, seeking to critique and thereby extend his insights. It does so at a time when the discussion of methodological issues appears less important to many empirical accounting researchers than demonstrating a familiarity with the growing range of theoretical perspectives available to pursue such enquiries. The paper initially outlines Laughlin's original and revised frameworks, following which a number of the resultant attributions of specific schools of thought are questioned. The original categorisation exercise is concluded still to offer an insightful basis on which to compare and contrast empirical research approaches. For this reason, the same exercise is extended to locate three further, currently popular ways of seeing: institutional theory, actor network theory and practice theory. The focus then shifts to a more detailed exploration of the relationship that exists between Laughlin's idea of middle range thinking and Merton's characterisation of middle range theory and theorisation. Informed by the resultant insights, the middle range or substantive theory credentials of a range of schools of thought currently widely subscribed in interdisciplinary accounting research are then examined. KW - Methodology KW - middle range theory KW - schools of thought KW - ways of seeing U2 - 10.1016/j.cpa.2012.07.005 DO - 10.1016/j.cpa.2012.07.005 M1 - Article JO - Critical Perspectives on Accounting JF - Critical Perspectives on Accounting SN - 1045-2354 IS - 3 VL - 24 SP - 228 EP - 241 ER - TY - JOUR T1 - Student and infection prevention and control nurses' hand hygiene decision making in simulated clinical scenarios T2 - A qualitative research study of hand washing, gel and glove use choices A1 - Lee,Karen AU - Lee,Karen PY - 2013/5 Y1 - 2013/5 N2 - Final year nursing students and infection prevention and control nurses were recorded verbalising their hand hygiene decision-making while working through clinical scenarios on a computer, to understand what factors they were taking into account in choosing a decontamination method (hand washing or alcohol based hand rub/gel) or to wear gloves. Results demonstrated an overuse of gloves, and underuse of gel. Three main themes emerged: 'Experience or expectation'; this was what they had seen on placement, or it was what 'we' do. 'Just in case,' was characterised by an awareness that what they would do wasn't actually necessary but they tended to do it anyway. Thirdly, 'gel doesn't feel clean,' was characterised by a feeling that using gel didn't make the nurses feel clean after 'dirty' tasks, even though gel is actually more effective. There was little evidence that participants were making risk assessments based on the individual patient characteristics given, or the tasks, as they had been taught to do. Choice of hand decontamination agent and whether to use gloves appeared to be based on an habitual characterisation of whether the task was 'clean' or 'dirty,' with a very low threshold for 'dirty' based on an excessive perception of risk to the student. © The Author(s) 2013. AB - Final year nursing students and infection prevention and control nurses were recorded verbalising their hand hygiene decision-making while working through clinical scenarios on a computer, to understand what factors they were taking into account in choosing a decontamination method (hand washing or alcohol based hand rub/gel) or to wear gloves. Results demonstrated an overuse of gloves, and underuse of gel. Three main themes emerged: 'Experience or expectation'; this was what they had seen on placement, or it was what 'we' do. 'Just in case,' was characterised by an awareness that what they would do wasn't actually necessary but they tended to do it anyway. Thirdly, 'gel doesn't feel clean,' was characterised by a feeling that using gel didn't make the nurses feel clean after 'dirty' tasks, even though gel is actually more effective. There was little evidence that participants were making risk assessments based on the individual patient characteristics given, or the tasks, as they had been taught to do. Choice of hand decontamination agent and whether to use gloves appeared to be based on an habitual characterisation of whether the task was 'clean' or 'dirty,' with a very low threshold for 'dirty' based on an excessive perception of risk to the student. © The Author(s) 2013. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84876453246&md5=3aba06410617b32375e51cdd904c91ca U2 - 10.1177/1757177413484784 DO - 10.1177/1757177413484784 M1 - Article JO - Journal of Infection Prevention JF - Journal of Infection Prevention SN - 1757-1774 IS - 3 VL - 14 SP - 96 EP - 103 ER - TY - JOUR T1 - The effects of identification with a support group on the mental health of people with multiple sclerosis A1 - Wakefield,Juliet R. H. A1 - Bickley,Sarah A1 - Sani,Fabio AU - Wakefield,Juliet R. H. AU - Bickley,Sarah AU - Sani,Fabio PY - 2013/5 Y1 - 2013/5 N2 - Multiple sclerosis (MS) is associated with various psychological problems, including depression and anxiety. Whilst MS support groups are intended to improve mental health, this goal is not always achieved. Taking a social identity approach, we hypothesise that it is the level of subjective identification with a support group (rather than simply support group membership per se) that positively affects the mental health of people with MS. AB - Multiple sclerosis (MS) is associated with various psychological problems, including depression and anxiety. Whilst MS support groups are intended to improve mental health, this goal is not always achieved. Taking a social identity approach, we hypothesise that it is the level of subjective identification with a support group (rather than simply support group membership per se) that positively affects the mental health of people with MS. U2 - 10.1016/j.jpsychores.2013.02.002 DO - 10.1016/j.jpsychores.2013.02.002 M1 - Article JO - Journal of Psychosomatic Research JF - Journal of Psychosomatic Research SN - 0022-3999 IS - 5 VL - 74 SP - 420 EP - 426 ER - TY - JOUR T1 - The role of healthcare support workers in providing palliative and end-of-life care in the community T2 - a systematic literature review A1 - Herber,Oliver R. A1 - Johnston,Bridget M. AU - Herber,Oliver R. AU - Johnston,Bridget M. PY - 2013/5 Y1 - 2013/5 N2 - Despite the widespread use of Health Care Support Workers (HCSWs) in providing palliative and end-of-life care, there is little information available about their contributions towards supporting patients who want to be cared for at home or to die at home. Between January and April 2011, a systematic review was conducted to address two questions: (i) What particular tasks/roles do HCSWs perform when caring for people at the end of life and their families to comply with their desire to remain at home?; (ii) What are the challenges and supporting factors that influence HCSWs' ability to provide palliative and end-of-life care in the community? Databases searched for relevant articles published between 1990 until April 2011 included CINAHL, EMBASE, PsychINFO, British Nursing Index, Web of Science, Medline and ASSIA. In total, 1695 papers were identified and their titles and abstracts were read. Ten papers met the eligibility criteria of the study. After the methodological quality of the studies was appraised, nine papers were included in the review. Judgements regarding eligibility and quality were undertaken independently by the authors. The findings indicate that HCSWs invest a great deal of their time on emotional and social support as well as on assisting in the provision of personal care. They are also involved in providing care for the dying, respite care for family members and offer domestic support. Although it is important to acknowledge the many positive aspects that HCSWs provide, the findings suggest three challenges in the HCSWs role: emotional attachment, role ambiguity and inadequate training. Support factors such as informal peer grief-support groups, sense of cohesiveness among HCSWs and task orientation enabled HCSWs to overcome these challenges. To conclude, induction and training programmes, a defined period of preceptorship, appropriate support, supervision and clearly defined role boundaries may be helpful in reducing the challenges identified in HCSWs' roles. AB - Despite the widespread use of Health Care Support Workers (HCSWs) in providing palliative and end-of-life care, there is little information available about their contributions towards supporting patients who want to be cared for at home or to die at home. Between January and April 2011, a systematic review was conducted to address two questions: (i) What particular tasks/roles do HCSWs perform when caring for people at the end of life and their families to comply with their desire to remain at home?; (ii) What are the challenges and supporting factors that influence HCSWs' ability to provide palliative and end-of-life care in the community? Databases searched for relevant articles published between 1990 until April 2011 included CINAHL, EMBASE, PsychINFO, British Nursing Index, Web of Science, Medline and ASSIA. In total, 1695 papers were identified and their titles and abstracts were read. Ten papers met the eligibility criteria of the study. After the methodological quality of the studies was appraised, nine papers were included in the review. Judgements regarding eligibility and quality were undertaken independently by the authors. The findings indicate that HCSWs invest a great deal of their time on emotional and social support as well as on assisting in the provision of personal care. They are also involved in providing care for the dying, respite care for family members and offer domestic support. Although it is important to acknowledge the many positive aspects that HCSWs provide, the findings suggest three challenges in the HCSWs role: emotional attachment, role ambiguity and inadequate training. Support factors such as informal peer grief-support groups, sense of cohesiveness among HCSWs and task orientation enabled HCSWs to overcome these challenges. To conclude, induction and training programmes, a defined period of preceptorship, appropriate support, supervision and clearly defined role boundaries may be helpful in reducing the challenges identified in HCSWs' roles. KW - Health Care Support Workers KW - Certified nursing assistant KW - Community setting KW - End-of-life care KW - Literature review KW - Palliative care U2 - 10.1111/j.1365-2524.2012.01092.x DO - 10.1111/j.1365-2524.2012.01092.x M1 - Article JO - Health and Social Care in the Community JF - Health and Social Care in the Community IS - 3 VL - 21 SP - 225 EP - 235 ER - TY - JOUR T1 - The vascular collar of the ilium T2 - Three-dimensional evaluation of the dominant nutrient foramen A1 - Cunningham,Craig A. A1 - Black,Sue M. AU - Cunningham,Craig A. AU - Black,Sue M. PY - 2013/5 Y1 - 2013/5 N2 - Nutrient arteries are the predominant blood supply to endochondral bones and are particularly important during the early stages of endochondral ossification and the active growth period. These nutrient vessels traverse the periosteal shell of a developing bone to invade the disintegrating cartilage matrix and bring about endochondral bone formation. This results in the formation of a nutrient foramen which is retained as the vascular conduit between the exterior and interior of the bone. This study examined the dominant nutrient foramen of the neonatal ilium using high resolution micro-computed (micro-CT) tomography. Three-dimensional reconstruction of micro-CT data consistently demonstrated the presence of a distinctive, yet poorly reported, collar of bone extending into the trabecular cavity beyond the endosteum. This study proposes that this collar of bone may have formed in response to osteogenic signaling from approximated arterial vasculature. Additionally, it is suggested that the formation of this collar may act as a protective mechanism to the dominant nutrient vessel and as a potential biomechanical anchor for surrounding trabeculae, aiding to increase the biomechanical competency around the area of the foramen. The documentation of this osteological structure is important from a clinical perspective to prevent the misinterpretation of fracturing and pathology on plain plate radiographs and clinical computed tomography scans. © 2013 Wiley Periodicals, Inc. AB - Nutrient arteries are the predominant blood supply to endochondral bones and are particularly important during the early stages of endochondral ossification and the active growth period. These nutrient vessels traverse the periosteal shell of a developing bone to invade the disintegrating cartilage matrix and bring about endochondral bone formation. This results in the formation of a nutrient foramen which is retained as the vascular conduit between the exterior and interior of the bone. This study examined the dominant nutrient foramen of the neonatal ilium using high resolution micro-computed (micro-CT) tomography. Three-dimensional reconstruction of micro-CT data consistently demonstrated the presence of a distinctive, yet poorly reported, collar of bone extending into the trabecular cavity beyond the endosteum. This study proposes that this collar of bone may have formed in response to osteogenic signaling from approximated arterial vasculature. Additionally, it is suggested that the formation of this collar may act as a protective mechanism to the dominant nutrient vessel and as a potential biomechanical anchor for surrounding trabeculae, aiding to increase the biomechanical competency around the area of the foramen. The documentation of this osteological structure is important from a clinical perspective to prevent the misinterpretation of fracturing and pathology on plain plate radiographs and clinical computed tomography scans. © 2013 Wiley Periodicals, Inc. KW - Vasculature KW - MicroCT KW - trabeulae KW - Juvenile KW - Bone UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872326041&md5=cb60ca1ae42d2145a66968c2159b53bc U2 - 10.1002/ca.22213 DO - 10.1002/ca.22213 M1 - Article JO - Clinical Anatomy JF - Clinical Anatomy SN - 0897-3806 IS - 4 VL - 26 SP - 502 EP - 508 ER - TY - JOUR T1 - Validation of the revised Bakas Caregiving Outcomes Scale in Greek caregivers of patients with advanced cancer receiving palliative radiotherapy A1 - Govina,Ourania A1 - Kotronoulas,Grigorios A1 - Mystakidou,Kyriaki A1 - Giannakopoulou,Margarita A1 - Galanos,Antonios A1 - Patiraki,Elisabeth AU - Govina,Ourania AU - Kotronoulas,Grigorios AU - Mystakidou,Kyriaki AU - Giannakopoulou,Margarita AU - Galanos,Antonios AU - Patiraki,Elisabeth PY - 2013/5 Y1 - 2013/5 N2 -

Caregiver burden considerably affects the lives of families providing care to people with advanced cancer. The aim of this study was to validate the Greek translation of the revised Bakas Caregiving Outcomes Scale (BCOS) with a sample of informal caregivers of people with advanced cancer receiving outpatient palliative radiotherapy.

Following a formal "forward-backward" method to translate the original BCOS into Greek, the scale was administered to 100 consecutive family caregivers. Participants also completed the Greek Hospital Anxiety and Depression Scale (G-HADS) and five quality-of-life related linear analogue scale assessment (LASA) scales. Validity and reliability analyses were performed.

The Cronbach's alpha coefficient for the total BCOS score was 0.83. Test-retest reliability analysis in a subgroup of caregivers (n = 40) revealed good short-term stability over a 2-week interval. Exploratory factor analysis generated a one-factor structure for the Greek translation, which was further confirmed through confirmatory factor analysis. Construct validity was supported through the scale's high correlations with G-HADS anxiety (-0.524; p <0.001) and depression (-0.533; p <0.001) scores, and LASA quality of life scores (0.696; p <0.001). The BCOS discriminated well between groups of caregivers with different levels of quality of life. A total score of 52.5 offered high sensitivity (91 %) and specificity (86 %) in detecting highly burdened caregivers.

The Greek version of the BCOS is a psychometrically sound instrument that can be usefully implemented into clinical practice to identify family caregivers in need for support, and stimulate relevant research in our country.

AB -

Caregiver burden considerably affects the lives of families providing care to people with advanced cancer. The aim of this study was to validate the Greek translation of the revised Bakas Caregiving Outcomes Scale (BCOS) with a sample of informal caregivers of people with advanced cancer receiving outpatient palliative radiotherapy.

Following a formal "forward-backward" method to translate the original BCOS into Greek, the scale was administered to 100 consecutive family caregivers. Participants also completed the Greek Hospital Anxiety and Depression Scale (G-HADS) and five quality-of-life related linear analogue scale assessment (LASA) scales. Validity and reliability analyses were performed.

The Cronbach's alpha coefficient for the total BCOS score was 0.83. Test-retest reliability analysis in a subgroup of caregivers (n = 40) revealed good short-term stability over a 2-week interval. Exploratory factor analysis generated a one-factor structure for the Greek translation, which was further confirmed through confirmatory factor analysis. Construct validity was supported through the scale's high correlations with G-HADS anxiety (-0.524; p <0.001) and depression (-0.533; p <0.001) scores, and LASA quality of life scores (0.696; p <0.001). The BCOS discriminated well between groups of caregivers with different levels of quality of life. A total score of 52.5 offered high sensitivity (91 %) and specificity (86 %) in detecting highly burdened caregivers.

The Greek version of the BCOS is a psychometrically sound instrument that can be usefully implemented into clinical practice to identify family caregivers in need for support, and stimulate relevant research in our country.

KW - FIT KW - DEMENTIA KW - QUALITY-OF-LIFE KW - Reliability KW - Validity KW - Bakas Caregiving Outcomes Scale KW - DEPRESSION SCALE KW - HEART-FAILURE KW - Family caregiver KW - HOSPITAL ANXIETY KW - BURDEN KW - MODELS KW - Caregiver burden KW - Advancedcancer U2 - 10.1007/s00520-012-1681-7 DO - 10.1007/s00520-012-1681-7 M1 - Article JO - Supportive Care in Cancer JF - Supportive Care in Cancer SN - 0941-4355 IS - 5 VL - 21 SP - 1395 EP - 1404 ER - TY - JOUR T1 - Was there a British Georgian Town? T2 - A comparison between selected Scottish burghs and English towns. A1 - McKean,Charles AU - McKean,Charles PY - 2013/5 Y1 - 2013/5 N2 - This article examines the nature of Scottish urban ambition during the Enlightenment period, through assessing the pattern of public building construction in selected burghs against the general historiography of Georgian towns. Using principally Scottish burgh council minutes and contemporary publications, it studies the improvement agenda as the context for civic building, and questions whether it provided a discernible process and chronology for the construction activity. In reviewing the symbolic role of public buildings in particular, the article ponders whether there was indeed a British urban experience toward the end of the first century of parliamentary union.1 It concludes that both in the historically different Scottish urbanism and the distinctive manner in which Scots burghs responded to improvement, the urban experience north and south of the border was significantly different. AB - This article examines the nature of Scottish urban ambition during the Enlightenment period, through assessing the pattern of public building construction in selected burghs against the general historiography of Georgian towns. Using principally Scottish burgh council minutes and contemporary publications, it studies the improvement agenda as the context for civic building, and questions whether it provided a discernible process and chronology for the construction activity. In reviewing the symbolic role of public buildings in particular, the article ponders whether there was indeed a British urban experience toward the end of the first century of parliamentary union.1 It concludes that both in the historically different Scottish urbanism and the distinctive manner in which Scots burghs responded to improvement, the urban experience north and south of the border was significantly different. U2 - 10.1111/1468-2281.12013 DO - 10.1111/1468-2281.12013 M1 - Article JO - Historical Research JF - Historical Research SN - 0950-3471 IS - 232 VL - 86 SP - 253 EP - 291 ER - TY - JOUR T1 - Systematic Screening of a Drosophila ORF Library In Vivo Uncovers Wnt/Wg Pathway Components A1 - Schertel,Claus A1 - Huang,Dashun A1 - Bjorklund,Mikael A1 - Bischof,Johannes A1 - Yin,Dingzi A1 - Li,Rongxia A1 - Wu,Yi A1 - Zeng,Rong A1 - Wu,Jiarui A1 - Taipale,Jussi A1 - Song,Haiyun A1 - Basler,Konrad AU - Schertel,Claus AU - Huang,Dashun AU - Bjorklund,Mikael AU - Bischof,Johannes AU - Yin,Dingzi AU - Li,Rongxia AU - Wu,Yi AU - Zeng,Rong AU - Wu,Jiarui AU - Taipale,Jussi AU - Song,Haiyun AU - Basler,Konrad PY - 2013/4/29 Y1 - 2013/4/29 N2 - We created a site-directed UAS-ORF library of 655 growth-regulating genes in Drosophila. This library represents a large collection of genes regulating cell cycle, cell size, and proliferation and will be a valuable resource for studying growth regulation in vivo. By using misexpression of genes, we prevent problems arising from genetic redundancy and can uncover novel gene functions. To validate the usefulness of this library, we screened for Wingless (Wg) pathway components. We used a combination of experimental and bioinformatic approaches to predict candidates and identified three serine/threonine kinases as regulators of Wg signaling. We show that one of these, Nek2, optimizes pathway response by direct phosphorylation of Dishevelled. In addition, we describe functional relations for roughly 5% of all Drosophila genes and identify a large number of genes that regulate cell size, proliferation, and final organ size upon misexpression. © 2013 Elsevier Inc. All rights reserved. AB - We created a site-directed UAS-ORF library of 655 growth-regulating genes in Drosophila. This library represents a large collection of genes regulating cell cycle, cell size, and proliferation and will be a valuable resource for studying growth regulation in vivo. By using misexpression of genes, we prevent problems arising from genetic redundancy and can uncover novel gene functions. To validate the usefulness of this library, we screened for Wingless (Wg) pathway components. We used a combination of experimental and bioinformatic approaches to predict candidates and identified three serine/threonine kinases as regulators of Wg signaling. We show that one of these, Nek2, optimizes pathway response by direct phosphorylation of Dishevelled. In addition, we describe functional relations for roughly 5% of all Drosophila genes and identify a large number of genes that regulate cell size, proliferation, and final organ size upon misexpression. © 2013 Elsevier Inc. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875920928&md5=81c8cf3dee1a9f92ccd5824bc53ef502 U2 - 10.1016/j.devcel.2013.02.019 DO - 10.1016/j.devcel.2013.02.019 M1 - Article JO - Developmental Cell JF - Developmental Cell SN - 1534-5807 IS - 2 VL - 25 SP - 207 EP - 219 ER - TY - JOUR T1 - The Sustainable Relationship T2 - What the United States and the United Kingdom Can Teach Each Other About Climate Change and Sustainable Development at the National Level A1 - Dernbach,John C. A1 - Ross,Andrea AU - Dernbach,John C. AU - Ross,Andrea PY - 2013/4/26 Y1 - 2013/4/26 N2 - As the urgency of climate change, biodiversity loss, severe poverty, and other global environmental and development challenges continues to grow, concerted international action to address them is becoming even harder. National efforts are thus more important than ever. An important example is the United Kingdom and the United States, which have stronger ties with each other than almost any other county — the so-called “special relationship.” They share a common language and history, and have similar legal systems and culture. The United States and the United Kingdom also aspire to international leadership, and often play that role. Accelerating the transition to sustainability requires six elements at the national level. These are a national strategy, legal integration mechanisms, governmental implementing or coordinating bodies, monitoring and review mechanisms, leadership, and a bottom-up sustainability movement. This article describes and compares key U.S. and U.K. actions on these elements, and suggests what each could learn from the other. AB - As the urgency of climate change, biodiversity loss, severe poverty, and other global environmental and development challenges continues to grow, concerted international action to address them is becoming even harder. National efforts are thus more important than ever. An important example is the United Kingdom and the United States, which have stronger ties with each other than almost any other county — the so-called “special relationship.” They share a common language and history, and have similar legal systems and culture. The United States and the United Kingdom also aspire to international leadership, and often play that role. Accelerating the transition to sustainability requires six elements at the national level. These are a national strategy, legal integration mechanisms, governmental implementing or coordinating bodies, monitoring and review mechanisms, leadership, and a bottom-up sustainability movement. This article describes and compares key U.S. and U.K. actions on these elements, and suggests what each could learn from the other. KW - Sustainable development, climate change, national, progress, US, UK UR - http://papers.ssrn.com/sol3/papers.cfm?abstract_id=2256983 M1 - Article IS - 3 VL - 30 SP - 30 EP - 34 ER - TY - JOUR T1 - Tumour Cell Labelling by Magnetic Nanoparticles with Determination of Intracellular Iron Content and Spatial Distribution of the Intracellular Iron A1 - Wang,Zhigang A1 - Cuschieri,Alfred AU - Wang,Zhigang AU - Cuschieri,Alfred PY - 2013/4/26 Y1 - 2013/4/26 N2 - Magnetically labelled cells are used for in vivo cell tracking by MRI, used for the clinical translation of cell-base therapies. Studies involving magnetic labelled cells may include separation of labelled cells, targeted delivery and controlled release of drugs, contrast enhanced MRI and magnetic hyperthermia for the in situ ablation of tumours. Dextran-coated super-paramagnetic iron oxide (SPIO) ferumoxides are used clinically as an MR contrast agents primarily for hepatic imaging. The material is also widely used for in vitro cell labelling, as are other SPIO-based particles. Our results on the uptake by human cancer cell lines of ferumoxides indicate that electroporation in the presence of protamine sulphate (PS) results in rapid high uptake of SPIO nanoparticles (SPIONs) by parenchymal tumour cells without significant impairment of cell viability. Quantitative determination of cellular iron uptake performed by colorimetric assay is in agreement with data from the literature. These results on intracellular iron content together with the intracellular distribution of SPIONs by magnetic force microscopy (MFM) following in vitro uptake by parenchymal tumour cells confirm the potential of this technique for clinical tumour cell detection and destruction. AB - Magnetically labelled cells are used for in vivo cell tracking by MRI, used for the clinical translation of cell-base therapies. Studies involving magnetic labelled cells may include separation of labelled cells, targeted delivery and controlled release of drugs, contrast enhanced MRI and magnetic hyperthermia for the in situ ablation of tumours. Dextran-coated super-paramagnetic iron oxide (SPIO) ferumoxides are used clinically as an MR contrast agents primarily for hepatic imaging. The material is also widely used for in vitro cell labelling, as are other SPIO-based particles. Our results on the uptake by human cancer cell lines of ferumoxides indicate that electroporation in the presence of protamine sulphate (PS) results in rapid high uptake of SPIO nanoparticles (SPIONs) by parenchymal tumour cells without significant impairment of cell viability. Quantitative determination of cellular iron uptake performed by colorimetric assay is in agreement with data from the literature. These results on intracellular iron content together with the intracellular distribution of SPIONs by magnetic force microscopy (MFM) following in vitro uptake by parenchymal tumour cells confirm the potential of this technique for clinical tumour cell detection and destruction. KW - magnetic nanoparticles KW - magnetic cell labelling KW - magnetic force microscopy KW - superparamagnetic UR - http://www.mdpi.com/1422-0067/14/5/9111 U2 - 10.3390/ijms14059111 DO - 10.3390/ijms14059111 M1 - Article JO - International Journal of Molecular Sciences JF - International Journal of Molecular Sciences SN - 1661-6596 IS - 5 VL - 14 SP - 9111 EP - 9125 ER - TY - JOUR T1 - Nitric oxide regulates cardiac intracellular Na(+) and Ca(2+) by modulating Na/K ATPase via PKCε and phospholemman-dependent mechanism A1 - Pavlovic,Davor A1 - Hall,Andrew R A1 - Kennington,Erika J A1 - Aughton,Karen A1 - Boguslavskyi,Andrii A1 - Fuller,William A1 - Despa,Sanda A1 - Bers,Donald M A1 - Shattock,Michael J AU - Pavlovic,Davor AU - Hall,Andrew R AU - Kennington,Erika J AU - Aughton,Karen AU - Boguslavskyi,Andrii AU - Fuller,William AU - Despa,Sanda AU - Bers,Donald M AU - Shattock,Michael J PY - 2013/4/20 Y1 - 2013/4/20 N2 - In the heart, Na/K-ATPase regulates intracellular Na(+) and Ca(2+) (via NCX), thereby preventing Na(+) and Ca(2+) overload and arrhythmias. Here, we test the hypothesis that nitric oxide (NO) regulates cardiac intracellular Na(+) and Ca(2+) and investigate mechanisms and physiological consequences involved. Effects of both exogenous NO (via NO-donors) and endogenously synthesized NO (via field-stimulation of ventricular myocytes) were assessed in this study. Field stimulation of rat ventricular myocytes significantly increased endogenous NO (18±2µM), PKCe activation (82±12%), phospholemman phosphorylation (at Ser-63 and Ser-68) and Na/K-ATPase activity (measured by DAF-FM dye, western-blotting and biochemical assay, respectively; p AB - In the heart, Na/K-ATPase regulates intracellular Na(+) and Ca(2+) (via NCX), thereby preventing Na(+) and Ca(2+) overload and arrhythmias. Here, we test the hypothesis that nitric oxide (NO) regulates cardiac intracellular Na(+) and Ca(2+) and investigate mechanisms and physiological consequences involved. Effects of both exogenous NO (via NO-donors) and endogenously synthesized NO (via field-stimulation of ventricular myocytes) were assessed in this study. Field stimulation of rat ventricular myocytes significantly increased endogenous NO (18±2µM), PKCe activation (82±12%), phospholemman phosphorylation (at Ser-63 and Ser-68) and Na/K-ATPase activity (measured by DAF-FM dye, western-blotting and biochemical assay, respectively; p U2 - 10.1016/j.yjmcc.2013.04.013 DO - 10.1016/j.yjmcc.2013.04.013 M1 - Article JO - Journal of Molecular and Cellular Cardiology JF - Journal of Molecular and Cellular Cardiology ER - TY - JOUR T1 - Dental neglect as a marker of broader neglect T2 - a qualitative investigation of public health Nurses' assessments of oral health in preschool children A1 - Bradbury-Jones,Caroline A1 - Innes,Nicola A1 - Evans,Dafydd A1 - Ballantyne,Fiona A1 - Taylor,Julie AU - Bradbury-Jones,Caroline AU - Innes,Nicola AU - Evans,Dafydd AU - Ballantyne,Fiona AU - Taylor,Julie PY - 2013/4/19 Y1 - 2013/4/19 N2 - Background
Child neglect is a pernicious child protection issue with adverse consequences that extend to adulthood. Simultaneously, though it remains prevalent, childhood dental caries is a preventable disease. Public health nurses play a pivotal role in assessing oral health in children as part of general health surveillance. However, little is known about how they assess dental neglect or what their thresholds are for initiating targeted support or instigating child protection measures. Understanding these factors is important to allow improvements to be made in care pathways.

Methods
We investigated public health nurses' assessment of oral health in preschool children in relation to dental neglect and any associations they make with child neglect more broadly. A qualitative study was conducted in Scotland during 2011/12. Sixteen public health nurses were recruited purposively from one health region. Individual, semi-structured interviews were undertaken and data were analyzed inductively using a framework approach. Categories were subsequently mapped to the research questions.

Results
Public health nurses assess oral health through proxy measures, opportunistic observation and through discussion with parents. Dental neglect is rarely an isolated issue that leads on its own to child protection referral. It tends to be other presenting issues that initiate a response. Threshold levels for targeted support were based on two broad indicators: social issues and concerns about child (and parental) dental health. Thresholds for child protection intervention were untreated dental caries or significant dental pain. Barriers to intervention are that dental neglect may be 'unseen' and 'unspoken'. The study revealed a communication gap in the care pathway for children where a significant dental problem is identified.

Conclusions
Public health nurses take their child protection role seriously, but rarely make a link between dental caries and child neglect. Clear guidance on oral health assessment is required for public health nurses. Establishing formal communication pathways between child dental care providers and public health nurses may help close gaps in care pathways. However, further research is required into how these communication mechanisms can be improved. AB - Background
Child neglect is a pernicious child protection issue with adverse consequences that extend to adulthood. Simultaneously, though it remains prevalent, childhood dental caries is a preventable disease. Public health nurses play a pivotal role in assessing oral health in children as part of general health surveillance. However, little is known about how they assess dental neglect or what their thresholds are for initiating targeted support or instigating child protection measures. Understanding these factors is important to allow improvements to be made in care pathways.

Methods
We investigated public health nurses' assessment of oral health in preschool children in relation to dental neglect and any associations they make with child neglect more broadly. A qualitative study was conducted in Scotland during 2011/12. Sixteen public health nurses were recruited purposively from one health region. Individual, semi-structured interviews were undertaken and data were analyzed inductively using a framework approach. Categories were subsequently mapped to the research questions.

Results
Public health nurses assess oral health through proxy measures, opportunistic observation and through discussion with parents. Dental neglect is rarely an isolated issue that leads on its own to child protection referral. It tends to be other presenting issues that initiate a response. Threshold levels for targeted support were based on two broad indicators: social issues and concerns about child (and parental) dental health. Thresholds for child protection intervention were untreated dental caries or significant dental pain. Barriers to intervention are that dental neglect may be 'unseen' and 'unspoken'. The study revealed a communication gap in the care pathway for children where a significant dental problem is identified.

Conclusions
Public health nurses take their child protection role seriously, but rarely make a link between dental caries and child neglect. Clear guidance on oral health assessment is required for public health nurses. Establishing formal communication pathways between child dental care providers and public health nurses may help close gaps in care pathways. However, further research is required into how these communication mechanisms can be improved. KW - Children KW - Dental KW - Neglect KW - Nurse KW - Oral KW - Public health KW - Qualitative KW - Threshold U2 - 10.1186/1471-2458-13-370 DO - 10.1186/1471-2458-13-370 M1 - Article JO - BMC Public Health JF - BMC Public Health SN - 1471-2458 VL - 13 ER - TY - PAT T1 - Improved sperm function / activity A1 - Barratt,Christopher A1 - Wyatt,Paul AU - Barratt,Christopher AU - Wyatt,Paul PY - 2013/4/18 Y1 - 2013/4/18 N2 - The present invention concerns phosphodiesterase inhibitors which may be used to modulate sperm motility, activity and/or function. Moreover the invention provides modulators of PDElGa which may be used to modulate the physiological processes occurring within a sperm cell. AB - The present invention concerns phosphodiesterase inhibitors which may be used to modulate sperm motility, activity and/or function. Moreover the invention provides modulators of PDElGa which may be used to modulate the physiological processes occurring within a sperm cell. UR - http://www.freepatentsonline.com/WO2013054111A1.html M1 - WO2013054111 A1 ER - TY - JOUR T1 - Schizophrenia is associated with excess multiple physical-health comorbidities but low levels of recorded cardiovascular disease in primary care T2 - cross-sectional study A1 - Smith,Daniel J A1 - Langan,Julie A1 - McLean,Gary A1 - Guthrie,Bruce A1 - Mercer,Stewart W AU - Smith,Daniel J AU - Langan,Julie AU - McLean,Gary AU - Guthrie,Bruce AU - Mercer,Stewart W PY - 2013/4/17 Y1 - 2013/4/17 N2 - OBJECTIVE: To assess the nature and extent of physical-health comorbidities in people with schizophrenia and related psychoses compared with controls. DESIGN: Cross-sectional study. SETTING: 314 primary care practices in Scotland. PARTICIPANTS: 9677 people with a primary care record of schizophrenia or a related psychosis and 1 414 701 controls. Main outcome measures Primary care records of 32 common chronic physical-health conditions and combinations of one, two and three or more physical-health comorbidities adjusted for age, gender and deprivation status. RESULTS: Compared with controls, people with schizophrenia were significantly more likely to have one physical-health comorbidity (OR 1.21, 95% CI 1.16 to 1.27), two physical-health comorbidities (OR 1.37, 95% CI 1.29 to 1.44) and three or more physical-health comorbidities (OR 1.19, 95% CI 1.12 to 1.27). Rates were highest for viral hepatitis (OR 3.98, 95% CI 2.81 to 5.64), constipation (OR 3.24, 95% CI 3.00 to 4.49) and Parkinson's disease (OR 3.07, 95% CI 2.42 to 3.88) but people with schizophrenia had lower recorded rates of cardiovascular disease, including atrial fibrillation (OR 0.62, 95% CI 0.51 to 0.73), hypertension (OR 0.71, 95% CI 0.67 to 0.76), coronary heart disease (OR 0.75, 95% CI 0.61 to 0.71) and peripheral vascular disease (OR 0.83, 95% CI 0.71 to 0.97). CONCLUSIONS: People with schizophrenia have a wide range of comorbid and multiple physical-health conditions but are less likely than people without schizophrenia to have a primary care record of cardiovascular disease. This suggests a systematic under-recognition and undertreatment of cardiovascular disease in people with schizophrenia, which might contribute to substantial premature mortality observed within this patient group. AB - OBJECTIVE: To assess the nature and extent of physical-health comorbidities in people with schizophrenia and related psychoses compared with controls. DESIGN: Cross-sectional study. SETTING: 314 primary care practices in Scotland. PARTICIPANTS: 9677 people with a primary care record of schizophrenia or a related psychosis and 1 414 701 controls. Main outcome measures Primary care records of 32 common chronic physical-health conditions and combinations of one, two and three or more physical-health comorbidities adjusted for age, gender and deprivation status. RESULTS: Compared with controls, people with schizophrenia were significantly more likely to have one physical-health comorbidity (OR 1.21, 95% CI 1.16 to 1.27), two physical-health comorbidities (OR 1.37, 95% CI 1.29 to 1.44) and three or more physical-health comorbidities (OR 1.19, 95% CI 1.12 to 1.27). Rates were highest for viral hepatitis (OR 3.98, 95% CI 2.81 to 5.64), constipation (OR 3.24, 95% CI 3.00 to 4.49) and Parkinson's disease (OR 3.07, 95% CI 2.42 to 3.88) but people with schizophrenia had lower recorded rates of cardiovascular disease, including atrial fibrillation (OR 0.62, 95% CI 0.51 to 0.73), hypertension (OR 0.71, 95% CI 0.67 to 0.76), coronary heart disease (OR 0.75, 95% CI 0.61 to 0.71) and peripheral vascular disease (OR 0.83, 95% CI 0.71 to 0.97). CONCLUSIONS: People with schizophrenia have a wide range of comorbid and multiple physical-health conditions but are less likely than people without schizophrenia to have a primary care record of cardiovascular disease. This suggests a systematic under-recognition and undertreatment of cardiovascular disease in people with schizophrenia, which might contribute to substantial premature mortality observed within this patient group. U2 - 10.1136/bmjopen-2013-002808 DO - 10.1136/bmjopen-2013-002808 M1 - Article JO - BMJ Open JF - BMJ Open SN - 2044-6055 IS - 4 VL - 3 ER - TY - JOUR T1 - Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality A1 - Makubate,B. A1 - Donnan,P. T. A1 - Dewar,J. A. A1 - Thompson,A. M. A1 - McCowan,C. AU - Makubate,B. AU - Donnan,P. T. AU - Dewar,J. A. AU - Thompson,A. M. AU - McCowan,C. PY - 2013/4/16 Y1 - 2013/4/16 N2 -

Background: Adjuvant endocrine therapy is recommended for women with oestrogen receptor-positive breast cancer, but many women do not take the medication as directed and they stop treatment before completing the standard 5-year duration.

Methods: This retrospective cohort study conducted between 1993 and 2008 of all women with incident breast cancer, who are residing in the Tayside region of Scotland, examined adherence to prescribed adjuvant tamoxifen or aromatase inhibitors (AIs). Survival analysis examined the effect of adherence on all-cause mortality, breast cancer death and recurrence, using linked prescribing, cancer registry, clinical cancer audit, hospital discharge and death records.

Results: A total of 3361 women with breast cancer were followed for a median 4.47 years (interquartile range (IQR) 2.04-8.55). The median overall adherence was 90% (IQR 90-100%), but the annual adherence reduced after a longer period from diagnosis. Low adherence of

Conclusion: Low adherence to all adjuvant endocrine therapy for women with breast cancer, whether tamoxifen or AI, increases the risk of death.

AB -

Background: Adjuvant endocrine therapy is recommended for women with oestrogen receptor-positive breast cancer, but many women do not take the medication as directed and they stop treatment before completing the standard 5-year duration.

Methods: This retrospective cohort study conducted between 1993 and 2008 of all women with incident breast cancer, who are residing in the Tayside region of Scotland, examined adherence to prescribed adjuvant tamoxifen or aromatase inhibitors (AIs). Survival analysis examined the effect of adherence on all-cause mortality, breast cancer death and recurrence, using linked prescribing, cancer registry, clinical cancer audit, hospital discharge and death records.

Results: A total of 3361 women with breast cancer were followed for a median 4.47 years (interquartile range (IQR) 2.04-8.55). The median overall adherence was 90% (IQR 90-100%), but the annual adherence reduced after a longer period from diagnosis. Low adherence of

Conclusion: Low adherence to all adjuvant endocrine therapy for women with breast cancer, whether tamoxifen or AI, increases the risk of death.

KW - NONADHERENCE KW - tamoxifen KW - ANASTROZOLE KW - TAMOXIFEN KW - OLDER WOMEN KW - aromatase inhibitors KW - PREDICTORS KW - breast cancer KW - adherence KW - recurrence KW - mortality KW - EARLY DISCONTINUATION KW - MEDICATION U2 - 10.1038/bjc.2013.116 DO - 10.1038/bjc.2013.116 M1 - Article JO - British Journal of Cancer JF - British Journal of Cancer SN - 0007-0920 IS - 7 VL - 108 SP - 1515 EP - 1524 ER - TY - JOUR T1 - LKB1 and AMPK and the cancer-metabolism link - ten years after A1 - Hardie,D. Grahame A1 - Alessi,Dario R. AU - Hardie,D. Grahame AU - Alessi,Dario R. PY - 2013/4/15 Y1 - 2013/4/15 N2 -

The identification of a complex containing the tumor suppressor LKB1 as
the critical upstream kinase required for the activation of
AMP-activated protein kinase (AMPK) by metabolic stress was reported in
an article in Journal of Biology in 2003. This finding represented the
first clear link between AMPK and cancer. Here we briefly discuss how
this discovery came about, and describe some of the insights, especially
into the role of AMPK in cancer, that have followed from it.In
September 2003, our groups published a joint paper 1 in Journal of
Biology (now BMC Biology) that identified the long-sought and elusive
upstream kinase acting on AMP-activated protein kinase (AMPK) as a
complex containing LKB1, a known tumor suppressor. Similar findings were
reported at about the same time by David Carling and Marian Carlson 2
and by Reuben Shaw and Lew Cantley 3; at the time of writing these three
papers have received between them a total of over 2,000 citations.
These findings provided a direct link between a protein kinase, AMPK,
which at the time was mainly associated with regulation of metabolism,
and another protein kinase, LKB1, which was known from genetic studies
to be a tumor suppressor. While the idea that cancer is in part a
metabolic disorder (first suggested by Warburg in the 1920s 4) is well
recognized today 5, this was not the case in 2003, and our paper perhaps
contributed towards its renaissance. The aim of this short review is to
recall how we made the original finding, and to discuss some of the
directions that these findings have taken the field in the ensuing ten
years.

AB -

The identification of a complex containing the tumor suppressor LKB1 as
the critical upstream kinase required for the activation of
AMP-activated protein kinase (AMPK) by metabolic stress was reported in
an article in Journal of Biology in 2003. This finding represented the
first clear link between AMPK and cancer. Here we briefly discuss how
this discovery came about, and describe some of the insights, especially
into the role of AMPK in cancer, that have followed from it.In
September 2003, our groups published a joint paper 1 in Journal of
Biology (now BMC Biology) that identified the long-sought and elusive
upstream kinase acting on AMP-activated protein kinase (AMPK) as a
complex containing LKB1, a known tumor suppressor. Similar findings were
reported at about the same time by David Carling and Marian Carlson 2
and by Reuben Shaw and Lew Cantley 3; at the time of writing these three
papers have received between them a total of over 2,000 citations.
These findings provided a direct link between a protein kinase, AMPK,
which at the time was mainly associated with regulation of metabolism,
and another protein kinase, LKB1, which was known from genetic studies
to be a tumor suppressor. While the idea that cancer is in part a
metabolic disorder (first suggested by Warburg in the 1920s 4) is well
recognized today 5, this was not the case in 2003, and our paper perhaps
contributed towards its renaissance. The aim of this short review is to
recall how we made the original finding, and to discuss some of the
directions that these findings have taken the field in the ensuing ten
years.

KW - DIABETIC-PATIENTS KW - PEUTZ-JEGHERS-SYNDROME KW - LKB1-AMPK PATHWAY KW - TUMOR-SUPPRESSOR LKB1 KW - ACTIVATED PROTEIN-KINASE KW - ACETYL-COA CARBOXYLASE KW - YEAST SNF1 KW - GLUCOSE-UPTAKE KW - UPSTREAM KINASES KW - CELLULAR-ENERGY U2 - 10.1186/1741-7007-11-36 DO - 10.1186/1741-7007-11-36 M1 - Article JO - BMC Biology JF - BMC Biology SN - 1741-7007 VL - 11 ER - TY - JOUR T1 - The P-body component USP52/PAN2 is a novel regulator of HIF1A mRNA stability A1 - Bett,John S. A1 - Ibrahim,Adel F.M. A1 - Garg,Amit K. A1 - Kelly,Van A1 - Pedrioli,Patrick A1 - Rocha,Sonia A1 - Hay,Ronald T. AU - Bett,John S. AU - Ibrahim,Adel F.M. AU - Garg,Amit K. AU - Kelly,Van AU - Pedrioli,Patrick AU - Rocha,Sonia AU - Hay,Ronald T. PY - 2013/4/15 Y1 - 2013/4/15 N2 - HIF1A (hypoxia-inducible factor 1a) is the master regulator of the cellular response to hypoxia and is implicated in cancer progression. Whereas the regulation of HIF1A protein in response to oxygen is well characterized, less is known about the fate of HIF1A mRNA. In the present study, we have identified the pseudo-DUB (deubiquitinating enzyme)/deadenylase USP52 (ubiquitin-specific protease 52)/PAN2 [poly(A) nuclease 2] as an important regulator of the HIF1A-mediated hypoxic response. Depletion of USP52 reduced HIF1A mRNA and protein levels and resulted in reduced expression of HIF1A-regulated hypoxic targets due to a 3-UTR (untranslated region)-dependent poly(A)- tail-length-independent destabilization in HIF1A mRNA. MS analysis revealed an association of USP52 with several P-body (processing body) components and we confirmed further that USP52 protein and HIF1A mRNA co-localized with cytoplasmic P-bodies. Importantly, P-body dispersal by knockdown of GW182 or LSM1 resulted in a reduction of HIF1A mRNA levels. These data uncover a novel role for P-bodies in regulating HIF1AmRNA stability, and demonstrate that USP52 is a key component of P-bodies required to prevent HIF1A mRNA degradation. © 2013 The Author(s). AB - HIF1A (hypoxia-inducible factor 1a) is the master regulator of the cellular response to hypoxia and is implicated in cancer progression. Whereas the regulation of HIF1A protein in response to oxygen is well characterized, less is known about the fate of HIF1A mRNA. In the present study, we have identified the pseudo-DUB (deubiquitinating enzyme)/deadenylase USP52 (ubiquitin-specific protease 52)/PAN2 [poly(A) nuclease 2] as an important regulator of the HIF1A-mediated hypoxic response. Depletion of USP52 reduced HIF1A mRNA and protein levels and resulted in reduced expression of HIF1A-regulated hypoxic targets due to a 3-UTR (untranslated region)-dependent poly(A)- tail-length-independent destabilization in HIF1A mRNA. MS analysis revealed an association of USP52 with several P-body (processing body) components and we confirmed further that USP52 protein and HIF1A mRNA co-localized with cytoplasmic P-bodies. Importantly, P-body dispersal by knockdown of GW182 or LSM1 resulted in a reduction of HIF1A mRNA levels. These data uncover a novel role for P-bodies in regulating HIF1AmRNA stability, and demonstrate that USP52 is a key component of P-bodies required to prevent HIF1A mRNA degradation. © 2013 The Author(s). UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875619809&md5=4f506f7413e779790d6ea6f6c0847758 U2 - 10.1042/BJ20130026 DO - 10.1042/BJ20130026 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 IS - 2 VL - 451 SP - 185 EP - 194 ER - TY - CONF T1 - Perception of ethics and ethical thinking of trainee educational psychologists T2 - implications for teaching ethics on a professional training programme A1 - Hannah,Elizabeth F.S. A1 - Murray,Patricia AU - Hannah,Elizabeth F.S. AU - Murray,Patricia PY - 2013/4/11 Y1 - 2013/4/11 N2 - Background
The ability to be alert to the ethical dimensions of practice and to acquire professional knowledge and skills to make informed ethical decisions is a core competency of educational psychologists. This paper reports an investigation into the perceptions of ethics and ethical thinking of a group of trainee educational psychologists on one professional training programme.
Design
This study was an ‘outer loop’ of a collaborative inquiry involving academics and practitioners from a range of disciplines.
Objectives
The primary objectives of the reported study were to: (a) gain an insight into the ethical awareness and understanding of trainees in the early stages of their professional training programme; and (b) inform the teaching of ethics within the professional training programme.
Methods
Focus group interviews were the preferred method given the perceived advantages of flexibility, cost-effectiveness, interactive nature of the process, and opportunity for learning from others. Fourteen trainees participated with the authors acting as facilitators. Questions explored their understanding of ethics and conflicts between personal, professional and interprofessional ethics. Sessions were audio recorded and transcribed data were thematically analysed by the authors using an inductive approach.
Results
Six main themes were identified: perspectives on ethics; ethics as a dynamic process; factors that inform ethical decision making; ethical dilemmas; ethical intentions and consequences; and personal values and career choice.
Conclusion
This investigation stimulated thinking about ways of supporting trainees’ ethical development through creating opportunities for learning and a supportive culture influenced by positive psychology. AB - Background
The ability to be alert to the ethical dimensions of practice and to acquire professional knowledge and skills to make informed ethical decisions is a core competency of educational psychologists. This paper reports an investigation into the perceptions of ethics and ethical thinking of a group of trainee educational psychologists on one professional training programme.
Design
This study was an ‘outer loop’ of a collaborative inquiry involving academics and practitioners from a range of disciplines.
Objectives
The primary objectives of the reported study were to: (a) gain an insight into the ethical awareness and understanding of trainees in the early stages of their professional training programme; and (b) inform the teaching of ethics within the professional training programme.
Methods
Focus group interviews were the preferred method given the perceived advantages of flexibility, cost-effectiveness, interactive nature of the process, and opportunity for learning from others. Fourteen trainees participated with the authors acting as facilitators. Questions explored their understanding of ethics and conflicts between personal, professional and interprofessional ethics. Sessions were audio recorded and transcribed data were thematically analysed by the authors using an inductive approach.
Results
Six main themes were identified: perspectives on ethics; ethics as a dynamic process; factors that inform ethical decision making; ethical dilemmas; ethical intentions and consequences; and personal values and career choice.
Conclusion
This investigation stimulated thinking about ways of supporting trainees’ ethical development through creating opportunities for learning and a supportive culture influenced by positive psychology. M1 - Poster ER - TY - JOUR T1 - The Jews and Irish in Modern Scotland T2 - Anti-Semitism, Sectarianism and Social Mobility A1 - Kenefick,William AU - Kenefick,William PY - 2013/4/9 Y1 - 2013/4/9 N2 - This article explores the experience of Scotland's largest Jewish community in Glasgow, as part of a larger comparison of the relationships between the Jews, the Catholic Irish and the host community in Scotland. More specifically, this study seeks to explain why the Jews of the Gorbals area of Glasgow by the mid-twentieth century ‘broke free’ of their ‘Glasgow ghetto’ before the Irish who had settled in the district a full generation earlier than the Jews. This remarkably speedy integration suggests that the Jewish experience of settlement in Glasgow and their relationship with the host community were more positive and certainly less problematic than those of the immigrant Irish. Above all, this article argues that there was a strong link between successful Jewish integration and social mobility and the limited anti-Semitism evident across Scotland, in marked contrast with the Christian sectarianism that largely defined the relationship between the Protestant host community and the Catholic Irish in twentieth century Scotland. AB - This article explores the experience of Scotland's largest Jewish community in Glasgow, as part of a larger comparison of the relationships between the Jews, the Catholic Irish and the host community in Scotland. More specifically, this study seeks to explain why the Jews of the Gorbals area of Glasgow by the mid-twentieth century ‘broke free’ of their ‘Glasgow ghetto’ before the Irish who had settled in the district a full generation earlier than the Jews. This remarkably speedy integration suggests that the Jewish experience of settlement in Glasgow and their relationship with the host community were more positive and certainly less problematic than those of the immigrant Irish. Above all, this article argues that there was a strong link between successful Jewish integration and social mobility and the limited anti-Semitism evident across Scotland, in marked contrast with the Christian sectarianism that largely defined the relationship between the Protestant host community and the Catholic Irish in twentieth century Scotland. KW - integration KW - social mobility KW - anti-semitism KW - christian sectarianism U2 - 10.1080/02619288.2013.781751 DO - 10.1080/02619288.2013.781751 M1 - Article JO - Immigrants & Minorities JF - Immigrants & Minorities ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture A1 - Berndt,S.I. A1 - Jacobs,K.B. A1 - Wang,Z. A1 - Gustafsson,S. A1 - Ingelsson,E. A1 - Fall,T. A1 - Grönberg,H. A1 - Hall,P. A1 - Magnusson,P.K. A1 - Pedersen,N. A1 - Pawitan,Y. A1 - Mägi,R. A1 - Randall,J.C. A1 - Prokopenko,I. A1 - McCarthy,M.I. A1 - Fischer,K. A1 - Milani,L. A1 - Ganna,A. A1 - Wheeler,E. A1 - Kanoni,S. A1 - Edkins,S. A1 - Hunt,S.E. A1 - Shin,S.-Y. A1 - Stirrups,K. A1 - Deloukas,P. A1 - Feitosa,M.F. A1 - Kraja,A.T. A1 - Province,M.A. A1 - Borecki,I.B. A1 - Justice,A.E. A1 - Monda,K.L. A1 - North,K.E. A1 - Croteau-Chonka,D.C. A1 - Mohlke,K.L. A1 - Day,F.R. A1 - Luan,J. A1 - Zhao,J.H. A1 - Wareham,N.J. A1 - Esko,T. A1 - Perola,M. A1 - Mihailov,E. A1 - Metspalu,A. A1 - Ferreira,T. A1 - Min,J.L. A1 - Lindgren,C.M. A1 - Gentilini,D. A1 - Di Blasio,A.M. A1 - Jackson,A.U. A1 - Bragg-Gresham,J.L. A1 - Abecasis,G.R. A1 - Boehnke,M. A1 - Vedantam,S. A1 - Hirschhorn,J.N. A1 - Willer,C.J. A1 - Winkler,T.W. A1 - Wood,A.R. A1 - Frayling,T. A1 - Workalemahu,T. A1 - Franks,P.W. A1 - Qi,L. A1 - Hunter,D. A1 - Hu,Y.-J. A1 - Lee,S.H. A1 - Liang,L. A1 - Lin,D.-Y. A1 - Neale,B.M. A1 - Thorleifsson,G. A1 - Steinthorsdottir,V. A1 - Yang,J. A1 - Medland,S.E. A1 - Montgomery,G.W. A1 - Martin,N.G. A1 - Albrecht,E. A1 - Gieger,C. A1 - Amin,N. A1 - Cadby,G. A1 - Palmer,L.J. A1 - den Heijer,M. A1 - Eklund,N. A1 - Kristiansson,K. A1 - Goel,A. A1 - Farrall,M. A1 - Ripatti,S. A1 - Watkins,H. A1 - Hottenga,J.-J. A1 - Willemsen,G. A1 - Boomsma,D.I. A1 - Huffman,J.E. A1 - Hayward,C. A1 - Vitart,V. A1 - Wright,A.F. A1 - Jarick,I. A1 - Johansson,A. A1 - Johnson,T. A1 - Munroe,P.B. A1 - Caulfield,M.J. A1 - Kleber,M.E. A1 - König,I.R. A1 - Kutalik,Z. A1 - Marek,D. A1 - Lamina,C. A1 - Lecoeur,C. A1 - Skrobek,B. A1 - Froguel,P. A1 - Meyre,D. A1 - Li,G. A1 - Mangino,M. A1 - Soranzo,N. A1 - Spector,T.D. A1 - McArdle,W.L. A1 - Medina-Gomez,C. A1 - Peters,M.J. A1 - Estrada,K. A1 - Rivadeneira,F. A1 - van Meurs,J.B.J. A1 - Witteman,J.C.M. A1 - Hofman,A. A1 - Uitterlinden,A.G. A1 - van Duijn,C.M. A1 - Zillikens,M.C. A1 - Müller-Nurasyid,M. A1 - Ngwa,J.S. A1 - Cupples,L.A. A1 - Nolte,I.M. A1 - Paternoster,L. A1 - Evans,D.M. A1 - Pechlivanis,S. A1 - Pütter,C. A1 - Jöckel,K.-H. A1 - Scherag,A. A1 - Surakka,I. A1 - Palotie,A. A1 - Widén,E. A1 - Preuss,M. A1 - Rose,L.M. A1 - Shi,J. A1 - Chanock,S.J. A1 - Shungin,D. A1 - Smith,A.V. A1 - Gudnason,V. A1 - Stefansson,K. A1 - Thorsteinsdottir,U. A1 - Strawbridge,R.J. A1 - Hamsten,A. A1 - Teumer,A. A1 - Homuth,G. A1 - Trip,M.D. A1 - Tyrer,J. A1 - Van Vliet-Ostaptchouk,J.V. A1 - Van der Klauw,M.M. A1 - Wolffenbuttel,B.H.R. A1 - Bruinenberg,M. A1 - Stolk,R.P. A1 - Snieder,H. A1 - Vandenput,L. A1 - Lorentzon,M. A1 - Waite,L.L. A1 - Absher,D. A1 - Ohlsson,C. A1 - Asselbergs,F.W. A1 - Atalay,M. A1 - Attwood,A.P. A1 - Ouwehand,W.H. A1 - Balmforth,A.J. A1 - Basart,H. A1 - Hovingh,K.G. A1 - Beilby,J. A1 - Bonnycastle,L.L. A1 - Chines,P.S. A1 - Collins,F.S. A1 - Narisu,N. A1 - Swift,A.J. A1 - Brambilla,P. A1 - Campbell,H. A1 - Rudan,I. A1 - Wild,S.H. A1 - Wilson,J.F. A1 - Chasman,D.I. A1 - Ridker,P.M. A1 - Connell,John M. A1 - Cookson,W.O. A1 - Moffatt,M.F. A1 - de Faire,U. A1 - de Vegt,F. A1 - Dei,M. A1 - Sanna,S. A1 - Dimitriou,M. A1 - Theodoraki,E.V. A1 - Dedoussis,G.V. A1 - Ferrario,M.M. A1 - Ferrières,J. A1 - Franke,L. A1 - Frau,F. A1 - Gejman,P.V. A1 - Sanders,A.R. A1 - Grallert,H. A1 - Hall,A.S. A1 - Hartikainen,A.-L. A1 - Heard-Costa,N.L. A1 - Heath,A.C. A1 - Madden,P.A. A1 - Hebebrand,J. A1 - Hinney,A. A1 - Hu,F.B. A1 - Hyppönen,E. A1 - Power,C. A1 - Iribarren,C. A1 - Jansson,J.-O. A1 - Jula,A. A1 - Kähönen,M. A1 - Kathiresan,S. A1 - Kee,F. A1 - Khaw,K.-T. A1 - Kivimäki,M. A1 - Kumari,M. A1 - Langenberg,C. A1 - Hingorani,A. A1 - Koenig,W. A1 - Kuulasmaa,K. A1 - Virtamo,J. A1 - Salomaa,V. A1 - Kuusisto,J. A1 - Laakso,M. A1 - Laitinen,J.H. A1 - Lakka,T.A. A1 - Ong,K.K. A1 - Loos,R.J.F. A1 - Launer,L.J. A1 - Harris,T.B. A1 - Lind,L. A1 - Lindström,J. A1 - Liu,J. A1 - Liuzzi,A. A1 - Lokki,M.-L. A1 - Manunta,P. A1 - März,W. A1 - Leach,I.M. A1 - van der Harst,P. A1 - McKnight,B. A1 - Mooser,V. A1 - Mühleisen,T.W. A1 - Musk,A.W. A1 - Navis,G. A1 - Nicholson,G. A1 - Nohr,E.A. A1 - Wong,A. A1 - Kuh,D. A1 - Oostra,B.A. A1 - Palmer,Colin N.A. A1 - Morris,Andrew D. A1 - Radhakrishnan,A. A1 - Barroso,I. A1 - Peden,J.F. A1 - Peters,A. A1 - Illig,T. A1 - Thorand,B. A1 - Polasek,O. A1 - Pouta,A. A1 - Pramstaller,P.P. A1 - Rendon,A. A1 - Sambrook,J.G. A1 - Stephens,J.C. A1 - Raitakari,O. A1 - Saaristo,T.E. A1 - Saramies,J. A1 - Schipf,S. A1 - Schreiber,S. A1 - Schunkert,H. A1 - Erdmann,J. A1 - Signorini,S. A1 - Sinisalo,J. A1 - Nieminen,M.S. A1 - Stančáková,A. A1 - Stark,K. A1 - Hengstenberg,C. A1 - Stumvoll,M. A1 - Tönjes,A. A1 - Tregouet,D.-A. A1 - Tremoli,E. A1 - Vermeulen,S.H. A1 - Kiemeney,L.A. A1 - Viikari,J. A1 - Waeber,G. A1 - Vollenweider,P. A1 - Winkelmann,B.R. A1 - Amouyel,P. A1 - Boehm,B.O. A1 - Boerwinkle,E. A1 - Cusi,D. A1 - Eriksson,J.G. A1 - Gyllensten,U. A1 - Hicks,A.A. A1 - Hveem,K. A1 - Jarvelin,M.-R. A1 - Keinanen-Kiukaanniemi,S.M. A1 - Lehtimäki,T. A1 - Levinson,D.F. A1 - Njølstad,I. A1 - Oldehinkel,A.J. A1 - Penninx,B. A1 - Psaty,B.M. A1 - Rauramaa,R. A1 - Samani,N.J. A1 - Sørensen,T.I.A. A1 - Tuomilehto,J. A1 - Uusitupa,M. A1 - Wallaschofski,H. A1 - Wichmann,H.-E. A1 - Heid,I.M. A1 - Assimes,T.L. A1 - Fox,C.S. A1 - Groop,L.C. A1 - Haritunian,T. A1 - Kaplan,R.C. A1 - Karpe,F. A1 - O'Connell,J.R. A1 - Schadt,E.E. A1 - Schlessinger,D. A1 - Strachan,D.P. A1 - Visscher,P.M. A1 - Speliotes,E.K. AU - Berndt,S.I. AU - Jacobs,K.B. AU - Wang,Z. AU - Gustafsson,S. AU - Ingelsson,E. AU - Fall,T. AU - Grönberg,H. AU - Hall,P. AU - Magnusson,P.K. AU - Pedersen,N. AU - Pawitan,Y. AU - Mägi,R. AU - Randall,J.C. AU - Prokopenko,I. AU - McCarthy,M.I. AU - Fischer,K. AU - Milani,L. AU - Ganna,A. AU - Wheeler,E. AU - Kanoni,S. AU - Edkins,S. AU - Hunt,S.E. AU - Shin,S.-Y. AU - Stirrups,K. AU - Deloukas,P. AU - Feitosa,M.F. AU - Kraja,A.T. AU - Province,M.A. AU - Borecki,I.B. AU - Justice,A.E. AU - Monda,K.L. AU - North,K.E. AU - Croteau-Chonka,D.C. AU - Mohlke,K.L. AU - Day,F.R. AU - Luan,J. AU - Zhao,J.H. AU - Wareham,N.J. AU - Esko,T. AU - Perola,M. AU - Mihailov,E. AU - Metspalu,A. AU - Ferreira,T. AU - Min,J.L. AU - Lindgren,C.M. AU - Gentilini,D. AU - Di Blasio,A.M. AU - Jackson,A.U. AU - Bragg-Gresham,J.L. AU - Abecasis,G.R. AU - Boehnke,M. AU - Vedantam,S. AU - Hirschhorn,J.N. AU - Willer,C.J. AU - Winkler,T.W. AU - Wood,A.R. AU - Frayling,T. AU - Workalemahu,T. AU - Franks,P.W. AU - Qi,L. AU - Hunter,D. AU - Hu,Y.-J. AU - Lee,S.H. AU - Liang,L. AU - Lin,D.-Y. AU - Neale,B.M. AU - Thorleifsson,G. AU - Steinthorsdottir,V. AU - Yang,J. AU - Medland,S.E. AU - Montgomery,G.W. AU - Martin,N.G. AU - Albrecht,E. AU - Gieger,C. AU - Amin,N. AU - Cadby,G. AU - Palmer,L.J. AU - den Heijer,M. AU - Eklund,N. AU - Kristiansson,K. AU - Goel,A. AU - Farrall,M. AU - Ripatti,S. AU - Watkins,H. AU - Hottenga,J.-J. AU - Willemsen,G. AU - Boomsma,D.I. AU - Huffman,J.E. AU - Hayward,C. AU - Vitart,V. AU - Wright,A.F. AU - Jarick,I. AU - Johansson,A. AU - Johnson,T. AU - Munroe,P.B. AU - Caulfield,M.J. AU - Kleber,M.E. AU - König,I.R. AU - Kutalik,Z. AU - Marek,D. AU - Lamina,C. AU - Lecoeur,C. AU - Skrobek,B. AU - Froguel,P. AU - Meyre,D. AU - Li,G. AU - Mangino,M. AU - Soranzo,N. AU - Spector,T.D. AU - McArdle,W.L. AU - Medina-Gomez,C. AU - Peters,M.J. AU - Estrada,K. AU - Rivadeneira,F. AU - van Meurs,J.B.J. AU - Witteman,J.C.M. AU - Hofman,A. AU - Uitterlinden,A.G. AU - van Duijn,C.M. AU - Zillikens,M.C. AU - Müller-Nurasyid,M. AU - Ngwa,J.S. AU - Cupples,L.A. AU - Nolte,I.M. AU - Paternoster,L. AU - Evans,D.M. AU - Pechlivanis,S. AU - Pütter,C. AU - Jöckel,K.-H. AU - Scherag,A. AU - Surakka,I. AU - Palotie,A. AU - Widén,E. AU - Preuss,M. AU - Rose,L.M. AU - Shi,J. AU - Chanock,S.J. AU - Shungin,D. AU - Smith,A.V. AU - Gudnason,V. AU - Stefansson,K. AU - Thorsteinsdottir,U. AU - Strawbridge,R.J. AU - Hamsten,A. AU - Teumer,A. AU - Homuth,G. AU - Trip,M.D. AU - Tyrer,J. AU - Van Vliet-Ostaptchouk,J.V. AU - Van der Klauw,M.M. AU - Wolffenbuttel,B.H.R. AU - Bruinenberg,M. AU - Stolk,R.P. AU - Snieder,H. AU - Vandenput,L. AU - Lorentzon,M. AU - Waite,L.L. AU - Absher,D. AU - Ohlsson,C. AU - Asselbergs,F.W. AU - Atalay,M. AU - Attwood,A.P. AU - Ouwehand,W.H. AU - Balmforth,A.J. AU - Basart,H. AU - Hovingh,K.G. AU - Beilby,J. AU - Bonnycastle,L.L. AU - Chines,P.S. AU - Collins,F.S. AU - Narisu,N. AU - Swift,A.J. AU - Brambilla,P. AU - Campbell,H. AU - Rudan,I. AU - Wild,S.H. AU - Wilson,J.F. AU - Chasman,D.I. AU - Ridker,P.M. AU - Connell,John M. AU - Cookson,W.O. AU - Moffatt,M.F. AU - de Faire,U. AU - de Vegt,F. AU - Dei,M. AU - Sanna,S. AU - Dimitriou,M. AU - Theodoraki,E.V. AU - Dedoussis,G.V. AU - Ferrario,M.M. AU - Ferrières,J. AU - Franke,L. AU - Frau,F. AU - Gejman,P.V. AU - Sanders,A.R. AU - Grallert,H. AU - Hall,A.S. AU - Hartikainen,A.-L. AU - Heard-Costa,N.L. AU - Heath,A.C. AU - Madden,P.A. AU - Hebebrand,J. AU - Hinney,A. AU - Hu,F.B. AU - Hyppönen,E. AU - Power,C. AU - Iribarren,C. AU - Jansson,J.-O. AU - Jula,A. AU - Kähönen,M. AU - Kathiresan,S. AU - Kee,F. AU - Khaw,K.-T. AU - Kivimäki,M. AU - Kumari,M. AU - Langenberg,C. AU - Hingorani,A. AU - Koenig,W. AU - Kuulasmaa,K. AU - Virtamo,J. AU - Salomaa,V. AU - Kuusisto,J. AU - Laakso,M. AU - Laitinen,J.H. AU - Lakka,T.A. AU - Ong,K.K. AU - Loos,R.J.F. AU - Launer,L.J. AU - Harris,T.B. AU - Lind,L. AU - Lindström,J. AU - Liu,J. AU - Liuzzi,A. AU - Lokki,M.-L. AU - Manunta,P. AU - März,W. AU - Leach,I.M. AU - van der Harst,P. AU - McKnight,B. AU - Mooser,V. AU - Mühleisen,T.W. AU - Musk,A.W. AU - Navis,G. AU - Nicholson,G. AU - Nohr,E.A. AU - Wong,A. AU - Kuh,D. AU - Oostra,B.A. AU - Palmer,Colin N.A. AU - Morris,Andrew D. AU - Radhakrishnan,A. AU - Barroso,I. AU - Peden,J.F. AU - Peters,A. AU - Illig,T. AU - Thorand,B. AU - Polasek,O. AU - Pouta,A. AU - Pramstaller,P.P. AU - Rendon,A. AU - Sambrook,J.G. AU - Stephens,J.C. AU - Raitakari,O. AU - Saaristo,T.E. AU - Saramies,J. AU - Schipf,S. AU - Schreiber,S. AU - Schunkert,H. AU - Erdmann,J. AU - Signorini,S. AU - Sinisalo,J. AU - Nieminen,M.S. AU - Stančáková,A. AU - Stark,K. AU - Hengstenberg,C. AU - Stumvoll,M. AU - Tönjes,A. AU - Tregouet,D.-A. AU - Tremoli,E. AU - Vermeulen,S.H. AU - Kiemeney,L.A. AU - Viikari,J. AU - Waeber,G. AU - Vollenweider,P. AU - Winkelmann,B.R. AU - Amouyel,P. AU - Boehm,B.O. AU - Boerwinkle,E. AU - Cusi,D. AU - Eriksson,J.G. AU - Gyllensten,U. AU - Hicks,A.A. AU - Hveem,K. AU - Jarvelin,M.-R. AU - Keinanen-Kiukaanniemi,S.M. AU - Lehtimäki,T. AU - Levinson,D.F. AU - Njølstad,I. AU - Oldehinkel,A.J. AU - Penninx,B. AU - Psaty,B.M. AU - Rauramaa,R. AU - Samani,N.J. AU - Sørensen,T.I.A. AU - Tuomilehto,J. AU - Uusitupa,M. AU - Wallaschofski,H. AU - Wichmann,H.-E. AU - Heid,I.M. AU - Assimes,T.L. AU - Fox,C.S. AU - Groop,L.C. AU - Haritunian,T. AU - Kaplan,R.C. AU - Karpe,F. AU - O'Connell,J.R. AU - Schadt,E.E. AU - Schlessinger,D. AU - Strachan,D.P. AU - Visscher,P.M. AU - Speliotes,E.K. PY - 2013/4/7 Y1 - 2013/4/7 N2 - Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. AB - Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875689586&md5=b028d7e5361ef8d8455c71dcd5215301 U2 - 10.1038/ng.2606 DO - 10.1038/ng.2606 M1 - Article JO - Nature Genetics JF - Nature Genetics SN - 1061-4036 ER - TY - JOUR T1 - Pharmacist-led management of chronic pain in primary care T2 - results from a randomised controlled exploratory trial A1 - Bruhn,Hanne A1 - Bond,Christine M A1 - Elliott,Alison M A1 - Hannaford,Philip C A1 - Lee,Amanda J A1 - McNamee,Paul A1 - Smith,Blair H A1 - Watson,Margaret C A1 - Holland,Richard A1 - Wright,David AU - Bruhn,Hanne AU - Bond,Christine M AU - Elliott,Alison M AU - Hannaford,Philip C AU - Lee,Amanda J AU - McNamee,Paul AU - Smith,Blair H AU - Watson,Margaret C AU - Holland,Richard AU - Wright,David PY - 2013/4/5 Y1 - 2013/4/5 N2 -

Objectives To compare the effectiveness of pharmacist medication review, with or without pharmacist prescribing, with standard care, for patients with chronic pain.

Design An exploratory randomised controlled trial.

Setting Six general practices with prescribing pharmacists in Grampian (3) and East Anglia (3).

Participants Patients on repeat prescribed pain medication (4815) were screened by general practitioners (GPs), and mailed invitations (1397). 196 were randomised and 180 (92%) completed. Exclusion criteria included: severe mental illness, terminally ill, cancer related pain, history of addiction.

Randomisation and intervention Patients were randomised using a remote telephone service to: (1) pharmacist medication review with face-to-face pharmacist prescribing; (2) pharmacist medication review with feedback to GP and no planned patient contact or (3) treatment as usual (TAU). Blinding was not possible.

Outcome measures Outcomes were the SF-12v2, the Chronic Pain Grade (CPG), the Health Utilities Index 3 and the Hospital Anxiety and Depression Scale (HADS). Outcomes were collected at 0, 3 and 6 months.

Results In the prescribing arm (n=70) two patients were excluded/nine withdrew. In the review arm (n=63) one was excluded/three withdrew. In the TAU arm (n=63) four withdrew. Compared with baseline, patients had an improved CPG in the prescribing arm, 47.7% (21/44; p=0.003) and in the review arm, 38.6% (17/44; p=0.001), but not the TAU group, 31.3% (15/48; ns). The SF-12 Physical Component Score showed no effect in the prescribing or review arms but improvement in TAU (p=0.02). The SF-12 Mental Component Score showed no effect for the prescribing or review arms and deterioration in the TAU arm (p=0.002). HADS scores improved within the prescribing arm for depression (p=0.022) and anxiety (p=0.007), between groups (p=0.022 and p=0.045, respectively).

Conclusions This is the first randomised controlled trial of pharmacist prescribing in the UK, and suggests that there may be a benefit for patients with chronic pain. A larger trial is required. AB -

Objectives To compare the effectiveness of pharmacist medication review, with or without pharmacist prescribing, with standard care, for patients with chronic pain.

Design An exploratory randomised controlled trial.

Setting Six general practices with prescribing pharmacists in Grampian (3) and East Anglia (3).

Participants Patients on repeat prescribed pain medication (4815) were screened by general practitioners (GPs), and mailed invitations (1397). 196 were randomised and 180 (92%) completed. Exclusion criteria included: severe mental illness, terminally ill, cancer related pain, history of addiction.

Randomisation and intervention Patients were randomised using a remote telephone service to: (1) pharmacist medication review with face-to-face pharmacist prescribing; (2) pharmacist medication review with feedback to GP and no planned patient contact or (3) treatment as usual (TAU). Blinding was not possible.

Outcome measures Outcomes were the SF-12v2, the Chronic Pain Grade (CPG), the Health Utilities Index 3 and the Hospital Anxiety and Depression Scale (HADS). Outcomes were collected at 0, 3 and 6 months.

Results In the prescribing arm (n=70) two patients were excluded/nine withdrew. In the review arm (n=63) one was excluded/three withdrew. In the TAU arm (n=63) four withdrew. Compared with baseline, patients had an improved CPG in the prescribing arm, 47.7% (21/44; p=0.003) and in the review arm, 38.6% (17/44; p=0.001), but not the TAU group, 31.3% (15/48; ns). The SF-12 Physical Component Score showed no effect in the prescribing or review arms but improvement in TAU (p=0.02). The SF-12 Mental Component Score showed no effect for the prescribing or review arms and deterioration in the TAU arm (p=0.002). HADS scores improved within the prescribing arm for depression (p=0.022) and anxiety (p=0.007), between groups (p=0.022 and p=0.045, respectively).

Conclusions This is the first randomised controlled trial of pharmacist prescribing in the UK, and suggests that there may be a benefit for patients with chronic pain. A larger trial is required. U2 - 10.1136/bmjopen-2012-002361 DO - 10.1136/bmjopen-2012-002361 M1 - Article JO - BMJ Open JF - BMJ Open SN - 2044-6055 IS - 4 VL - 3 ER - TY - JOUR T1 - Fluorescence-Based Methods for Detecting Caries Lesions T2 - Systematic Review, Meta-Analysis and Sources of Heterogeneity A1 - Gimenez,Thais A1 - Braga,Mariana Minatel A1 - Raggio,Daniela Proocida A1 - Deery,Chris A1 - Ricketts,David N. A1 - Mendes,Fausto Medieros AU - Gimenez,Thais AU - Braga,Mariana Minatel AU - Raggio,Daniela Proocida AU - Deery,Chris AU - Ricketts,David N. AU - Mendes,Fausto Medieros PY - 2013/4/4 Y1 - 2013/4/4 N2 - Background: Fluorescence-based methods have been proposed to aid caries lesion detection. Summarizing and analysing findings of studies about fluorescence-based methods could clarify their real benefits. Objective: We aimed to perform a comprehensive systematic review and meta-analysis to evaluate the accuracy of fluorescence-based methods in detecting caries lesions. Data Source: Two independent reviewers searched PubMed, Embase and Scopus through June 2012 to identify papers/articles published. Other sources were checked to identify non-published literature. Study Eligibility Criteria, Participants and Diagnostic Methods: The eligibility criteria were studies that: (1) have assessed the accuracy of fluorescence-based methods of detecting caries lesions on occlusal, approximal or smooth surfaces, in both primary or permanent human teeth, in the laboratory or clinical setting; (2) have used a reference standard; and (3) have reported sufficient data relating to the sample size and the accuracy of methods. Study Appraisal and Synthesis Methods: A diagnostic 2×2 table was extracted from included studies to calculate the pooled sensitivity, specificity and overall accuracy parameters (Diagnostic Odds Ratio and Summary Receiver-Operating curve). The analyses were performed separately for each method and different characteristics of the studies. The quality of the studies and heterogeneity were also evaluated. Results: Seventy five studies met the inclusion criteria from the 434 articles initially identified. The search of the grey or non-published literature did not identify any further studies. In general, the analysis demonstrated that the fluorescence-based method tend to have similar accuracy for all types of teeth, dental surfaces or settings. There was a trend of better performance of fluorescence methods in detecting more advanced caries lesions. We also observed moderate to high heterogeneity and evidenced publication bias. Conclusions: Fluorescence-based devices have similar overall performance; however, better accuracy in detecting more advanced caries lesions has been observed. © 2013 Gimenez et al. AB - Background: Fluorescence-based methods have been proposed to aid caries lesion detection. Summarizing and analysing findings of studies about fluorescence-based methods could clarify their real benefits. Objective: We aimed to perform a comprehensive systematic review and meta-analysis to evaluate the accuracy of fluorescence-based methods in detecting caries lesions. Data Source: Two independent reviewers searched PubMed, Embase and Scopus through June 2012 to identify papers/articles published. Other sources were checked to identify non-published literature. Study Eligibility Criteria, Participants and Diagnostic Methods: The eligibility criteria were studies that: (1) have assessed the accuracy of fluorescence-based methods of detecting caries lesions on occlusal, approximal or smooth surfaces, in both primary or permanent human teeth, in the laboratory or clinical setting; (2) have used a reference standard; and (3) have reported sufficient data relating to the sample size and the accuracy of methods. Study Appraisal and Synthesis Methods: A diagnostic 2×2 table was extracted from included studies to calculate the pooled sensitivity, specificity and overall accuracy parameters (Diagnostic Odds Ratio and Summary Receiver-Operating curve). The analyses were performed separately for each method and different characteristics of the studies. The quality of the studies and heterogeneity were also evaluated. Results: Seventy five studies met the inclusion criteria from the 434 articles initially identified. The search of the grey or non-published literature did not identify any further studies. In general, the analysis demonstrated that the fluorescence-based method tend to have similar accuracy for all types of teeth, dental surfaces or settings. There was a trend of better performance of fluorescence methods in detecting more advanced caries lesions. We also observed moderate to high heterogeneity and evidenced publication bias. Conclusions: Fluorescence-based devices have similar overall performance; however, better accuracy in detecting more advanced caries lesions has been observed. © 2013 Gimenez et al. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875962931&md5=08972fe687e0e600dc76b0314f7e868e U2 - 10.1371/journal.pone.0060421 DO - 10.1371/journal.pone.0060421 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 4 VL - 8 ER - TY - JOUR T1 - p53 Protein Isoforms T2 - Key Regulators in the Front Line of Pathogen Infections? A1 - Terrier,Olivier A1 - Bourdon,Jean-Christophe A1 - Rosa-Calatrava,Manuel AU - Terrier,Olivier AU - Bourdon,Jean-Christophe AU - Rosa-Calatrava,Manuel PY - 2013/4/4 Y1 - 2013/4/4 U2 - 10.1371/journal.ppat.1003246 DO - 10.1371/journal.ppat.1003246 M1 - Article JO - PLoS Pathogens JF - PLoS Pathogens SN - 1553-7366 IS - 4 VL - 9 SP - e1003246 ER - TY - JOUR T1 - PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development A1 - Venigalla,Ram K C A1 - McGuire,Victoria A A1 - Clarke,Rosemary A1 - Patterson-Kane,Janet C A1 - Najafov,Ayaz A1 - Toth,Rachel A1 - McCarthy,Pierre C A1 - Simeons,Frederick A1 - Stojanovski,Laste A1 - Arthur,J Simon C. AU - Venigalla,Ram K C AU - McGuire,Victoria A AU - Clarke,Rosemary AU - Patterson-Kane,Janet C AU - Najafov,Ayaz AU - Toth,Rachel AU - McCarthy,Pierre C AU - Simeons,Frederick AU - Stojanovski,Laste AU - Arthur,J Simon C. PY - 2013/4/3 Y1 - 2013/4/3 N2 - Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro-B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells. AB - Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro-B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells. U2 - 10.1038/emboj.2013.40 DO - 10.1038/emboj.2013.40 M1 - Article JO - EMBO Journal JF - EMBO Journal SN - 0261-4189 IS - 7 VL - 32 SP - 1008 EP - 1022 ER - TY - JOUR T1 - The architecture of EssB, an integral membrane component of the type VII secretion system A1 - Zoltner,Martin A1 - Norman,David G. A1 - Fyfe,Paul K. A1 - El Mkami,Hassane A1 - Palmer,Tracy A1 - Hunter,William N. AU - Zoltner,Martin AU - Norman,David G. AU - Fyfe,Paul K. AU - El Mkami,Hassane AU - Palmer,Tracy AU - Hunter,William N. PY - 2013/4/2 Y1 - 2013/4/2 N2 - The membrane-bound EssB is an integral and essential component of the bacterial type VII secretion system that can contribute to pathogenicity. The architecture of Geobacillus thermodenitrificans EssB has been investigated by combining crystallographic and EPR spectroscopic methods. The protein forms a dimer that straddles the cytoplasmic membrane. A helical fold is observed for the C-terminal segment, which is positioned on the exterior of the membrane. This segment contributes most to dimer formation. The N-terminal segment displays a structure related to the pseudokinase fold and may contribute to function by recognizing substrates or secretion system partners. The remaining part of EssB may serve as an anchor point for the secretion apparatus, which is embedded in the cytoplasmic membrane with the C-terminal domain protruding out to interact with partner proteins or components of peptidoglycan. © 2013 Elsevier Ltd. AB - The membrane-bound EssB is an integral and essential component of the bacterial type VII secretion system that can contribute to pathogenicity. The architecture of Geobacillus thermodenitrificans EssB has been investigated by combining crystallographic and EPR spectroscopic methods. The protein forms a dimer that straddles the cytoplasmic membrane. A helical fold is observed for the C-terminal segment, which is positioned on the exterior of the membrane. This segment contributes most to dimer formation. The N-terminal segment displays a structure related to the pseudokinase fold and may contribute to function by recognizing substrates or secretion system partners. The remaining part of EssB may serve as an anchor point for the secretion apparatus, which is embedded in the cytoplasmic membrane with the C-terminal domain protruding out to interact with partner proteins or components of peptidoglycan. © 2013 Elsevier Ltd. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875903606&md5=98fe6a8a263bc1ddbae6710033f00baf U2 - 10.1016/j.str.2013.02.007 DO - 10.1016/j.str.2013.02.007 M1 - Article JO - Structure JF - Structure SN - 0969-2126 IS - 4 VL - 21 SP - 595 EP - 603 ER - TY - CHAP T1 - Cadenus and Vanessa T2 - Reading Swift A1 - Cook,Daniel AU - Cook,Daniel PB - William Fink CY - Munich PY - 2013/4/1 Y1 - 2013/4/1 UR - http://www.fink.de/katalog/titel/978-3-7705-5430-0.html M1 - Chapter SN - 9783770554300 BT - Reading Swift A2 - Real,Hermann J. ED - Real,Hermann J. ER - TY - JOUR T1 - Increasing survival of hepatocellular carcinoma patients in Scotland T2 - a review of national cancer registry data A1 - Dunbar,John K. A1 - Dillon,John A1 - Garden,James A1 - Brewster,David H. AU - Dunbar,John K. AU - Dillon,John AU - Garden,James AU - Brewster,David H. PY - 2013/4/1 Y1 - 2013/4/1 N2 - Objectives: This study describes changes in the survival of patients with hepatocellular carcinoma (HCC) registered with the Scottish Cancer Registry between 1985 and 2008. AB - Objectives: This study describes changes in the survival of patients with hepatocellular carcinoma (HCC) registered with the Scottish Cancer Registry between 1985 and 2008. U2 - 10.1111/j.1477-2574.2012.00567.x DO - 10.1111/j.1477-2574.2012.00567.x M1 - Article JO - HPB JF - HPB SN - 1365-182X IS - 4 VL - 15 SP - 279 EP - 285 ER - TY - JOUR T1 - People's experiences of being mechanically ventilated in an ICU T2 - A qualitative study A1 - Engstrom,Asa A1 - Nystrom,Natalie A1 - Sundelin,Gunilla A1 - Rattray,Janice AU - Engstrom,Asa AU - Nystrom,Natalie AU - Sundelin,Gunilla AU - Rattray,Janice PY - 2013/4/1 Y1 - 2013/4/1 N2 - Objectives: In previous studies people receiving mechanical ventilation treatment have described experiencing distress over their inability to speak and feelings such as anxiety. More research is needed to improve their experience in the intensive care unit and promote recovery. The aim of this study was to describe the intensive care unit experiences of people undergoing mechanical ventilation. Method: Qualitative, personal interviews were conducted during 2011 with eight people who were mechanically ventilated in an intensive care unit in the northern part of Sweden. Interview transcripts were analysed using qualitative content analysis. Findings: Two themes emerged, with four and three categories, respectively. Being dependent for survival on other people and technical medical equipment created a sense of being vulnerable in an anxious situation and a feeling of uncertainty about one's own capacity to breathe. Having lines and tubes in one's body was stressful. Being given a diary and follow-up visit to the intensive care unit after the stay were important tools for filling in the missing time, but there was also one participant who did not want to remember his stay in the intensive care unit. Conclusion: To be dependent on other people and technical medical equipment for survival creates a sense of being delivered into the hands of others, as the people being mechanically ventilated could not trust their body to function. © 2012 Elsevier Ltd. AB - Objectives: In previous studies people receiving mechanical ventilation treatment have described experiencing distress over their inability to speak and feelings such as anxiety. More research is needed to improve their experience in the intensive care unit and promote recovery. The aim of this study was to describe the intensive care unit experiences of people undergoing mechanical ventilation. Method: Qualitative, personal interviews were conducted during 2011 with eight people who were mechanically ventilated in an intensive care unit in the northern part of Sweden. Interview transcripts were analysed using qualitative content analysis. Findings: Two themes emerged, with four and three categories, respectively. Being dependent for survival on other people and technical medical equipment created a sense of being vulnerable in an anxious situation and a feeling of uncertainty about one's own capacity to breathe. Having lines and tubes in one's body was stressful. Being given a diary and follow-up visit to the intensive care unit after the stay were important tools for filling in the missing time, but there was also one participant who did not want to remember his stay in the intensive care unit. Conclusion: To be dependent on other people and technical medical equipment for survival creates a sense of being delivered into the hands of others, as the people being mechanically ventilated could not trust their body to function. © 2012 Elsevier Ltd. KW - Mechanical ventilation KW - Experiences KW - Nursing care KW - Interviews KW - Qualitative content analysis UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84873741676&md5=bdb3f1d3ff1908bca24bebec11ea6610 U2 - 10.1016/j.iccn.2012.07.003 DO - 10.1016/j.iccn.2012.07.003 M1 - Article JO - Intensive and Critical Care Nursing JF - Intensive and Critical Care Nursing SN - 0964-3397 IS - 2 VL - 29 SP - 88 EP - 95 ER - TY - JOUR T1 - The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms T2 - disease-causing mutations in KLHL3 and WNK4 disrupt interaction A1 - Ohta,Akihito A1 - Schumacher,Frances-Rose A1 - Mehellou,Youcef A1 - Johnson,Clare A1 - Knebel,Axel A1 - Macartney,Thomas J. A1 - Wood,Nicola T. A1 - Alessi,Dario R. A1 - Kurz,Thimo AU - Ohta,Akihito AU - Schumacher,Frances-Rose AU - Mehellou,Youcef AU - Johnson,Clare AU - Knebel,Axel AU - Macartney,Thomas J. AU - Wood,Nicola T. AU - Alessi,Dario R. AU - Kurz,Thimo PY - 2013/4/1 Y1 - 2013/4/1 N2 - The WNK (with no lysine kinase)-SPAK (SPS1-related proline/alanine-rich kinase)/OSR1 (oxidative stress-responsive kinase 1) signalling pathway plays an important role in controlling mammalian blood pressure by modulating the activity of ion co-transporters in the kidney. Recent studies have identified Gordon's hypertension syndrome patients with mutations in either CUL3 (Cullin-3) or the BTB protein KLHL3 (Kelch-like 3). CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3, but not with other components of the pathway [SPAK/OSR1 or NCC (Na(+)/Cl(-) co-transporter)/NKCC1 (Na(+)/K(+)/2Cl(-) co-transporter 1)]. Strikingly, 13 out of the 15 dominant KLHL3 disease mutations analysed inhibited binding to WNK1 or CUL3. The recombinant wild-type CUL3-KLHL3 E3 ligase complex, but not a disease-causing CUL3-KLHL3[R528H] mutant complex, ubiquitylated WNK1 in vitro. Moreover, siRNA (small interfering RNA)-mediated knockdown of CUL3 increased WNK1 protein levels and kinase activity in HeLa cells. We mapped the KLHL3 interaction site in WNK1 to a non-catalytic region (residues 479-667). Interestingly, the equivalent region in WNK4 encompasses residues that are mutated in Gordon's syndrome patients. Strikingly, we found that the Gordon's disease-causing WNK4[E562K] and WNK4[Q565E] mutations, as well as the equivalent mutation in the WNK1[479-667] fragment, abolished the ability to interact with KLHL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms. The findings of the present study also emphasize that the missense mutations in WNK4 that cause Gordon's syndrome strongly inhibit interaction with KLHL3. This could elevate blood pressure by increasing the expression of WNK4 thereby stimulating inappropriate salt retention in the kidney by promoting activation of the NCC/NKCC2 ion co-transporters. The present study reveals how mutations that disrupt the ability of an E3 ligase to interact with and ubiquitylate a critical cellular substrate such as WNK isoforms can trigger a chronic disease such as hypertension. AB - The WNK (with no lysine kinase)-SPAK (SPS1-related proline/alanine-rich kinase)/OSR1 (oxidative stress-responsive kinase 1) signalling pathway plays an important role in controlling mammalian blood pressure by modulating the activity of ion co-transporters in the kidney. Recent studies have identified Gordon's hypertension syndrome patients with mutations in either CUL3 (Cullin-3) or the BTB protein KLHL3 (Kelch-like 3). CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3, but not with other components of the pathway [SPAK/OSR1 or NCC (Na(+)/Cl(-) co-transporter)/NKCC1 (Na(+)/K(+)/2Cl(-) co-transporter 1)]. Strikingly, 13 out of the 15 dominant KLHL3 disease mutations analysed inhibited binding to WNK1 or CUL3. The recombinant wild-type CUL3-KLHL3 E3 ligase complex, but not a disease-causing CUL3-KLHL3[R528H] mutant complex, ubiquitylated WNK1 in vitro. Moreover, siRNA (small interfering RNA)-mediated knockdown of CUL3 increased WNK1 protein levels and kinase activity in HeLa cells. We mapped the KLHL3 interaction site in WNK1 to a non-catalytic region (residues 479-667). Interestingly, the equivalent region in WNK4 encompasses residues that are mutated in Gordon's syndrome patients. Strikingly, we found that the Gordon's disease-causing WNK4[E562K] and WNK4[Q565E] mutations, as well as the equivalent mutation in the WNK1[479-667] fragment, abolished the ability to interact with KLHL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms. The findings of the present study also emphasize that the missense mutations in WNK4 that cause Gordon's syndrome strongly inhibit interaction with KLHL3. This could elevate blood pressure by increasing the expression of WNK4 thereby stimulating inappropriate salt retention in the kidney by promoting activation of the NCC/NKCC2 ion co-transporters. The present study reveals how mutations that disrupt the ability of an E3 ligase to interact with and ubiquitylate a critical cellular substrate such as WNK isoforms can trigger a chronic disease such as hypertension. KW - PSEUDOHYPOALDOSTERONISM TYPE-II KW - SPAK KW - BTB-KELCH PROTEINS KW - BLOOD-PRESSURE KW - ADAPTER KW - NA+-CL-COTRANSPORTER KW - BTB domain KW - DOMINANT RETINITIS-PIGMENTOSA KW - Na+/K+/2Cl(-) co-transporter 2 (NKCC2) KW - ubiquitin KW - SPS1-related proline/alanine-rich kinase/oxidative stress-responsive kinase 1 (SPAK/OSR1) KW - Na+/Cl- co-transporter (NCC) KW - RING UBIQUITIN LIGASES KW - OSR1 KW - KINASES KW - Cullin-RING E3 ligase (CRL) KW - Kelch-like domain (KLHL domain) U2 - 10.1042/BJ20121903 DO - 10.1042/BJ20121903 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 IS - 1 VL - 451 SP - 111 EP - 122 ER - TY - JOUR T1 - AMPK T2 - opposing the metabolic changes in both tumour cells and inflammatory cells? A1 - Dandapani,Madhumita A1 - Hardie,D. Grahame AU - Dandapani,Madhumita AU - Hardie,D. Grahame PY - 2013/4 Y1 - 2013/4 N2 -

AMPK (AMP-activated protein kinase) is a sensor of cellular energy status that appears to have arisen during early eukaryotic evolution. In the unicellular eukaryote Saccharomyces cerevisiae, the AMPK orthologue is activated by glucose starvation and is required for the switch from glycolysis (fermentation) to oxidative metabolism when glucose runs low. In mammals, rapidly proliferating cells (including tumour cells) and immune cells involved in inflammation both tend to utilize rapid glucose uptake and glycolysis (termed the Warburg effect or aerobic glycolysis) rather than oxidative metabolism to satisfy their high demand for ATP. Since mammalian AMPK, similar to its yeast orthologue, tends to promote the more energy-efficient oxidative metabolism at the expense of glycolysis, it might be expected that drugs that activate AMPK would inhibit cell proliferation and and hence cancer, as well as exerting anti-inflammatory effects. Evidence supporting this view is discussed, including our findings that AMPK is activated by the classic anti-inflammatory drug salicylate.

AB -

AMPK (AMP-activated protein kinase) is a sensor of cellular energy status that appears to have arisen during early eukaryotic evolution. In the unicellular eukaryote Saccharomyces cerevisiae, the AMPK orthologue is activated by glucose starvation and is required for the switch from glycolysis (fermentation) to oxidative metabolism when glucose runs low. In mammals, rapidly proliferating cells (including tumour cells) and immune cells involved in inflammation both tend to utilize rapid glucose uptake and glycolysis (termed the Warburg effect or aerobic glycolysis) rather than oxidative metabolism to satisfy their high demand for ATP. Since mammalian AMPK, similar to its yeast orthologue, tends to promote the more energy-efficient oxidative metabolism at the expense of glycolysis, it might be expected that drugs that activate AMPK would inhibit cell proliferation and and hence cancer, as well as exerting anti-inflammatory effects. Evidence supporting this view is discussed, including our findings that AMPK is activated by the classic anti-inflammatory drug salicylate.

KW - ENERGY SENSOR KW - inflammation KW - metabolism KW - AMP-activated protein kinase (AMPK) KW - PHOSPHORYLATION KW - CANCER KW - SKELETAL-MUSCLE KW - LKB1 KW - ACTIVATED PROTEIN-KINASE KW - CARBOXYLATION KW - GROWTH KW - innate immunity KW - YEAST SNF1 KW - cancer KW - INHIBITION U2 - 10.1042/BST20120351 DO - 10.1042/BST20120351 M1 - Article JO - Biochemical Society Transactions JF - Biochemical Society Transactions SN - 0300-5127 IS - 2 VL - 41 SP - 687 EP - 693 ER - TY - JOUR T1 - AMPKα1 T2 - a glucose sensor that controls CD8 T-cell memory A1 - Rolf,Julia A1 - Zarrouk,Marouan A1 - Finlay,David K. A1 - Foretz,Marc A1 - Viollet,Benoit A1 - Cantrell,Doreen A. AU - Rolf,Julia AU - Zarrouk,Marouan AU - Finlay,David K. AU - Foretz,Marc AU - Viollet,Benoit AU - Cantrell,Doreen A. PY - 2013/4 Y1 - 2013/4 N2 -

The adenosine monophosphate-activated protein kinase (AMPK) is activated by antigen receptor signals and energy stress in T cells. In many cell types, AMPK can maintain energy homeostasis and can enforce quiescence to limit energy demands. We consequently evaluated the importance of AMPK for controlling the transition of metabolically active effector CD8 T lymphocytes to the metabolically quiescent catabolic memory T cells during the contraction phase of the immune response. We show that AMPK1 activates rapidly in response to the metabolic stress caused by glucose deprivation of CD8 cytotoxic T lymphocytes (CTLs). Moreover, AMPK1 restrains mammalian target of rapamycin complex 1 activity under conditions of glucose stress. AMPK1 activity is dispensable for proliferation and differentiation of CTLs. However, AMPK1 is required for in vivo survival of CTLs following withdrawal of immune stimulation. AMPK1null T cells also show a striking defect in their ability to generate memory CD8 T-cell responses during Listeria monocytogenes infection. These results show that AMPK1 monitors energy stress in CTLs and controls CD8 T-cell memory.

AB -

The adenosine monophosphate-activated protein kinase (AMPK) is activated by antigen receptor signals and energy stress in T cells. In many cell types, AMPK can maintain energy homeostasis and can enforce quiescence to limit energy demands. We consequently evaluated the importance of AMPK for controlling the transition of metabolically active effector CD8 T lymphocytes to the metabolically quiescent catabolic memory T cells during the contraction phase of the immune response. We show that AMPK1 activates rapidly in response to the metabolic stress caused by glucose deprivation of CD8 cytotoxic T lymphocytes (CTLs). Moreover, AMPK1 restrains mammalian target of rapamycin complex 1 activity under conditions of glucose stress. AMPK1 activity is dispensable for proliferation and differentiation of CTLs. However, AMPK1 is required for in vivo survival of CTLs following withdrawal of immune stimulation. AMPK1null T cells also show a striking defect in their ability to generate memory CD8 T-cell responses during Listeria monocytogenes infection. These results show that AMPK1 monitors energy stress in CTLs and controls CD8 T-cell memory.

KW - ENERGY SENSOR KW - LYMPHOCYTES KW - Listeria monocytogenes KW - METFORMIN KW - REGULATOR KW - Energy stress KW - EFFECTOR KW - AMPK KW - DIFFERENTIATION KW - Memory KW - ACTIVATED PROTEIN-KINASE KW - GROWTH KW - METABOLISM KW - Cytotoxic T lymphocyte KW - Metabolism U2 - 10.1002/eji.201243008 DO - 10.1002/eji.201243008 M1 - Article JO - European Journal of Immunology JF - European Journal of Immunology SN - 0014-2980 IS - 4 VL - 43 SP - 889 EP - 896 ER - TY - JOUR T1 - An investigation of rheumatoid arthritis loci in patients with early-onset psoriasis validates association of the REL gene A1 - Ali,F. R. A1 - Barton,A. A1 - Smith,R. L. I. A1 - Bowes,J. A1 - Flynn,E. A1 - Mangino,M. A1 - Bataille,V. A1 - Foerster,J. P. A1 - Worthington,J. A1 - Griffiths,C. E. M. A1 - Warren,R. B. AU - Ali,F. R. AU - Barton,A. AU - Smith,R. L. I. AU - Bowes,J. AU - Flynn,E. AU - Mangino,M. AU - Bataille,V. AU - Foerster,J. P. AU - Worthington,J. AU - Griffiths,C. E. M. AU - Warren,R. B. PY - 2013/4 Y1 - 2013/4 N2 -

Background Phenotypically diverse autoimmune conditions share common genetic susceptibility loci and underlying molecular pathways.

Objectives By systematically searching for single nucleotide polymorphisms (SNPs) associated with another autoimmune disease, rheumatoid arthritis (RA), we aimed to elucidate novel genetic markers of psoriasis.

Methods We investigated 18 SNPs, previously confirmed as being associated with RA, in a U. K. cohort of 623 patients with early-onset psoriasis (presenting before age 40 years), comparing them with 2662 control subjects.

Results Our findings confirm the association of early-onset psoriasis with REL (rs13031237, P = 0.0027). The minor allele of REL had opposing effects upon susceptibility to disease in patients with psoriasis and RA.

Conclusion Similar exploration of additional autoimmune loci and fine mapping of such regions may provide further insight into the genetics and molecular pathophysiology of psoriasis.

AB -

Background Phenotypically diverse autoimmune conditions share common genetic susceptibility loci and underlying molecular pathways.

Objectives By systematically searching for single nucleotide polymorphisms (SNPs) associated with another autoimmune disease, rheumatoid arthritis (RA), we aimed to elucidate novel genetic markers of psoriasis.

Methods We investigated 18 SNPs, previously confirmed as being associated with RA, in a U. K. cohort of 623 patients with early-onset psoriasis (presenting before age 40 years), comparing them with 2662 control subjects.

Results Our findings confirm the association of early-onset psoriasis with REL (rs13031237, P = 0.0027). The minor allele of REL had opposing effects upon susceptibility to disease in patients with psoriasis and RA.

Conclusion Similar exploration of additional autoimmune loci and fine mapping of such regions may provide further insight into the genetics and molecular pathophysiology of psoriasis.

KW - GENOME-WIDE ASSOCIATION KW - SUSCEPTIBILITY LOCI KW - CROHN DISEASE U2 - 10.1111/bjd.12106 DO - 10.1111/bjd.12106 M1 - Article JO - British Journal of Dermatology JF - British Journal of Dermatology SN - 0007-0963 IS - 4 VL - 168 SP - 864 EP - 866 ER - TY - JOUR T1 - Association Between BMI Measured Within a Year After Diagnosis of Type 2 Diabetes and Mortality A1 - Logue,Jennifer A1 - Walker,Jeremy J. A1 - Leese,Graham A1 - Lindsay,Robert A1 - McKnight,John A1 - Morris,Andrew A1 - Philip,Sam A1 - Wild,Sarah A1 - Sattar,Naveed A1 - Scottish Diabetes Research Network Epidemiology Group AU - Logue,Jennifer AU - Walker,Jeremy J. AU - Leese,Graham AU - Lindsay,Robert AU - McKnight,John AU - Morris,Andrew AU - Philip,Sam AU - Wild,Sarah AU - Sattar,Naveed AU - Scottish Diabetes Research Network Epidemiology Group PY - 2013/4 Y1 - 2013/4 N2 -

OBJECTIVE-To describe the association of BMI with mortality in patients diagnosed with type 2 diabetes.

RESEARCH DESIGN AND METHODS-Using records of 106,640 patients in Scotland, we investigated the association between BMI recorded around the diagnosis of type 2 diabetes mellitus (T2DM) and mortality using Cox proportional hazards regression adjusted for age and smoking status, with BMI 25 to

RESULTS-A total of 9,631 deaths occurred between 2001 and 2007. Compared with the reference group, mortality risk was higher in patients with BMI 20 to = 35 kg/m(2) (for example, 1.70 [1.24-2.34] in men and 1.81 [1.46-2.24] in women for BMI 45 to 30 kg/m(2) by 24% (15-35%) in men and 23%(14-32%) in women, but was lower below this threshold. The results were similar after further adjustment for HbA(1c), year of diagnosis, lipids, blood pressure, and socioeconomic status.

CONCLUSIONS-Patients categorized as normal weight or obese with T2DM within a year of diagnosis of T2DM exhibit variably higher mortality outcomes compared with the overweight group, confirming a U-shaped association of BMI with mortality. Whether weight loss interventions reduce mortality in all T2DM patients requires study. Diabetes Care 36:887-893, 2013

AB -

OBJECTIVE-To describe the association of BMI with mortality in patients diagnosed with type 2 diabetes.

RESEARCH DESIGN AND METHODS-Using records of 106,640 patients in Scotland, we investigated the association between BMI recorded around the diagnosis of type 2 diabetes mellitus (T2DM) and mortality using Cox proportional hazards regression adjusted for age and smoking status, with BMI 25 to

RESULTS-A total of 9,631 deaths occurred between 2001 and 2007. Compared with the reference group, mortality risk was higher in patients with BMI 20 to = 35 kg/m(2) (for example, 1.70 [1.24-2.34] in men and 1.81 [1.46-2.24] in women for BMI 45 to 30 kg/m(2) by 24% (15-35%) in men and 23%(14-32%) in women, but was lower below this threshold. The results were similar after further adjustment for HbA(1c), year of diagnosis, lipids, blood pressure, and socioeconomic status.

CONCLUSIONS-Patients categorized as normal weight or obese with T2DM within a year of diagnosis of T2DM exhibit variably higher mortality outcomes compared with the overweight group, confirming a U-shaped association of BMI with mortality. Whether weight loss interventions reduce mortality in all T2DM patients requires study. Diabetes Care 36:887-893, 2013

KW - RISK-FACTORS KW - CORONARY HEART-DISEASE KW - FOLLOW-UP KW - MODEL KW - DEATH KW - HEALTH KW - COHORT KW - BODY-MASS-INDEX KW - ADULTS KW - OBESITY U2 - 10.2337/dc12-0944 DO - 10.2337/dc12-0944 M1 - Article JO - Diabetes Care JF - Diabetes Care SN - 0149-5992 IS - 4 VL - 36 SP - 887 EP - 893 ER - TY - JOUR T1 - Azacitidine-eligibility in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukaemia T2 - A registry-based study A1 - Durairaj,Senthilkumar A1 - Keenan,Norene A1 - Hyslop,Ann A1 - Groves,Michael J. A1 - Bowen,David T. A1 - Tauro,Sudhir AU - Durairaj,Senthilkumar AU - Keenan,Norene AU - Hyslop,Ann AU - Groves,Michael J. AU - Bowen,David T. AU - Tauro,Sudhir PY - 2013/4 Y1 - 2013/4 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875810483&md5=4198b90054b95a707634deffc77cfc1f U2 - 10.1111/bjh.12204 DO - 10.1111/bjh.12204 M1 - Letter JO - British Journal of Haematology JF - British Journal of Haematology SN - 0007-1048 IS - 2 VL - 161 SP - 280 EP - 282 ER - TY - JOUR T1 - Commentary T2 - Summary of: a comparative study of bonded and non-bonded amalgam restorations in general dental practice A1 - Chadwick,R. G. AU - Chadwick,R. G. PY - 2013/4 Y1 - 2013/4 U2 - 10.1038/sj.bdj.2013.351 DO - 10.1038/sj.bdj.2013.351 M1 - Comment/debate JO - British Dental Journal JF - British Dental Journal SN - 0007-0610 IS - 7 VL - 214 SP - 353 ER - TY - JOUR T1 - Correlative imaging of fluorescent proteins in resin-embedded plant material A1 - Bell,Karen A1 - Mitchell,Steve A1 - Paultre,Danae A1 - Posch,Markus A1 - Oparka,Karl AU - Bell,Karen AU - Mitchell,Steve AU - Paultre,Danae AU - Posch,Markus AU - Oparka,Karl PY - 2013/4 Y1 - 2013/4 N2 - Fluorescent proteins (FPs) were developed for live-cell imaging and have revolutionized cell biology. However, not all plant tissues are accessible to live imaging using confocal microscopy, necessitating alternative approaches for protein localization. An example is the phloem, a tissue embedded deep within plant organs and sensitive to damage. To facilitate accurate localization of FPs within recalcitrant tissues, we developed a simple method for retaining FPs after resin embedding. This method is based on low-temperature fixation and dehydration, followed by embedding in London Resin White, and avoids the need for cryosections. We show that a palette of FPs can be localized in plant tissues while retaining good structural cell preservation, and that the polymerized block face can be counterstained with cell wall probes. Using this method we have been able to image green fluorescent protein-labeled plasmodesmata to a depth of more than 40 mm beneath the resin surface. Using correlative light and electron microscopy of the phloem, we were able to locate the same FP-labeled sieve elements in semithin and ultrathin sections. Sections were amenable to antibody labeling, and allowed a combination of confocal and superresolution imaging (three-dimensional-structured illumination microscopy) on the same cells. These correlative imaging methods should find several uses in plant cell biology. © 2013 American Society of Plant Biologists. All Rights Reserved. AB - Fluorescent proteins (FPs) were developed for live-cell imaging and have revolutionized cell biology. However, not all plant tissues are accessible to live imaging using confocal microscopy, necessitating alternative approaches for protein localization. An example is the phloem, a tissue embedded deep within plant organs and sensitive to damage. To facilitate accurate localization of FPs within recalcitrant tissues, we developed a simple method for retaining FPs after resin embedding. This method is based on low-temperature fixation and dehydration, followed by embedding in London Resin White, and avoids the need for cryosections. We show that a palette of FPs can be localized in plant tissues while retaining good structural cell preservation, and that the polymerized block face can be counterstained with cell wall probes. Using this method we have been able to image green fluorescent protein-labeled plasmodesmata to a depth of more than 40 mm beneath the resin surface. Using correlative light and electron microscopy of the phloem, we were able to locate the same FP-labeled sieve elements in semithin and ultrathin sections. Sections were amenable to antibody labeling, and allowed a combination of confocal and superresolution imaging (three-dimensional-structured illumination microscopy) on the same cells. These correlative imaging methods should find several uses in plant cell biology. © 2013 American Society of Plant Biologists. All Rights Reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875758663&md5=de9838188a40e8e88f54d69cbfed109b U2 - 10.1104/pp.112.212365 DO - 10.1104/pp.112.212365 M1 - Article JO - Plant Physiology JF - Plant Physiology SN - 0032-0889 IS - 4 VL - 161 SP - 1595 EP - 1603 ER - TY - JOUR T1 - Cost-effectiveness of self-management methods for the treatment of chronic pain in an aging adult population T2 - a systematic review of the literature A1 - Boyers,Dwayne A1 - McNamee,Paul A1 - Clarke,Amanda A1 - Jones,Derek A1 - Martin,Denis A1 - Schofield,Pat A1 - Smith,Blair H. AU - Boyers,Dwayne AU - McNamee,Paul AU - Clarke,Amanda AU - Jones,Derek AU - Martin,Denis AU - Schofield,Pat AU - Smith,Blair H. PY - 2013/4 Y1 - 2013/4 N2 - OBJECTIVE:: To determine the cost-effectiveness of self-management techniques for older populations (65 and over) with chronic pain and in the absence of such evidence to investigate this question in an aging adult population (average age 60 and over). METHODS:: Systematic review of randomized controlled trials (RCTs) with cost-effectiveness data and at least 6 months' follow-up, up to December 2010. RESULTS:: No RCT studies reported cost-effectiveness of self-management exclusively in the over 65 age group. Ten RCTs reported participants with an average age of 60 years or over and met all other inclusion criteria. All of these studies measured cost-effectiveness as cost per improvement in primary outcome, 7 of them using the Western Ontario and McMaster Universities Osteoarthritis Index score, of which 6 reported the pain dimension. Six studies reported cost per quality-adjusted life year (QALY)-gained information, with a further 1 reporting EQ-5D. In 7 studies, relative to usual care, self-management was effective, and in the remaining 3 studies, there was no significant difference. Among those reporting cost per QALY-gained results, self-management did not lead to statistically significant QALY gains relative to usual care (with only one exception). Eight studies suggested that the cost of developing and delivering self-management interventions may be partly offset by savings from reduced subsequent health care resource use. CONCLUSIONS:: Self-management is effective among an aging adult population (mean age over 60) with chronic pain and may be cost-effective when outcomes are measured using the Western Ontario and McMaster Universities Osteoarthritis Index pain score. Cost-effectiveness is less certain when measured using the QALY metric. Uncertainty over conclusions regarding cost-effectiveness exists partly due to lack of information regarding societal willingness to pay for pain improvement. There is a need for large multicentred high-quality RCTs to confirm the findings of this review exclusively among older aged populations, such as those who have already reached the statutory retirement age. Copyright © 2012 by Lippincott Williams & Wilkins. AB - OBJECTIVE:: To determine the cost-effectiveness of self-management techniques for older populations (65 and over) with chronic pain and in the absence of such evidence to investigate this question in an aging adult population (average age 60 and over). METHODS:: Systematic review of randomized controlled trials (RCTs) with cost-effectiveness data and at least 6 months' follow-up, up to December 2010. RESULTS:: No RCT studies reported cost-effectiveness of self-management exclusively in the over 65 age group. Ten RCTs reported participants with an average age of 60 years or over and met all other inclusion criteria. All of these studies measured cost-effectiveness as cost per improvement in primary outcome, 7 of them using the Western Ontario and McMaster Universities Osteoarthritis Index score, of which 6 reported the pain dimension. Six studies reported cost per quality-adjusted life year (QALY)-gained information, with a further 1 reporting EQ-5D. In 7 studies, relative to usual care, self-management was effective, and in the remaining 3 studies, there was no significant difference. Among those reporting cost per QALY-gained results, self-management did not lead to statistically significant QALY gains relative to usual care (with only one exception). Eight studies suggested that the cost of developing and delivering self-management interventions may be partly offset by savings from reduced subsequent health care resource use. CONCLUSIONS:: Self-management is effective among an aging adult population (mean age over 60) with chronic pain and may be cost-effective when outcomes are measured using the Western Ontario and McMaster Universities Osteoarthritis Index pain score. Cost-effectiveness is less certain when measured using the QALY metric. Uncertainty over conclusions regarding cost-effectiveness exists partly due to lack of information regarding societal willingness to pay for pain improvement. There is a need for large multicentred high-quality RCTs to confirm the findings of this review exclusively among older aged populations, such as those who have already reached the statutory retirement age. Copyright © 2012 by Lippincott Williams & Wilkins. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84874943142&md5=e572dcf199c6729a408d5327c8a5af51 U2 - 10.1097/AJP.0b013e318250f539 DO - 10.1097/AJP.0b013e318250f539 M1 - Article JO - Clinical Journal of Pain JF - Clinical Journal of Pain IS - 4 VL - 29 SP - 366 EP - 375 ER - TY - JOUR T1 - Creative learning environments in education T2 - A systematic literature review A1 - Davies,Dan A1 - Jindal-Snape,Divya A1 - Collier,Chris A1 - Digby,Rebecca A1 - Hay,Penny A1 - Howe,Alan AU - Davies,Dan AU - Jindal-Snape,Divya AU - Collier,Chris AU - Digby,Rebecca AU - Hay,Penny AU - Howe,Alan PY - 2013/4 Y1 - 2013/4 N2 - This paper reports on a systematic review of 210 pieces of educational research, policy and professional literature relating to creative environments for learning in schools, commissioned by Learning and Teaching Scotland (LTS). Despite the volume of academic literature in this field, the team of six reviewers found comparatively few empirical studies published in the period 2005-2011 providing findings addressing the review objectives. There was, however a reasonable weight of research evidence to support the importance of the following factors in supporting creative skills development in children and young people: flexible use of space and time; availability of appropriate materials; working outside the classroom/school; 'playful' or 'games-bases' approaches with a degree of learner autonomy; respectful relationships between teachers and learners; opportunities for peer collaboration; partnerships with outside agencies; awareness of learners' needs; and non-prescriptive planning. The review also found evidence for impact of creative environments on pupil attainment and the development of teacher professionalism. LTS intend to use the review as a basis for recommendations to Scottish schools in promoting creativity within Curriculum for Excellence. However, the findings of the review and methodological gaps in the reviewed studies have implications for policy, practice and research internationally. © 2012 Elsevier Ltd. All rights reserved. AB - This paper reports on a systematic review of 210 pieces of educational research, policy and professional literature relating to creative environments for learning in schools, commissioned by Learning and Teaching Scotland (LTS). Despite the volume of academic literature in this field, the team of six reviewers found comparatively few empirical studies published in the period 2005-2011 providing findings addressing the review objectives. There was, however a reasonable weight of research evidence to support the importance of the following factors in supporting creative skills development in children and young people: flexible use of space and time; availability of appropriate materials; working outside the classroom/school; 'playful' or 'games-bases' approaches with a degree of learner autonomy; respectful relationships between teachers and learners; opportunities for peer collaboration; partnerships with outside agencies; awareness of learners' needs; and non-prescriptive planning. The review also found evidence for impact of creative environments on pupil attainment and the development of teacher professionalism. LTS intend to use the review as a basis for recommendations to Scottish schools in promoting creativity within Curriculum for Excellence. However, the findings of the review and methodological gaps in the reviewed studies have implications for policy, practice and research internationally. © 2012 Elsevier Ltd. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84865076636&md5=e5bb89907316542b80ee71b588277043 U2 - 10.1016/j.tsc.2012.07.004 DO - 10.1016/j.tsc.2012.07.004 M1 - Article JO - Thinking Skills and Creativity JF - Thinking Skills and Creativity SN - 1871-1871 VL - 8 SP - 80 EP - 91 ER - TY - JOUR T1 - Cross-border flow of health information T2 - Is 'privacy by design' enough? Privacy performance assessment in EUBIROD A1 - Di Iorio,C.T. A1 - Carinci,F. A1 - Brillante,Massimo A1 - Cunningham,Scott G. A1 - Azzopardi,J. A1 - Beck,P. A1 - Bratina,N. A1 - De Beaufort,C. A1 - Debacker,N. A1 - Jarosz-Chobot,P. A1 - Jecht,M. A1 - Lindblad,U. A1 - Moulton,T. A1 - Metelko,Ž. A1 - Nagy,A. A1 - Olympios,G. A1 - Pruna,S. A1 - Røder,M. A1 - Skeie,S. A1 - Storms,F. A1 - Massi Benedetti,M. AU - Di Iorio,C.T. AU - Carinci,F. AU - Brillante,Massimo AU - Cunningham,Scott G. AU - Azzopardi,J. AU - Beck,P. AU - Bratina,N. AU - De Beaufort,C. AU - Debacker,N. AU - Jarosz-Chobot,P. AU - Jecht,M. AU - Lindblad,U. AU - Moulton,T. AU - Metelko,Ž. AU - Nagy,A. AU - Olympios,G. AU - Pruna,S. AU - Røder,M. AU - Skeie,S. AU - Storms,F. AU - Massi Benedetti,M. PY - 2013/4 Y1 - 2013/4 N2 - Background: The EUBIROD project aims to perform a cross-border flow of diabetes information across 19 European countries using the BIRO information system, which embeds privacy principles and data protection mechanisms in its architecture (privacy by design). A specific task of EUBIROD was to investigate the variability in the implementation of the EU Data Protection Directive (DPD) across participating centres. Methods: Compliance with privacy requirements was assessed by means of a specific questionnaire administered to all participating diabetes registers. Items included relevant issues e.g. patient consent, accountability of data custodian, communication (openness) and complaint procedures (challenging compliance), authority to disclose, accuracy, access and use of personal information, and anonymization. The identification of an ad hoc scoring system and statistical software allowed an overall quali-quantitative analysis and independent evaluation of questionnaire responses, automated through a dedicated IT platform ('privacy performance assessment'). Results: A total of 18 diabetes registers from different countries completed the survey. Over 50% of the registers recorded a maximum score for accountability, openness, anonymization and challenging compliance. Low average values were found for disclosure and disposition, access, consent, use of personal information and accuracy. A high heterogeneity was found for anonymization, consent, accuracy and access. Conclusions: The novel method of privacy performance assessment realized in EUBIROD may improve the respect of privacy in each data source, reduce overall variability in the implementation of privacy principles and favour a sound and legitimate cross-border exchange of high quality data across Europe. © 2012 Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved. AB - Background: The EUBIROD project aims to perform a cross-border flow of diabetes information across 19 European countries using the BIRO information system, which embeds privacy principles and data protection mechanisms in its architecture (privacy by design). A specific task of EUBIROD was to investigate the variability in the implementation of the EU Data Protection Directive (DPD) across participating centres. Methods: Compliance with privacy requirements was assessed by means of a specific questionnaire administered to all participating diabetes registers. Items included relevant issues e.g. patient consent, accountability of data custodian, communication (openness) and complaint procedures (challenging compliance), authority to disclose, accuracy, access and use of personal information, and anonymization. The identification of an ad hoc scoring system and statistical software allowed an overall quali-quantitative analysis and independent evaluation of questionnaire responses, automated through a dedicated IT platform ('privacy performance assessment'). Results: A total of 18 diabetes registers from different countries completed the survey. Over 50% of the registers recorded a maximum score for accountability, openness, anonymization and challenging compliance. Low average values were found for disclosure and disposition, access, consent, use of personal information and accuracy. A high heterogeneity was found for anonymization, consent, accuracy and access. Conclusions: The novel method of privacy performance assessment realized in EUBIROD may improve the respect of privacy in each data source, reduce overall variability in the implementation of privacy principles and favour a sound and legitimate cross-border exchange of high quality data across Europe. © 2012 Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875996953&md5=48e49c9af309de2dc92e7d32b33111d1 U2 - 10.1093/eurpub/cks043 DO - 10.1093/eurpub/cks043 M1 - Article JO - European Journal of Public Health JF - European Journal of Public Health SN - 1101-1262 IS - 2 VL - 23 SP - 247 EP - 253 ER - TY - JOUR T1 - Cross-cultural adaptation and translation of a quality of life tool for new mothers T2 - a methodological and experiential account from six countries A1 - Symon,Andrew A1 - Nagpal,Jitender A1 - Maniecka-Bryła,Irena A1 - Nowakowska-Głab,Agata A1 - Rashidian,Arash A1 - Khabiri,Roghayeh A1 - Mendes,Isabel A1 - Pinheiro,Ana Karina A1 - de Oliveira,Mirna A1 - Wu,Liping AU - Symon,Andrew AU - Nagpal,Jitender AU - Maniecka-Bryła,Irena AU - Nowakowska-Głab,Agata AU - Rashidian,Arash AU - Khabiri,Roghayeh AU - Mendes,Isabel AU - Pinheiro,Ana Karina AU - de Oliveira,Mirna AU - Wu,Liping PY - 2013/4 Y1 - 2013/4 N2 - Aim: To examine the challenges and solutions encountered in the translation and cross-cultural adaptation of an English language quality of life tool in India, China, Iran, Portugal, Brazil, and Poland. Background: Those embarking on research involving translation and cross-cultural adaptation must address certain practical and conceptual issues. These include instrument choice, linguistic factors, and cultural or philosophical differences, which may render an instrument inappropriate, even when expertly translated. Publication bias arises when studies encountering difficulties do not admit to these, or are not published at all. As an educative guide to the potential pitfalls involved in the cross-cultural adaptation process, this article reports the conceptual, linguistic, and methodological experiences of researchers in six countries, who translated and adapted the Mother-Generated Index, a quality of life tool originally developed in English. Data sources: Principal investigator experience from six stand-alone studies (two published) ranging from postgraduate research to citywide surveys. Discussion/implications for nursing: This analysis of a series of stand-alone cross-cultural studies provides lessons about how conceptual issues, such as the uniqueness of perceived quality of life and the experience of new motherhood, can be addressed. This original international approach highlights practical lessons relating to instrument choice, and the resources available to researchers with different levels of experience. Although researchers may be confident of effective translation, conceptual and practical difficulties may be more problematic. Conclusion: Instrument choice is crucial. Researchers must negotiate adequate resources for cross-cultural research, including time, translation facilities, and expert advice about conceptual issues. © 2012 Blackwell Publishing Ltd. AB - Aim: To examine the challenges and solutions encountered in the translation and cross-cultural adaptation of an English language quality of life tool in India, China, Iran, Portugal, Brazil, and Poland. Background: Those embarking on research involving translation and cross-cultural adaptation must address certain practical and conceptual issues. These include instrument choice, linguistic factors, and cultural or philosophical differences, which may render an instrument inappropriate, even when expertly translated. Publication bias arises when studies encountering difficulties do not admit to these, or are not published at all. As an educative guide to the potential pitfalls involved in the cross-cultural adaptation process, this article reports the conceptual, linguistic, and methodological experiences of researchers in six countries, who translated and adapted the Mother-Generated Index, a quality of life tool originally developed in English. Data sources: Principal investigator experience from six stand-alone studies (two published) ranging from postgraduate research to citywide surveys. Discussion/implications for nursing: This analysis of a series of stand-alone cross-cultural studies provides lessons about how conceptual issues, such as the uniqueness of perceived quality of life and the experience of new motherhood, can be addressed. This original international approach highlights practical lessons relating to instrument choice, and the resources available to researchers with different levels of experience. Although researchers may be confident of effective translation, conceptual and practical difficulties may be more problematic. Conclusion: Instrument choice is crucial. Researchers must negotiate adequate resources for cross-cultural research, including time, translation facilities, and expert advice about conceptual issues. © 2012 Blackwell Publishing Ltd. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84864070168&md5=69479ba8d06407d5b3c1befb782e8604 U2 - 10.1111/j.1365-2648.2012.06098.x DO - 10.1111/j.1365-2648.2012.06098.x M1 - Article JO - Journal of Advanced Nursing JF - Journal of Advanced Nursing SN - 0309-2402 IS - 4 VL - 69 SP - 970 EP - 980 ER - TY - JOUR T1 - Current Account Adjustment in Developing Countries T2 - The Role of Exchange Rate Regimes A1 - Mu,Xiaoyi A1 - Ye,Haichun AU - Mu,Xiaoyi AU - Ye,Haichun PY - 2013/4 Y1 - 2013/4 N2 - This article employs hazard models to investigate the role of exchange rate regimes in the timing of current account adjustment in developing countries. We identify high current account deficit spells and find that fixed exchange rate regimes increase the duration of high deficit spells and thus delay current account adjustment. The result is robust to a variety of model specifications and alternative classifications of exchange rate regimes. When distinguishing between hard pegs and soft pegs, we notice that the delay in the current account adjustment is primarily driven by hard pegs rather than soft pegs. AB - This article employs hazard models to investigate the role of exchange rate regimes in the timing of current account adjustment in developing countries. We identify high current account deficit spells and find that fixed exchange rate regimes increase the duration of high deficit spells and thus delay current account adjustment. The result is robust to a variety of model specifications and alternative classifications of exchange rate regimes. When distinguishing between hard pegs and soft pegs, we notice that the delay in the current account adjustment is primarily driven by hard pegs rather than soft pegs. KW - : exchange rate regimes, current account adjustment, duration models, hazard U2 - 10.1111/j.1465-7295.2012.00502.x DO - 10.1111/j.1465-7295.2012.00502.x M1 - Article JO - Economic Inquiry JF - Economic Inquiry IS - 2 VL - 51 SP - 1566 EP - 1581 ER - TY - JOUR T1 - Cutaneous distribution after brachial plexus blockade A1 - Raju,P. K. B. C. A1 - Coventry,D. M. AU - Raju,P. K. B. C. AU - Coventry,D. M. PY - 2013/4 Y1 - 2013/4 U2 - 10.1111/anae.12169 DO - 10.1111/anae.12169 M1 - Meeting abstract JO - Anaesthesia JF - Anaesthesia SN - 0003-2409 IS - 4 VL - 68 SP - 442 EP - 442 ER - TY - JOUR T1 - Decoding the SUMO signal A1 - Hay,Ronald T. AU - Hay,Ronald T. PY - 2013/4 Y1 - 2013/4 N2 -

SUMO (small ubiquitin-like modifier) emerged from the shadow of the well-established ubiquitin some 15 years ago when it was shown that a distinct conjugation pathway was responsible for SUMO modification. Since then it has been established that SUMO modifies over a thousand substrates and plays diverse roles in many important biological processes. Recognition of SUMO is mediated by short peptide sequences known as SIMs (SUMO-interaction motifs) that allow effector proteins to engage SUMO-modified substrates. Like ubiquitin, SUMO can form polymeric chains, and these chains can be recognized by proteins containing multiple SIMs. One protein that contains such a sequence of SIMs also contains a RING (really interesting new gene) domain that is the hallmark of a ubiquitin E3 ligase. This ubiquitin ligase known as RNF4 (RING finger protein 4) has the unique property that it can recognize SUMO-modified proteins and target them for ubiquitin-mediated proteolysis. Structural and biochemical analyses of RNF4 has shed light on the long sought after mechanism of ubiquitin transfer and illustrates how its RING domain primes the ubiquitin-loaded E2 for catalysis.

AB -

SUMO (small ubiquitin-like modifier) emerged from the shadow of the well-established ubiquitin some 15 years ago when it was shown that a distinct conjugation pathway was responsible for SUMO modification. Since then it has been established that SUMO modifies over a thousand substrates and plays diverse roles in many important biological processes. Recognition of SUMO is mediated by short peptide sequences known as SIMs (SUMO-interaction motifs) that allow effector proteins to engage SUMO-modified substrates. Like ubiquitin, SUMO can form polymeric chains, and these chains can be recognized by proteins containing multiple SIMs. One protein that contains such a sequence of SIMs also contains a RING (really interesting new gene) domain that is the hallmark of a ubiquitin E3 ligase. This ubiquitin ligase known as RNF4 (RING finger protein 4) has the unique property that it can recognize SUMO-modified proteins and target them for ubiquitin-mediated proteolysis. Structural and biochemical analyses of RNF4 has shed light on the long sought after mechanism of ubiquitin transfer and illustrates how its RING domain primes the ubiquitin-loaded E2 for catalysis.

KW - ACUTE PROMYELOCYTIC LEUKEMIA KW - UBIQUITIN E3 LIGASE KW - TRANSCRIPTION FACTOR KW - PML NUCLEAR-BODIES KW - CONJUGATING ENZYME KW - E3 ligase KW - ubiquitin KW - DNA damage KW - small ubiquitin-like modifier (SUMO) KW - RAR-ALPHA KW - MODIFIER SUMO KW - RING finger protein 4 (RNF4) KW - DNA-DAMAGE RESPONSE KW - PORE COMPLEX KW - really interesting new gene (RING) KW - BINDING MOTIF U2 - 10.1042/BST20130015 DO - 10.1042/BST20130015 M1 - Article JO - Biochemical Society Transactions JF - Biochemical Society Transactions SN - 0300-5127 IS - 2 VL - 41 SP - 463 EP - 473 ER - TY - JOUR T1 - Degradation characteristics of the major PML isoforms in response to arsenic A1 - Hands,K. J. A1 - Cuchet-Lourenco,D. A1 - Everett,R. D. A1 - Hay,R. T. AU - Hands,K. J. AU - Cuchet-Lourenco,D. AU - Everett,R. D. AU - Hay,R. T. PY - 2013/4 Y1 - 2013/4 U2 - 10.1111/bjh.12263 DO - 10.1111/bjh.12263 M1 - Meeting abstract JO - British Journal of Haematology JF - British Journal of Haematology SN - 0007-1048 IS - Suppl. 1 VL - 161 SP - 17 ER - TY - JOUR T1 - Dental therapists/hygienists working in remote-rural primary care T2 - a structured review of effectiveness, efficiency, sustainability, acceptability and affordability A1 - Freeman,Ruth A1 - Lush,Cathy A1 - MacGillveray,Steve A1 - Themessl-Huber,Markus A1 - Richards,Derek AU - Freeman,Ruth AU - Lush,Cathy AU - MacGillveray,Steve AU - Themessl-Huber,Markus AU - Richards,Derek PY - 2013/4 Y1 - 2013/4 N2 - Aim To examine the use of dental therapist/hygienists to provide primary dental treatment in remote-rural areas with regard to their effectiveness, efficiency, sustainability, acceptability and costs (affordability). Method The structured literature review of studies indexed in Medline, Embase and CinAHL was conducted using search terms relevant to 'dental therapists' and 'remote-rural'. Remote-rural was defined as 'those (individuals) with a greater than 30-minute drive time to the nearest settlement with a population of greater than 10,000'. Results From 1,175 publications screened, 21 studies from 19 publications were initially included. Only seven studies were included that explicitly focused on remote-rural areas. Four were surveys and three were qualitative studies. All of the included studies were reported within the last 7 years. The methodological quality of the surveys varied, particularly with regard to their response rates. All three of the qualitative studies were assessed as potentially weak methodologies. Regarding the research question, none of the studies included provided data relevant to understanding efficiency, cost issues or the acceptability of dental therapists. The available empirical evidence contained only indirect indicators about the sustainability of dental therapy in rural areas. Conclusions The available data indicates that dental therapist/hygienists have suitable skills and could constitute a valuable asset to meet the dental demands in remote-rural areas. However, the evidence base is limited and of a poor quality. There is a need to put in place 'well-designed interventions with robust evaluation to examine cost-effectiveness and benefits to patients and the health workforce'. © 2013 FDI World Dental Federation. AB - Aim To examine the use of dental therapist/hygienists to provide primary dental treatment in remote-rural areas with regard to their effectiveness, efficiency, sustainability, acceptability and costs (affordability). Method The structured literature review of studies indexed in Medline, Embase and CinAHL was conducted using search terms relevant to 'dental therapists' and 'remote-rural'. Remote-rural was defined as 'those (individuals) with a greater than 30-minute drive time to the nearest settlement with a population of greater than 10,000'. Results From 1,175 publications screened, 21 studies from 19 publications were initially included. Only seven studies were included that explicitly focused on remote-rural areas. Four were surveys and three were qualitative studies. All of the included studies were reported within the last 7 years. The methodological quality of the surveys varied, particularly with regard to their response rates. All three of the qualitative studies were assessed as potentially weak methodologies. Regarding the research question, none of the studies included provided data relevant to understanding efficiency, cost issues or the acceptability of dental therapists. The available empirical evidence contained only indirect indicators about the sustainability of dental therapy in rural areas. Conclusions The available data indicates that dental therapist/hygienists have suitable skills and could constitute a valuable asset to meet the dental demands in remote-rural areas. However, the evidence base is limited and of a poor quality. There is a need to put in place 'well-designed interventions with robust evaluation to examine cost-effectiveness and benefits to patients and the health workforce'. © 2013 FDI World Dental Federation. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875836074&md5=6e68487ec3e1454a5fc8d12fc195687c U2 - 10.1111/idj.12025 DO - 10.1111/idj.12025 M1 - Article JO - International Dental Journal JF - International Dental Journal SN - 0020-6539 IS - 2 VL - 63 SP - 103 EP - 112 ER - TY - JOUR T1 - Does the anticholinergic risk score predict death in older people after discharge from inpatient rehabilitation? A1 - Walesby,K. E. A1 - Sumukadas,D. A1 - Ramage,L. A1 - McMurdo,M. E. A1 - Mangoni,A. A. A1 - Witham,M. D. AU - Walesby,K. E. AU - Sumukadas,D. AU - Ramage,L. AU - McMurdo,M. E. AU - Mangoni,A. A. AU - Witham,M. D. PY - 2013/4 Y1 - 2013/4 U2 - 10.1111/jgs.12263 DO - 10.1111/jgs.12263 M1 - Meeting abstract JO - Journal of the American Geriatrics Society JF - Journal of the American Geriatrics Society SN - 0002-8614 IS - Suppl. 1 VL - 61 SP - S142 ER - TY - JOUR T1 - Does the choice of antiepileptic drug have an impact on the survival of glioblastoma multiforme? A1 - Guthrie,Greg A1 - Eljamel,Sam AU - Guthrie,Greg AU - Eljamel,Sam PY - 2013/4 Y1 - 2013/4 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875864214&md5=2e2b1b8e01ad1f3a8bd48988fba2afad U2 - 10.3109/02688697.2013.772101 DO - 10.3109/02688697.2013.772101 M1 - Letter JO - British Journal of Neurosurgery JF - British Journal of Neurosurgery SN - 0268-8697 IS - 2 VL - 27 SP - 270 ER - TY - JOUR T1 - Editor's Choice T2 - Evaluating the potential for adverse interactions within genetically engineered breeding stacks A1 - Steiner,Henry-York A1 - Halpin,Claire A1 - Jez,Joseph M. A1 - Kough,John A1 - Parrott,Wayne A1 - Underhill,Lynne A1 - Weber,Natalie A1 - Curtis Hannah,L. AU - Steiner,Henry-York AU - Halpin,Claire AU - Jez,Joseph M. AU - Kough,John AU - Parrott,Wayne AU - Underhill,Lynne AU - Weber,Natalie AU - Curtis Hannah,L. PY - 2013/4 Y1 - 2013/4 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875747186&md5=672f388328c5bdf472eb7dcce8f6ab6f U2 - 10.1104/pp.112.209817 DO - 10.1104/pp.112.209817 M1 - Article JO - Plant Physiology JF - Plant Physiology SN - 0032-0889 IS - 4 VL - 161 SP - 1587 EP - 1594 ER - TY - JOUR T1 - Energy absorption of foamed concrete from low-velocity impacts A1 - Jones,M. Roderick A1 - Zheng,Li AU - Jones,M. Roderick AU - Zheng,Li PY - 2013/4 Y1 - 2013/4 N2 - Foamed concrete has existing uses as an energy absorber for large-scale and low-cost applications, such as explosion prevention in mines and military engineering projects and aircraft arresting systems. However, there is little information enumerating the energy absorption characteristics of different foamed concretes; this paper describes a study that determined these using low-velocity impact tests. A range of foamed concretes were tested with plastic densities varying from 500 to 1400 kg/m3, which are typical of those produced commercially. The tests used hemispherical projectiles with a range of masses from 1·2 to 8·4 kg, dropped from a fixed height of 4·7 m. The resulting ‘damage' was measured and related to the impact energy imparted to the test specimen. A classification, using five different failure modes, was established and the mode in which the test specimen neither caused ‘rebound' of the projectile nor itself fractured was selected as representing ‘ideal' energy absorption behaviour. Making the assumption of no energy losses and using the conservation of energy law, the energy absorption capacity of foamed concrete was calculated and was found to vary from 4 to 15 MJ/m3 for different mixes. The optimum energy absorption was noted for the 1000 kg/m3 mix at water to cement (w/c) ratios from 0·6 to 0·7, which allowed a debris field of crushed foamed concrete to form and be pushed into the concrete bubble space ahead of the nose of the projectile, without fracturing. AB - Foamed concrete has existing uses as an energy absorber for large-scale and low-cost applications, such as explosion prevention in mines and military engineering projects and aircraft arresting systems. However, there is little information enumerating the energy absorption characteristics of different foamed concretes; this paper describes a study that determined these using low-velocity impact tests. A range of foamed concretes were tested with plastic densities varying from 500 to 1400 kg/m3, which are typical of those produced commercially. The tests used hemispherical projectiles with a range of masses from 1·2 to 8·4 kg, dropped from a fixed height of 4·7 m. The resulting ‘damage' was measured and related to the impact energy imparted to the test specimen. A classification, using five different failure modes, was established and the mode in which the test specimen neither caused ‘rebound' of the projectile nor itself fractured was selected as representing ‘ideal' energy absorption behaviour. Making the assumption of no energy losses and using the conservation of energy law, the energy absorption capacity of foamed concrete was calculated and was found to vary from 4 to 15 MJ/m3 for different mixes. The optimum energy absorption was noted for the 1000 kg/m3 mix at water to cement (w/c) ratios from 0·6 to 0·7, which allowed a debris field of crushed foamed concrete to form and be pushed into the concrete bubble space ahead of the nose of the projectile, without fracturing. U2 - 10.1680/macr.12.00054 DO - 10.1680/macr.12.00054 M1 - Article JO - Magazine of Concrete Research JF - Magazine of Concrete Research SN - 0024-9831 IS - 4 VL - 65 SP - 209 EP - 219 ER - TY - JOUR T1 - Esperanto for histones T2 - CENP-A, not CenH3, is the centromeric histone H3 variant A1 - Earnshaw,W.C. A1 - Allshire,R.C. A1 - Black,B.E. A1 - Bloom,K. A1 - Salmon,E.D. A1 - Brinkley,B.R. A1 - Brown,W. A1 - Cheeseman,I.M. A1 - Choo,K.H.A. A1 - Copenhaver,G.P. A1 - DeLuca,J.G. A1 - Luger,K. A1 - Desai,A. A1 - Oegema,K. A1 - Cleveland,D.W. A1 - Diekmann,S. A1 - Erhardt,S. A1 - Fitzgerald-Hayes,M. A1 - Foltz,D. A1 - Fukagawa,T. A1 - Gassmann,R. A1 - Maiato,H. A1 - Gerlich,D.W. A1 - Glover,D.M. A1 - Gorbsky,G.J. A1 - Harrison,S.C. A1 - Heun,P. A1 - Hirota,T. A1 - Jansen,L.E.T. A1 - Karpen,G. A1 - Kops,G.J.P.L. A1 - Lampson,M.A. A1 - Lens,S.M. A1 - Losada,A. A1 - Maddox,P.S. A1 - Margolis,R.L. A1 - Masumoto,H. A1 - McAinsh,A.D. A1 - Mellone,B.G. A1 - O'Neill,R.J. A1 - Meraldi,P. A1 - Musacchio,A. A1 - Scott,K.C. A1 - Sullivan,B.A. A1 - Straight,A.F. A1 - Stukenberg,P.T. A1 - Sullivan,K.F. A1 - Sunkel,C.E. A1 - Swedlow,J.R. A1 - Walczak,C.E. A1 - Warburton,P.E. A1 - Westermann,S. A1 - Willard,H.F. A1 - Wordeman,L. A1 - Yanagida,M. A1 - Yen,T.J. A1 - Yoda,K. AU - Earnshaw,W.C. AU - Allshire,R.C. AU - Black,B.E. AU - Bloom,K. AU - Salmon,E.D. AU - Brinkley,B.R. AU - Brown,W. AU - Cheeseman,I.M. AU - Choo,K.H.A. AU - Copenhaver,G.P. AU - DeLuca,J.G. AU - Luger,K. AU - Desai,A. AU - Oegema,K. AU - Cleveland,D.W. AU - Diekmann,S. AU - Erhardt,S. AU - Fitzgerald-Hayes,M. AU - Foltz,D. AU - Fukagawa,T. AU - Gassmann,R. AU - Maiato,H. AU - Gerlich,D.W. AU - Glover,D.M. AU - Gorbsky,G.J. AU - Harrison,S.C. AU - Heun,P. AU - Hirota,T. AU - Jansen,L.E.T. AU - Karpen,G. AU - Kops,G.J.P.L. AU - Lampson,M.A. AU - Lens,S.M. AU - Losada,A. AU - Maddox,P.S. AU - Margolis,R.L. AU - Masumoto,H. AU - McAinsh,A.D. AU - Mellone,B.G. AU - O'Neill,R.J. AU - Meraldi,P. AU - Musacchio,A. AU - Scott,K.C. AU - Sullivan,B.A. AU - Straight,A.F. AU - Stukenberg,P.T. AU - Sullivan,K.F. AU - Sunkel,C.E. AU - Swedlow,J.R. AU - Walczak,C.E. AU - Warburton,P.E. AU - Westermann,S. AU - Willard,H.F. AU - Wordeman,L. AU - Yanagida,M. AU - Yen,T.J. AU - Yoda,K. PY - 2013/4 Y1 - 2013/4 N2 - The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres. © 2013 The Author(s). AB - The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres. © 2013 The Author(s). UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875965328&md5=2d8b88d9bb99e0d8d0a26674119a4dbc U2 - 10.1007/s10577-013-9347-y DO - 10.1007/s10577-013-9347-y M1 - Article JO - Chromosome Research JF - Chromosome Research SN - 0967-3849 IS - 2 VL - 21 SP - 101 EP - 106 ER - TY - JOUR T1 - Hypocupremia associated cytopenia and myelopathy T2 - a national retrospective review A1 - Gebreyes,A. A. A1 - Abbasi,H. A1 - Forbes,K. P. A1 - McQuaker,G. A1 - Duncan,A. A1 - Morrison,I. AU - Gebreyes,A. A. AU - Abbasi,H. AU - Forbes,K. P. AU - McQuaker,G. AU - Duncan,A. AU - Morrison,I. PY - 2013/4 Y1 - 2013/4 U2 - 10.1111/bjh.12263 DO - 10.1111/bjh.12263 M1 - Meeting abstract JO - British Journal of Haematology JF - British Journal of Haematology SN - 0007-1048 IS - Suppl. 1 VL - 161 SP - 10 ER - TY - JOUR T1 - Impact of particular antiepileptic drugs on the survival of patients with glioblastoma multiforme T2 - Clinical article A1 - Guthrie,Greg D. A1 - Eljamel,Sam AU - Guthrie,Greg D. AU - Eljamel,Sam PY - 2013/4 Y1 - 2013/4 N2 - Object. Glioblastoma multiforme (GBM) is the most common astrocytic brain tumor and carries a dire prognosis. Despite current therapeutic options-surgery, radiotherapy, and chemotherapy-survival varies from 11.3 to 14.6 months. A group of drugs known as histone deacetylase inhibitors (HDIs) has demonstrated a potentially beneficial role in cancer treatment, particularly in combination with other therapies. A drug that exhibits potential as an HDI is sodium valproate (VPA), which is frequently used to treat seizures in patients with cerebral neoplasms. The present study was undertaken to investigate the role of VPA as an antitumor agent in the management of patients with GBM. Methods. A review was conducted in terms of how HDIs work, the use of antiepileptic drugs (AEDs), and the effects of AEDs on survival in a local cohort of patients diagnosed with GBM. The local cohort of patients was determined by reviewing the electronic histopathology and AED informatics systems. A meta-analysis of papers on the use of AEDs in GBM was also performed. Results. The local cohort consisted of 236 patients with GBM, 210 of whom had complete data available for analysis, a median age of 62 years, and 1-year survival of 26%. Patients treated with AEDs had a significantly longer survival than those who were not (Mantel-Cox log-rank test 19.617, p <0.001). Those treated with VPA had significantly longer survival than those who did not receive an AED (Mantel-Cox log-rank test 17.506, p <0.001), and patients treated with VPA had a significantly longer survival than those who had received other AEDs (Mantel-Cox log-rank test 5.303, p <0.02). Conclusions. Authors of this study demonstrated evidence supporting the theory that VPA may benefit patients with GBM in terms of survival. © 2013 AANS. AB - Object. Glioblastoma multiforme (GBM) is the most common astrocytic brain tumor and carries a dire prognosis. Despite current therapeutic options-surgery, radiotherapy, and chemotherapy-survival varies from 11.3 to 14.6 months. A group of drugs known as histone deacetylase inhibitors (HDIs) has demonstrated a potentially beneficial role in cancer treatment, particularly in combination with other therapies. A drug that exhibits potential as an HDI is sodium valproate (VPA), which is frequently used to treat seizures in patients with cerebral neoplasms. The present study was undertaken to investigate the role of VPA as an antitumor agent in the management of patients with GBM. Methods. A review was conducted in terms of how HDIs work, the use of antiepileptic drugs (AEDs), and the effects of AEDs on survival in a local cohort of patients diagnosed with GBM. The local cohort of patients was determined by reviewing the electronic histopathology and AED informatics systems. A meta-analysis of papers on the use of AEDs in GBM was also performed. Results. The local cohort consisted of 236 patients with GBM, 210 of whom had complete data available for analysis, a median age of 62 years, and 1-year survival of 26%. Patients treated with AEDs had a significantly longer survival than those who were not (Mantel-Cox log-rank test 19.617, p <0.001). Those treated with VPA had significantly longer survival than those who did not receive an AED (Mantel-Cox log-rank test 17.506, p <0.001), and patients treated with VPA had a significantly longer survival than those who had received other AEDs (Mantel-Cox log-rank test 5.303, p <0.02). Conclusions. Authors of this study demonstrated evidence supporting the theory that VPA may benefit patients with GBM in terms of survival. © 2013 AANS. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875862383&md5=272c29bff21f8d3909c4196761510ef2 U2 - 10.3171/2012.10.JNS12169 DO - 10.3171/2012.10.JNS12169 M1 - Article JO - British Journal of Neurosurgery JF - British Journal of Neurosurgery SN - 0268-8697 IS - 4 VL - 118 SP - 859 EP - 865 ER - TY - JOUR T1 - Modulation of p53 C-terminal acetylation by mdm2, p14ARF, and cytoplasmic SirT2 A1 - van Leeuwen,Ingeborg M. M. A1 - Higgins,Maureen A1 - Campbell,Johanna A1 - McCarthy,Anna R. A1 - Sachweh,Marijke C. C. A1 - Navarro,Ana Marin A1 - Lain,Sonia AU - van Leeuwen,Ingeborg M. M. AU - Higgins,Maureen AU - Campbell,Johanna AU - McCarthy,Anna R. AU - Sachweh,Marijke C. C. AU - Navarro,Ana Marin AU - Lain,Sonia PY - 2013/4 Y1 - 2013/4 N2 -

Acetylation of C-terminal lysine residues in the p53 tumor suppressor is associated with increased stability and transcription factor activity. The function, protein level, and acetylation of p53 are downregulated by mdm2, which in its turn is inhibited by the p14(ARF) tumor suppressor. Here, we show that p14(ARF) increases the level of p53 acetylated at lysine 382 in a nuclear chromatin-rich fraction. Unexpectedly, this accumulation of p53AcK382 is dramatically enhanced in the presence of ectopic mdm2. In light of these observations, we propose that p14(ARF) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. Supporting this notion, we show that p53AcK382 can be deacetylated in the cytoplasm and that sirtuin SirT2 catalyzes this reaction. These results help understand why inhibition of both SirT1 and SirT2 is needed to achieve effective activation of p53 by small-molecule sirtuin inhibitors. Mol Cancer Ther; 12(4); 471-80. (C) 2013 AACR.

AB -

Acetylation of C-terminal lysine residues in the p53 tumor suppressor is associated with increased stability and transcription factor activity. The function, protein level, and acetylation of p53 are downregulated by mdm2, which in its turn is inhibited by the p14(ARF) tumor suppressor. Here, we show that p14(ARF) increases the level of p53 acetylated at lysine 382 in a nuclear chromatin-rich fraction. Unexpectedly, this accumulation of p53AcK382 is dramatically enhanced in the presence of ectopic mdm2. In light of these observations, we propose that p14(ARF) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. Supporting this notion, we show that p53AcK382 can be deacetylated in the cytoplasm and that sirtuin SirT2 catalyzes this reaction. These results help understand why inhibition of both SirT1 and SirT2 is needed to achieve effective activation of p53 by small-molecule sirtuin inhibitors. Mol Cancer Ther; 12(4); 471-80. (C) 2013 AACR.

KW - ACTIVATION KW - LOCALIZATION KW - DEACETYLATION KW - COMPLEX KW - PROTEIN KW - TUMOR-SUPPRESSOR KW - DEGRADATION KW - IN-VIVO KW - PATHWAY KW - ONCOPROTEIN MDM2 U2 - 10.1158/1535-7163.MCT-12-0904 DO - 10.1158/1535-7163.MCT-12-0904 M1 - Article JO - Molecular Cancer Therapeutics JF - Molecular Cancer Therapeutics SN - 1535-7163 IS - 4 VL - 12 SP - 471 EP - 480 ER - TY - JOUR T1 - MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop A1 - MacKenzie,Kirsty F. A1 - Van den Bosch,Mirjam W. M. A1 - Naqvi,Shaista A1 - Elcombe,Suzanne E. A1 - McGuire,Victoria A. A1 - Reith,Alastair D. A1 - Blackshear,Perry J. A1 - Dean,Jonathan L. E. A1 - Arthur,J. Simon C. AU - MacKenzie,Kirsty F. AU - Van den Bosch,Mirjam W. M. AU - Naqvi,Shaista AU - Elcombe,Suzanne E. AU - McGuire,Victoria A. AU - Reith,Alastair D. AU - Blackshear,Perry J. AU - Dean,Jonathan L. E. AU - Arthur,J. Simon C. PY - 2013/4 Y1 - 2013/4 N2 -

Prostaglandin production is catalyzed by cyclooxygenase 2 (cox-2). We demonstrate here that MSK1 and MSK2 (MSK1/2) can exert control on the induction of cox-2 mRNA by Toll-like receptor (TLR) agonists. In the initial phase of cox-2 induction, MSK1/2 knockout macrophages confirmed a role for MSK in the positive regulation of transcription. However, at later time points both lipopolysaccharide (LPS)-induced prostaglandin and cox-2 protein levels were increased in MSK1/2 knockout. Further analysis found that while MSKs promoted cox-2 mRNA transcription, following longer LPS stimulation MSKs also promoted degradation of cox-2 mRNA. This was found to be the result of an interleukin 10 (IL-10) feedback mechanism, with endogenously produced IL-10 promoting cox-2 degradation. The ability of IL-10 to do this was dependent on the mRNA binding protein TTP through a p38/MK2-mediated mechanism. As MSKs regulate IL-10 production in response to LPS, MSK1/2 knockout results in reduced IL-10 secretion and therefore reduced feedback from IL-10 on cox-2 mRNA stability. Following LPS stimulation, this increased mRNA stability correlated to an elevated induction of both of cox-2 protein and prostaglandin secretion in MSK1/2 knockout macrophages relative to that in wild-type cells. This was not restricted to isolated macrophages, as a similar effect of MSK1/2 knockout was seen on plasma prostaglandin E-2 (PGE(2)) levels following intraperitoneal injection of LPS.

AB -

Prostaglandin production is catalyzed by cyclooxygenase 2 (cox-2). We demonstrate here that MSK1 and MSK2 (MSK1/2) can exert control on the induction of cox-2 mRNA by Toll-like receptor (TLR) agonists. In the initial phase of cox-2 induction, MSK1/2 knockout macrophages confirmed a role for MSK in the positive regulation of transcription. However, at later time points both lipopolysaccharide (LPS)-induced prostaglandin and cox-2 protein levels were increased in MSK1/2 knockout. Further analysis found that while MSKs promoted cox-2 mRNA transcription, following longer LPS stimulation MSKs also promoted degradation of cox-2 mRNA. This was found to be the result of an interleukin 10 (IL-10) feedback mechanism, with endogenously produced IL-10 promoting cox-2 degradation. The ability of IL-10 to do this was dependent on the mRNA binding protein TTP through a p38/MK2-mediated mechanism. As MSKs regulate IL-10 production in response to LPS, MSK1/2 knockout results in reduced IL-10 secretion and therefore reduced feedback from IL-10 on cox-2 mRNA stability. Following LPS stimulation, this increased mRNA stability correlated to an elevated induction of both of cox-2 protein and prostaglandin secretion in MSK1/2 knockout macrophages relative to that in wild-type cells. This was not restricted to isolated macrophages, as a similar effect of MSK1/2 knockout was seen on plasma prostaglandin E-2 (PGE(2)) levels following intraperitoneal injection of LPS.

KW - NF-KAPPA-B KW - STRESS-INDUCED PHOSPHORYLATION KW - NECROSIS-FACTOR-ALPHA KW - ACTIVATED PROTEIN-KINASE KW - CYCLOOXYGENASE-2 MESSENGER-RNA KW - P38 MAPK PATHWAY KW - 3'-UNTRANSLATED REGION KW - RAW 264.7 MACROPHAGES KW - BINDING-PROTEIN KW - GENE-TRANSCRIPTION U2 - 10.1128/MCB.01690-12 DO - 10.1128/MCB.01690-12 M1 - Article JO - Molecular and Cellular Biology JF - Molecular and Cellular Biology IS - 7 VL - 33 SP - 1456 EP - 1467 ER - TY - JOUR T1 - NAD(P) H T2 - quinone oxidoreductase 1 inducer activity of some Saudi Arabian medicinal plants A1 - Shahat,Abdelaaty A. A1 - Alsaid,Mansour S. A1 - Alyahya,Muhammad A. A1 - Higgins,Maureen A1 - Dinkova-Kostova,Albena T. AU - Shahat,Abdelaaty A. AU - Alsaid,Mansour S. AU - Alyahya,Muhammad A. AU - Higgins,Maureen AU - Dinkova-Kostova,Albena T. PY - 2013/4 Y1 - 2013/4 N2 -

Medicinal plants are a rich source of biologically-active phytochemicals and have been used in traditional medicine for centuries. Specific phytochemicals and extracts of their plant sources have the ability to reduce the risk for chronic degenerative diseases by induction of enzymes involved in xenobiotic metabolism, many of which also have antioxidant and anti-inflammatory functions. One such multifunctional cytoprotective enzyme is NAD(P)H: quinone oxidoreductase. In this study, we prepared extracts of 27 Saudi Arabian medicinal plants which belong to 18 different plant families and tested their ability to induce NAD(P)H: quinone oxidoreductase in murine hepatoma cells grown in microtiter plate wells. In addition to the Brassicaceae, a known source of NAD(P)H: quinone oxidoreductase inducer activity, we found substantial inducer activity in extracts from the Apiaceae, Apocynaceae, and the Asteraceae families. Five out of a total of eight active extracts are from plants which belong to the Asteraceae family. We further show that artemisinin, an agent which is used clinically for the treatment of malaria, contributes but does not fully account for the inducer activity of the extract of Artemisia monosperma. In contrast to artemisinin, deoxyartemisinin is inactive in this assay, demonstrating the critical role of the endoperoxide moiety of artemisinin for inducer activity. Thus, the NAD(P)H: quinone oxidoreductase inducer activity of extracts of some Saudi Arabian medicinal plants indicates the presence of specific phytochemicals which have the potential to protect against chronic degenerative diseases.

AB -

Medicinal plants are a rich source of biologically-active phytochemicals and have been used in traditional medicine for centuries. Specific phytochemicals and extracts of their plant sources have the ability to reduce the risk for chronic degenerative diseases by induction of enzymes involved in xenobiotic metabolism, many of which also have antioxidant and anti-inflammatory functions. One such multifunctional cytoprotective enzyme is NAD(P)H: quinone oxidoreductase. In this study, we prepared extracts of 27 Saudi Arabian medicinal plants which belong to 18 different plant families and tested their ability to induce NAD(P)H: quinone oxidoreductase in murine hepatoma cells grown in microtiter plate wells. In addition to the Brassicaceae, a known source of NAD(P)H: quinone oxidoreductase inducer activity, we found substantial inducer activity in extracts from the Apiaceae, Apocynaceae, and the Asteraceae families. Five out of a total of eight active extracts are from plants which belong to the Asteraceae family. We further show that artemisinin, an agent which is used clinically for the treatment of malaria, contributes but does not fully account for the inducer activity of the extract of Artemisia monosperma. In contrast to artemisinin, deoxyartemisinin is inactive in this assay, demonstrating the critical role of the endoperoxide moiety of artemisinin for inducer activity. Thus, the NAD(P)H: quinone oxidoreductase inducer activity of extracts of some Saudi Arabian medicinal plants indicates the presence of specific phytochemicals which have the potential to protect against chronic degenerative diseases.

KW - INDUCTION KW - BROCCOLI KW - ESSENTIAL OIL KW - RATS KW - REDUCTASE KW - ENZYMES KW - CARCINOGENS KW - PROTECT KW - ARTEMISININ KW - EXTRACT KW - NQO1 KW - traditional healers KW - Saudi Arabian medicinal plants KW - chemoprotection U2 - 10.1055/s-0032-1328322 DO - 10.1055/s-0032-1328322 M1 - Article JO - Planta Medica JF - Planta Medica SN - 0032-0943 IS - 6 VL - 79 SP - 459 EP - 464 ER - TY - JOUR T1 - Nonlinear Interaction of Friction and Interpolation Errors in Unsteady Flow Analyses A1 - Shimada,Masashi A1 - Vardy,A. AU - Shimada,Masashi AU - Vardy,A. PY - 2013/4 Y1 - 2013/4 N2 -

Explicit analytical assessments of numerical errors in solutions of decaying standing waves in pipes are obtained using analyses based on the fixed-grid method of characteristics and are used as a quantitative basis for comparing alternative grid types, sizes, and shapes. It is shown that the influences of friction and interpolation combine in a nonlinear manner, but that the combination has the form of a product so that the two effects may be considered independently to a certain extent. The analysis is presented for finite pipes, thus creating both upper and lower limits for the range of possible standing wave frequencies. It is found that frequencies in the upper half of the range are strongly damped. The performances of diamond and rectangular grids are compared, but there is no clear winner because, for equivalent computer resources, each has both advantages and disadvantages. The overall purposes of the paper are to move toward methods of (1) relieving untrained software users from tasks related to grid selection and (2) assisting third parties in assessing the validity of numerical results undertaken by others. DOI: 10.1061/(ASCE)HY.1943-7900.0000685. (C) 2013 American Society of Civil Engineers.

AB -

Explicit analytical assessments of numerical errors in solutions of decaying standing waves in pipes are obtained using analyses based on the fixed-grid method of characteristics and are used as a quantitative basis for comparing alternative grid types, sizes, and shapes. It is shown that the influences of friction and interpolation combine in a nonlinear manner, but that the combination has the form of a product so that the two effects may be considered independently to a certain extent. The analysis is presented for finite pipes, thus creating both upper and lower limits for the range of possible standing wave frequencies. It is found that frequencies in the upper half of the range are strongly damped. The performances of diamond and rectangular grids are compared, but there is no clear winner because, for equivalent computer resources, each has both advantages and disadvantages. The overall purposes of the paper are to move toward methods of (1) relieving untrained software users from tasks related to grid selection and (2) assisting third parties in assessing the validity of numerical results undertaken by others. DOI: 10.1061/(ASCE)HY.1943-7900.0000685. (C) 2013 American Society of Civil Engineers.

KW - Time-line interpolation KW - PIPELINE TRANSIENTS KW - LEAK DETECTION KW - Friction KW - Method of characteristics KW - Pipe flows KW - Water hammer KW - Diamond grids KW - MODELS KW - Numerical errors KW - Rectangular grids KW - TIME-LINE INTERPOLATIONS U2 - 10.1061/(ASCE)HY.1943-7900.0000685 DO - 10.1061/(ASCE)HY.1943-7900.0000685 M1 - Article JO - Journal of Hydraulic Engineering JF - Journal of Hydraulic Engineering SN - 0733-9429 IS - 4 VL - 139 SP - 397 EP - 409 ER - TY - JOUR T1 - Nonlinear rocking stiffness of foundations A1 - Gazetas,G. A1 - Anastasopoulos,I. A1 - Adamidis,O. A1 - Kontoroupi,T. AU - Gazetas,G. AU - Anastasopoulos,I. AU - Adamidis,O. AU - Kontoroupi,T. PY - 2013/4 Y1 - 2013/4 N2 - The response of surface foundations to large overturning moments is studied under undrained conditions. Rigid circular, strip, and rectangular footings of various aspect ratios are considered, with the soil modeled as an inelastic homogeneous deposit, characterized by an elastic (small-strain) shear modulus G, an undrained shear strength S, and a G/G versus ? curve appropriate for medium-plasticity clays. Three stages of foundation performance, ranging from the initial elastic fully-bonded response, to the nearly-elastic but nonlinear response with the foundation partially detaching and uplifting from the soil, and finally to the ultimate stage where full mobilization of soil bearing failure mechanisms develop. Simple to use formulas or charts are developed for all stages of response in terms of dimensionless parameters, prominent among which is the static factor of safety against bearing-capacity failure under purely-vertical loading. © 2013 Elsevier Ltd. AB - The response of surface foundations to large overturning moments is studied under undrained conditions. Rigid circular, strip, and rectangular footings of various aspect ratios are considered, with the soil modeled as an inelastic homogeneous deposit, characterized by an elastic (small-strain) shear modulus G, an undrained shear strength S, and a G/G versus ? curve appropriate for medium-plasticity clays. Three stages of foundation performance, ranging from the initial elastic fully-bonded response, to the nearly-elastic but nonlinear response with the foundation partially detaching and uplifting from the soil, and finally to the ultimate stage where full mobilization of soil bearing failure mechanisms develop. Simple to use formulas or charts are developed for all stages of response in terms of dimensionless parameters, prominent among which is the static factor of safety against bearing-capacity failure under purely-vertical loading. © 2013 Elsevier Ltd. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875806768&md5=fcb60d59214fab5f00fcee4dd0591e7e U2 - 10.1016/j.soildyn.2012.12.011 DO - 10.1016/j.soildyn.2012.12.011 M1 - Article JO - Soil Dynamics and Earthquake Engineering JF - Soil Dynamics and Earthquake Engineering SN - 0267-7261 VL - 47 SP - 83 EP - 91 ER - TY - JOUR T1 - Palliative care for patients with gastrointestinal cancer dying under surgical care T2 - a case for acute palliative care units? A1 - Young,J. A. A1 - Waugh,L. A1 - McPhillips,G. A1 - Levack,P. A1 - Thompson,A. M. AU - Young,J. A. AU - Waugh,L. AU - McPhillips,G. AU - Levack,P. AU - Thompson,A. M. PY - 2013/4 Y1 - 2013/4 N2 - Background and aims: Patients with advanced gastrointestinal cancer may present late to hospital services and die under surgical care. The aim of this study was to examine end of life care in patients dying of gastrointestinal cancer in Scottish hospital surgical wards. Methods: The Scottish Audit of Surgical Mortality prospectively peer reviews all inpatient deaths under the care of a consultant surgeon. Patients who died with gastrointestinal cancer under surgical care from 1994 to 2006 were evaluated for operative interventions, adverse events, and palliative care provision. Data was compared with inpatient data from the Information Statistics Division of NHS Scotland. Results: A total of 8019 patients died with gastrointestinal cancer on a surgical ward over 12 years. For 4350 (54%), no operation or endoscopy was performed during the final admission and adverse events were identified in only 86 (2%) of these patients, most commonly due to a complication of an interventional procedures. Specialist palliative care was provided to 57% of patients and was not influenced by cancer site. Conclusion: A substantial proportion of patients die with gastrointestinal cancer on general surgical wards without operative or endoscopic intervention and may receive better end of life care in an acute palliative care setting. © 2012 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. AB - Background and aims: Patients with advanced gastrointestinal cancer may present late to hospital services and die under surgical care. The aim of this study was to examine end of life care in patients dying of gastrointestinal cancer in Scottish hospital surgical wards. Methods: The Scottish Audit of Surgical Mortality prospectively peer reviews all inpatient deaths under the care of a consultant surgeon. Patients who died with gastrointestinal cancer under surgical care from 1994 to 2006 were evaluated for operative interventions, adverse events, and palliative care provision. Data was compared with inpatient data from the Information Statistics Division of NHS Scotland. Results: A total of 8019 patients died with gastrointestinal cancer on a surgical ward over 12 years. For 4350 (54%), no operation or endoscopy was performed during the final admission and adverse events were identified in only 86 (2%) of these patients, most commonly due to a complication of an interventional procedures. Specialist palliative care was provided to 57% of patients and was not influenced by cancer site. Conclusion: A substantial proportion of patients die with gastrointestinal cancer on general surgical wards without operative or endoscopic intervention and may receive better end of life care in an acute palliative care setting. © 2012 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84864502292&md5=6825ec971706b09514301c11c60e7eb0 U2 - 10.1016/j.surge.2012.07.003 DO - 10.1016/j.surge.2012.07.003 M1 - Article JO - Surgeon: Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland JF - Surgeon: Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland SN - 1479-666X IS - 2 VL - 11 SP - 72 EP - 75 ER - TY - JOUR T1 - QuaNCAT T2 - Quantitating proteome dynamics in primary cells A1 - Howden,Andrew J.M. A1 - Geoghegan,V. A1 - Katsch,K. A1 - Efstathiou,G. A1 - Thomas,B. A1 - Trudgian,D.C. A1 - Acuto,O. A1 - Bhushan,B. A1 - Boutureira,O. A1 - Davis,B.G. A1 - Kessler,B.M. A1 - Dieterich,D.C. AU - Howden,Andrew J.M. AU - Geoghegan,V. AU - Katsch,K. AU - Efstathiou,G. AU - Thomas,B. AU - Trudgian,D.C. AU - Acuto,O. AU - Bhushan,B. AU - Boutureira,O. AU - Davis,B.G. AU - Kessler,B.M. AU - Dieterich,D.C. PY - 2013/4 Y1 - 2013/4 N2 - Here we demonstrate quantitation of stimuli-induced proteome dynamics in primary cells by combining the power of bio-orthogonal noncanonical amino acid tagging (BONCAT) and stable-isotope labeling of amino acids in cell culture (SILAC). In conjunction with nanoscale liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS), quantitative noncanonical amino acid tagging (QuaNCAT) allowed us to monitor the early expression changes of >600 proteins in primary resting T cells subjected to activation stimuli. © 2013 Nature America, Inc. All rights reserved. AB - Here we demonstrate quantitation of stimuli-induced proteome dynamics in primary cells by combining the power of bio-orthogonal noncanonical amino acid tagging (BONCAT) and stable-isotope labeling of amino acids in cell culture (SILAC). In conjunction with nanoscale liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS), quantitative noncanonical amino acid tagging (QuaNCAT) allowed us to monitor the early expression changes of >600 proteins in primary resting T cells subjected to activation stimuli. © 2013 Nature America, Inc. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875755186&md5=e590f8c5712a0e6b09bed34eefca1748 U2 - 10.1038/nmeth.2401 DO - 10.1038/nmeth.2401 M1 - Article JO - Nature Methods JF - Nature Methods SN - 1548-7091 IS - 4 VL - 10 SP - 343 EP - 346 ER - TY - JOUR T1 - Recessive mutations in the gene encoding frizzled 6 cause twenty nail dystrophy T2 - Expanding the differential diagnosis for pachyonychia congenita A1 - Wilson,Neil J. A1 - Hansen,C.David A1 - Azkur,Dilek A1 - Kocabas,Can N. A1 - Metin,Ayse A1 - Coskun,Zeynep A1 - Schwartz,Mary E. A1 - Hull,Peter R. A1 - McLean,W.H.Irwin A1 - Smith,Frances J.D. AU - Wilson,Neil J. AU - Hansen,C.David AU - Azkur,Dilek AU - Kocabas,Can N. AU - Metin,Ayse AU - Coskun,Zeynep AU - Schwartz,Mary E. AU - Hull,Peter R. AU - McLean,W.H.Irwin AU - Smith,Frances J.D. PY - 2013/4 Y1 - 2013/4 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875814154&md5=8cf6b159762f5228932766fdfa8e38f3 U2 - 10.1016/j.jdermsci.2012.12.005 DO - 10.1016/j.jdermsci.2012.12.005 M1 - Letter JO - Journal of Dermatological Science JF - Journal of Dermatological Science SN - 0923-1811 IS - 1 VL - 70 SP - 58 EP - 60 ER - TY - JOUR T1 - Reformed Religion, Regime change, Scottish Whigs and the Struggle for the 'Soul' of Scotland, c.1688-c.1788 A1 - Whatley,Christopher A. AU - Whatley,Christopher A. PY - 2013/4 Y1 - 2013/4 UR - http://library.dundee.ac.uk:80/F/?func=direct&local_base=DUN01&doc_number= 000154565 U2 - 10.3366/shr.2013.0138 DO - 10.3366/shr.2013.0138 M1 - Article JO - Scottish Historical Review JF - Scottish Historical Review SN - 0036-9241 IS - 233 VL - 92(1) SP - 66 EP - 99 ER - TY - JOUR T1 - Reliability and validity of genotyping filaggrin null mutations A1 - Margolis,D.J. A1 - Apter,A.J. A1 - Mitra,N. A1 - Gupta,J. A1 - Hoffstad,O. A1 - Papadopoulos,M. A1 - Rebbeck,T.R. A1 - MacCallum,Stephanie A1 - Campbell,Linda E. A1 - Sandilands,Aileen A1 - McLean,W.H.Irwin AU - Margolis,D.J. AU - Apter,A.J. AU - Mitra,N. AU - Gupta,J. AU - Hoffstad,O. AU - Papadopoulos,M. AU - Rebbeck,T.R. AU - MacCallum,Stephanie AU - Campbell,Linda E. AU - Sandilands,Aileen AU - McLean,W.H.Irwin PY - 2013/4 Y1 - 2013/4 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875806518&md5=e2988bd3e41b9547acd090c1df54a932 U2 - 10.1016/j.jdermsci.2012.11.594 DO - 10.1016/j.jdermsci.2012.11.594 M1 - Letter JO - Journal of Dermatological Science JF - Journal of Dermatological Science SN - 0923-1811 IS - 1 VL - 70 SP - 67 EP - 68 ER - TY - JOUR T1 - Rubisco T2 - still the most abundant protein of Earth? A1 - Raven,John A. AU - Raven,John A. PY - 2013/4 Y1 - 2013/4 UR - http://europepmc.org/abstract/MED/23432200 U2 - 10.1111/nph.12197 DO - 10.1111/nph.12197 M1 - Article JO - New Phytologist JF - New Phytologist SN - 0028-646X IS - 1 VL - 198 SP - 1 EP - 3 ER - TY - JOUR T1 - Swansong biospheres T2 - refuges for life and novel microbial biospheres on terrestrial planets near the end of their habitable lifetimes A1 - O'Malley-James,Jack T. A1 - Greaves,Jane S. A1 - Raven,John A. A1 - Cockell,Charles S. AU - O'Malley-James,Jack T. AU - Greaves,Jane S. AU - Raven,John A. AU - Cockell,Charles S. PY - 2013/4 Y1 - 2013/4 N2 -

The future biosphere on Earth (as with its past) will be made up predominantly of unicellular micro-organisms. Unicellular life was probably present for at least 2.5 Gyr before multicellular life appeared and will likely be the only form of life capable of surviving on the planet in the far future, when the ageing Sun causes environmental conditions to become more hostile to more complex forms of life. Therefore, it is statistically more likely that habitable Earth-like exoplanets we discover will be at a stage in their habitable lifetime more conducive to supporting unicellular, rather than multicellular life. The end stage of habitability on Earth is the focus of this work. A simple, latitude-based climate model incorporating eccentricity and obliquity variations is used as a guide to the temperature evolution of the Earth over the next 3 Gyr. This allows inferences to be made about potential refuges for life, particularly in mountains and cold-trap (ice) caves and what forms of life could live in these environments. Results suggest that in high latitude regions, unicellular life could persist for up to 2.8 Gyr from present. This begins to answer the question of how the habitability of Earth will evolve at local scales alongside the Sun's main sequence evolution and, by extension, how the habitability of Earth-like planets would evolve over time with their own host stars.

AB -

The future biosphere on Earth (as with its past) will be made up predominantly of unicellular micro-organisms. Unicellular life was probably present for at least 2.5 Gyr before multicellular life appeared and will likely be the only form of life capable of surviving on the planet in the far future, when the ageing Sun causes environmental conditions to become more hostile to more complex forms of life. Therefore, it is statistically more likely that habitable Earth-like exoplanets we discover will be at a stage in their habitable lifetime more conducive to supporting unicellular, rather than multicellular life. The end stage of habitability on Earth is the focus of this work. A simple, latitude-based climate model incorporating eccentricity and obliquity variations is used as a guide to the temperature evolution of the Earth over the next 3 Gyr. This allows inferences to be made about potential refuges for life, particularly in mountains and cold-trap (ice) caves and what forms of life could live in these environments. Results suggest that in high latitude regions, unicellular life could persist for up to 2.8 Gyr from present. This begins to answer the question of how the habitability of Earth will evolve at local scales alongside the Sun's main sequence evolution and, by extension, how the habitability of Earth-like planets would evolve over time with their own host stars.

KW - CARBON FIXATION PATHWAYS KW - SEA-FLOOR KW - Earth KW - BIOMASS PRODUCTION KW - SEDIMENTARY-ROCKS KW - Climate KW - ENERGY-SOURCE KW - HYDROTHERMAL SYSTEM KW - LONG-TERM EVOLUTION KW - INORGANIC CARBON KW - Biosignatures KW - Exoplanets KW - Habitability KW - DEEP SUBSURFACE KW - CLIMATE-CHANGE KW - Solar evolution U2 - 10.1017/S147355041200047X DO - 10.1017/S147355041200047X M1 - Article IS - 2 VL - 12 SP - 99 EP - 112 ER - TY - JOUR T1 - Tailored second-line therapy in asthmatic children with the Arg16 genotype A1 - Lipworth,Brian J. A1 - Basu,Kaninika A1 - Donald,Helen P. A1 - Tavendale,Roger A1 - MacGregor,Donald F. A1 - Ogston,Simon A. A1 - Palmer,Colin N. A. A1 - Mukhopadhyay,Somnath AU - Lipworth,Brian J. AU - Basu,Kaninika AU - Donald,Helen P. AU - Tavendale,Roger AU - MacGregor,Donald F. AU - Ogston,Simon A. AU - Palmer,Colin N. A. AU - Mukhopadhyay,Somnath PY - 2013/4 Y1 - 2013/4 N2 - The Arg16 ß2 receptor genotype confers increased susceptibility to exacerbations in asthmatic children taking regular LABA (long-acting ß2 agonists). We therefore evaluated using montelukast as an alternative to salmeterol as tailored second-line asthma controller therapy in children expressing this susceptible genotype. A total of 62 persistent asthmatic children with the homozygous Arg16 genotype were randomized to receive salmeterol (50 µg, b.i.d.) or montelukast (5 or 10 mg, once daily) as an add-on to inhaled fluticasone for 1 year. School absences (the primary outcome) were reduced with montelukast compared with salmeterol {difference in score=-0.40 [95% CI (confidence interval), -0.22 to -0.58]; P=0.005}. Salbutamol use was also reduced with montelukast compared with salmeterol [difference in score=-0.47 (95% CI, -0.16 to -0.79); P<0.0001]. Greater improvements occurred in both symptom and quality of life scores with montelukast against salmeterol, whereas there was no difference in FEV1 (forced expiratory volume in 1 s). In conclusion, montelukast may be suitable as tailored second-line controller therapy instead of salmeterol in asthmatic children expressing the susceptible Arg16 genotype, a move towards a personalized medicine approach to management.

CLINICAL PERSPECTIVES

The FDA has recently highlighted concerns about long-term safety of LABA exposure, especially in children.
Our study evaluated second-line therapy in 15% of genetically susceptible asthmatic children possessing the Arg16 genotype.
We show that patients with the Arg16 genotype may fare better by using montelukast than salmeterol as add-on therapy to inhaled corticosteroids. This in turn provides evidence for genotype directed personalized medicine.
AB - The Arg16 ß2 receptor genotype confers increased susceptibility to exacerbations in asthmatic children taking regular LABA (long-acting ß2 agonists). We therefore evaluated using montelukast as an alternative to salmeterol as tailored second-line asthma controller therapy in children expressing this susceptible genotype. A total of 62 persistent asthmatic children with the homozygous Arg16 genotype were randomized to receive salmeterol (50 µg, b.i.d.) or montelukast (5 or 10 mg, once daily) as an add-on to inhaled fluticasone for 1 year. School absences (the primary outcome) were reduced with montelukast compared with salmeterol {difference in score=-0.40 [95% CI (confidence interval), -0.22 to -0.58]; P=0.005}. Salbutamol use was also reduced with montelukast compared with salmeterol [difference in score=-0.47 (95% CI, -0.16 to -0.79); P<0.0001]. Greater improvements occurred in both symptom and quality of life scores with montelukast against salmeterol, whereas there was no difference in FEV1 (forced expiratory volume in 1 s). In conclusion, montelukast may be suitable as tailored second-line controller therapy instead of salmeterol in asthmatic children expressing the susceptible Arg16 genotype, a move towards a personalized medicine approach to management.

CLINICAL PERSPECTIVES

The FDA has recently highlighted concerns about long-term safety of LABA exposure, especially in children.
Our study evaluated second-line therapy in 15% of genetically susceptible asthmatic children possessing the Arg16 genotype.
We show that patients with the Arg16 genotype may fare better by using montelukast than salmeterol as add-on therapy to inhaled corticosteroids. This in turn provides evidence for genotype directed personalized medicine.
KW - Asthma KW - beta(2) receptor KW - Children KW - GENOTYPE KW - montelukast KW - Salmeterol UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872373809&md5=54903e0d8e26b0951fa04ed3a34f6f38 U2 - 10.1042/CS20120528 DO - 10.1042/CS20120528 M1 - Article JO - Clinical Science JF - Clinical Science SN - 0143-5221 IS - 8 VL - 124 SP - 521 EP - 528 ER - TY - JOUR T1 - Targeting the small airways asthma phenotype T2 - if we can reach it, should we treat it? A1 - Lipworth,Brian AU - Lipworth,Brian PY - 2013/4 Y1 - 2013/4 N2 - To review the available methods of evaluating the small airways disease in asthma and the therapeutic strategies to achieve better control using emerging extrafine particle inhaler technologies. AB - To review the available methods of evaluating the small airways disease in asthma and the therapeutic strategies to achieve better control using emerging extrafine particle inhaler technologies. U2 - 10.1016/j.anai.2013.02.009 DO - 10.1016/j.anai.2013.02.009 M1 - Article JO - Annals of Allergy, Asthma & Immunology JF - Annals of Allergy, Asthma & Immunology SN - 1081-1206 IS - 4 VL - 110 SP - 233 EP - 239 ER - TY - JOUR T1 - Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner A1 - McCarthy,Anna R. A1 - Sachweh,Marijke C. C. A1 - Higgins,Maureen A1 - Campbell,Johanna A1 - Drummond,Catherine J. A1 - van Leeuwen,Ingeborg M. M. A1 - Pirrie,Lisa A1 - Ladds,Marcus J. G. W. A1 - Westwood,Nicholas J. A1 - Lain,Sonia AU - McCarthy,Anna R. AU - Sachweh,Marijke C. C. AU - Higgins,Maureen AU - Campbell,Johanna AU - Drummond,Catherine J. AU - van Leeuwen,Ingeborg M. M. AU - Pirrie,Lisa AU - Ladds,Marcus J. G. W. AU - Westwood,Nicholas J. AU - Lain,Sonia PY - 2013/4 Y1 - 2013/4 N2 -

While small-molecule inhibitors of class I/II histone deacetylases (HDAC) have been approved for cancer treatment, inhibitors of the sirtuins (a family of class III HDACs) still require further validation and optimization to enter clinical trials. Recent studies show that tenovin-6, a small-molecule inhibitor of sirtuins SirT1 and SirT2, reduces tumor growth in vivo and eliminates leukemic stem cells in a murine model for chronic myelogenous leukemia. Here, we describe a tenovin analogue, tenovin-D3, that preferentially inhibits sirtuin SirT2 and induces predicted phenotypes for SirT2 inhibition. Unlike tenovin-6 and in agreement with its weak effect on SirT1 (a p53 deacetylase), tenovin-D3 fails to increase p53 levels or transcription factor activity. However, tenovin-D3 promotes expression of the cell-cycle regulator and p53 target p21(WAF1/CIP1) (CDKN1A) in a p53-independent manner. Structure-activity relationship studies strongly support that the ability of tenovin-D3 to inhibit SirT2 contributes to this p53-independent induction of p21. The ability of tenovin-D3 to increase p21mRNA and protein levels is shared with class I/II HDAC inhibitors currently used in the clinic and therefore suggests that SirT2 inhibition and class I/II HDAC inhibitors have similar effects on cell-cycle progression. Mol Cancer Ther; 12(4);352-60. (C) 2013 AACR.

AB -

While small-molecule inhibitors of class I/II histone deacetylases (HDAC) have been approved for cancer treatment, inhibitors of the sirtuins (a family of class III HDACs) still require further validation and optimization to enter clinical trials. Recent studies show that tenovin-6, a small-molecule inhibitor of sirtuins SirT1 and SirT2, reduces tumor growth in vivo and eliminates leukemic stem cells in a murine model for chronic myelogenous leukemia. Here, we describe a tenovin analogue, tenovin-D3, that preferentially inhibits sirtuin SirT2 and induces predicted phenotypes for SirT2 inhibition. Unlike tenovin-6 and in agreement with its weak effect on SirT1 (a p53 deacetylase), tenovin-D3 fails to increase p53 levels or transcription factor activity. However, tenovin-D3 promotes expression of the cell-cycle regulator and p53 target p21(WAF1/CIP1) (CDKN1A) in a p53-independent manner. Structure-activity relationship studies strongly support that the ability of tenovin-D3 to inhibit SirT2 contributes to this p53-independent induction of p21. The ability of tenovin-D3 to increase p21mRNA and protein levels is shared with class I/II HDAC inhibitors currently used in the clinic and therefore suggests that SirT2 inhibition and class I/II HDAC inhibitors have similar effects on cell-cycle progression. Mol Cancer Ther; 12(4);352-60. (C) 2013 AACR.

KW - ACETYLATION KW - ACTIVATION KW - HISTONE DEACETYLASE INHIBITORS KW - ENZYME KW - RESVERATROL KW - STRESS KW - MECHANISM KW - P53 KW - DISEASE KW - PLURIPOTENT STEM-CELLS U2 - 10.1158/1535-7163.MCT-12-0900 DO - 10.1158/1535-7163.MCT-12-0900 M1 - Article JO - Molecular Cancer Therapeutics JF - Molecular Cancer Therapeutics SN - 1535-7163 IS - 4 VL - 12 SP - 352 EP - 360 ER - TY - JOUR T1 - Test of age-related variation in the craniometry of the adult human foramen magnum region T2 - implications for sex determination methods A1 - Gapert,Rene A1 - Black,Sue A1 - Last,Jason AU - Gapert,Rene AU - Black,Sue AU - Last,Jason PY - 2013/4 Y1 - 2013/4 N2 - Sex differences in the foramen magnum region of the cranial base have been identified with varying rates of success. Recent publications demonstrate a continuing strong interest in metric analysis of the foramen magnum region for sex determination despite the generally low expression of cranial base sexual dimorphism. It is important to identify possible age effects on skull base morphometric variables as most reported discriminant analyses use pooled-age samples without assessing the influence of aging on sexual dimorphism. This study examined 135 adult cranial bases (69 males and 66 females) from the St. Bride's documented skeletal collection in London. Traditional craniometric measurements were recorded and the effect of age on sexual dimorphism of this anatomical region was tested using a variety of statistical analyses including MANOVA and discriminant function analysis. Age-dependent discriminant functions for 50 years of age were developed and compared. The cross-validated results showed that the 50 years function achieved 81.3 % correct predictions. However, the high sex biases of these functions (14.4 % and -17.5 %) severely limit their practical application. A pooled-age discriminant function permitted 71.9 % correct prediction with a sex bias of only -1.7 %. The statistical analyses also showed no significant age effect on any of the variables, suggesting that a separation by age is not necessary for the development of sex determination methods. © 2013 Springer Science+Business Media New York. AB - Sex differences in the foramen magnum region of the cranial base have been identified with varying rates of success. Recent publications demonstrate a continuing strong interest in metric analysis of the foramen magnum region for sex determination despite the generally low expression of cranial base sexual dimorphism. It is important to identify possible age effects on skull base morphometric variables as most reported discriminant analyses use pooled-age samples without assessing the influence of aging on sexual dimorphism. This study examined 135 adult cranial bases (69 males and 66 females) from the St. Bride's documented skeletal collection in London. Traditional craniometric measurements were recorded and the effect of age on sexual dimorphism of this anatomical region was tested using a variety of statistical analyses including MANOVA and discriminant function analysis. Age-dependent discriminant functions for 50 years of age were developed and compared. The cross-validated results showed that the 50 years function achieved 81.3 % correct predictions. However, the high sex biases of these functions (14.4 % and -17.5 %) severely limit their practical application. A pooled-age discriminant function permitted 71.9 % correct prediction with a sex bias of only -1.7 %. The statistical analyses also showed no significant age effect on any of the variables, suggesting that a separation by age is not necessary for the development of sex determination methods. © 2013 Springer Science+Business Media New York. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875930535&md5=d9669064f69d6024ec073ebaa412e0d5 U2 - 10.1007/s12024-013-9437-3 DO - 10.1007/s12024-013-9437-3 M1 - Article JO - Forensic Science, Medicine and Pathology JF - Forensic Science, Medicine and Pathology SN - 1547-769X SP - 1 EP - 11 ER - TY - JOUR T1 - The clinical significance of calcium-signalling pathways mediating human sperm hyperactivation A1 - Alasmari,Wardah A1 - Barratt,Christopher L.R. A1 - Publicover,Stephen J. A1 - Whalley,Katherine M. A1 - Foster,Erica A1 - Kay,Vanessa A1 - Martins Da Silva,Sarah A1 - Oxenham,Senga K. AU - Alasmari,Wardah AU - Barratt,Christopher L.R. AU - Publicover,Stephen J. AU - Whalley,Katherine M. AU - Foster,Erica AU - Kay,Vanessa AU - Martins Da Silva,Sarah AU - Oxenham,Senga K. PY - 2013/4 Y1 - 2013/4 N2 - STUDY QUESTION What is the prevalence of defects in the Ca2+-signalling pathways mediating hyperactivation (calcium influx and store mobilization) among donors and sub-fertile patients and are they functionally significant, i.e. related to fertilization success at IVF?

SUMMARY ANSWER This study identifies, for the first time, the prevalence of Ca2+ store defects in sperm from research donors, IVF and ICSI patients. It highlights the biological role and importance of Ca2+ signalling (Ca2+ store mobilization) for fertilization at IVF.

WHAT IS KNOWN ALREADY Sperm motility and hyperactivation (HA) are important for fertility, mice with sperm incapable of HA are sterile. Recently, there has been significant progress in our knowledge of the factors controlling these events, in particular the generation and regulation of calcium signals. Both pH-regulated membrane Ca2+ channels (CatSper) and Ca2+ stores (potentially activating store-operated Ca2+ channels) have been implicated in controlling HA.

STUDY DESIGN, SIZE, AND DURATION This was a prospective study examining a panel of 68 donors and 181 sub-fertile patients attending the Assisted Conception Unit, Ninewells Hospital Dundee for IVF and ICSI. Twenty-five of the donors gave a second sample (~4 weeks later) to confirm consistency/reliability of the recorded responses. Ca2+ signalling was manipulated using three agonists, NH4Cl (activates CatSper via pH), progesterone (direct activation of CatSper channels, potentially enhancing mobilization of stored Ca2+ by CICR) and 4-aminopyridine (4-AP) (effect on pH equivalent to NH4Cl and mobilizes stored Ca2+). The broad-spectrum phosphodiesterase inhibitor 3-isobutyl-1-methyxanthine (IBMX), a potent activator of HA was also used for comparison. For patient samples, an aliquot surplus to requirements for IVF/ICSI treatment was examined, allowing direct comparison of Ca2+ signalling and motility data with functional competence of the sperm.

MATERIALS, SETTING, METHODS The donors and sub-fertile patients were screened for HA (using CASA) and changes in intracellular Ca2+ were assessed by loading with Fura-2 and measuring fluorescence using a plate reader (FluoStar).

MAIN RESULTS AND THE ROLE OF CHANCE The relative efficacy of the stimuli in inducing HA was 4-AP >> IBMX > progesterone. NH4Cl increased [Ca2+]i similarly to 4-AP and progesterone but did not induce a significant increase in HA. Failure of samples to generate HA (no significant increase in response to stimulation with 4-AP) was seen in just 2% of research donors but occurred in 10% of IVF patients (P = 0.025). All donor samples generated a significant [Ca2+]i increase when stimulated with 4-AP but 3.3% of IVF and 28.6% of ICSI patients failed to respond. Amplitudes of HA and [Ca2+]i responses to 4-AP were correlated with fertilization rate at IVF (P= 0.029; P = 0.031, respectively). Progesterone reliably induced [Ca2+]i responses (97% of donors, 100% of IVF patients) but was significantly less effective than 4-AP in inducing HA. Twenty seven per cent of ICSI patients failed to generate a [Ca2+]i response to progesterone (P= 0.035). Progesterone-induced [Ca2+]i responses were correlated with fertilization rate at IVF (P= 0.037) but induction of HA was not. In donor samples examined on more than one occasion consistent responses for 4-AP-induced [Ca2+]i (R2 = 0.97) and HA (R2 = 0.579) were obtained. In summary, the data indicate that defects in Ca2+ signalling leading to poor HA do occur and that ability to undergo Ca2+ -induced HA affects IVF fertilizing capacity. The data also confirm that release of stored Ca2+ is the crucial component of Ca2+ signals leading to HA and that Ca2+ store defects may therefore underlie HA failure.

LIMITATIONS, REASONS FOR CAUTION This is an in vitro study of sperm function. While the repeatability of the [Ca2+]i and HA responses in samples from the same donor were confirmed, data for patients were from 1 assessment and thus the robustness of the failed responses in patients’ needs to be established. The focus of this study was on using 4AP, which mobilizes stored Ca2+ and is a potent inducer of HA. The n values for other agonists, especially calcium assessments, are smaller.

WIDER IMPLICATIONS OF THE FINDINGS Previous studies have shown a significant relationship between basal levels of HA, calcium responses to progesterone and IVF fertilization rates. Here, we have systematically investigated the ability/failure of human sperm to generate Ca2+ signals and HA in response to targeted pharmacological challenge and, related defects in these responses to IVF success. [Ca2+]i signalling is fundamental for sperm motility and data from this study will lead to assessment of the nature of these defects using techniques such as single-cell imaging and patch clamping.

STUDY FUNDING/COMPETING INTEREST(S) Resources from a Wellcome Trust Project Grant (#086470, Publicover and Barratt PI) primarily funded the study. The authors have no competing interests.
AB - STUDY QUESTION What is the prevalence of defects in the Ca2+-signalling pathways mediating hyperactivation (calcium influx and store mobilization) among donors and sub-fertile patients and are they functionally significant, i.e. related to fertilization success at IVF?

SUMMARY ANSWER This study identifies, for the first time, the prevalence of Ca2+ store defects in sperm from research donors, IVF and ICSI patients. It highlights the biological role and importance of Ca2+ signalling (Ca2+ store mobilization) for fertilization at IVF.

WHAT IS KNOWN ALREADY Sperm motility and hyperactivation (HA) are important for fertility, mice with sperm incapable of HA are sterile. Recently, there has been significant progress in our knowledge of the factors controlling these events, in particular the generation and regulation of calcium signals. Both pH-regulated membrane Ca2+ channels (CatSper) and Ca2+ stores (potentially activating store-operated Ca2+ channels) have been implicated in controlling HA.

STUDY DESIGN, SIZE, AND DURATION This was a prospective study examining a panel of 68 donors and 181 sub-fertile patients attending the Assisted Conception Unit, Ninewells Hospital Dundee for IVF and ICSI. Twenty-five of the donors gave a second sample (~4 weeks later) to confirm consistency/reliability of the recorded responses. Ca2+ signalling was manipulated using three agonists, NH4Cl (activates CatSper via pH), progesterone (direct activation of CatSper channels, potentially enhancing mobilization of stored Ca2+ by CICR) and 4-aminopyridine (4-AP) (effect on pH equivalent to NH4Cl and mobilizes stored Ca2+). The broad-spectrum phosphodiesterase inhibitor 3-isobutyl-1-methyxanthine (IBMX), a potent activator of HA was also used for comparison. For patient samples, an aliquot surplus to requirements for IVF/ICSI treatment was examined, allowing direct comparison of Ca2+ signalling and motility data with functional competence of the sperm.

MATERIALS, SETTING, METHODS The donors and sub-fertile patients were screened for HA (using CASA) and changes in intracellular Ca2+ were assessed by loading with Fura-2 and measuring fluorescence using a plate reader (FluoStar).

MAIN RESULTS AND THE ROLE OF CHANCE The relative efficacy of the stimuli in inducing HA was 4-AP >> IBMX > progesterone. NH4Cl increased [Ca2+]i similarly to 4-AP and progesterone but did not induce a significant increase in HA. Failure of samples to generate HA (no significant increase in response to stimulation with 4-AP) was seen in just 2% of research donors but occurred in 10% of IVF patients (P = 0.025). All donor samples generated a significant [Ca2+]i increase when stimulated with 4-AP but 3.3% of IVF and 28.6% of ICSI patients failed to respond. Amplitudes of HA and [Ca2+]i responses to 4-AP were correlated with fertilization rate at IVF (P= 0.029; P = 0.031, respectively). Progesterone reliably induced [Ca2+]i responses (97% of donors, 100% of IVF patients) but was significantly less effective than 4-AP in inducing HA. Twenty seven per cent of ICSI patients failed to generate a [Ca2+]i response to progesterone (P= 0.035). Progesterone-induced [Ca2+]i responses were correlated with fertilization rate at IVF (P= 0.037) but induction of HA was not. In donor samples examined on more than one occasion consistent responses for 4-AP-induced [Ca2+]i (R2 = 0.97) and HA (R2 = 0.579) were obtained. In summary, the data indicate that defects in Ca2+ signalling leading to poor HA do occur and that ability to undergo Ca2+ -induced HA affects IVF fertilizing capacity. The data also confirm that release of stored Ca2+ is the crucial component of Ca2+ signals leading to HA and that Ca2+ store defects may therefore underlie HA failure.

LIMITATIONS, REASONS FOR CAUTION This is an in vitro study of sperm function. While the repeatability of the [Ca2+]i and HA responses in samples from the same donor were confirmed, data for patients were from 1 assessment and thus the robustness of the failed responses in patients’ needs to be established. The focus of this study was on using 4AP, which mobilizes stored Ca2+ and is a potent inducer of HA. The n values for other agonists, especially calcium assessments, are smaller.

WIDER IMPLICATIONS OF THE FINDINGS Previous studies have shown a significant relationship between basal levels of HA, calcium responses to progesterone and IVF fertilization rates. Here, we have systematically investigated the ability/failure of human sperm to generate Ca2+ signals and HA in response to targeted pharmacological challenge and, related defects in these responses to IVF success. [Ca2+]i signalling is fundamental for sperm motility and data from this study will lead to assessment of the nature of these defects using techniques such as single-cell imaging and patch clamping.

STUDY FUNDING/COMPETING INTEREST(S) Resources from a Wellcome Trust Project Grant (#086470, Publicover and Barratt PI) primarily funded the study. The authors have no competing interests.
KW - calcium signaling KW - Sperm KW - Male fertility KW - Hyperactivation KW - sperm motility KW - IVF U2 - 10.1093/humrep/des467 DO - 10.1093/humrep/des467 M1 - Article JO - Human Reproduction JF - Human Reproduction SN - 0268-1161 IS - 4 VL - 28 SP - 866 EP - 876 ER - TY - JOUR T1 - The endophytic lifestyle of Escherichia coli O157:H7 T2 - quantification and internal localization in roots A1 - Wright,Kathryn M. A1 - Chapman,Sean A1 - McGeachy,Kara A1 - Humphris,Sonia A1 - Campbell,Emma A1 - Toth,Ian K. A1 - Holden,Nicola J. AU - Wright,Kathryn M. AU - Chapman,Sean AU - McGeachy,Kara AU - Humphris,Sonia AU - Campbell,Emma AU - Toth,Ian K. AU - Holden,Nicola J. PY - 2013/4 Y1 - 2013/4 N2 -

The foodborne pathogen Escherichia coil O157:H7 is increasingly associated with fresh produce (fruit and vegetables). Bacterial colonization of fresh produce plants can occur to high levels on the external tissue but bacteria have also been detected within plant tissue. However, questions remain about the extent of internalization, its molecular basis, and internal location of the bacteria. We have determined the extent of internalization of E. coli O157:H7 in live spinach and lettuce plants and used high-resolution microscopy to examine colony formation in roots and pathways to internalization. E. coli O157:H7 was found within internal tissue of both produce species. Colonization occurred within the apoplast between plant cells. Furthermore, colonies were detected inside the cell wall of epidermal and cortical cells of spinach and Nicotiana benthamiana roots. Internal colonization of epidermal cells resembled that of the phytopathogen Pectobacterium atrosepticum on potato. In contrast, only sporadic cells of the laboratory strain of E. coli K-12 were found on spinach, with no internal bacteria evident. The data extend previous findings that internal colonization of plants appears to be limited to a specific group of plant-interacting bacteria, including E. coil O157:H7, and demonstrates its ability to invade the cells of living plants.

AB -

The foodborne pathogen Escherichia coil O157:H7 is increasingly associated with fresh produce (fruit and vegetables). Bacterial colonization of fresh produce plants can occur to high levels on the external tissue but bacteria have also been detected within plant tissue. However, questions remain about the extent of internalization, its molecular basis, and internal location of the bacteria. We have determined the extent of internalization of E. coli O157:H7 in live spinach and lettuce plants and used high-resolution microscopy to examine colony formation in roots and pathways to internalization. E. coli O157:H7 was found within internal tissue of both produce species. Colonization occurred within the apoplast between plant cells. Furthermore, colonies were detected inside the cell wall of epidermal and cortical cells of spinach and Nicotiana benthamiana roots. Internal colonization of epidermal cells resembled that of the phytopathogen Pectobacterium atrosepticum on potato. In contrast, only sporadic cells of the laboratory strain of E. coli K-12 were found on spinach, with no internal bacteria evident. The data extend previous findings that internal colonization of plants appears to be limited to a specific group of plant-interacting bacteria, including E. coil O157:H7, and demonstrates its ability to invade the cells of living plants.

KW - PLANT PATHOGEN KW - BACTERIAL ENDOPHYTES KW - IN-VITRO KW - SALMONELLA-ENTERICA KW - endophyte KW - STRAIN KW - O157-H7 KW - COLONIZATION KW - GENOME SEQUENCE KW - LETTUCE LEAVES KW - rhizosphere KW - ARABIDOPSIS-THALIANA U2 - 10.1094/PHYTO-08-12-0209-FI DO - 10.1094/PHYTO-08-12-0209-FI M1 - Article JO - Phytopathology JF - Phytopathology SN - 0031-949X IS - 4 VL - 103 SP - 333 EP - 340 ER - TY - JOUR T1 - The Later Affluence of W. B. Yeats and Wallace Stevens. By Edward Clarke A1 - Morris,Timothy AU - Morris,Timothy PY - 2013/4 Y1 - 2013/4 UR - http://www.jstor.org/action/showPublication?journalCode=modelangrevi U2 - 10.5699/modelangrevi.108.2.0638 DO - 10.5699/modelangrevi.108.2.0638 M1 - Book/Film/Article review JO - Modern Language Review JF - Modern Language Review SN - 0026-7937 IS - 2 VL - 108 SP - 638 EP - 639 ER - TY - JOUR T1 - Therapeutic mammaplasty T2 - Extending indications and achieving low incomplete excision rates A1 - Schaverien,M. V. A1 - Raine,C. A1 - Majdak-Paredes,E. A1 - Dixon,J. M. AU - Schaverien,M. V. AU - Raine,C. AU - Majdak-Paredes,E. AU - Dixon,J. M. PY - 2013/4 Y1 - 2013/4 N2 -

Aims: The aim of this study was to report the outcomes of the first 50 consecutive therapeutic mammaplasty procedures at the Edinburgh Breast Unit.

Methods: A retrospective case-notes analysis was performed. In addition a validated patient satisfaction and outcomes questionnaire was sent to all patients.

Results: Fifty therapeutic mammaplasty procedures were performed in 48 patients, with contralateral synchronous breast reduction performed in 42 of these patients. The median age was 58 years (range, 34-81). The median total tumour size was 28 mm (range, 7-83 mm) and 11 patients had multifocal tumours. The median wide local excision weight was 119 g (range, 15-815) and the median total excision weight was 354 g (range, 20-1725). Neoadjuvant letrozole was used in 16 patients and neoadjuvant chemotherapy was given in six. Incomplete excision (DCIS) occurred in only one patient who underwent reexcision. Complications occurred in 19 breasts overall, delaying adjuvant chemotherapy in one patient. Median reported patient satisfaction with appearance was 9.5 out of ten, with 33 of 35 respondents reporting that they definitely or probably would choose the same operation again.

Conclusions: Therapeutic mammaplasty can be performed with a low rate of incomplete excision and complications, and high patient satisfaction, even with large tumours and multifocal disease. In this study the use of neoadjuvant letrozole in selected oestrogen receptor positive tumours, intraoperative radiographic imaging of specimens, and targeting further excision to around the tumour bed, was associated with a very low rate of incomplete excision. (C) 2013 Elsevier Ltd. All rights reserved.

AB -

Aims: The aim of this study was to report the outcomes of the first 50 consecutive therapeutic mammaplasty procedures at the Edinburgh Breast Unit.

Methods: A retrospective case-notes analysis was performed. In addition a validated patient satisfaction and outcomes questionnaire was sent to all patients.

Results: Fifty therapeutic mammaplasty procedures were performed in 48 patients, with contralateral synchronous breast reduction performed in 42 of these patients. The median age was 58 years (range, 34-81). The median total tumour size was 28 mm (range, 7-83 mm) and 11 patients had multifocal tumours. The median wide local excision weight was 119 g (range, 15-815) and the median total excision weight was 354 g (range, 20-1725). Neoadjuvant letrozole was used in 16 patients and neoadjuvant chemotherapy was given in six. Incomplete excision (DCIS) occurred in only one patient who underwent reexcision. Complications occurred in 19 breasts overall, delaying adjuvant chemotherapy in one patient. Median reported patient satisfaction with appearance was 9.5 out of ten, with 33 of 35 respondents reporting that they definitely or probably would choose the same operation again.

Conclusions: Therapeutic mammaplasty can be performed with a low rate of incomplete excision and complications, and high patient satisfaction, even with large tumours and multifocal disease. In this study the use of neoadjuvant letrozole in selected oestrogen receptor positive tumours, intraoperative radiographic imaging of specimens, and targeting further excision to around the tumour bed, was associated with a very low rate of incomplete excision. (C) 2013 Elsevier Ltd. All rights reserved.

KW - Therapeutic mammaplasties KW - TRIAL KW - Cosmesis KW - 20-YEAR FOLLOW-UP KW - CANCER KW - Oncoplastic breast surgery KW - OUTCOMES KW - MASTECTOMY KW - Breast conserving surgery KW - BREAST-CONSERVING SURGERY KW - REDUCTION KW - ONCOPLASTIC SURGERY KW - Margins breast cancer KW - LETROZOLE U2 - 10.1016/j.ejso.2013.01.006 DO - 10.1016/j.ejso.2013.01.006 M1 - Article JO - European Journal of Surgical Oncology JF - European Journal of Surgical Oncology SN - 0748-7983 IS - 4 VL - 39 SP - 329 EP - 333 ER - TY - JOUR T1 - Trimethoprim prescription and subsequent resistance in childhood urinary infection T2 - multilevel modelling analysis A1 - Duffy,Mary A A1 - Hernandez-Santiago,Virginia A1 - Orange,Gillian A1 - Davey,Peter G A1 - Guthrie,Bruce AU - Duffy,Mary A AU - Hernandez-Santiago,Virginia AU - Orange,Gillian AU - Davey,Peter G AU - Guthrie,Bruce PY - 2013/4 Y1 - 2013/4 N2 - Background:
Antibiotic resistance is a growing concern and antibiotic usage the main contributing factor, but there are few studies examining antibiotic use and resistance in children.

Aim:
To investigate the association between previous trimethoprim prescribing and resistance in urinary Escherichia coli (E. coli) isolates in children.

Design and setting:
Retrospective, population cohort study in Tayside, Scotland.

Method:
Multilevel modelling of linked microbiology and dispensed prescribing data for 1373 =16-year-olds with E. coli urinary isolates in 2004-2009, examining the association between prior trimethoprim prescription and subsequent trimethoprim resistance in people with urinary E. coli isolates.

Results:
Trimethoprim resistance was common (26.6%, 95% confidence interval [CI] = 24.6 to 28.6). Previous trimethoprim prescription was associated with subsequent culture of trimethoprim-resistant E. coli, with more recent prescription being more strongly associated with resistance. After adjusting for the number of previous E. coli isolates and sample year, trimethoprim prescribing in the previous 84 days remained significantly associated with culturing trimethoprim-resistant E. coli (adjusted OR 4.71, 95% CI = 1.83 to 12.16 for the previous 15-28 days versus never prescribed; adjusted OR 3.16, 95% CI = 1.63 to 6.13 for the previous 29-84 days); however, associations were not statistically significant for longer periods since prior exposure.

Conclusion:
Trimethoprim prescription has implications for future resistance in individual children, as well as at population level. Clinicians must ensure appropriateness of treatment choice and duration, and alternative antibiotics should be considered for childhood urinary tract infections if trimethoprim has been prescribed in the preceding 3 months. AB - Background:
Antibiotic resistance is a growing concern and antibiotic usage the main contributing factor, but there are few studies examining antibiotic use and resistance in children.

Aim:
To investigate the association between previous trimethoprim prescribing and resistance in urinary Escherichia coli (E. coli) isolates in children.

Design and setting:
Retrospective, population cohort study in Tayside, Scotland.

Method:
Multilevel modelling of linked microbiology and dispensed prescribing data for 1373 =16-year-olds with E. coli urinary isolates in 2004-2009, examining the association between prior trimethoprim prescription and subsequent trimethoprim resistance in people with urinary E. coli isolates.

Results:
Trimethoprim resistance was common (26.6%, 95% confidence interval [CI] = 24.6 to 28.6). Previous trimethoprim prescription was associated with subsequent culture of trimethoprim-resistant E. coli, with more recent prescription being more strongly associated with resistance. After adjusting for the number of previous E. coli isolates and sample year, trimethoprim prescribing in the previous 84 days remained significantly associated with culturing trimethoprim-resistant E. coli (adjusted OR 4.71, 95% CI = 1.83 to 12.16 for the previous 15-28 days versus never prescribed; adjusted OR 3.16, 95% CI = 1.63 to 6.13 for the previous 29-84 days); however, associations were not statistically significant for longer periods since prior exposure.

Conclusion:
Trimethoprim prescription has implications for future resistance in individual children, as well as at population level. Clinicians must ensure appropriateness of treatment choice and duration, and alternative antibiotics should be considered for childhood urinary tract infections if trimethoprim has been prescribed in the preceding 3 months. U2 - 10.3399/bjgp13X665198 DO - 10.3399/bjgp13X665198 M1 - Article JO - British Journal of General Practice JF - British Journal of General Practice SN - 0960-1643 IS - 609 VL - 63 SP - 238 EP - 243 ER - TY - JOUR T1 - What should it take to describe a substance or product as 'sperm-safe' A1 - Mortimer,D. A1 - Barratt,Christopher L.R. A1 - Björndahl,L. A1 - de Jager,C. A1 - Jequier,A.M. A1 - Muller,C.H. AU - Mortimer,D. AU - Barratt,Christopher L.R. AU - Björndahl,L. AU - de Jager,C. AU - Jequier,A.M. AU - Muller,C.H. PY - 2013/4 Y1 - 2013/4 N2 - Background: Male reproductive potential continues to be adversely affected by many environmental, industrial and pharmaceutical toxins. Pre-emptive testing for reproductive toxicological (side-)effects remains limited, or even non-existent. Many products that come into direct contact with spermatozoa lack adequate testing for the absence of adverse effects, and numerous products that are intended for exposure to spermatozoa have only a general assumption of safety based on the absence of evidence of actual harm. Such assumptions can have unfortunate adverse impacts on at-risk individuals (e.g. couples who are trying to conceive), illustrating a clear need for appropriate up-front testing to establish actual 'sperm safety'. METHODS: After compiling a list of general areas within the reviews scope, relevant literature and other information was obtained from the authors personal professional libraries and archives, and supplemented as necessary using PubMed and Google searches. Review by co-authors identified and eliminated errors of omission or bias. Results: This review provides an overview of the broad range of substances, materials and products that can affect male fertility, especially through sperm fertilizing ability, along with a discussion of practical methods and bioassays for their evaluation. It is concluded that products can only be claimed to be sperm-safe after performing objective, properly designed experimental studies; extrapolation from supposed predicate products or other assumptions cannot be trusted. CONCLUSIONS: We call for adopting the precautionary principle, especially when exposure to a product might affect not only a couples fertility potential but also the health of resulting offspring and perhaps future generations. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. AB - Background: Male reproductive potential continues to be adversely affected by many environmental, industrial and pharmaceutical toxins. Pre-emptive testing for reproductive toxicological (side-)effects remains limited, or even non-existent. Many products that come into direct contact with spermatozoa lack adequate testing for the absence of adverse effects, and numerous products that are intended for exposure to spermatozoa have only a general assumption of safety based on the absence of evidence of actual harm. Such assumptions can have unfortunate adverse impacts on at-risk individuals (e.g. couples who are trying to conceive), illustrating a clear need for appropriate up-front testing to establish actual 'sperm safety'. METHODS: After compiling a list of general areas within the reviews scope, relevant literature and other information was obtained from the authors personal professional libraries and archives, and supplemented as necessary using PubMed and Google searches. Review by co-authors identified and eliminated errors of omission or bias. Results: This review provides an overview of the broad range of substances, materials and products that can affect male fertility, especially through sperm fertilizing ability, along with a discussion of practical methods and bioassays for their evaluation. It is concluded that products can only be claimed to be sperm-safe after performing objective, properly designed experimental studies; extrapolation from supposed predicate products or other assumptions cannot be trusted. CONCLUSIONS: We call for adopting the precautionary principle, especially when exposure to a product might affect not only a couples fertility potential but also the health of resulting offspring and perhaps future generations. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875766124&md5=44ef3de000d1a6f6e20812a5185bd7fb U2 - 10.1093/humupd/dmt008 DO - 10.1093/humupd/dmt008 M1 - Article JO - Human Reproduction Update JF - Human Reproduction Update SN - 1355-4786 IS - SUPPL1 VL - 19 SP - i1-i45 ER - TY - JOUR T1 - Women's health T2 - what's new worldwide A1 - Kirtley,Shona A1 - Chien,Patrick AU - Kirtley,Shona AU - Chien,Patrick PY - 2013/4 Y1 - 2013/4 U2 - 10.1111/1471-0528.12205 DO - 10.1111/1471-0528.12205 M1 - Article JO - BJOG: An International Journal of Obstetrics & Gynaecology JF - BJOG: An International Journal of Obstetrics & Gynaecology SN - 1470-0328 IS - 5 VL - 120 SP - 652 EP - 654 ER - TY - JOUR T1 - Workplace dietary improvement initiatives ought not to be discouraged by modest returns from low-intensity interventions A1 - Mooney,John D. A1 - Frank,John A1 - Anderson,Annie S. AU - Mooney,John D. AU - Frank,John AU - Anderson,Annie S. PY - 2013/4 Y1 - 2013/4 U2 - 10.1093/eurpub/ckt012 DO - 10.1093/eurpub/ckt012 M1 - Article JO - European Journal of Public Health JF - European Journal of Public Health SN - 1101-1262 IS - 2 VL - 23 SP - 193 EP - 194 ER - TY - JOUR T1 - Diffusion dynamics of the Keap1-Cullin3 interaction in single live cells A1 - Baird,L. A1 - Dinkova-Kostova,Albena T. AU - Baird,L. AU - Dinkova-Kostova,Albena T. PY - 2013/3/29 Y1 - 2013/3/29 N2 - Transcription factor NF-E2 p45-related factor 2 (Nrf2) regulates the expression of a network of genes encoding drug-detoxification, anti-inflammatory, and metabolic enzymes, as well as proteins involved in the regulation of cellular redox homeostasis. Under basal conditions, Kelch-like ECH associated protein 1 (Keap1) targets Nrf2 for ubiquitination and proteasomal degradation via association with Cullin3 (Cul3)-based Rbx1 E3 ubiquitin ligase. Various small molecules (inducers) activate Nrf2 leading to upregulation of cytoprotective gene expression. Inducers chemically modify specific cysteine residues of Keap1 which ultimately loses its ability to target Nrf2 for degradation. Dissociation of the Keap1-Cul3 complex by inducers is one possible mechanism, but evidence in single live cells is lacking. To investigate the diffusion dynamics of the Keap1-Cul3 interaction and the effect of inducers, we developed a quantitative fluorescence recovery after photobleaching (FRAP)-based system using Keap1-EGFP and mCherry-Cul3 fusion proteins. We show that Keap1-EGFP and mCherry-Cul3 interact in single live cells. Exposure for 1. h to small-molecule inducers of 4 different types, the oleanane triterpenoid CDDO, the isothiocyanate sulforaphane, the sulfoxythiocarbamate STCA, and the oxidant hydrogen peroxide which target distinct cysteine sensors within Keap1 with potencies which differ by nearly 4000-fold, does not dissociate the Keap1-Cul3 complex. As inducers cause conformational changes in Keap1, we conclude that changes in conformation rather than dissociation from Cul3 inactivate the repressor function of Keap1 leading to Nrf2 stabilization. © 2013 Elsevier Inc. AB - Transcription factor NF-E2 p45-related factor 2 (Nrf2) regulates the expression of a network of genes encoding drug-detoxification, anti-inflammatory, and metabolic enzymes, as well as proteins involved in the regulation of cellular redox homeostasis. Under basal conditions, Kelch-like ECH associated protein 1 (Keap1) targets Nrf2 for ubiquitination and proteasomal degradation via association with Cullin3 (Cul3)-based Rbx1 E3 ubiquitin ligase. Various small molecules (inducers) activate Nrf2 leading to upregulation of cytoprotective gene expression. Inducers chemically modify specific cysteine residues of Keap1 which ultimately loses its ability to target Nrf2 for degradation. Dissociation of the Keap1-Cul3 complex by inducers is one possible mechanism, but evidence in single live cells is lacking. To investigate the diffusion dynamics of the Keap1-Cul3 interaction and the effect of inducers, we developed a quantitative fluorescence recovery after photobleaching (FRAP)-based system using Keap1-EGFP and mCherry-Cul3 fusion proteins. We show that Keap1-EGFP and mCherry-Cul3 interact in single live cells. Exposure for 1. h to small-molecule inducers of 4 different types, the oleanane triterpenoid CDDO, the isothiocyanate sulforaphane, the sulfoxythiocarbamate STCA, and the oxidant hydrogen peroxide which target distinct cysteine sensors within Keap1 with potencies which differ by nearly 4000-fold, does not dissociate the Keap1-Cul3 complex. As inducers cause conformational changes in Keap1, we conclude that changes in conformation rather than dissociation from Cul3 inactivate the repressor function of Keap1 leading to Nrf2 stabilization. © 2013 Elsevier Inc. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875803470&md5=baa474b3c7d67bfeeeee094ef2261c78 U2 - 10.1016/j.bbrc.2013.02.065 DO - 10.1016/j.bbrc.2013.02.065 M1 - Article JO - Biochemical and Biophysical Research Communications JF - Biochemical and Biophysical Research Communications SN - 0006-291X IS - 1 VL - 433 SP - 58 EP - 65 ER - TY - JOUR T1 - C-elegans ring finger protein RNF-113 is involved in interstrand DNA crosslink repair and interacts with a RAD51C homolog A1 - Lee,Hyojin A1 - Alpi,Arno F. A1 - Park,Mi So A1 - Rose,Ann A1 - Koo,Hyeon-Sook AU - Lee,Hyojin AU - Alpi,Arno F. AU - Park,Mi So AU - Rose,Ann AU - Koo,Hyeon-Sook PY - 2013/3/28 Y1 - 2013/3/28 N2 -

The Fanconi anemia (FA) pathway recognizes interstrand DNA crosslinks (ICLs) and contributes to their conversion into double-strand DNA breaks, which can be repaired by homologous recombination. Seven orthologs of the 15 proteins associated with Fanconi anemia are functionally conserved in the model organism C. elegans. Here we report that RNF-113, a ubiquitin ligase, is required for RAD-51 focus formation after inducing ICLs in C. elegans. However, the formation of foci of RPA-1 or FCD-2/FANCD2 in the FA pathway was not affected by depletion of RNF-113. Nevertheless, the RPA-1 foci formed did not disappear with time in the depleted worms, implying serious defects in ICL repair. As a result, RNF-113 depletion increased embryonic lethality after ICL treatment in wild-type worms, but it did not increase the ICL-induced lethality of rfs-1/rad51C mutants. In addition, the persistence of RPA-1 foci was suppressed in doubly-deficient rnf-113;rfs-1 worms, suggesting that there is an epistatic interaction between the two genes. These results lead us to suggest that RNF-113 and RFS-1 interact to promote the displacement of RPA-1 by RAD-51 on single-stranded DNA derived from ICLs.

AB -

The Fanconi anemia (FA) pathway recognizes interstrand DNA crosslinks (ICLs) and contributes to their conversion into double-strand DNA breaks, which can be repaired by homologous recombination. Seven orthologs of the 15 proteins associated with Fanconi anemia are functionally conserved in the model organism C. elegans. Here we report that RNF-113, a ubiquitin ligase, is required for RAD-51 focus formation after inducing ICLs in C. elegans. However, the formation of foci of RPA-1 or FCD-2/FANCD2 in the FA pathway was not affected by depletion of RNF-113. Nevertheless, the RPA-1 foci formed did not disappear with time in the depleted worms, implying serious defects in ICL repair. As a result, RNF-113 depletion increased embryonic lethality after ICL treatment in wild-type worms, but it did not increase the ICL-induced lethality of rfs-1/rad51C mutants. In addition, the persistence of RPA-1 foci was suppressed in doubly-deficient rnf-113;rfs-1 worms, suggesting that there is an epistatic interaction between the two genes. These results lead us to suggest that RNF-113 and RFS-1 interact to promote the displacement of RPA-1 by RAD-51 on single-stranded DNA derived from ICLs.

KW - CORE COMPLEX KW - STRAND BREAK REPAIR KW - RECOMBINATION KW - CAENORHABDITIS-ELEGANS KW - FANCD2 KW - REPLICATION STRESS KW - FANCONI-ANEMIA PATHWAY KW - CANCER KW - SACCHAROMYCES-CEREVISIAE KW - DAMAGE RESPONSE U2 - 10.1371/journal.pone.0060071 DO - 10.1371/journal.pone.0060071 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 3 VL - 8 ER - TY - JOUR T1 - Operative caries management in adults and children A1 - Ricketts,David A1 - Lamont,Thomas A1 - Innes,Nicola P.T. A1 - Kidd,Edwina A1 - Clarkson,Jan E AU - Ricketts,David AU - Lamont,Thomas AU - Innes,Nicola P.T. AU - Kidd,Edwina AU - Clarkson,Jan E PY - 2013/3/28 Y1 - 2013/3/28 N2 - The management of dental caries has traditionally involved removal of all soft demineralised dentine before a filling is placed. However, the benefits of complete caries removal have been questioned because of concerns about the possible adverse effects of removing all soft dentine from the tooth. Three groups of studies have also challenged the doctrine of complete caries removal by sealing caries into teeth using three different techniques. The first technique removes caries in stages over two visits some months apart, allowing the dental pulp time to lay down reparative dentine (the stepwise excavation technique). The second removes part of the dentinal caries and seals the residual caries into the tooth permanently (partial caries removal) and the third technique removes no dentinal caries prior to sealing or restoring (no dentinal caries removal). This is an update of a Cochrane review first published in 2006. AB - The management of dental caries has traditionally involved removal of all soft demineralised dentine before a filling is placed. However, the benefits of complete caries removal have been questioned because of concerns about the possible adverse effects of removing all soft dentine from the tooth. Three groups of studies have also challenged the doctrine of complete caries removal by sealing caries into teeth using three different techniques. The first technique removes caries in stages over two visits some months apart, allowing the dental pulp time to lay down reparative dentine (the stepwise excavation technique). The second removes part of the dentinal caries and seals the residual caries into the tooth permanently (partial caries removal) and the third technique removes no dentinal caries prior to sealing or restoring (no dentinal caries removal). This is an update of a Cochrane review first published in 2006. U2 - 10.1002/14651858.CD003808.pub3 DO - 10.1002/14651858.CD003808.pub3 M1 - Article JO - Cochrane Database of Systematic Reviews JF - Cochrane Database of Systematic Reviews SN - 1469-493X VL - 3 ER - TY - JOUR T1 - Cholinergic pesticides cause mushroom body neuronal inactivation in honeybees A1 - Palmer,Mary J A1 - Moffat,Christopher A1 - Saranzewa,Nastja A1 - Harvey,Jenni A1 - Wright,Geraldine A A1 - Connolly,Christopher N AU - Palmer,Mary J AU - Moffat,Christopher AU - Saranzewa,Nastja AU - Harvey,Jenni AU - Wright,Geraldine A AU - Connolly,Christopher N PY - 2013/3/27 Y1 - 2013/3/27 N2 - Pesticides that target cholinergic neurotransmission are highly effective, but their use has been implicated in insect pollinator population decline. Honeybees are exposed to two widely used classes of cholinergic pesticide: neonicotinoids (nicotinic receptor agonists) and organophosphate miticides (acetylcholinesterase inhibitors). Although sublethal levels of neonicotinoids are known to disrupt honeybee learning and behaviour, the neurophysiological basis of these effects has not been shown. Here, using recordings from mushroom body Kenyon cells in acutely isolated honeybee brain, we show that the neonicotinoids imidacloprid and clothianidin, and the organophosphate miticide coumaphos oxon, cause a depolarization-block of neuronal firing and inhibit nicotinic responses. These effects are observed at concentrations that are encountered by foraging honeybees and within the hive, and are additive with combined application. Our findings demonstrate a neuronal mechanism that may account for the cognitive impairments caused by neonicotinoids, and predict that exposure to multiple pesticides that target cholinergic signalling will cause enhanced toxicity to pollinators. © 2013 Macmillan Publishers Limited. All rights reserved. AB - Pesticides that target cholinergic neurotransmission are highly effective, but their use has been implicated in insect pollinator population decline. Honeybees are exposed to two widely used classes of cholinergic pesticide: neonicotinoids (nicotinic receptor agonists) and organophosphate miticides (acetylcholinesterase inhibitors). Although sublethal levels of neonicotinoids are known to disrupt honeybee learning and behaviour, the neurophysiological basis of these effects has not been shown. Here, using recordings from mushroom body Kenyon cells in acutely isolated honeybee brain, we show that the neonicotinoids imidacloprid and clothianidin, and the organophosphate miticide coumaphos oxon, cause a depolarization-block of neuronal firing and inhibit nicotinic responses. These effects are observed at concentrations that are encountered by foraging honeybees and within the hive, and are additive with combined application. Our findings demonstrate a neuronal mechanism that may account for the cognitive impairments caused by neonicotinoids, and predict that exposure to multiple pesticides that target cholinergic signalling will cause enhanced toxicity to pollinators. © 2013 Macmillan Publishers Limited. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875910463&md5=c5c0e2a418bbbb4ac7b116aa7d9a147d U2 - 10.1038/ncomms2648 DO - 10.1038/ncomms2648 M1 - Article JO - Nature Communications JF - Nature Communications VL - 4 ER - TY - JOUR T1 - CSN-and CAND1-dependent remodelling of the budding yeast SCF complex A1 - Zemla,Aleksandra A1 - Thomas,Yann A1 - Kedziora,Sylvia A1 - Knebel,Axel A1 - Wood,Nicola T. A1 - Rabut,Gwenael A1 - Kurz,Thimo AU - Zemla,Aleksandra AU - Thomas,Yann AU - Kedziora,Sylvia AU - Knebel,Axel AU - Wood,Nicola T. AU - Rabut,Gwenael AU - Kurz,Thimo PY - 2013/3/27 Y1 - 2013/3/27 N2 - Cullin-RING ligases (CRLs) are ubiquitin E3 enzymes with variable substrate-adaptor and-receptor subunits. All CRLs are activated by modification of the cullin subunit with the ubiquitin-like protein Nedd8 (neddylation). The protein CAND1 (Cullin-associated-Nedd8-dissociated-1) also promotes CRL activity, even though it only interacts with inactive ligase complexes. The molecular mechanism underlying this behaviour remains largely unclear. Here, we find that yeast SCF (Skp1-Cdc53-F-box) Cullin-RING complexes are remodelled in a CAND1-dependent manner, when cells are switched from growth in fermentable to non-fermentable carbon sources. Mechanistically, CAND1 promotes substrate adaptor release following SCF deneddylation by the COP9 signalosome (CSN). CSN-or CAND1-mutant cells fail to release substrate adaptors. This delays the formation of new complexes during SCF reactivation and results in substrate degradation defects. Our results shed light on how CAND1 regulates CRL activity and demonstrate that the cullin neddylation-deneddylation cycle is not only required to activate CRLs, but also to regulate substrate specificity through dynamic substrate adaptor exchange. © 2013 Macmillan Publishers Limited. All rights reserved. AB - Cullin-RING ligases (CRLs) are ubiquitin E3 enzymes with variable substrate-adaptor and-receptor subunits. All CRLs are activated by modification of the cullin subunit with the ubiquitin-like protein Nedd8 (neddylation). The protein CAND1 (Cullin-associated-Nedd8-dissociated-1) also promotes CRL activity, even though it only interacts with inactive ligase complexes. The molecular mechanism underlying this behaviour remains largely unclear. Here, we find that yeast SCF (Skp1-Cdc53-F-box) Cullin-RING complexes are remodelled in a CAND1-dependent manner, when cells are switched from growth in fermentable to non-fermentable carbon sources. Mechanistically, CAND1 promotes substrate adaptor release following SCF deneddylation by the COP9 signalosome (CSN). CSN-or CAND1-mutant cells fail to release substrate adaptors. This delays the formation of new complexes during SCF reactivation and results in substrate degradation defects. Our results shed light on how CAND1 regulates CRL activity and demonstrate that the cullin neddylation-deneddylation cycle is not only required to activate CRLs, but also to regulate substrate specificity through dynamic substrate adaptor exchange. © 2013 Macmillan Publishers Limited. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875768399&md5=e8d0a012264a052f5c95085cbf353141 U2 - 10.1038/ncomms2628 DO - 10.1038/ncomms2628 M1 - Article JO - Nature Communications JF - Nature Communications SN - 2041-1723 VL - 4 ER - TY - JOUR T1 - The Effect of Protonation State on the Stability of Amyloid Oligomers Assembled From TTR(105-115) A1 - Porrini,Massimiliano A1 - Zachariae,Ulrich A1 - Barran,Perdita E. A1 - MacPhee,Cait E. AU - Porrini,Massimiliano AU - Zachariae,Ulrich AU - Barran,Perdita E. AU - MacPhee,Cait E. PY - 2013/3/27 Y1 - 2013/3/27 N2 - Amyloid fibrils are self-assembled aggregates of polypeptides that are implicated in the development of several human diseases. A peptide derived from amino acids 105–115 of the human plasma protein transthyretin forms homogeneous and well-defined fibrils and, as a model system, has been the focus of a number of studies investigating the formation and structure of this class of aggregates. Self-assembly of TTR(105–115) occurs at low pH, and this work explores the effect of protonation on the growth and stability of small cross-ß aggregates. Using molecular dynamics simulations of structures up to the decamer in both protonated and deprotonated states, we find that, whereas hexamers are more stable for protonated peptides, higher order oligomers are more stable when the peptides are deprotonated. Our findings imply a change in the acid pK of the protonated C-terminal group during the formation of fibrils, which leads to stabilization of higher-order oligomers through electrostatic interactions. AB - Amyloid fibrils are self-assembled aggregates of polypeptides that are implicated in the development of several human diseases. A peptide derived from amino acids 105–115 of the human plasma protein transthyretin forms homogeneous and well-defined fibrils and, as a model system, has been the focus of a number of studies investigating the formation and structure of this class of aggregates. Self-assembly of TTR(105–115) occurs at low pH, and this work explores the effect of protonation on the growth and stability of small cross-ß aggregates. Using molecular dynamics simulations of structures up to the decamer in both protonated and deprotonated states, we find that, whereas hexamers are more stable for protonated peptides, higher order oligomers are more stable when the peptides are deprotonated. Our findings imply a change in the acid pK of the protonated C-terminal group during the formation of fibrils, which leads to stabilization of higher-order oligomers through electrostatic interactions. U2 - 10.1021/jz400372u DO - 10.1021/jz400372u M1 - Article JO - Journal of Physical Chemistry Letters JF - Journal of Physical Chemistry Letters IS - 8 VL - 4 SP - 1233 EP - 1238 ER - TY - JOUR T1 - Dexterous manipulation of microparticles using Bessel-function acoustic pressure fields A1 - Courtney,C.R.P. A1 - Drinkwater,B.W. A1 - Demore,Christine E.M. A1 - Cochran,Sandy A1 - Grinenko,A. A1 - Wilcox,P.D. AU - Courtney,C.R.P. AU - Drinkwater,B.W. AU - Demore,Christine E.M. AU - Cochran,Sandy AU - Grinenko,A. AU - Wilcox,P.D. PY - 2013/3/25 Y1 - 2013/3/25 N2 - We show that Bessel-function acoustic pressure fields can be used to trap and controllably position microparticles. A circular, 16-element ultrasound array generates and manipulates an acoustic field within a chamber, trapping microparticles and agglomerates. Changes in the phase of the sinusoidal signals applied to the array elements result in the movement of the Bessel-function pressure field and hence the microparticles. This demonstrates ultrasonic manipulation analogous to holographic optical tweezers. The manipulation limits of the device are explained by the existence of unwanted resonances within the manipulation chamber. © 2013 American Institute of Physics. AB - We show that Bessel-function acoustic pressure fields can be used to trap and controllably position microparticles. A circular, 16-element ultrasound array generates and manipulates an acoustic field within a chamber, trapping microparticles and agglomerates. Changes in the phase of the sinusoidal signals applied to the array elements result in the movement of the Bessel-function pressure field and hence the microparticles. This demonstrates ultrasonic manipulation analogous to holographic optical tweezers. The manipulation limits of the device are explained by the existence of unwanted resonances within the manipulation chamber. © 2013 American Institute of Physics. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875923507&md5=869ae5b2c15652c2b5a3cc33aa084045 U2 - 10.1063/1.4798584 DO - 10.1063/1.4798584 M1 - Article JO - Applied Physics Letters JF - Applied Physics Letters SN - 0003-6951 IS - 12 VL - 102 ER - TY - JOUR T1 - Identification and Characterisation CRN Effectors in Phytophthora capsici Shows Modularity and Functional Diversity A1 - Stam,Remco A1 - Jupe,Julietta A1 - Howden,Andrew J. M. A1 - Morris,Jenny A. A1 - Boevink,Petra C. A1 - Hedley,Pete E. A1 - Huitema,Edgar AU - Stam,Remco AU - Jupe,Julietta AU - Howden,Andrew J. M. AU - Morris,Jenny A. AU - Boevink,Petra C. AU - Hedley,Pete E. AU - Huitema,Edgar PY - 2013/3/25 Y1 - 2013/3/25 N2 -

Phytophthora species secrete a large array of effectors during infection of their host plants. The Crinkler (CRN) gene family encodes a ubiquitous but understudied class of effectors with possible but as of yet unknown roles in infection. To appreciate CRN effector function in Phytophthora, we devised a simple Crn gene identification and annotation pipeline to improve effector prediction rates. We predicted 84 full-length CRN coding genes and assessed CRN effector domain diversity in sequenced Oomycete genomes. These analyses revealed evidence of CRN domain innovation in Phytophthora and expansion in the Peronosporales. We performed gene expression analyses to validate and define two classes of CRN effectors, each possibly contributing to infection at different stages. CRN localisation studies revealed that P. capsici CRN effector domains target the nucleus and accumulate in specific sub-nuclear compartments. Phenotypic analyses showed that few CRN domains induce necrosis when expressed in planta and that one cell death inducing effector, enhances P. capsici virulence on Nicotiana benthamiana. These results suggest that the CRN protein family form an important class of intracellular effectors that target the host nucleus during infection. These results combined with domain expansion in hemibiotrophic and necrotrophic pathogens, suggests specific contributions to pathogen lifestyles. This work will bolster CRN identification efforts in other sequenced oomycete species and set the stage for future functional studies towards understanding CRN effector functions.

AB -

Phytophthora species secrete a large array of effectors during infection of their host plants. The Crinkler (CRN) gene family encodes a ubiquitous but understudied class of effectors with possible but as of yet unknown roles in infection. To appreciate CRN effector function in Phytophthora, we devised a simple Crn gene identification and annotation pipeline to improve effector prediction rates. We predicted 84 full-length CRN coding genes and assessed CRN effector domain diversity in sequenced Oomycete genomes. These analyses revealed evidence of CRN domain innovation in Phytophthora and expansion in the Peronosporales. We performed gene expression analyses to validate and define two classes of CRN effectors, each possibly contributing to infection at different stages. CRN localisation studies revealed that P. capsici CRN effector domains target the nucleus and accumulate in specific sub-nuclear compartments. Phenotypic analyses showed that few CRN domains induce necrosis when expressed in planta and that one cell death inducing effector, enhances P. capsici virulence on Nicotiana benthamiana. These results suggest that the CRN protein family form an important class of intracellular effectors that target the host nucleus during infection. These results combined with domain expansion in hemibiotrophic and necrotrophic pathogens, suggests specific contributions to pathogen lifestyles. This work will bolster CRN identification efforts in other sequenced oomycete species and set the stage for future functional studies towards understanding CRN effector functions.

KW - DATABASE KW - GENOME SEQUENCES KW - PREDICTION KW - PROTEINS KW - RXLR EFFECTORS KW - INFESTANS KW - PLANT PATHOGEN PHYTOPHTHORA KW - OOMYCETE EFFECTORS KW - EVOLUTION KW - DELIVERY U2 - 10.1371/journal.pone.0059517 DO - 10.1371/journal.pone.0059517 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 3 VL - 8 ER - TY - JOUR T1 - Dectin-1 Regulates IL-10 Production via a MSK1/2 and CREB Dependent Pathway and Promotes the Induction of Regulatory Macrophage Markers A1 - Elcombe,Suzanne E. A1 - Naqvi,Shaista A1 - Van den Bosch,Mirjam W. M. A1 - MacKenzie,Kirsty F. A1 - Cianfanelli,Francesca A1 - Brown,Gordon D. A1 - Arthur,J Simon C. AU - Elcombe,Suzanne E. AU - Naqvi,Shaista AU - Van den Bosch,Mirjam W. M. AU - MacKenzie,Kirsty F. AU - Cianfanelli,Francesca AU - Brown,Gordon D. AU - Arthur,J Simon C. PY - 2013/3/22 Y1 - 2013/3/22 N2 -

In response to infection by fungal pathogens, the innate immune system recognises specific fungal pathogen associated molecular patterns (PAMPs) via pattern recognition receptors including the C-type lectin dectin-1 and members of the Toll Like Receptor (TLR) family. Stimulation of these receptors leads to the induction of both pro- and anti-inflammatory cytokines. The protein kinases MSK1 and 2 are known to be important in limiting inflammatory cytokine production by macrophages in response to the TLR4 agonist LPS. In this study we show that MSKs are also activated in macrophages by the fungal derived ligand zymosan, as well as the dectin-1 specific agonists curdlan and depleted zymosan, via the ERK1/2 and p38 alpha MAPK pathways. Furthermore, we show that MSKs regulate dectin-1 induced IL-10 production, and that this regulation is dependent on the ability of MSKs to phosphorylate the transcription factor CREB. IL-10 secreted in response to zymosan was able to promote STAT3 phosphorylation via an autocrine feedback loop. Consistent with the decreased IL-10 secretion in MSK1/2 knockout macrophages, these cells also had decreased STAT3 tyrosine phosphorylation relative to wild type controls after stimulation with zymosan. We further show that the reduction in IL-10 production in the MSK1/2 macrophages results in increased secretion of IL-12p40 in response to zymosan relative to wild type controls. The production of high levels of IL-10 but low levels of IL-12 has previously been associated with an M2b or 'regulatory' macrophage phenotype, which was initially described in macrophages stimulated with a combination of immune complexes and LPS. We found that zymosan, via dectin-1 activation, also leads to the expression of SphK1 and LIGHT, markers of a regulatory like phenotype in mouse macrophages. The expression of these makers was further reinforced by the high level of IL-10 secreted in response to zymosan stimulation.

AB -

In response to infection by fungal pathogens, the innate immune system recognises specific fungal pathogen associated molecular patterns (PAMPs) via pattern recognition receptors including the C-type lectin dectin-1 and members of the Toll Like Receptor (TLR) family. Stimulation of these receptors leads to the induction of both pro- and anti-inflammatory cytokines. The protein kinases MSK1 and 2 are known to be important in limiting inflammatory cytokine production by macrophages in response to the TLR4 agonist LPS. In this study we show that MSKs are also activated in macrophages by the fungal derived ligand zymosan, as well as the dectin-1 specific agonists curdlan and depleted zymosan, via the ERK1/2 and p38 alpha MAPK pathways. Furthermore, we show that MSKs regulate dectin-1 induced IL-10 production, and that this regulation is dependent on the ability of MSKs to phosphorylate the transcription factor CREB. IL-10 secreted in response to zymosan was able to promote STAT3 phosphorylation via an autocrine feedback loop. Consistent with the decreased IL-10 secretion in MSK1/2 knockout macrophages, these cells also had decreased STAT3 tyrosine phosphorylation relative to wild type controls after stimulation with zymosan. We further show that the reduction in IL-10 production in the MSK1/2 macrophages results in increased secretion of IL-12p40 in response to zymosan relative to wild type controls. The production of high levels of IL-10 but low levels of IL-12 has previously been associated with an M2b or 'regulatory' macrophage phenotype, which was initially described in macrophages stimulated with a combination of immune complexes and LPS. We found that zymosan, via dectin-1 activation, also leads to the expression of SphK1 and LIGHT, markers of a regulatory like phenotype in mouse macrophages. The expression of these makers was further reinforced by the high level of IL-10 secreted in response to zymosan stimulation.

KW - STRESS-INDUCED PHOSPHORYLATION KW - GENE-EXPRESSION KW - TRANSCRIPTION FACTORS KW - CYTOKINE PRODUCTION KW - IMMUNE-RESPONSES KW - DENDRITIC CELLS KW - BETA-GLUCAN RECEPTOR KW - IN-VIVO KW - TOLL-LIKE RECEPTOR-2 KW - CANDIDA-ALBICANS U2 - 10.1371/journal.pone.0060086 DO - 10.1371/journal.pone.0060086 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 3 VL - 8 ER - TY - JOUR T1 - LKB1 Mediates the Development of Conventional and Innate T Cells via AMP-Dependent Kinase Autonomous Pathways A1 - Zarrouk,Marouan A1 - Rolf,Julia A1 - Cantrell,Doreen Ann AU - Zarrouk,Marouan AU - Rolf,Julia AU - Cantrell,Doreen Ann PY - 2013/3/22 Y1 - 2013/3/22 N2 -

The present study has examined the role of the serine/threonine kinase LKB1 in the survival and differentiation of CD4/8 double positive thymocytes. LKB1-null DPs can respond to signals from the mature alpha/beta T-cell-antigen receptor and initiate positive selection. However, in the absence of LKB1, thymocytes fail to mature to conventional single positive cells causing severe lymphopenia in the peripheral lymphoid tissues. LKB1 thus appears to be dispensable for positive selection but important for the maturation of positively selected thymocytes. LKB1 also strikingly prevented the development of invariant V alpha 14 NKT cells and innate TCR alpha beta gut lymphocytes. Previous studies with gain of function mutants have suggested that the role of LKB1 in T cell development is mediated by its substrate the AMP-activated protein kinase ( AMPK). The present study now analyses the impact of AMPK deletion in DP thymocytes and shows that the role of LKB1 during the development of both conventional and innate T cells is mediated by AMPK-independent pathways.

AB -

The present study has examined the role of the serine/threonine kinase LKB1 in the survival and differentiation of CD4/8 double positive thymocytes. LKB1-null DPs can respond to signals from the mature alpha/beta T-cell-antigen receptor and initiate positive selection. However, in the absence of LKB1, thymocytes fail to mature to conventional single positive cells causing severe lymphopenia in the peripheral lymphoid tissues. LKB1 thus appears to be dispensable for positive selection but important for the maturation of positively selected thymocytes. LKB1 also strikingly prevented the development of invariant V alpha 14 NKT cells and innate TCR alpha beta gut lymphocytes. Previous studies with gain of function mutants have suggested that the role of LKB1 in T cell development is mediated by its substrate the AMP-activated protein kinase ( AMPK). The present study now analyses the impact of AMPK deletion in DP thymocytes and shows that the role of LKB1 during the development of both conventional and innate T cells is mediated by AMPK-independent pathways.

KW - ACTIVATION KW - C-MYC KW - PRECURSORS KW - THYMUS KW - INTESTINAL INTRAEPITHELIAL LYMPHOCYTES U2 - 10.1371/journal.pone.0060217 DO - 10.1371/journal.pone.0060217 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 3 VL - 8 ER - TY - JOUR T1 - Enhancing citizen engagement in cancer screening through deliberative democracy A1 - Rychetnik,L. A1 - Carter,S.M. A1 - Abelson,J. A1 - Thornton,H. A1 - Barratt,A. A1 - Entwistle,Vikki A. A1 - Mackenzie,Geraldine A1 - Salkeld,G. A1 - Glasziou,P. AU - Rychetnik,L. AU - Carter,S.M. AU - Abelson,J. AU - Thornton,H. AU - Barratt,A. AU - Entwistle,Vikki A. AU - Mackenzie,Geraldine AU - Salkeld,G. AU - Glasziou,P. PY - 2013/3/20 Y1 - 2013/3/20 N2 - Cancer screening is widely practiced and participation is promoted by various social, technical, and commercial drivers, but there are growing concerns about the emerging harms, risks, and costs of cancer screening. Deliberative democracy methods engage citizens in dialogue on substantial and complex problems: especially when evidence and values are important and people need time to understand and consider the relevant issues. Information derived from such deliberations can provide important guidance to cancer screening policies: citizens' values are made explicit, revealing what really matters to people and why. Policy makers can see what informed, rather than uninformed, citizens would decide on the provision of services and information on cancer screening. Caveats can be elicited to guide changes to existing policies and practices. Policies that take account of citizens' opinions through a deliberative democracy process can be considered more legitimate, justifiable, and feasible than those that don't. © 2013 The Author. AB - Cancer screening is widely practiced and participation is promoted by various social, technical, and commercial drivers, but there are growing concerns about the emerging harms, risks, and costs of cancer screening. Deliberative democracy methods engage citizens in dialogue on substantial and complex problems: especially when evidence and values are important and people need time to understand and consider the relevant issues. Information derived from such deliberations can provide important guidance to cancer screening policies: citizens' values are made explicit, revealing what really matters to people and why. Policy makers can see what informed, rather than uninformed, citizens would decide on the provision of services and information on cancer screening. Caveats can be elicited to guide changes to existing policies and practices. Policies that take account of citizens' opinions through a deliberative democracy process can be considered more legitimate, justifiable, and feasible than those that don't. © 2013 The Author. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875626979&md5=71aee33516dd887613939097fcbe64b9 U2 - 10.1093/jnci/djs649 DO - 10.1093/jnci/djs649 M1 - Article JO - Journal of the National Cancer Institute JF - Journal of the National Cancer Institute SN - 0027-8874 IS - 6 VL - 105 SP - 380 EP - 386 ER - TY - JOUR T1 - Crystal structure and functional mechanism of a human antimicrobial membrane channel A1 - Song,C. A1 - Weichbrodt,C. A1 - Salnikov,E.S. A1 - Dynowski,M. A1 - Forsberg,B.O. A1 - Bechinger,B. A1 - Steinem,C. A1 - De Groot,B.L. A1 - Zachariae,U. A1 - Zeth,K. AU - Song,C. AU - Weichbrodt,C. AU - Salnikov,E.S. AU - Dynowski,M. AU - Forsberg,B.O. AU - Bechinger,B. AU - Steinem,C. AU - De Groot,B.L. AU - Zachariae,U. AU - Zeth,K. PY - 2013/3/19 Y1 - 2013/3/19 N2 - Multicellular organisms fight bacterial and fungal infections by producing peptide-derived broad-spectrum antibiotics. These hostdefense peptides compromise the integrity of microbial cell membranes and thus evade pathways by which bacteria develop rapid antibiotic resistance. Although more than 1,700 host-defense peptides have been identified, the structural and mechanistic basis of their action remains speculative. This impedes the desired rational development of these agents into next-generation antibiotics. We present the X-ray crystal structure as well as solid-state NMR spectroscopy, electrophysiology, and MD simulations of human dermcidin in membranes that reveal the antibiotic mechanism of this major human antimicrobial, found to suppress Staphylococcus aureus growth on the epidermal surface. Dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidate the unusual membrane permeation pathway for ions and show adjustment of the pore to various membranes. Our study unravels the comprehensive mechanism for the membrane-disruptive action of this mammalian host-defense peptide at atomistic level. The results may form a foundation for the structure-based design of peptide antibiotics. AB - Multicellular organisms fight bacterial and fungal infections by producing peptide-derived broad-spectrum antibiotics. These hostdefense peptides compromise the integrity of microbial cell membranes and thus evade pathways by which bacteria develop rapid antibiotic resistance. Although more than 1,700 host-defense peptides have been identified, the structural and mechanistic basis of their action remains speculative. This impedes the desired rational development of these agents into next-generation antibiotics. We present the X-ray crystal structure as well as solid-state NMR spectroscopy, electrophysiology, and MD simulations of human dermcidin in membranes that reveal the antibiotic mechanism of this major human antimicrobial, found to suppress Staphylococcus aureus growth on the epidermal surface. Dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidate the unusual membrane permeation pathway for ions and show adjustment of the pore to various membranes. Our study unravels the comprehensive mechanism for the membrane-disruptive action of this mammalian host-defense peptide at atomistic level. The results may form a foundation for the structure-based design of peptide antibiotics. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875272220&md5=ea39ae1acd4d2cccfa18001e92553de0 U2 - 10.1073/pnas.1214739110 DO - 10.1073/pnas.1214739110 M1 - Article JO - Proceedings of the National Academy of Sciences of the United States of America JF - Proceedings of the National Academy of Sciences of the United States of America SN - 0027-8424 IS - 12 VL - 110 SP - 4586 EP - 4591 ER - TY - JOUR T1 - Topoisomerase IIα promotes activation of RNA polymerase i transcription by facilitating pre-initiation complex formation A1 - Ray,Swagat A1 - Panova,Tatiana A1 - Miller,Gail A1 - Volkov,Arsen A1 - Porter,Andrew C.G. A1 - Russell,Jackie A1 - Panov,Konstantin I. A1 - Zomerdijk,Joost C.B.M. AU - Ray,Swagat AU - Panova,Tatiana AU - Miller,Gail AU - Volkov,Arsen AU - Porter,Andrew C.G. AU - Russell,Jackie AU - Panov,Konstantin I. AU - Zomerdijk,Joost C.B.M. PY - 2013/3/19 Y1 - 2013/3/19 N2 - Type II DNA topoisomerases catalyse DNA double-strand cleavage, passage and re-ligation to effect topological changes. There is considerable interest in elucidating topoisomerase II roles, particularly as these proteins are targets for anti-cancer drugs. Here we uncover a role for topoisomerase IIa in RNA polymerase I-directed ribosomal RNA gene transcription, which drives cell growth and proliferation and is upregulated in cancer cells. Our data suggest that topoisomerase IIa is a component of the initiation-competent RNA polymerase Iß complex and interacts directly with RNA polymerase I-associated transcription factor RRN3, which targets the polymerase to promoter-bound SL1 in pre-initiation complex formation. In cells, activation of rDNA transcription is reduced by inhibition or depletion of topoisomerase II, and this is accompanied by reduced transient double-strand DNA cleavage in the rDNA-promoter region and reduced pre-initiation complex formation. We propose that topoisomerase IIa functions in RNA polymerase I transcription to produce topological changes at the rDNA promoter that facilitate efficient de novo pre-initiation complex formation. © 2013 Macmillan Publishers Limited. All rights reserved. AB - Type II DNA topoisomerases catalyse DNA double-strand cleavage, passage and re-ligation to effect topological changes. There is considerable interest in elucidating topoisomerase II roles, particularly as these proteins are targets for anti-cancer drugs. Here we uncover a role for topoisomerase IIa in RNA polymerase I-directed ribosomal RNA gene transcription, which drives cell growth and proliferation and is upregulated in cancer cells. Our data suggest that topoisomerase IIa is a component of the initiation-competent RNA polymerase Iß complex and interacts directly with RNA polymerase I-associated transcription factor RRN3, which targets the polymerase to promoter-bound SL1 in pre-initiation complex formation. In cells, activation of rDNA transcription is reduced by inhibition or depletion of topoisomerase II, and this is accompanied by reduced transient double-strand DNA cleavage in the rDNA-promoter region and reduced pre-initiation complex formation. We propose that topoisomerase IIa functions in RNA polymerase I transcription to produce topological changes at the rDNA promoter that facilitate efficient de novo pre-initiation complex formation. © 2013 Macmillan Publishers Limited. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875853142&md5=5315372de66965d47545227127c8042a U2 - 10.1038/ncomms2599 DO - 10.1038/ncomms2599 M1 - Article JO - Nature Communications JF - Nature Communications SN - 2041-1723 VL - 4 ER - TY - GEN T1 - International law T2 - facilitating transboundary water cooperation A1 - Wouters,Patricia AU - Wouters,Patricia PY - 2013/3/18 Y1 - 2013/3/18 UR - http://www.gwp.org/en/gwp-in-action/News-and-Activities/Transboundary-Law-and-Economic-Value-of-Water-New-Background-Papers-from-GWP-Technical-Committee-/ M1 - Special issue ER - TY - JOUR T1 - Sialoadhesin ligand expression identifies a subpopulation of Foxp3- T cells with a distinct activation and glycosylation profile A1 - Kidder,D A1 - Richards,H E A1 - Ziltener,H J A1 - Garden,O A A1 - Crocker,P R AU - Kidder,D AU - Richards,H E AU - Ziltener,H J AU - Garden,O A AU - Crocker,P R PY - 2013/3/15 Y1 - 2013/3/15 N2 - Sialoadhesin (Sn) is a sialic acid–binding Ig-like lectin expressed selectively on macrophage subsets. In a model of experimental autoimmune encephalomyelitis, Sn interacted with sialylated ligands expressed selectively on CD4+Foxp3+ regulatory T cells (Tregs) and inhibited their proliferation. In this study, we examined the induction of Sn ligands (SnL) on all splenic CD4+ T cells following in vitro activation. Most CD4+ Tregs strongly upregulated SnL, whereas only a small subset of ~20% CD4+Foxp3- T cells (effector T cells [Teffs]) upregulated SnL. SnL+ Teffs displayed higher levels of activation markers CD25 and CD69, exhibited increased proliferation, and produced higher amounts of IL-2 and IFN-? than corresponding SnL- Teffs. Coculture of activated Teffs with Sn+ macrophages or Sn+ Chinese hamster ovary cells resulted in increased cell death, suggesting a regulatory role for Sn–SnL interactions. The key importance of a2,3-sialylation in SnL expression was demonstrated by increased binding of a2,3-linkage–specific Maackia amurensis lectin, increased expression of a2,3-sialyltransferase ST3GalVI, and loss of SnL following treatment with an a2,3-linkage–specific sialidase. The induction of SnL on activated CD4+ T cells was dependent on N-glycan rather than O-glycan biosynthesis and independent of the mucin-like molecules CD43 and P-selectin glycoprotein ligand-1, previously implicated in Sn interactions. Induction of ligands on CD4+Foxp3- Teffs was also observed in vivo using the New Zealand Black × New Zealand White F1 murine model of spontaneous lupus and SnL levels on Teffs correlated strongly with the degree of proteinuria. Collectively, these data indicate that SnL is a novel marker of activated CD4+ Teffs that are implicated in the pathogenesis of autoimmune diseases. AB - Sialoadhesin (Sn) is a sialic acid–binding Ig-like lectin expressed selectively on macrophage subsets. In a model of experimental autoimmune encephalomyelitis, Sn interacted with sialylated ligands expressed selectively on CD4+Foxp3+ regulatory T cells (Tregs) and inhibited their proliferation. In this study, we examined the induction of Sn ligands (SnL) on all splenic CD4+ T cells following in vitro activation. Most CD4+ Tregs strongly upregulated SnL, whereas only a small subset of ~20% CD4+Foxp3- T cells (effector T cells [Teffs]) upregulated SnL. SnL+ Teffs displayed higher levels of activation markers CD25 and CD69, exhibited increased proliferation, and produced higher amounts of IL-2 and IFN-? than corresponding SnL- Teffs. Coculture of activated Teffs with Sn+ macrophages or Sn+ Chinese hamster ovary cells resulted in increased cell death, suggesting a regulatory role for Sn–SnL interactions. The key importance of a2,3-sialylation in SnL expression was demonstrated by increased binding of a2,3-linkage–specific Maackia amurensis lectin, increased expression of a2,3-sialyltransferase ST3GalVI, and loss of SnL following treatment with an a2,3-linkage–specific sialidase. The induction of SnL on activated CD4+ T cells was dependent on N-glycan rather than O-glycan biosynthesis and independent of the mucin-like molecules CD43 and P-selectin glycoprotein ligand-1, previously implicated in Sn interactions. Induction of ligands on CD4+Foxp3- Teffs was also observed in vivo using the New Zealand Black × New Zealand White F1 murine model of spontaneous lupus and SnL levels on Teffs correlated strongly with the degree of proteinuria. Collectively, these data indicate that SnL is a novel marker of activated CD4+ Teffs that are implicated in the pathogenesis of autoimmune diseases. UR - http://www.ncbi.nlm.nih.gov/pubmed/23408841?dopt=Abstract U2 - 10.4049/jimmunol.1201172 DO - 10.4049/jimmunol.1201172 M1 - Article JO - Journal of Immunology JF - Journal of Immunology SN - 0022-1767 IS - 6 VL - 190 SP - 2593 EP - 2602 ER - TY - JOUR T1 - Siglec-E is a negative regulator of acute pulmonary neutrophil inflammation and suppresses CD11b beta2-integrin-dependent signalling A1 - McMillan,Sarah J A1 - Sharma,Ritu S A1 - McKenzie,Emma J A1 - Richards,Hannah E A1 - Zhang,Jiquan A1 - Prescott,Alan A1 - Crocker,Paul R AU - McMillan,Sarah J AU - Sharma,Ritu S AU - McKenzie,Emma J AU - Richards,Hannah E AU - Zhang,Jiquan AU - Prescott,Alan AU - Crocker,Paul R PY - 2013/3/14 Y1 - 2013/3/14 N2 - Neutrophil entry into the lung tissues is a key step in host defense to bacterial and yeast infections, but if uncontrolled can lead to severe tissue damage. Here, we demonstrate for the first time that sialic acid binding Ig-like lectin E (siglec-E) functions to selectively regulate early neutrophil recruitment into the lung. In a model of acute lung inflammation induced by aerosolized lipopolysaccharide, siglec-E–deficient mice exhibited exaggerated neutrophil recruitment that was reversed by blockade of the ß2 integrin, CD11b. Siglec-E suppressed CD11b “outside-in” signaling, because siglec-E–deficient neutrophils plated on the CD11b ligand fibrinogen showed exaggerated phosphorylation of Syk and p38 mitogen-activated protein kinase. Sialidase treatment of fibrinogen reversed the suppressive effect of siglec-E on CD11b signaling, suggesting that sialic acid recognition by siglec-E is required for its inhibitory function. Siglec-E in neutrophils was constitutively associated with the tyrosine phosphatase SHP-1 and may therefore function to constitutively dampen inflammatory responses of neutrophils. These data reveal that siglec-E is an important negative regulator of neutrophil recruitment to the lung and ß2 integrin–dependent signaling. Our findings have implications for the human functional ortholog, siglec-9, and its potential role in regulating inflammatory lung disease. AB - Neutrophil entry into the lung tissues is a key step in host defense to bacterial and yeast infections, but if uncontrolled can lead to severe tissue damage. Here, we demonstrate for the first time that sialic acid binding Ig-like lectin E (siglec-E) functions to selectively regulate early neutrophil recruitment into the lung. In a model of acute lung inflammation induced by aerosolized lipopolysaccharide, siglec-E–deficient mice exhibited exaggerated neutrophil recruitment that was reversed by blockade of the ß2 integrin, CD11b. Siglec-E suppressed CD11b “outside-in” signaling, because siglec-E–deficient neutrophils plated on the CD11b ligand fibrinogen showed exaggerated phosphorylation of Syk and p38 mitogen-activated protein kinase. Sialidase treatment of fibrinogen reversed the suppressive effect of siglec-E on CD11b signaling, suggesting that sialic acid recognition by siglec-E is required for its inhibitory function. Siglec-E in neutrophils was constitutively associated with the tyrosine phosphatase SHP-1 and may therefore function to constitutively dampen inflammatory responses of neutrophils. These data reveal that siglec-E is an important negative regulator of neutrophil recruitment to the lung and ß2 integrin–dependent signaling. Our findings have implications for the human functional ortholog, siglec-9, and its potential role in regulating inflammatory lung disease. U2 - 10.1182/blood-2012-08-449983 DO - 10.1182/blood-2012-08-449983 M1 - Article JO - Blood JF - Blood SN - 0006-4971 IS - 11 VL - 121 SP - 2084 EP - 2094 ER - TY - CHAP T1 - Generation of tunable visible picosecond pulses by frequency-doubling of a quantum-dot laser in a PPKTP waveguide A1 - Fedorova,Ksenia A. A1 - Sokolovskii,Grigorii S. A1 - Nikitichev,Daniil I. A1 - Battle,P. R. A1 - Livshits,Daniil A1 - Rafailov,Edik U. AU - Fedorova,Ksenia A. AU - Sokolovskii,Grigorii S. AU - Nikitichev,Daniil I. AU - Battle,P. R. AU - Livshits,Daniil AU - Rafailov,Edik U. PB - SPIE-International Society for Optical Engineering CY - Washington PY - 2013/3/12 Y1 - 2013/3/12 KW - ferroelectric materials KW - Lasers KW - mode locking KW - picosecond phenomena KW - Quantum dots KW - refractive index KW - second harmonic generation KW - waveguides UR - http://proceedings.spiedigitallibrary.org/proceeding.aspx?articleid=1661816 U2 - 10.1117/12.2002869 DO - 10.1117/12.2002869 M1 - Conference contribution SN - 0277-786X VL - 8604 BT - Proceedings SPIE 8604, Nonlinear Frequency Generation and Conversion T2 - Proceedings SPIE 8604, Nonlinear Frequency Generation and Conversion SP - 8604 EP - 8605 ER - TY - JOUR T1 - The Microaerophilic Microbiota of De-Novo Paediatric Inflammatory Bowel Disease T2 - The BISCUIT Study A1 - Hansen,Richard A1 - Berry,Susan H. A1 - Mukhopadhya,Indrani A1 - Thomson,John M. A1 - Saunders,Karin A. A1 - Nicholl,Charlotte E. A1 - Bisset,W. Michael A1 - Loganathan,Sabarinathan A1 - Mahdi,Gamal A1 - Kastner-Cole,Dagmar A1 - Barclay,Andy R. A1 - Bishop,Jon A1 - Flynn,Diana M. A1 - McGrogan,Paraic A1 - Russell,Richard K. A1 - El-Omar,Emad M. A1 - Hold,Georgina L. AU - Hansen,Richard AU - Berry,Susan H. AU - Mukhopadhya,Indrani AU - Thomson,John M. AU - Saunders,Karin A. AU - Nicholl,Charlotte E. AU - Bisset,W. Michael AU - Loganathan,Sabarinathan AU - Mahdi,Gamal AU - Kastner-Cole,Dagmar AU - Barclay,Andy R. AU - Bishop,Jon AU - Flynn,Diana M. AU - McGrogan,Paraic AU - Russell,Richard K. AU - El-Omar,Emad M. AU - Hold,Georgina L. PY - 2013/3/12 Y1 - 2013/3/12 N2 -

Introduction: Children presenting for the first time with inflammatory bowel disease (IBD) offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD.

Patients and Methods: 100 children undergoing colonoscopy were recruited including 44 treatment naive de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis.

Results: 129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates). Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae). No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312).

Conclusions: This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon.

AB -

Introduction: Children presenting for the first time with inflammatory bowel disease (IBD) offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD.

Patients and Methods: 100 children undergoing colonoscopy were recruited including 44 treatment naive de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis.

Results: 129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates). Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae). No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312).

Conclusions: This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon.

KW - COLITIS KW - BILE KW - CHILDREN KW - CROHNS-DISEASE KW - IDENTIFICATION KW - ASSOCIATION KW - POPULATION KW - DIVERSITY KW - CAMPYLOBACTER-CONCISUS KW - PCR U2 - 10.1371/journal.pone.0058825 DO - 10.1371/journal.pone.0058825 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 3 VL - 8 ER - TY - JOUR T1 - Do as eye say T2 - Gaze cueing and language in a real-world social interaction A1 - MacDonald,Ross G. A1 - Tatler,Benjamin W. AU - MacDonald,Ross G. AU - Tatler,Benjamin W. PY - 2013/3/11 Y1 - 2013/3/11 N2 - Gaze cues are important in communication. In social interactions gaze cues usually occur with spoken language, yet most previous research has used artificial paradigms without dialogue. The present study investigates the interaction between gaze and language using a real-world paradigm. Each participant followed instructions to build a series of abstract structures out of building blocks, while their eye movements were recorded. The instructor varied the specificity of the instructions (unambiguous or ambiguous) and the presence of gaze cues (present or absent) between participants. Fixations to the blocks were recorded and task performance was measured. The presence of gaze cues led to more accurate performance, more accurate visual selection of the target block and more fixations towards the instructor when ambiguous instructions were given, but not when unambiguous instructions were given. We conclude that people only utilize the gaze cues of others when the cues provide useful information. AB - Gaze cues are important in communication. In social interactions gaze cues usually occur with spoken language, yet most previous research has used artificial paradigms without dialogue. The present study investigates the interaction between gaze and language using a real-world paradigm. Each participant followed instructions to build a series of abstract structures out of building blocks, while their eye movements were recorded. The instructor varied the specificity of the instructions (unambiguous or ambiguous) and the presence of gaze cues (present or absent) between participants. Fixations to the blocks were recorded and task performance was measured. The presence of gaze cues led to more accurate performance, more accurate visual selection of the target block and more fixations towards the instructor when ambiguous instructions were given, but not when unambiguous instructions were given. We conclude that people only utilize the gaze cues of others when the cues provide useful information. KW - eye movements KW - joint attention KW - spoken language KW - real world KW - social interaction U2 - 10.1167/13.4.6 DO - 10.1167/13.4.6 M1 - Article JO - Journal of Vision JF - Journal of Vision SN - 1534-7362 IS - 4 VL - 13 SP - 1 ER - TY - JOUR T1 - State of play of pharmacogenetics and personalized medicine in heart failure A1 - Parry,Helen M A1 - Doney,Alex Sf A1 - Palmer,Colin Na A1 - Lang,Chim C AU - Parry,Helen M AU - Doney,Alex Sf AU - Palmer,Colin Na AU - Lang,Chim C PY - 2013/3/11 Y1 - 2013/3/11 N2 - Heart failure is a common disease with high levels of morbidity and mortality. A large body of evidence guiding treatment shows prognostic benefit with beta blockers and ACE inhibitors, while diuretics are commonly prescribed for symptomatic benefit. Wide variation in drug response between clinically similar patients is a significant problem. Evidence suggests this may have a genetic component. © 2013 Blackwell Publishing Ltd. AB - Heart failure is a common disease with high levels of morbidity and mortality. A large body of evidence guiding treatment shows prognostic benefit with beta blockers and ACE inhibitors, while diuretics are commonly prescribed for symptomatic benefit. Wide variation in drug response between clinically similar patients is a significant problem. Evidence suggests this may have a genetic component. © 2013 Blackwell Publishing Ltd. U2 - 10.1111/1755-5922.12030 DO - 10.1111/1755-5922.12030 M1 - Article JO - Cardiovascular Therapeutics JF - Cardiovascular Therapeutics ER - TY - JOUR T1 - Analysis of skeletal muscle has potential value in the assessment of cocaine-related deaths A1 - Rees,Kelly A. A1 - Seulin,Saskia A1 - Yonamine,Mauricio A1 - Leyton,Vilma A1 - Munoz,Daniel R. A1 - Gianvecchio,Victor A.P. A1 - Pounder,Derrick J. A1 - Osselton,M.David AU - Rees,Kelly A. AU - Seulin,Saskia AU - Yonamine,Mauricio AU - Leyton,Vilma AU - Munoz,Daniel R. AU - Gianvecchio,Victor A.P. AU - Pounder,Derrick J. AU - Osselton,M.David PY - 2013/3/10 Y1 - 2013/3/10 N2 - This study assesses the interpretive value of cocaine, benzoylecgonine (BZE) and cocaethylene (COET) in skeletal muscle (rectus femoris) in cocaine-using decedents. The distribution of these analytes in cardiac muscle (CM), vitreous humour (VH), femoral blood (FB) and cardiac blood (CB) is also reported. In rectus femoris muscle, the spatial distribution of the analytes was examined across the whole rectus femoris muscle collected from seven fatalities in which cocaine was detected. In six of these cases, death was attributed to trauma and in one case the cause of death was undetermined but suspected to be drug related. In two additional cases analytes were detected in the blood and/or VH but not in the muscle. The muscle was sectioned into 12-15 approximately equal segments, each of which was analysed after homogenisation. Tissue and bio-fluid samples were extracted by solid phase extraction with confirmation and quantification by GC-ion trap-MS/MS. No significant variation was observed in the concentration of any analyte throughout the muscle in the 7 cases analysed. The results reported here are in contrast to a previous study in which great variation in the concentration of some basic drugs (mainly tricyclic antidepressants and benzodiazepines) was observed throughout the thigh muscle bulk (Williams and Pounder, 1997). Analyte concentrations in skeletal muscle (SM) correlated well with those in FB (p <0.01). In general, the concentration of cocaine and COET followed the order VH > CM > SM > FB = CB. Cocaine concentrations measured in VH were significantly higher than in blood and muscle. Inter-matrix variations in the concentrations of BZE and COET were less marked. The concentration of BZE exceeded that of cocaine in all matrices and in all cases except one where the time between death and drug intake was suspected to be short. In this case, the cocaine to BZE ratio measured in SM (2.66), CM (2.91) and VH (2.19) was higher than that measured in FB (0.97). Given that the concentrations of cocaine and its metabolites were uniformly distributed throughout the muscle and considering the good correlation observed between muscle and blood, muscle could be of interpretive value in cocaine related deaths. Further, since cocaine is known to have greater post-mortem stability in muscle than blood, concentrations measured in muscle may reflect more closely those at the time of death and might be of particular value in cases with an extended period between death and tissue sampling. © 2012 Elsevier Ireland Ltd. All rights reserved. AB - This study assesses the interpretive value of cocaine, benzoylecgonine (BZE) and cocaethylene (COET) in skeletal muscle (rectus femoris) in cocaine-using decedents. The distribution of these analytes in cardiac muscle (CM), vitreous humour (VH), femoral blood (FB) and cardiac blood (CB) is also reported. In rectus femoris muscle, the spatial distribution of the analytes was examined across the whole rectus femoris muscle collected from seven fatalities in which cocaine was detected. In six of these cases, death was attributed to trauma and in one case the cause of death was undetermined but suspected to be drug related. In two additional cases analytes were detected in the blood and/or VH but not in the muscle. The muscle was sectioned into 12-15 approximately equal segments, each of which was analysed after homogenisation. Tissue and bio-fluid samples were extracted by solid phase extraction with confirmation and quantification by GC-ion trap-MS/MS. No significant variation was observed in the concentration of any analyte throughout the muscle in the 7 cases analysed. The results reported here are in contrast to a previous study in which great variation in the concentration of some basic drugs (mainly tricyclic antidepressants and benzodiazepines) was observed throughout the thigh muscle bulk (Williams and Pounder, 1997). Analyte concentrations in skeletal muscle (SM) correlated well with those in FB (p <0.01). In general, the concentration of cocaine and COET followed the order VH > CM > SM > FB = CB. Cocaine concentrations measured in VH were significantly higher than in blood and muscle. Inter-matrix variations in the concentrations of BZE and COET were less marked. The concentration of BZE exceeded that of cocaine in all matrices and in all cases except one where the time between death and drug intake was suspected to be short. In this case, the cocaine to BZE ratio measured in SM (2.66), CM (2.91) and VH (2.19) was higher than that measured in FB (0.97). Given that the concentrations of cocaine and its metabolites were uniformly distributed throughout the muscle and considering the good correlation observed between muscle and blood, muscle could be of interpretive value in cocaine related deaths. Further, since cocaine is known to have greater post-mortem stability in muscle than blood, concentrations measured in muscle may reflect more closely those at the time of death and might be of particular value in cases with an extended period between death and tissue sampling. © 2012 Elsevier Ireland Ltd. All rights reserved. KW - Cocaine KW - tissue distribution KW - MUSCLE KW - vitreous KW - Blood KW - post-mortem UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871671448&md5=214ad8964ded6822e19969daaf1dede7 U2 - 10.1016/j.forsciint.2012.12.005 DO - 10.1016/j.forsciint.2012.12.005 M1 - Article JO - Forensic Science International JF - Forensic Science International SN - 0379-0738 IS - 1-3 VL - 226 SP - 46 EP - 53 ER - TY - JOUR T1 - Distribution of opiates in femoral blood and vitreous humour in heroin/morphine-related deaths A1 - Rees,K.A. A1 - Pounder,Derrick J. A1 - Osselton,M.D. AU - Rees,K.A. AU - Pounder,Derrick J. AU - Osselton,M.D. PY - 2013/3/10 Y1 - 2013/3/10 N2 - The distribution of free morphine (FM), codeine and 6-acetylmorphine (6AM) in vitreous humour (VH) and femoral blood (FB) was measured in 70 cases involving heroin/morphine. The relationship between tissue drug concentrations was assessed with respect to case circumstances. Total morphine (TM) concentrations in FB are also reported. The relative concentrations of FM in VH and FB were influenced by survival time. In rapid deaths (3h; n=12) the VH concentration (median 0.15mg/L) was higher than in FB (0.092mg/L; p>.05). Free morphine VH/FB ratios were significantly higher in delayed (median 1.3) compared to rapid deaths (0.64). Although these findings indicate a lag in the distribution of morphine into the VH, overlaps were observed in the VH/FB ratio in rapid and delayed death groups which limits the interpretive use of VH/FB ratios. Codeine and 6AM appeared to distribute more rapidly into the VH. Despite the observation that all opiate analytes were correlated between FB and VH (r=61; p AB - The distribution of free morphine (FM), codeine and 6-acetylmorphine (6AM) in vitreous humour (VH) and femoral blood (FB) was measured in 70 cases involving heroin/morphine. The relationship between tissue drug concentrations was assessed with respect to case circumstances. Total morphine (TM) concentrations in FB are also reported. The relative concentrations of FM in VH and FB were influenced by survival time. In rapid deaths (3h; n=12) the VH concentration (median 0.15mg/L) was higher than in FB (0.092mg/L; p>.05). Free morphine VH/FB ratios were significantly higher in delayed (median 1.3) compared to rapid deaths (0.64). Although these findings indicate a lag in the distribution of morphine into the VH, overlaps were observed in the VH/FB ratio in rapid and delayed death groups which limits the interpretive use of VH/FB ratios. Codeine and 6AM appeared to distribute more rapidly into the VH. Despite the observation that all opiate analytes were correlated between FB and VH (r=61; p UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875634676&md5=d2224f6c5c4f27e890ea056e31f32d30 U2 - 10.1016/j.forsciint.2013.01.002 DO - 10.1016/j.forsciint.2013.01.002 M1 - Article JO - Forensic Science International JF - Forensic Science International SN - 0379-0738 IS - 1-3 VL - 226 SP - 152 EP - 159 ER - TY - JOUR T1 - Obesity and lifestyle advice in colorectal cancer survivors - How well are clinicians prepared? A1 - Anderson,A. S. A1 - Caswell,S. A1 - Wells,M. A1 - Steele,R. J. C. AU - Anderson,A. S. AU - Caswell,S. AU - Wells,M. AU - Steele,R. J. C. PY - 2013/3/9 Y1 - 2013/3/9 N2 -

Aim: This study aimed to assess colorectal clinicians' knowledge and understanding about the risks and benefits of weight management, to document current practice and to identify perceived barriers to providing lifestyle advice to colorectal cancer survivors

Methods: Questionnaires were sent to 768 clinicians (doctors and nurses) working in colorectal cancer, identified from professional databases. These data were complemented by in-depth interviews exploring opportunities and barriers to giving lifestyle advice.

Results: A total of 323 replies were received (42% response rate) and twenty respondents completed in-depth interviews. Half (52%) reported they were familiar with guidance for lifestyle advice for cancer survivors. Most (77%) thought reducing weight was important for improving the health of those who were overweight and 75% thought it appropriate to offer lifestyle advice to people with body mass index (BMI) over 30kg/m2. Half (50%) reported that weight reduction was an important service priority for normal clinical practice Half (50%) of respondents said that they would value additional training in this area. Interview data revealed that current practice is influenced by the lack of evidence for the impact of weight management, and a belief that "weight gain is good and weight loss bad" in the cancer setting. Patient sensitivity, time available, role constraints and lack of skills in weight management were also factors.

Conclusion: There is an awareness of the importance of weight management amongst colorectal clinicians and some indication of advice being provided. However, current perceptions, knowledge and skills suggest scope for further training.

© 2013 The Authors. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.

AB -

Aim: This study aimed to assess colorectal clinicians' knowledge and understanding about the risks and benefits of weight management, to document current practice and to identify perceived barriers to providing lifestyle advice to colorectal cancer survivors

Methods: Questionnaires were sent to 768 clinicians (doctors and nurses) working in colorectal cancer, identified from professional databases. These data were complemented by in-depth interviews exploring opportunities and barriers to giving lifestyle advice.

Results: A total of 323 replies were received (42% response rate) and twenty respondents completed in-depth interviews. Half (52%) reported they were familiar with guidance for lifestyle advice for cancer survivors. Most (77%) thought reducing weight was important for improving the health of those who were overweight and 75% thought it appropriate to offer lifestyle advice to people with body mass index (BMI) over 30kg/m2. Half (50%) reported that weight reduction was an important service priority for normal clinical practice Half (50%) of respondents said that they would value additional training in this area. Interview data revealed that current practice is influenced by the lack of evidence for the impact of weight management, and a belief that "weight gain is good and weight loss bad" in the cancer setting. Patient sensitivity, time available, role constraints and lack of skills in weight management were also factors.

Conclusion: There is an awareness of the importance of weight management amongst colorectal clinicians and some indication of advice being provided. However, current perceptions, knowledge and skills suggest scope for further training.

© 2013 The Authors. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.

U2 - 10.1111/codi.12203 DO - 10.1111/codi.12203 M1 - Article JO - Colorectal Disease JF - Colorectal Disease ER - TY - JOUR T1 - Incompatible effects of p53 and HDAC inhibition on p21 expression and cell cycle progression A1 - Sachweh,M.C.C. A1 - Drummond,C.J. A1 - Higgins,M. A1 - Campbell,J. A1 - Lain,S. AU - Sachweh,M.C.C. AU - Drummond,C.J. AU - Higgins,M. AU - Campbell,J. AU - Lain,S. PY - 2013/3/7 Y1 - 2013/3/7 N2 - Nutlin-3 selectively activates p53 by inhibiting the interaction of this tumor suppressor with its negative regulator murine double minute 2 (mdm2), while trichostatin A (TSA) is one of the most potent histone deacetylase (HDAC) inhibitors currently available. As both Nutlin-3 and TSA increase the levels of the cell cycle inhibitor p21(cip1/waf1) in cells, we investigated whether a combination of these compounds would further augment p21 levels. Contrary to expectations, we found that short-term exposure to Nutlin-3 and TSA in combination did not have an additive effect on p21 expression. Instead, we observed that activation of p53 prevented the ability of TSA to increase p21 levels. Furthermore, TSA inhibited Nutlin-3-induced expression of p53-dependent mRNAs including P21. This negative effect of TSA on Nutlin-3 was significantly less pronounced in the case of hdm2, another p53 downstream target. Aside from suggesting a model to explain these incompatible effects of Nutlin-3 and TSA, we discuss the implications of our findings in cancer therapy and cell reprogramming. © 2013 Macmillan Publishers Limited. AB - Nutlin-3 selectively activates p53 by inhibiting the interaction of this tumor suppressor with its negative regulator murine double minute 2 (mdm2), while trichostatin A (TSA) is one of the most potent histone deacetylase (HDAC) inhibitors currently available. As both Nutlin-3 and TSA increase the levels of the cell cycle inhibitor p21(cip1/waf1) in cells, we investigated whether a combination of these compounds would further augment p21 levels. Contrary to expectations, we found that short-term exposure to Nutlin-3 and TSA in combination did not have an additive effect on p21 expression. Instead, we observed that activation of p53 prevented the ability of TSA to increase p21 levels. Furthermore, TSA inhibited Nutlin-3-induced expression of p53-dependent mRNAs including P21. This negative effect of TSA on Nutlin-3 was significantly less pronounced in the case of hdm2, another p53 downstream target. Aside from suggesting a model to explain these incompatible effects of Nutlin-3 and TSA, we discuss the implications of our findings in cancer therapy and cell reprogramming. © 2013 Macmillan Publishers Limited. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875874820&md5=90b264c314c3a5297909175fcb7329d4 U2 - 10.1038/cddis.2013.61 DO - 10.1038/cddis.2013.61 M1 - Article JO - Cell Death and Disease JF - Cell Death and Disease SN - 2041-4889 VL - 4 ER - TY - JOUR T1 - Termination of pregnancy T2 - The 'conscientious objection' clause A1 - Symon,Andrew AU - Symon,Andrew PY - 2013/3/7 Y1 - 2013/3/7 N2 - Termination of pregnancy [TOP] is one of the most sensitive and divisive issues in health care. Two senior midwives in Scotland have lodged an appeal against the ruling given in a court action last year concerning participation in this procedure (Dabrowski, 2013). AB - Termination of pregnancy [TOP] is one of the most sensitive and divisive issues in health care. Two senior midwives in Scotland have lodged an appeal against the ruling given in a court action last year concerning participation in this procedure (Dabrowski, 2013). UR - http://www.intermid.co.uk/cgi-bin/go.pl/library/abstract.html?uid=97383 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875135627&md5=ebe3962f8b4187c4117d49aeba8a2297 M1 - Article JO - British Journal of Midwifery JF - British Journal of Midwifery SN - 0969-4900 IS - 3 VL - 21 SP - 221 EP - 222 ER - TY - JOUR T1 - The effect of interstitial pressure on tumor growth T2 - Coupling with the blood and lymphatic vascular systems A1 - Wu,M. A1 - Frieboes,H.B. A1 - McDougall,S.R. A1 - Chaplain,Mark A.J. A1 - Cristini,Vittorio A1 - Lowengrub,J. AU - Wu,M. AU - Frieboes,H.B. AU - McDougall,S.R. AU - Chaplain,Mark A.J. AU - Cristini,Vittorio AU - Lowengrub,J. PY - 2013/3/7 Y1 - 2013/3/7 N2 - The flow of interstitial fluid and the associated interstitial fluid pressure (IFP) in solid tumors and surrounding host tissues have been identified as critical elements in cancer growth and vascularization. Both experimental and theoretical studies have shown that tumors may present elevated IFP, which can be a formidable physical barrier for delivery of cell nutrients and small molecules into the tumor. Elevated IFP may also exacerbate gradients of biochemical signals such as angiogenic factors released by tumors into the surrounding tissues. These studies have helped to understand both biochemical signaling and treatment prognosis. Building upon previous work, here we develop a vascular tumor growth model by coupling a continuous growth model with a discrete angiogenesis model. We include fluid/oxygen extravasation as well as a continuous lymphatic field, and study the micro-environmental fluid dynamics and their effect on tumor growth by accounting for blood flow, transcapillary fluid flux, interstitial fluid flow, and lymphatic drainage. We thus elucidate further the non-trivial relationship between the key elements contributing to the effects of interstitial pressure in solid tumors. In particular, we study the effect of IFP on oxygen extravasation and show that small blood/lymphatic vessel resistance and collapse may contribute to lower transcapillary fluid/oxygen flux, thus decreasing the rate of tumor growth. We also investigate the effect of tumor vascular pathologies, including elevated vascular and interstitial hydraulic conductivities inside the tumor as well as diminished osmotic pressure differences, on the fluid flow across the tumor capillary bed, the lymphatic drainage, and the IFP. Our results reveal that elevated interstitial hydraulic conductivity together with poor lymphatic function is the root cause of the development of plateau profiles of the IFP in the tumor, which have been observed in experiments, and contributes to a more uniform distribution of oxygen, solid tumor pressure and a broad-based collapse of the tumor lymphatics. We also find that the rate that IFF is fluxed into the lymphatics and host tissue is largely controlled by an elevated vascular hydraulic conductivity in the tumor. We discuss the implications of these results on microenvironmental transport barriers, and the tumor invasive and metastatic potential. Our results suggest the possibility of developing strategies of targeting tumor cells based on the cues in the interstitial fluid. © 2012 Elsevier Ltd. AB - The flow of interstitial fluid and the associated interstitial fluid pressure (IFP) in solid tumors and surrounding host tissues have been identified as critical elements in cancer growth and vascularization. Both experimental and theoretical studies have shown that tumors may present elevated IFP, which can be a formidable physical barrier for delivery of cell nutrients and small molecules into the tumor. Elevated IFP may also exacerbate gradients of biochemical signals such as angiogenic factors released by tumors into the surrounding tissues. These studies have helped to understand both biochemical signaling and treatment prognosis. Building upon previous work, here we develop a vascular tumor growth model by coupling a continuous growth model with a discrete angiogenesis model. We include fluid/oxygen extravasation as well as a continuous lymphatic field, and study the micro-environmental fluid dynamics and their effect on tumor growth by accounting for blood flow, transcapillary fluid flux, interstitial fluid flow, and lymphatic drainage. We thus elucidate further the non-trivial relationship between the key elements contributing to the effects of interstitial pressure in solid tumors. In particular, we study the effect of IFP on oxygen extravasation and show that small blood/lymphatic vessel resistance and collapse may contribute to lower transcapillary fluid/oxygen flux, thus decreasing the rate of tumor growth. We also investigate the effect of tumor vascular pathologies, including elevated vascular and interstitial hydraulic conductivities inside the tumor as well as diminished osmotic pressure differences, on the fluid flow across the tumor capillary bed, the lymphatic drainage, and the IFP. Our results reveal that elevated interstitial hydraulic conductivity together with poor lymphatic function is the root cause of the development of plateau profiles of the IFP in the tumor, which have been observed in experiments, and contributes to a more uniform distribution of oxygen, solid tumor pressure and a broad-based collapse of the tumor lymphatics. We also find that the rate that IFF is fluxed into the lymphatics and host tissue is largely controlled by an elevated vascular hydraulic conductivity in the tumor. We discuss the implications of these results on microenvironmental transport barriers, and the tumor invasive and metastatic potential. Our results suggest the possibility of developing strategies of targeting tumor cells based on the cues in the interstitial fluid. © 2012 Elsevier Ltd. KW - Vascular growth KW - Angiogenesis KW - Microenvironmental transport barriers KW - interstitual fluid flow UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872477242&md5=417ac8a5e54b9daa23577c5bb9f4ec43 U2 - 10.1016/j.jtbi.2012.11.031 DO - 10.1016/j.jtbi.2012.11.031 M1 - Article JO - Journal of Theoretical Biology JF - Journal of Theoretical Biology SN - 0022-5193 VL - 320 SP - 131 EP - 151 ER - TY - JOUR T1 - High-Dose Allopurinol reduces left ventricular mass in patients with ischemic heart disease A1 - Rekhraj,Sushma A1 - Gandy,Stephen J. A1 - Szwejkowski,Benjamin R. A1 - Nadir,M. Adnan A1 - Noman,Awsan A1 - Houston,Graeme A1 - Lang,Chim C. A1 - George,Jacob A1 - Struthers,Allan D. AU - Rekhraj,Sushma AU - Gandy,Stephen J. AU - Szwejkowski,Benjamin R. AU - Nadir,M. Adnan AU - Noman,Awsan AU - Houston,Graeme AU - Lang,Chim C. AU - George,Jacob AU - Struthers,Allan D. PY - 2013/3/5 Y1 - 2013/3/5 N2 - Objectives This study sought to ascertain if high-dose allopurinol regresses left ventricular mass (LVM) in patients with ischemic heart disease (IHD).
Background LV hypertrophy (LVH) is common in patients with IHD including normotensive patients. Allopurinol, a xanthine oxidase inhibitor, has been shown to reduce LV afterload in IHD and may therefore also regress LVH.
Methods A randomized, double-blind, placebo-controlled, parallel group study was conducted in 66 patients with IHD and LVH, comparing 600 mg/day allopurinol versus placebo therapy for 9 months. The primary outcome measure was change in LVM, assessed by cardiac magnetic resonance imaging (CMR). Secondary outcome measures were changes in LV volumes by CMR, changes in endothelial function by flow-mediated dilation (FMD), and arterial stiffness by applanation tonometry.
Results Compared to placebo, allopurinol significantly reduced LVM (allopurinol _5.2 _ 5.8 g vs. placebo _1.3 _ 4.48 g; p _ 0.007) and LVM index (LVMI) (allopurinol _2.2 _ 2.78 g/m2 vs. placebo _0.53 _ 2.5 g/m2; p _ 0.023). The absolute mean difference between groups for change in LVM and LVMI was _3.89 g (95% confidence interval: _1.1 to _6.7) and _1.67 g/m2 (95% confidence interval: _0.23 to _3.1), respectively. Allopurinol also reduced LV endsystolic volume (allopurinol _2.81 _ 7.8 mls vs. placebo _1.3 _ 7.22 mls; p _ 0.047), improved FMD (allopurinol _0.82% _ 1.8% vs. placebo _0.69% _ 2.8%; p _ 0.017) and augmentation index (allopurinol _2.8 _ 5.1% vs. placebo _0.9 _ 7%; p _ 0.02).
Conclusions High-dose allopurinol regresses LVH, reduces LV end-systolic volume, and improves endothelial function in patients with IHD and LVH. This raises the possibility that allopurinol might reduce future cardiovascular events and mortality in these patients. (Does a Drug Allopurinol Reduce Heart Muscle Mass and Improve Blood Vessel Function in Patients With Normal Blood Pressure and Stable Angina
AB - Objectives This study sought to ascertain if high-dose allopurinol regresses left ventricular mass (LVM) in patients with ischemic heart disease (IHD).
Background LV hypertrophy (LVH) is common in patients with IHD including normotensive patients. Allopurinol, a xanthine oxidase inhibitor, has been shown to reduce LV afterload in IHD and may therefore also regress LVH.
Methods A randomized, double-blind, placebo-controlled, parallel group study was conducted in 66 patients with IHD and LVH, comparing 600 mg/day allopurinol versus placebo therapy for 9 months. The primary outcome measure was change in LVM, assessed by cardiac magnetic resonance imaging (CMR). Secondary outcome measures were changes in LV volumes by CMR, changes in endothelial function by flow-mediated dilation (FMD), and arterial stiffness by applanation tonometry.
Results Compared to placebo, allopurinol significantly reduced LVM (allopurinol _5.2 _ 5.8 g vs. placebo _1.3 _ 4.48 g; p _ 0.007) and LVM index (LVMI) (allopurinol _2.2 _ 2.78 g/m2 vs. placebo _0.53 _ 2.5 g/m2; p _ 0.023). The absolute mean difference between groups for change in LVM and LVMI was _3.89 g (95% confidence interval: _1.1 to _6.7) and _1.67 g/m2 (95% confidence interval: _0.23 to _3.1), respectively. Allopurinol also reduced LV endsystolic volume (allopurinol _2.81 _ 7.8 mls vs. placebo _1.3 _ 7.22 mls; p _ 0.047), improved FMD (allopurinol _0.82% _ 1.8% vs. placebo _0.69% _ 2.8%; p _ 0.017) and augmentation index (allopurinol _2.8 _ 5.1% vs. placebo _0.9 _ 7%; p _ 0.02).
Conclusions High-dose allopurinol regresses LVH, reduces LV end-systolic volume, and improves endothelial function in patients with IHD and LVH. This raises the possibility that allopurinol might reduce future cardiovascular events and mortality in these patients. (Does a Drug Allopurinol Reduce Heart Muscle Mass and Improve Blood Vessel Function in Patients With Normal Blood Pressure and Stable Angina
KW - Allopurinol KW - Ischemic heart disease KW - Oxidative stress KW - Ventricular hypertrophy U2 - 10.1016/j.jacc.2012.09.066 DO - 10.1016/j.jacc.2012.09.066 M1 - Article JO - Journal of the American College of Cardiology JF - Journal of the American College of Cardiology SN - 0735-1097 IS - 9 VL - 61 SP - 926 EP - 932 ER - TY - JOUR T1 - Regulation of A20 and other OTU deubiquitinases by reversible oxidation A1 - Kulathu,Yogesh A1 - Garcia,F.J. A1 - Mevissen,T.E.T. A1 - Busch,M. A1 - Arnaudo,N. A1 - Carroll,K.S. A1 - Barford,D. A1 - Komander,D. AU - Kulathu,Yogesh AU - Garcia,F.J. AU - Mevissen,T.E.T. AU - Busch,M. AU - Arnaudo,N. AU - Carroll,K.S. AU - Barford,D. AU - Komander,D. PY - 2013/3/5 Y1 - 2013/3/5 N2 - Protein ubiquitination is a highly versatile post-translational modification that regulates as diverse processes as protein degradation and kinase activation. Deubiquitinases hydrolyse ubiquitin modifications from proteins and are hence key regulators of the ubiquitin system. Ovarian tumour deubiquitinases comprise a family of fourteen human enzymes, many of which regulate cellular signalling pathways. Ovarian tumour deubiquitinases are cysteine proteases that cleave polyubiquitin chains in vitro and in cells, but little is currently known about their regulation. Here we show that ovarian tumour deubiquitinases are susceptible to reversible oxidation of the catalytic cysteine residue. High-resolution crystal structures of the catalytic domain of A0 in four different oxidation states reveal that the reversible form of A0 oxidation is a cysteine sulphenic acid intermediate, which is stabilised by the architecture of the catalytic centre. Using chemical tools to detect sulphenic acid intermediates, we show that many ovarian tumour deubiquitinases undergo reversible oxidation upon treatment with H O , revealing a new mechanism to regulate deubiquitinase activity. © 2013 Macmillan Publishers Limited. All rights reserved. AB - Protein ubiquitination is a highly versatile post-translational modification that regulates as diverse processes as protein degradation and kinase activation. Deubiquitinases hydrolyse ubiquitin modifications from proteins and are hence key regulators of the ubiquitin system. Ovarian tumour deubiquitinases comprise a family of fourteen human enzymes, many of which regulate cellular signalling pathways. Ovarian tumour deubiquitinases are cysteine proteases that cleave polyubiquitin chains in vitro and in cells, but little is currently known about their regulation. Here we show that ovarian tumour deubiquitinases are susceptible to reversible oxidation of the catalytic cysteine residue. High-resolution crystal structures of the catalytic domain of A0 in four different oxidation states reveal that the reversible form of A0 oxidation is a cysteine sulphenic acid intermediate, which is stabilised by the architecture of the catalytic centre. Using chemical tools to detect sulphenic acid intermediates, we show that many ovarian tumour deubiquitinases undergo reversible oxidation upon treatment with H O , revealing a new mechanism to regulate deubiquitinase activity. © 2013 Macmillan Publishers Limited. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875886251&md5=372a8f21c438de492215db039b697d06 U2 - 10.1038/ncomms2567 DO - 10.1038/ncomms2567 M1 - Article JO - Nature Communications JF - Nature Communications SN - 2041-1723 VL - 4 ER - TY - JOUR T1 - Characterisation of a pre-export enzyme-chaperone complex on the twin-arginine transport pathway A1 - Dow,Jennifer M A1 - Gabel,Frank A1 - Sargent,Frank A1 - Palmer,Tracy AU - Dow,Jennifer M AU - Gabel,Frank AU - Sargent,Frank AU - Palmer,Tracy PY - 2013/3/1 Y1 - 2013/3/1 N2 - The twin-arginine translocation (Tat) system is a protein targeting pathway utilised by prokaryotes and chloroplasts. Tat substrates are produced with distinctive N-terminal signal peptides and are translocated as fully folded proteins. In Escherichia coli Tat-dependent proteins often contain redox cofactors that must be loaded before translocation. Trimethylamine N-oxide reductase (TorA) is a model bacterial Tat substrate and is a molybdenum cofactor-dependent enzyme. Co-ordination of cofactor loading and translocation of TorA is directed by the TorD protein, which is a cytoplasmic chaperone known to physically interact with the TorA signal peptide. In this work, a pre-export TorAD complex has been characterised using biochemical and biophysical techniques, including SAXS. A stable, cofactor-free TorAD complex was isolated, which revealed a 1:1 binding stoichiometry. Surprisingly, a TorAD complex with similar architecture can be isolated in the complete absence of the 39-residue TorA signal peptide. This work demonstrates that two high-affinity binding sites for TorD are present on TorA, and that a single TorD protein binds both of those simultaneously. Further characterisation suggested that the C-terminal 'Domain IV' of TorA remained solvent-exposed in the cofactor-free pre-export TorAD complex. It is possible that correct folding of Domain IV upon cofactor loading is the trigger for TorD release and subsequent export of TorA. AB - The twin-arginine translocation (Tat) system is a protein targeting pathway utilised by prokaryotes and chloroplasts. Tat substrates are produced with distinctive N-terminal signal peptides and are translocated as fully folded proteins. In Escherichia coli Tat-dependent proteins often contain redox cofactors that must be loaded before translocation. Trimethylamine N-oxide reductase (TorA) is a model bacterial Tat substrate and is a molybdenum cofactor-dependent enzyme. Co-ordination of cofactor loading and translocation of TorA is directed by the TorD protein, which is a cytoplasmic chaperone known to physically interact with the TorA signal peptide. In this work, a pre-export TorAD complex has been characterised using biochemical and biophysical techniques, including SAXS. A stable, cofactor-free TorAD complex was isolated, which revealed a 1:1 binding stoichiometry. Surprisingly, a TorAD complex with similar architecture can be isolated in the complete absence of the 39-residue TorA signal peptide. This work demonstrates that two high-affinity binding sites for TorD are present on TorA, and that a single TorD protein binds both of those simultaneously. Further characterisation suggested that the C-terminal 'Domain IV' of TorA remained solvent-exposed in the cofactor-free pre-export TorAD complex. It is possible that correct folding of Domain IV upon cofactor loading is the trigger for TorD release and subsequent export of TorA. U2 - 10.1042/BJ20121832 DO - 10.1042/BJ20121832 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 ER - TY - JOUR T1 - Knowledge exchange T2 - a review and research agenda for environmental management A1 - Fazey,Ioan A1 - Evely,Anna C. A1 - Reed,Mark S. A1 - Stringer,Lindsay C. A1 - Kruijsen,Joanneke A1 - White,Piran C. L. A1 - Newsham,Andrew A1 - Jin,Lixian A1 - Cortazzi,Martin A1 - Phillipson,Jeremy A1 - Blackstock,Kirsty A1 - Entwistle,Noel A1 - Sheate,William A1 - Armstrong,Fiona A1 - Blackmore,Chris A1 - Fazey,John A1 - Ingram,Julie A1 - Gregson,Jon A1 - Lowe,Philip A1 - Morton,Sarah A1 - Trevitt,Chris AU - Fazey,Ioan AU - Evely,Anna C. AU - Reed,Mark S. AU - Stringer,Lindsay C. AU - Kruijsen,Joanneke AU - White,Piran C. L. AU - Newsham,Andrew AU - Jin,Lixian AU - Cortazzi,Martin AU - Phillipson,Jeremy AU - Blackstock,Kirsty AU - Entwistle,Noel AU - Sheate,William AU - Armstrong,Fiona AU - Blackmore,Chris AU - Fazey,John AU - Ingram,Julie AU - Gregson,Jon AU - Lowe,Philip AU - Morton,Sarah AU - Trevitt,Chris PY - 2013/3/1 Y1 - 2013/3/1 N2 - There is increasing emphasis on the need for effective ways of sharing knowledge to enhance environmental management and sustainability. Knowledge exchange (KE) are processes that generate, share and/or use knowledge through various methods appropriate to the context, purpose, and participants involved. KE includes concepts such as sharing, generation, coproduction, comanagement, and brokerage of knowledge. This paper elicits the expert knowledge of academics involved in research and practice of KE from different disciplines and backgrounds to review research themes, identify gaps and questions, and develop a research agenda for furthering understanding about KE. Results include 80 research questions prefaced by a review of research themes. Key conclusions are: (1) there is a diverse range of questions relating to KE that require attention; (2) there is a particular need for research on understanding the process of KE and how KE can be evaluated; and (3) given the strong interdependency of research questions, an integrated approach to understanding KE is required. To improve understanding of KE, action research methodologies and embedding evaluation as a normal part of KE research and practice need to be encouraged. This will foster more adaptive approaches to learning about KE and enhance effectiveness of environmental management. © 2012 Foundation for Environmental Conservation. AB - There is increasing emphasis on the need for effective ways of sharing knowledge to enhance environmental management and sustainability. Knowledge exchange (KE) are processes that generate, share and/or use knowledge through various methods appropriate to the context, purpose, and participants involved. KE includes concepts such as sharing, generation, coproduction, comanagement, and brokerage of knowledge. This paper elicits the expert knowledge of academics involved in research and practice of KE from different disciplines and backgrounds to review research themes, identify gaps and questions, and develop a research agenda for furthering understanding about KE. Results include 80 research questions prefaced by a review of research themes. Key conclusions are: (1) there is a diverse range of questions relating to KE that require attention; (2) there is a particular need for research on understanding the process of KE and how KE can be evaluated; and (3) given the strong interdependency of research questions, an integrated approach to understanding KE is required. To improve understanding of KE, action research methodologies and embedding evaluation as a normal part of KE research and practice need to be encouraged. This will foster more adaptive approaches to learning about KE and enhance effectiveness of environmental management. © 2012 Foundation for Environmental Conservation. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84873327282&md5=cbf1d2fd9bcf8693c0a4a61a4b267469 U2 - 10.1017/S037689291200029X DO - 10.1017/S037689291200029X M1 - Article JO - Environmental Conservation JF - Environmental Conservation SN - 0376-8929 IS - 1 VL - 40 SP - 19 EP - 36 ER - TY - JOUR T1 - Postcolonial print cultures A1 - Brouillette,Sarah A1 - Finkelstein,David AU - Brouillette,Sarah AU - Finkelstein,David PY - 2013/3/1 Y1 - 2013/3/1 N2 - This article provides an overview of the contributions to a special issue on "Postcolonial Print Cultures". © The Author(s) 2013. AB - This article provides an overview of the contributions to a special issue on "Postcolonial Print Cultures". © The Author(s) 2013. KW - print culture, postcolonial literature UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875832575&md5=c504ce8132e6c27fea1981fc1ffd38a3 U2 - 10.1177/0021989412470944 DO - 10.1177/0021989412470944 M1 - Special issue JO - Journal of Commonwealth Literature JF - Journal of Commonwealth Literature SN - 0021-9894 IS - 1 VL - 48 SP - 3 EP - 7 ER - TY - JOUR T1 - Proteasomal degradation of herpes simplex virus capsids in macrophages releases DNA to the cytosol for recognition by DNA sensors A1 - Horan,Kristy A. A1 - Hansen,Kathrine A1 - Jakobsen,Martin R. A1 - Holm,Christian K. A1 - Søby,Stine A1 - Unterholzner,Leonie A1 - Thompson,Mikayla A1 - West,John A. A1 - Iversen,Marie B. A1 - Rasmussen,Simon B. A1 - Ellermann-Eriksen,Svend A1 - Kurt-Jones,Evelyn A1 - Landolfo,Santo A1 - Damania,Blossom A1 - Melchjorsen,Jesper A1 - Bowie,Andrew G. A1 - Fitzgerald,Katherine A. A1 - Paludan,Søren R. AU - Horan,Kristy A. AU - Hansen,Kathrine AU - Jakobsen,Martin R. AU - Holm,Christian K. AU - Søby,Stine AU - Unterholzner,Leonie AU - Thompson,Mikayla AU - West,John A. AU - Iversen,Marie B. AU - Rasmussen,Simon B. AU - Ellermann-Eriksen,Svend AU - Kurt-Jones,Evelyn AU - Landolfo,Santo AU - Damania,Blossom AU - Melchjorsen,Jesper AU - Bowie,Andrew G. AU - Fitzgerald,Katherine A. AU - Paludan,Søren R. PY - 2013/3/1 Y1 - 2013/3/1 N2 - The innate immune system is important for control of infections, including herpesvirus infections. Intracellular DNA potently stimulates antiviral IFN responses. It is known that plasmacytoid dendritic cells sense herpesvirus DNA in endosomes via TLR9 and that nonimmune tissue cells can sense herpesvirus DNA in the nucleus. However, it remains unknown how and where myeloid cells, such as macrophages and conventional dendritic cells, detect infections with herpesviruses. In this study, we demonstrate that the HSV-1 capsid was ubiquitinated in the cytosol and degraded by the proteasome, hence releasing genomic DNA into the cytoplasm for detection by DNA sensors. In this context, the DNA sensor IFN-?-inducible 16 is important for induction of IFN-ß in human macrophages postinfection with HSV-1 and CMV. Viral DNA localized to the same cytoplasmic regions as did IFN-?-inducible 16, with DNA sensing being independent of viral nuclear entry. Thus, proteasomal degradation of herpesvirus capsids releases DNA to the cytoplasm for recognition by DNA sensors. AB - The innate immune system is important for control of infections, including herpesvirus infections. Intracellular DNA potently stimulates antiviral IFN responses. It is known that plasmacytoid dendritic cells sense herpesvirus DNA in endosomes via TLR9 and that nonimmune tissue cells can sense herpesvirus DNA in the nucleus. However, it remains unknown how and where myeloid cells, such as macrophages and conventional dendritic cells, detect infections with herpesviruses. In this study, we demonstrate that the HSV-1 capsid was ubiquitinated in the cytosol and degraded by the proteasome, hence releasing genomic DNA into the cytoplasm for detection by DNA sensors. In this context, the DNA sensor IFN-?-inducible 16 is important for induction of IFN-ß in human macrophages postinfection with HSV-1 and CMV. Viral DNA localized to the same cytoplasmic regions as did IFN-?-inducible 16, with DNA sensing being independent of viral nuclear entry. Thus, proteasomal degradation of herpesvirus capsids releases DNA to the cytoplasm for recognition by DNA sensors. U2 - 10.4049/jimmunol.1202749 DO - 10.4049/jimmunol.1202749 M1 - Article JO - Journal of Immunology JF - Journal of Immunology SN - 0022-1767 IS - 5 VL - 190 SP - 2311 EP - 2319 ER - TY - JOUR T1 - A Multi-disciplinary Approach to the Archaeological Investigation of a Bedrock-Dominated Shallow-Marine Landscape T2 - An example from the Bay of Firth, Orkney, UK A1 - Bates,Martin R. A1 - Nayling,Nigel A1 - Bates,Richard A1 - Dawson,Sue A1 - Huws,Dei A1 - Wickham-Jones,Caroline AU - Bates,Martin R. AU - Nayling,Nigel AU - Bates,Richard AU - Dawson,Sue AU - Huws,Dei AU - Wickham-Jones,Caroline PY - 2013/3 Y1 - 2013/3 N2 - Investigation of shallow-marine environments for submerged prehistoric archaeology can be hampered in many localities by extensive bedrock exposure and thus limited preservation potential. Using the concept of 'seamless archaeology' where land-based archaeology is integrated across the intertidal zone through to the offshore, a multi-disciplinary approach is essential. This approach taken in the Bay of Firth, Orkney uses geophysics, historical archive and ethno-archaeology, coastal geomorphology, palaeo-environmental analyses and sea-level science, and allows a clearer understanding of the landscape in which prehistoric settlers lived. While acknowledging the limitations of the preserved environment, we are successful in identifying areas of archaeological potential on the sea-bed for both upstanding structural elements as well as sediment preservation that contains evidence for human occupation. This has wider implications beyond Orkney's World Heritage sites to provide a blueprint for similar studies elsewhere in the coastal zone. © 2012 The Nautical Archaeology Society. AB - Investigation of shallow-marine environments for submerged prehistoric archaeology can be hampered in many localities by extensive bedrock exposure and thus limited preservation potential. Using the concept of 'seamless archaeology' where land-based archaeology is integrated across the intertidal zone through to the offshore, a multi-disciplinary approach is essential. This approach taken in the Bay of Firth, Orkney uses geophysics, historical archive and ethno-archaeology, coastal geomorphology, palaeo-environmental analyses and sea-level science, and allows a clearer understanding of the landscape in which prehistoric settlers lived. While acknowledging the limitations of the preserved environment, we are successful in identifying areas of archaeological potential on the sea-bed for both upstanding structural elements as well as sediment preservation that contains evidence for human occupation. This has wider implications beyond Orkney's World Heritage sites to provide a blueprint for similar studies elsewhere in the coastal zone. © 2012 The Nautical Archaeology Society. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84873253401&md5=fa44c6a86db0062fb082bc947be504c0 U2 - 10.1111/j.1095-9270.2012.00360.x DO - 10.1111/j.1095-9270.2012.00360.x M1 - Article JO - International Journal of Nautical Archaeology JF - International Journal of Nautical Archaeology SN - 1057-2414 IS - 1 VL - 42 SP - 24 EP - 43 ER - TY - JOUR T1 - A Pliocene age and origin for the strandflat of the Western Isles of Scotland: T2 - a speculative hypothesis. A1 - Dawson,Alastair G. A1 - Dawson,Sue A1 - Cooper,J. Andrew G. A1 - Gemmell,Alastair A1 - Bates,Richard AU - Dawson,Alastair G. AU - Dawson,Sue AU - Cooper,J. Andrew G. AU - Gemmell,Alastair AU - Bates,Richard PY - 2013/3 Y1 - 2013/3 N2 - A series of very wide (up to 15 km) raised shore platforms in the Scottish Hebrides are identified and described for the first time and are considered part of a high rock platform shoreline in the western isles of Scotland described by W. B. Wright in his classic Geological Magazine paper a century ago as a ‘preglacial’ feature. Subsequent interpretations suggesting that the platforms were produced during the Pleistocene are rejected here in favour of a speculative hypothesis that the features are part of the well-known strandflat that is extensively developed across large areas of the northern hemisphere. It is argued that the Scottish strandflat developed during the Pliocene and was later subjected to extensive Pleistocene glacial erosion such that only a few areas of platform have survived in the Scottish Inner Hebrides (ice-proximal) while they are well-preserved in the Outer Hebrides (ice-distal). Support for a Pliocene hypothesis is provided by the marine oxygen isotope record for this time interval which points to prolonged periods of relative sea level stability as would be required for the production of such wide features. This hypothesis for the formation of a Scottish strandflat not only provides an elegant explanation for the origin and age of the raised rock platform fragments that occur throughout the western isles of Scotland, but it may also have relevance for other coastal areas of the northern hemisphere (e.g. Norway, Greenland, Alaska) where the strandflat is a well-developed feature. AB - A series of very wide (up to 15 km) raised shore platforms in the Scottish Hebrides are identified and described for the first time and are considered part of a high rock platform shoreline in the western isles of Scotland described by W. B. Wright in his classic Geological Magazine paper a century ago as a ‘preglacial’ feature. Subsequent interpretations suggesting that the platforms were produced during the Pleistocene are rejected here in favour of a speculative hypothesis that the features are part of the well-known strandflat that is extensively developed across large areas of the northern hemisphere. It is argued that the Scottish strandflat developed during the Pliocene and was later subjected to extensive Pleistocene glacial erosion such that only a few areas of platform have survived in the Scottish Inner Hebrides (ice-proximal) while they are well-preserved in the Outer Hebrides (ice-distal). Support for a Pliocene hypothesis is provided by the marine oxygen isotope record for this time interval which points to prolonged periods of relative sea level stability as would be required for the production of such wide features. This hypothesis for the formation of a Scottish strandflat not only provides an elegant explanation for the origin and age of the raised rock platform fragments that occur throughout the western isles of Scotland, but it may also have relevance for other coastal areas of the northern hemisphere (e.g. Norway, Greenland, Alaska) where the strandflat is a well-developed feature. KW - coastal rock paltform KW - sea level change KW - Glacio-isostasy KW - Pleistocene KW - Pliocene KW - eustasy KW - glaciations U2 - 10.1017/S0016756812000568 DO - 10.1017/S0016756812000568 M1 - Article JO - Geological Magazine JF - Geological Magazine IS - 2 VL - 150 SP - 360 EP - 366 ER - TY - JOUR T1 - Adrenal suppression with fluticasone furoate A1 - Lipworth,Brian J AU - Lipworth,Brian J PY - 2013/3 Y1 - 2013/3 U2 - 10.1016/j.anai.2012.12.009 DO - 10.1016/j.anai.2012.12.009 M1 - Letter JO - Annals of Allergy, Asthma & Immunology JF - Annals of Allergy, Asthma & Immunology SN - 1081-1206 IS - 3 VL - 110 SP - 213 ER - TY - JOUR T1 - An inventory of European data sources for the long-term safety evaluation of methylphenidate A1 - Murray,Macey L A1 - Insuk,Suppachai A1 - Banaschewski,Tobias A1 - Neubert,Antje C A1 - McCarthy,Suzanne A1 - Buitelaar,Jan K A1 - Coghill,David A1 - Dittmann,Ralf W A1 - Konrad,Kerstin A1 - Panei,Pietro A1 - Rosenthal,Eric A1 - Sonuga-Barke,Edmund J A1 - Wong,Ian C K AU - Murray,Macey L AU - Insuk,Suppachai AU - Banaschewski,Tobias AU - Neubert,Antje C AU - McCarthy,Suzanne AU - Buitelaar,Jan K AU - Coghill,David AU - Dittmann,Ralf W AU - Konrad,Kerstin AU - Panei,Pietro AU - Rosenthal,Eric AU - Sonuga-Barke,Edmund J AU - Wong,Ian C K PY - 2013/3 Y1 - 2013/3 N2 - To compile an inventory of European healthcare databases with potential to study long-term effects of methylphenidate (MPH) in patients with attention deficit hyperactivity disorder (ADHD). Potential databases were identified through expert opinion, the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, and literature search. An online survey was conducted among database providers/coordinators to ascertain the databases' appropriateness for inclusion into the inventory. It included questions about database characteristics, sample size, availability of information on drug exposure, clinical data and accessibility. Forty-two databases from 11 countries were identified and their coordinators invited to participate; responses were obtained for 22 (52.4 %) databases of which 15 record ADHD diagnoses. Eleven had sufficient data on ADHD diagnosis, drug exposure, and at least one type of outcome information (symptoms/clinical events, weight, height, blood pressure, heart rate) to assess MPH safety. These were Aarhus University Prescription Database, Danish National Birth Cohort (Denmark); German Health Interview and Examination Survey for Children and Adolescents; Health Search Database Thales, Italian ADHD Register, Lombardy Region ADHD Database (Italy); Avon Longitudinal Study of Parents and Children, General Practice Research Database, The Health Improvement Network, QResearch (UK) and IMS Disease Analyzer (UK, Germany, France). Of the 20 databases with no responses, information on seven from publications and/or websites was obtained; Pedianet and the Integrated Primary Care Information database were considered suitable. Many European healthcare databases can be used for multinational long-term safety studies of MPH. Methodological research is underway to investigate the feasibility of their pooling and analysis. AB - To compile an inventory of European healthcare databases with potential to study long-term effects of methylphenidate (MPH) in patients with attention deficit hyperactivity disorder (ADHD). Potential databases were identified through expert opinion, the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, and literature search. An online survey was conducted among database providers/coordinators to ascertain the databases' appropriateness for inclusion into the inventory. It included questions about database characteristics, sample size, availability of information on drug exposure, clinical data and accessibility. Forty-two databases from 11 countries were identified and their coordinators invited to participate; responses were obtained for 22 (52.4 %) databases of which 15 record ADHD diagnoses. Eleven had sufficient data on ADHD diagnosis, drug exposure, and at least one type of outcome information (symptoms/clinical events, weight, height, blood pressure, heart rate) to assess MPH safety. These were Aarhus University Prescription Database, Danish National Birth Cohort (Denmark); German Health Interview and Examination Survey for Children and Adolescents; Health Search Database Thales, Italian ADHD Register, Lombardy Region ADHD Database (Italy); Avon Longitudinal Study of Parents and Children, General Practice Research Database, The Health Improvement Network, QResearch (UK) and IMS Disease Analyzer (UK, Germany, France). Of the 20 databases with no responses, information on seven from publications and/or websites was obtained; Pedianet and the Integrated Primary Care Information database were considered suitable. Many European healthcare databases can be used for multinational long-term safety studies of MPH. Methodological research is underway to investigate the feasibility of their pooling and analysis. U2 - 10.1007/s00787-013-0386-x DO - 10.1007/s00787-013-0386-x M1 - Article JO - European Child & Adolescent Psychiatry JF - European Child & Adolescent Psychiatry SN - 1018-8827 ER - TY - JOUR T1 - At Home? T2 - Discoursing on the Commonwealth at the 1965 Commonwealth Arts Festival A1 - Low,Gail AU - Low,Gail PY - 2013/3 Y1 - 2013/3 N2 - The Commonwealth Arts Festival was staged in Britain in 1965. With
the working title of `The Commonwealth At Home' , the Fesitval was
designed, ostensibly, to bring together far flung lands, connected by the
legacy of empire, to establish goodwill through culture and the arts. This
paper explores the cultural work to which the 1965 Festival was put to by
advocates and detractors. Looking at archival sources from proposed plans
for the London events, committee minutes, festival programmes and
letters to the staging of the `Verse and Voice’ festival of Commonwealth
Poetry at the Royal Court Theatre in London, the paper fleshes out some
of the rationales and motivations for the event, examines tropes and
metaphors used, and also situates the events within the context of recently
passed British anti-immigration laws. The paper argues that who the
Commonwealth was for - its locus and its meaning - can be excavated from
the geo-political tropic deployment of space in its discoursing. In particular,
the depiction of what was imagined as being at home and what was
represented as distant lands tell revealing stories of disavowal for an
empire (and a colonial legacy) that occurred somewhere else and to
someone else. In this manner, Britain’s `fit of absence of mind’ also
became a way of disposing of unwanted histories. AB - The Commonwealth Arts Festival was staged in Britain in 1965. With
the working title of `The Commonwealth At Home' , the Fesitval was
designed, ostensibly, to bring together far flung lands, connected by the
legacy of empire, to establish goodwill through culture and the arts. This
paper explores the cultural work to which the 1965 Festival was put to by
advocates and detractors. Looking at archival sources from proposed plans
for the London events, committee minutes, festival programmes and
letters to the staging of the `Verse and Voice’ festival of Commonwealth
Poetry at the Royal Court Theatre in London, the paper fleshes out some
of the rationales and motivations for the event, examines tropes and
metaphors used, and also situates the events within the context of recently
passed British anti-immigration laws. The paper argues that who the
Commonwealth was for - its locus and its meaning - can be excavated from
the geo-political tropic deployment of space in its discoursing. In particular,
the depiction of what was imagined as being at home and what was
represented as distant lands tell revealing stories of disavowal for an
empire (and a colonial legacy) that occurred somewhere else and to
someone else. In this manner, Britain’s `fit of absence of mind’ also
became a way of disposing of unwanted histories. U2 - 10.1177/0021989412471838 DO - 10.1177/0021989412471838 M1 - Article JO - Journal of Commonwealth Literature JF - Journal of Commonwealth Literature SN - 0021-9894 IS - 1 VL - 48 SP - 97 EP - 111 ER - TY - JOUR T1 - Beta-secretase 1 (BACE1) inhibition improves obese and diabetic phenotypes in a leptin dependent manner A1 - Meakin,P. J. A1 - Jalicy,S. M. A1 - Irvine,S. W. A1 - Ashford,M. L. J. AU - Meakin,P. J. AU - Jalicy,S. M. AU - Irvine,S. W. AU - Ashford,M. L. J. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_1 DO - 10.1111/dme.12091_1 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 41 EP - 41 ER - TY - JOUR T1 - Bifurcation of ensemble oscillations and acoustic emissions from early stage cavitation clouds in focused ultrasound A1 - Gerold,B. A1 - Rachmilevitch,I. A1 - Prentice,Paul AU - Gerold,B. AU - Rachmilevitch,I. AU - Prentice,Paul PY - 2013/3 Y1 - 2013/3 N2 - The acoustic emissions from single cavitation clouds at an early stage of development in 0.521 MHz focused ultrasound of varying intensity, are detected and directly correlated to high-speed microscopic observations, recorded at 1 × 10 frames per second. At lower intensities, a stable regime of cloud response is identified whereby bubble-ensembles exhibit oscillations at half the driving frequency, which is also detected in the acoustic emission spectra. Higher intensities generate clouds that develop more rapidly, with increased nonlinearity evidenced by a bifurcation in the frequency of ensemble response, and in the acoustic emissions. A single bubble oscillation model is subject to equivalent ultrasound conditions and fitted to features in the hydrophone and high-speed spectral data, allowing an effective quiescent radius to be inferred for the clouds that evolve at each intensity. The approach indicates that the acoustic emissions originate from the ensemble dynamics and that the cloud acts as a single bubble of equivalent radius in terms of the scattered field. Jetting from component cavities on the periphery of clouds is regularly observed at higher intensities. The results may be of relevance for monitoring and controlling cavitation in therapeutic applications of focused ultrasound, where the phenomenon has the potential to mediate drug delivery from vasculature. © IOP Publishing and Deutsche Physikalische Gesellschaft. AB - The acoustic emissions from single cavitation clouds at an early stage of development in 0.521 MHz focused ultrasound of varying intensity, are detected and directly correlated to high-speed microscopic observations, recorded at 1 × 10 frames per second. At lower intensities, a stable regime of cloud response is identified whereby bubble-ensembles exhibit oscillations at half the driving frequency, which is also detected in the acoustic emission spectra. Higher intensities generate clouds that develop more rapidly, with increased nonlinearity evidenced by a bifurcation in the frequency of ensemble response, and in the acoustic emissions. A single bubble oscillation model is subject to equivalent ultrasound conditions and fitted to features in the hydrophone and high-speed spectral data, allowing an effective quiescent radius to be inferred for the clouds that evolve at each intensity. The approach indicates that the acoustic emissions originate from the ensemble dynamics and that the cloud acts as a single bubble of equivalent radius in terms of the scattered field. Jetting from component cavities on the periphery of clouds is regularly observed at higher intensities. The results may be of relevance for monitoring and controlling cavitation in therapeutic applications of focused ultrasound, where the phenomenon has the potential to mediate drug delivery from vasculature. © IOP Publishing and Deutsche Physikalische Gesellschaft. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875947832&md5=ab39228ad9c16978e47b94713e5c263d U2 - 10.1088/1367-2630/15/3/033044 DO - 10.1088/1367-2630/15/3/033044 M1 - Article JO - New Journal of Physics JF - New Journal of Physics SN - 1367-2630 VL - 15 ER - TY - JOUR T1 - Clinical predictors of rate of progression of type 2 diabetes T2 - an extreme case-control study A1 - Donnelly,L. A. A1 - Zhou,K. A1 - Palmer,C. N. A. A1 - Doney,A. S. F. A1 - Morris,A. D. A1 - Pearson,E. R. AU - Donnelly,L. A. AU - Zhou,K. AU - Palmer,C. N. A. AU - Doney,A. S. F. AU - Morris,A. D. AU - Pearson,E. R. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_2 DO - 10.1111/dme.12091_2 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 94 EP - 94 ER - TY - JOUR T1 - Complicity, entanglement and translation T2 - Three English/Afrikaans texts A1 - Devarenne,Nicole AU - Devarenne,Nicole PY - 2013/3 Y1 - 2013/3 N2 - Using Mark Sanders’ definition, Afrikaans is a “complicit” language, both in terms of the assistance it has given to apartheid, and in the way it evidences cultural and linguistic entanglement. But the texts examined in this article—J.M. Coetzee’s In the Heart of the Country (1977), Antjie Krog’s Country of My Skull (1998) and A.H.M. Scholtz’s Vatmaar (1995)—also show a keen awareness of English’s role as an instrument of cultural imperialism. They are not composed in—or translated into—English in an attempt to distance themselves from complicity so much as to reveal it. They also speak of the opportunities writing in a hybridised English, or in a mixture of English and Afrikaans, offers to those who wish to describe intimacies gained, resisted, invited or ignored in opposition to apartheid. As Afrikaans-speaking writers writing in English and vice versa, Coetzee, Krog and Scholtz complicate the relationship between language and identity which apartheid sought to codify and secure and which local and global literary markets often reinforce. Their texts tend to offer linguistic hybridity, if not always as a practice, at least as an ideal in the pursuit of which such fixed categories are destabilised, and the folded-togetherness of South African languages and identities can be realised in textual and material terms. In considering the interaction of textual studies, literary studies and print culture around questions of translation and translingualism in South Africa, it is hoped that we might create more space for the publication and critical reception of texts that re-fashion national and personal histories in radically productive ways. AB - Using Mark Sanders’ definition, Afrikaans is a “complicit” language, both in terms of the assistance it has given to apartheid, and in the way it evidences cultural and linguistic entanglement. But the texts examined in this article—J.M. Coetzee’s In the Heart of the Country (1977), Antjie Krog’s Country of My Skull (1998) and A.H.M. Scholtz’s Vatmaar (1995)—also show a keen awareness of English’s role as an instrument of cultural imperialism. They are not composed in—or translated into—English in an attempt to distance themselves from complicity so much as to reveal it. They also speak of the opportunities writing in a hybridised English, or in a mixture of English and Afrikaans, offers to those who wish to describe intimacies gained, resisted, invited or ignored in opposition to apartheid. As Afrikaans-speaking writers writing in English and vice versa, Coetzee, Krog and Scholtz complicate the relationship between language and identity which apartheid sought to codify and secure and which local and global literary markets often reinforce. Their texts tend to offer linguistic hybridity, if not always as a practice, at least as an ideal in the pursuit of which such fixed categories are destabilised, and the folded-togetherness of South African languages and identities can be realised in textual and material terms. In considering the interaction of textual studies, literary studies and print culture around questions of translation and translingualism in South Africa, it is hoped that we might create more space for the publication and critical reception of texts that re-fashion national and personal histories in radically productive ways. KW - South Africa, Print cultures, Translation, Afrikaans Literature, English Literature U2 - 10.1177/0021989412470942 DO - 10.1177/0021989412470942 M1 - Article JO - Journal of Commonwealth Literature JF - Journal of Commonwealth Literature SN - 0021-9894 IS - 1 VL - 48 SP - 61 EP - 76 ER - TY - JOUR T1 - Contributions of roots and rootstocks to sustainable, intensified crop production A1 - Gregory,Peter J. A1 - Atkinson,Christopher J. A1 - Bengough,A. Glyn A1 - Else,Mark A. A1 - Fernandez-Fernandez,Felicidad A1 - Harrison,Richard J. A1 - Schmidt,Sonja AU - Gregory,Peter J. AU - Atkinson,Christopher J. AU - Bengough,A. Glyn AU - Else,Mark A. AU - Fernandez-Fernandez,Felicidad AU - Harrison,Richard J. AU - Schmidt,Sonja PY - 2013/3 Y1 - 2013/3 N2 -

Sustainable intensification is seen as the main route for meeting the worlds increasing demands for food and fibre. As demands mount for greater efficiency in the use of resources to achieve this goal, so the focus on roots and rootstocks and their role in acquiring water and nutrients, and overcoming pests and pathogens, is increasing. The purpose of this review is to explore some of the ways in which understanding root systems and their interactions with soils could contribute to the development of more sustainable systems of intensive production. Physical interactions with soil particles limit root growth if soils are dense, but rootsoil contact is essential for optimal growth and uptake of water and nutrients. X-ray microtomography demonstrated that maize roots elongated more rapidly with increasing rootsoil contact, as long as mechanical impedance was not limiting root elongation, while lupin was less sensitive to changes in rootsoil contact. In addition to selecting for root architecture and rhizosphere properties, the growth of many plants in cultivated systems is profoundly affected by selection of an appropriate rootstock. Several mechanisms for scion control by rootstocks have been suggested, but the causal signals are still uncertain and may differ between crop species. Linkage map locations for quantitative trait loci for disease resistance and other traits of interest in rootstock breeding are becoming available. Designing root systems and rootstocks for specific environments is becoming a feasible target.

AB -

Sustainable intensification is seen as the main route for meeting the worlds increasing demands for food and fibre. As demands mount for greater efficiency in the use of resources to achieve this goal, so the focus on roots and rootstocks and their role in acquiring water and nutrients, and overcoming pests and pathogens, is increasing. The purpose of this review is to explore some of the ways in which understanding root systems and their interactions with soils could contribute to the development of more sustainable systems of intensive production. Physical interactions with soil particles limit root growth if soils are dense, but rootsoil contact is essential for optimal growth and uptake of water and nutrients. X-ray microtomography demonstrated that maize roots elongated more rapidly with increasing rootsoil contact, as long as mechanical impedance was not limiting root elongation, while lupin was less sensitive to changes in rootsoil contact. In addition to selecting for root architecture and rhizosphere properties, the growth of many plants in cultivated systems is profoundly affected by selection of an appropriate rootstock. Several mechanisms for scion control by rootstocks have been suggested, but the causal signals are still uncertain and may differ between crop species. Linkage map locations for quantitative trait loci for disease resistance and other traits of interest in rootstock breeding are becoming available. Designing root systems and rootstocks for specific environments is becoming a feasible target.

KW - resource use KW - rootshoot communication KW - XYLEM SAP KW - rootsoil contact KW - FIRE BLIGHT RESISTANCE KW - HYDRAULIC CONDUCTANCE KW - QTL KW - APPLE ROOTSTOCKS KW - Biopores KW - rootstock KW - SHOOT GROWTH KW - WINTER-WHEAT KW - root distribution KW - ABSCISIC-ACID KW - LONG-DISTANCE TRAFFICKING KW - SOIL CONTACT KW - root systems KW - THIN-SECTION TECHNIQUE U2 - 10.1093/jxb/ers385 DO - 10.1093/jxb/ers385 M1 - Scientific review JO - Journal of Experimental Botany JF - Journal of Experimental Botany SN - 0022-0957 IS - 5 VL - 64 SP - 1209 EP - 1222 ER - TY - JOUR T1 - Deleuze, Nietzsche, and the Overcoming of Nihilism A1 - Woodward,Ashley AU - Woodward,Ashley PY - 2013/3 Y1 - 2013/3 N2 - This paper critically examines Deleuze’s treatment of the Nietzschean problem of nihilism. Of all the major figures in contemporary continental thought, Deleuze is at once one of the most luminous, and practically a lone voice in suggesting that nihilism may successfully be overcome. Whether or not he is correct on this point is thus a commanding question in relation to our understanding of the issue. Many commentators on Nietzsche have argued that his project of overcoming nihilism is destined to failure because of the affinity between the problem of nihilism and the logic of negation. While Nietzsche wants an absolute affirmation of life, Spinoza’s principle that “all determination is negation,” as well as Hegel’s dialectical conception of negation, suggest that affirmation free of negation is not possible. However, some commentators indicate that Deleuze successfully shows how overcoming nihilism is possible because his “logic of difference” allows for an affirmation which is not dialectically reappropriated by negation. This paper argues that beyond such logical considerations, there are metaphysical and existential reasons why Deleuze’s interpretation of nihilism fails to show that it can be overcome. For Deleuze, the overcoming of nihilism hinges not just on a logic of difference, but on a radical interpretation of Nietzsche’s doctrine of eternal return as “selective being.” Drawing on recent scholarship and on Nietzsche’s own writings I argue that this is not a tenable interpretation, and also, more importantly, that the metaphysical and existential implications of this understanding of eternal return reinstate nihilism at the very point where it is supposedly overcome. Moreover, I argue that there are attendant ethical and political dangers to Deleuze’s position on nihilism. AB - This paper critically examines Deleuze’s treatment of the Nietzschean problem of nihilism. Of all the major figures in contemporary continental thought, Deleuze is at once one of the most luminous, and practically a lone voice in suggesting that nihilism may successfully be overcome. Whether or not he is correct on this point is thus a commanding question in relation to our understanding of the issue. Many commentators on Nietzsche have argued that his project of overcoming nihilism is destined to failure because of the affinity between the problem of nihilism and the logic of negation. While Nietzsche wants an absolute affirmation of life, Spinoza’s principle that “all determination is negation,” as well as Hegel’s dialectical conception of negation, suggest that affirmation free of negation is not possible. However, some commentators indicate that Deleuze successfully shows how overcoming nihilism is possible because his “logic of difference” allows for an affirmation which is not dialectically reappropriated by negation. This paper argues that beyond such logical considerations, there are metaphysical and existential reasons why Deleuze’s interpretation of nihilism fails to show that it can be overcome. For Deleuze, the overcoming of nihilism hinges not just on a logic of difference, but on a radical interpretation of Nietzsche’s doctrine of eternal return as “selective being.” Drawing on recent scholarship and on Nietzsche’s own writings I argue that this is not a tenable interpretation, and also, more importantly, that the metaphysical and existential implications of this understanding of eternal return reinstate nihilism at the very point where it is supposedly overcome. Moreover, I argue that there are attendant ethical and political dangers to Deleuze’s position on nihilism. KW - Deleuze KW - Eternal return KW - Nihilism KW - Nietzsche U2 - 10.1007/s11007-013-9245-1 DO - 10.1007/s11007-013-9245-1 M1 - Article JO - Continental Philosophy Review JF - Continental Philosophy Review SN - 1387-2842 ER - TY - JOUR T1 - Diabetes and schizophrenia T2 - exploring the associations: determining the extent of diabetes and the quality of diabetes care within a clozapine (schizophrenia) clinic in Edinburgh A1 - Perera,S. M. A1 - Cochrane,L. A1 - Wang,Y. A1 - MacIntyre,D. J. A1 - Wake,D. AU - Perera,S. M. AU - Cochrane,L. AU - Wang,Y. AU - MacIntyre,D. J. AU - Wake,D. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_2 DO - 10.1111/dme.12091_2 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 180 EP - 181 ER - TY - JOUR T1 - DNA break site at fragile subtelomeres determines probability and mechanism of antigenic variation in African trypanosomes A1 - Glover,Lucy A1 - Alsford,Sam A1 - Horn,David AU - Glover,Lucy AU - Alsford,Sam AU - Horn,David PY - 2013/3 Y1 - 2013/3 N2 -

Antigenic variation in African trypanosomes requires monoallelic transcription and switching of variant surface glycoprotein (VSG) genes. The transcribed VSG, always flanked by '70 bp'-repeats and telomeric-repeats, is either replaced through DNA double-strand break (DSB) repair or transcriptionally inactivated. However, little is known about the subtelomeric DSBs that naturally trigger antigenic variation in Trypanosoma brucei, the subsequent DNA damage responses, or how these responses determine the mechanism of VSG switching. We found that DSBs naturally accumulate close to both transcribed and non-transcribed telomeres. We then induced high-efficiency meganuclease-mediated DSBs and monitored DSB-responses and DSB-survivors. By inducing breaks at distinct sites within both transcribed and silent VSG transcription units and assessing local DNA resection, histone modification, G2/M-checkpoint activation, and both RAD51-dependent and independent repair, we reveal how breaks at different sites trigger distinct responses and, in 'active-site' survivors, different switching mechanisms. At the active site, we find that promoter-adjacent breaks typically failed to trigger switching, 70 bp-repeat-adjacent breaks almost always triggered switching through 70 bp-repeat recombination (similar to 60% RAD51-dependent), and telomere-repeat-adjacent breaks triggered switching through loss of the VSG expression site (25% of survivors). Expression site loss was associated with G2/M-checkpoint bypass, while 70 bp-repeat-recombination was associated with DNA-resection, ? H2A-focus assembly and a G2/M-checkpoint. Thus, the probability and mechanism of antigenic switching are highly dependent upon the location of the break. We conclude that 70 bp-repeat-adjacent and telomere-repeat-adjacent breaks trigger distinct checkpoint responses and VSG switching pathways. Our results show how subtelomere fragility can generate the triggers for the major antigenic variation mechanisms in the African trypanosome.

AB -

Antigenic variation in African trypanosomes requires monoallelic transcription and switching of variant surface glycoprotein (VSG) genes. The transcribed VSG, always flanked by '70 bp'-repeats and telomeric-repeats, is either replaced through DNA double-strand break (DSB) repair or transcriptionally inactivated. However, little is known about the subtelomeric DSBs that naturally trigger antigenic variation in Trypanosoma brucei, the subsequent DNA damage responses, or how these responses determine the mechanism of VSG switching. We found that DSBs naturally accumulate close to both transcribed and non-transcribed telomeres. We then induced high-efficiency meganuclease-mediated DSBs and monitored DSB-responses and DSB-survivors. By inducing breaks at distinct sites within both transcribed and silent VSG transcription units and assessing local DNA resection, histone modification, G2/M-checkpoint activation, and both RAD51-dependent and independent repair, we reveal how breaks at different sites trigger distinct responses and, in 'active-site' survivors, different switching mechanisms. At the active site, we find that promoter-adjacent breaks typically failed to trigger switching, 70 bp-repeat-adjacent breaks almost always triggered switching through 70 bp-repeat recombination (similar to 60% RAD51-dependent), and telomere-repeat-adjacent breaks triggered switching through loss of the VSG expression site (25% of survivors). Expression site loss was associated with G2/M-checkpoint bypass, while 70 bp-repeat-recombination was associated with DNA-resection, ? H2A-focus assembly and a G2/M-checkpoint. Thus, the probability and mechanism of antigenic switching are highly dependent upon the location of the break. We conclude that 70 bp-repeat-adjacent and telomere-repeat-adjacent breaks trigger distinct checkpoint responses and VSG switching pathways. Our results show how subtelomere fragility can generate the triggers for the major antigenic variation mechanisms in the African trypanosome.

KW - CELL-CYCLE ARREST KW - CHECKPOINT KW - DELETION KW - HOMOLOGOUS RECOMBINATION KW - GENE-EXPRESSION SITE KW - PLASMODIUM-FALCIPARUM KW - CHROMOSOME KW - MAMMALIAN TELOMERES KW - YEAST KW - BRUCEI U2 - 10.1371/journal.ppat.1003260 DO - 10.1371/journal.ppat.1003260 M1 - Article JO - PLoS Pathogens JF - PLoS Pathogens SN - 1553-7374 IS - 3 VL - 9 ER - TY - JOUR T1 - Drug resistance in African trypanosomiasis T2 - the melarsoprol and pentamidine story A1 - Baker,Nicola A1 - de Koning,Harry P. A1 - Maeser,Pascal A1 - Horn,David AU - Baker,Nicola AU - de Koning,Harry P. AU - Maeser,Pascal AU - Horn,David PY - 2013/3 Y1 - 2013/3 N2 -

Melarsoprol and pentamidine represent the two main classes of drugs, the arsenicals and diamidines, historically used to treat the diseases caused by African trypanosomes: sleeping sickness in humans and Nagana in livestock. Cross-resistance to these drugs was first observed over 60 years ago and remains the only example of cross-resistance among sleeping sickness therapies. A Trypanosome brucei adenosine transporter is well known for its role in the uptake of both drugs. More recently, aquaglyceroporin 2 (AQP2) loss of function was linked to melarsoprol-pentamidine cross-resistance. AQP2, a channel that appears to facilitate drug accumulation, may also be linked to clinical cases of resistance. Here, we review these findings and consider some new questions as well as future prospects for tackling the devastating diseases caused by these parasites. 'Cellular therapy is a consequence of cellular nutrition, for only those compounds can affect the cell that are actually eaten by it.' - Paul Ehrlich, 1907 [1].

AB -

Melarsoprol and pentamidine represent the two main classes of drugs, the arsenicals and diamidines, historically used to treat the diseases caused by African trypanosomes: sleeping sickness in humans and Nagana in livestock. Cross-resistance to these drugs was first observed over 60 years ago and remains the only example of cross-resistance among sleeping sickness therapies. A Trypanosome brucei adenosine transporter is well known for its role in the uptake of both drugs. More recently, aquaglyceroporin 2 (AQP2) loss of function was linked to melarsoprol-pentamidine cross-resistance. AQP2, a channel that appears to facilitate drug accumulation, may also be linked to clinical cases of resistance. Here, we review these findings and consider some new questions as well as future prospects for tackling the devastating diseases caused by these parasites. 'Cellular therapy is a consequence of cellular nutrition, for only those compounds can affect the cell that are actually eaten by it.' - Paul Ehrlich, 1907 [1].

KW - BRUCEI-GAMBIENSE TRYPANOSOMIASIS KW - AT1 KW - ABC TRANSPORTERS KW - P2 ADENOSINE TRANSPORTER KW - COMBINATION THERAPY KW - MRPA KW - CROSS-RESISTANCE KW - AQP2 KW - MIP KW - SLEEPING SICKNESS KW - NUCLEOSIDE TRANSPORTER KW - MULTIDRUG-RESISTANCE KW - drug resistance KW - 3 AQUAGLYCEROPORINS KW - Trypanosoma brucei KW - BLOOD-STREAM FORM U2 - 10.1016/j.pt.2012.12.005 DO - 10.1016/j.pt.2012.12.005 M1 - Scientific review JO - Trends in Parasitology JF - Trends in Parasitology SN - 1471-4922 IS - 3 VL - 29 SP - 110 EP - 118 ER - TY - JOUR T1 - Efficient multiplex simple sequence repeat genotyping of the oomycete plant pathogen Phytophthora infestans A1 - Li,Ying A1 - Cooke,David E. L. A1 - Jacobsen,Evert A1 - van der Lee,Theo AU - Li,Ying AU - Cooke,David E. L. AU - Jacobsen,Evert AU - van der Lee,Theo PY - 2013/3 Y1 - 2013/3 N2 -

Genotyping is fundamental to population analysis. To accommodate fast, accurate and cost-effective genotyping, a one-step multiplex PCR method employing twelve simple sequence repeat (SSR) markers was developed for high-throughput screening of Phytophthora infestans populations worldwide. The SSR markers reported for this species were evaluated and the twelve most informative and easily scored were selected. To accomplish a single step genotyping procedure, we optimized primers, fluorescent labels and PCR conditions to genotype using a capillary electrophoresis system with four fluorescent labels (FAM, NED, PET and VIC) and a labeled LIZ standard for sizing of the SSR fragments. The results obtained using commercially available multiplex PCR kits on a set of reference isolates were in agreement with that obtained using primer pairs in simplex reactions. In testing on many thousands of isolates, we have found the markers appropriate for resolving distinct multilocus genotypes (MLGs) of isolates of European and wider populations. Here we demonstrate the utility of the assay on a set of 19 reference isolates plus 77 others sampled from The Netherlands and Great Britain. In most isolates one to two alleles were observed at each locus but the presence of three alleles at a single locus in some isolates was consistent with increased ploidy. Methods are presented that are appropriate for the analysis of datasets comprising isolates of mixed ploidy levels. We also report on the direct P. infestans genotyping from infected field material to collect, store and extract pathogen DNA. A critical step in this multiplex method was the standardization of the protocol between two laboratories in The Netherlands and Great Britain. Reference isolates were exchanged and an allele nomenclature and scoring system agreed. Such co-operation is facilitating the genotyping of international collections of P. infestans isolates in wider networks of laboratories and providing the data required to expand an existing international database of pathogen diversity. (c) 2012 Elsevier B.V. All rights reserved.

AB -

Genotyping is fundamental to population analysis. To accommodate fast, accurate and cost-effective genotyping, a one-step multiplex PCR method employing twelve simple sequence repeat (SSR) markers was developed for high-throughput screening of Phytophthora infestans populations worldwide. The SSR markers reported for this species were evaluated and the twelve most informative and easily scored were selected. To accomplish a single step genotyping procedure, we optimized primers, fluorescent labels and PCR conditions to genotype using a capillary electrophoresis system with four fluorescent labels (FAM, NED, PET and VIC) and a labeled LIZ standard for sizing of the SSR fragments. The results obtained using commercially available multiplex PCR kits on a set of reference isolates were in agreement with that obtained using primer pairs in simplex reactions. In testing on many thousands of isolates, we have found the markers appropriate for resolving distinct multilocus genotypes (MLGs) of isolates of European and wider populations. Here we demonstrate the utility of the assay on a set of 19 reference isolates plus 77 others sampled from The Netherlands and Great Britain. In most isolates one to two alleles were observed at each locus but the presence of three alleles at a single locus in some isolates was consistent with increased ploidy. Methods are presented that are appropriate for the analysis of datasets comprising isolates of mixed ploidy levels. We also report on the direct P. infestans genotyping from infected field material to collect, store and extract pathogen DNA. A critical step in this multiplex method was the standardization of the protocol between two laboratories in The Netherlands and Great Britain. Reference isolates were exchanged and an allele nomenclature and scoring system agreed. Such co-operation is facilitating the genotyping of international collections of P. infestans isolates in wider networks of laboratories and providing the data required to expand an existing international database of pathogen diversity. (c) 2012 Elsevier B.V. All rights reserved.

KW - Phytophthora infestans KW - Genotyping KW - GENETIC-LINKAGE MAPS KW - BLIGHT KW - MICROSATELLITE MARKERS KW - PCR KW - Multiplex PCR KW - POPULATION-GENETICS KW - ORIGIN KW - POTATO KW - NETHERLANDS KW - Population KW - SSR KW - MIGRATIONS U2 - 10.1016/j.mimet.2012.11.021 DO - 10.1016/j.mimet.2012.11.021 M1 - Article JO - Journal of Microbiological Methods JF - Journal of Microbiological Methods SN - 0167-7012 IS - 3 VL - 92 SP - 316 EP - 322 ER - TY - JOUR T1 - Estimating United States Phillips Curves with Expectations Consistent with the Statistical Process of Inflation A1 - Russell,Bill A1 - Chowdhury,Rosen Azad AU - Russell,Bill AU - Chowdhury,Rosen Azad PY - 2013/3 Y1 - 2013/3 N2 - ‘Modern’ Phillips curve theories predict inflation is an integrated, or near integrated, process. However, inflation appears bounded above and below in developed economies and so cannot be ‘truly’ integrated and more likely stationary around a shifting mean. If agents believe inflation is integrated as in the ‘modern’ theories then they are making systematic errors concerning the statistical process of inflation. An alternative theory of the Phillips curve is developed that is consistent with the ‘true’ statistical process of inflation. It is demonstrated that United States inflation data are consistent with the alternative theory but not with the existing ‘modern’ theories. AB - ‘Modern’ Phillips curve theories predict inflation is an integrated, or near integrated, process. However, inflation appears bounded above and below in developed economies and so cannot be ‘truly’ integrated and more likely stationary around a shifting mean. If agents believe inflation is integrated as in the ‘modern’ theories then they are making systematic errors concerning the statistical process of inflation. An alternative theory of the Phillips curve is developed that is consistent with the ‘true’ statistical process of inflation. It is demonstrated that United States inflation data are consistent with the alternative theory but not with the existing ‘modern’ theories. U2 - 10.1016/j.jmacro.2012.11.004 DO - 10.1016/j.jmacro.2012.11.004 M1 - Article JO - Journal of Macroeconomics JF - Journal of Macroeconomics SN - 0164-0704 VL - 35 SP - 24 EP - 38 ER - TY - JOUR T1 - Experimental investigation of induced suction distributions in a grass-covered soil A1 - Ng,C. W. W. A1 - Woon,K. X. A1 - Leung,A. K. A1 - Chu,L. M. AU - Ng,C. W. W. AU - Woon,K. X. AU - Leung,A. K. AU - Chu,L. M. PY - 2013/3 Y1 - 2013/3 N2 - Evapotranspiration from a grass-covered ground is known to induce suction by soil evaporation and grass transpiration. However, grass-induced suction in the ground when it is subjected to wetting and drying are not yet well understood. In this study, a laboratory test program was conducted to investigate the magnitude and distribution of suction induced by Bermuda grass growing in silty sand. In total, four test boxes compacted with silty sand were prepared, three of them covered with Bermuda grass while one test box was left bare as control. All the four test boxes were subjected to wetting and drying in a plant room with temperature and humidity controlled. Under identical atmospheric conditions and initial conditions, peak suction induced within the root zone in grassed soil was 1.5 times higher than that in bare soil after 20 days of drying. A vertical suction influence zone was identified to be up to four times the root depth while the lateral suction influence zone was one diameter of ring collar away from the centre of the plot. Upon wetting, suction retained at depth right below the root zone in grassed soil was found to be 40% higher than that in bare soil. For three grass replicates that were germinated under identical atmospheric conditions, they produced different shoot lengths and induced different magnitudes of suction. No direct correlation between grass shoot length and grass-induced suction could be found. AB - Evapotranspiration from a grass-covered ground is known to induce suction by soil evaporation and grass transpiration. However, grass-induced suction in the ground when it is subjected to wetting and drying are not yet well understood. In this study, a laboratory test program was conducted to investigate the magnitude and distribution of suction induced by Bermuda grass growing in silty sand. In total, four test boxes compacted with silty sand were prepared, three of them covered with Bermuda grass while one test box was left bare as control. All the four test boxes were subjected to wetting and drying in a plant room with temperature and humidity controlled. Under identical atmospheric conditions and initial conditions, peak suction induced within the root zone in grassed soil was 1.5 times higher than that in bare soil after 20 days of drying. A vertical suction influence zone was identified to be up to four times the root depth while the lateral suction influence zone was one diameter of ring collar away from the centre of the plot. Upon wetting, suction retained at depth right below the root zone in grassed soil was found to be 40% higher than that in bare soil. For three grass replicates that were germinated under identical atmospheric conditions, they produced different shoot lengths and induced different magnitudes of suction. No direct correlation between grass shoot length and grass-induced suction could be found. KW - Evapotranspiration KW - Root-water uptake KW - Suction distribution KW - Wetting KW - Suction influence zone KW - Bermuda grass U2 - 10.1016/j.ecoleng.2012.11.013 DO - 10.1016/j.ecoleng.2012.11.013 M1 - Article JO - Ecological Engineering JF - Ecological Engineering SN - 0925-8574 VL - 52 SP - 219 EP - 223 ER - TY - JOUR T1 - Functions and mechanisms of fibroblast growth factor (FGF) signalling in Drosophila melanogaster A1 - Muha,Villö A1 - Muller,Hans-Arno J. AU - Muha,Villö AU - Muller,Hans-Arno J. PY - 2013/3 Y1 - 2013/3 N2 -

Intercellular signalling via growth factors plays an important role in controlling cell differentiation and cell movements during the development of multicellular animals. Fibroblast Growth Factor (FGF) signalling induces changes in cellular behaviour allowing cells in the embryo to move, to survive, to divide or to differentiate. Several examples argue that FGF signalling is used in multi-step morphogenetic processes to achieve and maintain a transitional state of the cells required for the control of cell fate. In the genetic model Drosophila melanogaster, FGF signalling via the receptor tyrosine kinases Heartless (Htl) and Breathless (Btl) is particularly well studied. These FGF receptors affect gene expression, cell shape and cell-cell interactions during mesoderm layer formation, caudal visceral muscle (CVM) formation, tracheal morphogenesis and glia differentiation. Here, we will address the current knowledge of the biological functions of FGF signalling in the fly on the tissue, at a cellular and molecular level.

AB -

Intercellular signalling via growth factors plays an important role in controlling cell differentiation and cell movements during the development of multicellular animals. Fibroblast Growth Factor (FGF) signalling induces changes in cellular behaviour allowing cells in the embryo to move, to survive, to divide or to differentiate. Several examples argue that FGF signalling is used in multi-step morphogenetic processes to achieve and maintain a transitional state of the cells required for the control of cell fate. In the genetic model Drosophila melanogaster, FGF signalling via the receptor tyrosine kinases Heartless (Htl) and Breathless (Btl) is particularly well studied. These FGF receptors affect gene expression, cell shape and cell-cell interactions during mesoderm layer formation, caudal visceral muscle (CVM) formation, tracheal morphogenesis and glia differentiation. Here, we will address the current knowledge of the biological functions of FGF signalling in the fly on the tissue, at a cellular and molecular level.

KW - cell migration KW - development KW - SYSTEM KW - differentiation KW - fibroblast growth factor KW - EMBRYONIC MESODERM KW - BRANCHING MORPHOGENESIS KW - MESODERM MIGRATION KW - TRACHEAL CELL-MIGRATION KW - HEARTLESS KW - cell signalling KW - ENCODES KW - HEPARAN-SULFATE KW - Drosophila KW - RECEPTOR HOMOLOG KW - EXCHANGE FACTOR PEBBLE U2 - 10.3390/ijms14035920 DO - 10.3390/ijms14035920 M1 - Scientific review JO - International Journal of Molecular Sciences JF - International Journal of Molecular Sciences SN - 1422-0067 IS - 3 VL - 14 SP - 5920 EP - 5937 ER - TY - JOUR T1 - Genome-wide association study meta-analysis of chronic widespread pain T2 - evidence for involvement of the 5p15.2 region A1 - Peters,M.J. A1 - Broer,L. A1 - Willemen,H.L.D.M. A1 - Eiriksdottir,G. A1 - Hocking,L.J. A1 - Holliday,K.L. A1 - Horan,M.A. A1 - Meulenbelt,I. A1 - Neogi,T. A1 - Popham,M. A1 - Schmidt,C.O. A1 - Soni,A. A1 - Valdes,A.M. A1 - Amin,N. A1 - Dennison,E.M. A1 - Eijkelkamp,N. A1 - Harris,T.B. A1 - Hart,D.J. A1 - Hofman,A. A1 - Huygen,F.J.P.M. A1 - Jameson,K.A. A1 - Jones,G.T. A1 - Launer,L.J. A1 - Kerkhof,H.J.M. A1 - De Kruijf,M. A1 - McBeth,J. A1 - Kloppenburg,M. A1 - Ollier,W.E. A1 - Oostra,B. A1 - Payton,A. A1 - Rivadeneira,F. A1 - Smith,Blair H A1 - Smith,A.V. A1 - Stolk,L. A1 - Teumer,A. A1 - Thomson,W. A1 - Uitterlinden,A.G. A1 - Wang,K. A1 - Van Wingerden,S.H. A1 - Arden,N.K. A1 - Cooper,C. A1 - Felson,D. A1 - Gudnason,V. A1 - Macfarlane,G.J. A1 - Pendleton,N. A1 - Slagboom,P.E. A1 - Spector,T.D. A1 - Völzke,H. A1 - Kavelaars,A. A1 - Van Duijn,C.M. A1 - Williams,F.M.K. A1 - Van Meurs,J.B.J. AU - Peters,M.J. AU - Broer,L. AU - Willemen,H.L.D.M. AU - Eiriksdottir,G. AU - Hocking,L.J. AU - Holliday,K.L. AU - Horan,M.A. AU - Meulenbelt,I. AU - Neogi,T. AU - Popham,M. AU - Schmidt,C.O. AU - Soni,A. AU - Valdes,A.M. AU - Amin,N. AU - Dennison,E.M. AU - Eijkelkamp,N. AU - Harris,T.B. AU - Hart,D.J. AU - Hofman,A. AU - Huygen,F.J.P.M. AU - Jameson,K.A. AU - Jones,G.T. AU - Launer,L.J. AU - Kerkhof,H.J.M. AU - De Kruijf,M. AU - McBeth,J. AU - Kloppenburg,M. AU - Ollier,W.E. AU - Oostra,B. AU - Payton,A. AU - Rivadeneira,F. AU - Smith,Blair H AU - Smith,A.V. AU - Stolk,L. AU - Teumer,A. AU - Thomson,W. AU - Uitterlinden,A.G. AU - Wang,K. AU - Van Wingerden,S.H. AU - Arden,N.K. AU - Cooper,C. AU - Felson,D. AU - Gudnason,V. AU - Macfarlane,G.J. AU - Pendleton,N. AU - Slagboom,P.E. AU - Spector,T.D. AU - Völzke,H. AU - Kavelaars,A. AU - Van Duijn,C.M. AU - Williams,F.M.K. AU - Van Meurs,J.B.J. PY - 2013/3 Y1 - 2013/3 N2 - BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain. AB - BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84873744735&md5=9bba31d3509671e7a5717692dfeb18e7 U2 - 10.1136/annrheumdis-2012-201742 DO - 10.1136/annrheumdis-2012-201742 M1 - Article JO - Annals of the Rheumatic Diseases JF - Annals of the Rheumatic Diseases SN - 0003-4967 IS - 3 VL - 72 SP - 427 EP - 436 ER - TY - JOUR T1 - Getting to the heart of inpatient diabetes care A1 - Jordan,L. V. M. A1 - Voigt,D. J. A1 - Brennan,G. AU - Jordan,L. V. M. AU - Voigt,D. J. AU - Brennan,G. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_2 DO - 10.1111/dme.12091_2 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 151 EP - 151 ER - TY - JOUR T1 - Global subcellular characterization of protein degradation using quantitative proteomics A1 - Larance,Mark A1 - Ahmad,Yasmeen A1 - Kirkwood,Kathryn J. A1 - Ly,Tony A1 - Lamond,Angus I. AU - Larance,Mark AU - Ahmad,Yasmeen AU - Kirkwood,Kathryn J. AU - Ly,Tony AU - Lamond,Angus I. PY - 2013/3 Y1 - 2013/3 N2 -

Protein degradation provides an important regulatory mechanism used to control cell cycle progression and many other cellular pathways. To comprehensively analyze the spatial control of protein degradation in U2OS osteosarcoma cells, we have combined drug treatment and SILAC-based quantitative mass spectrometry with subcellular and protein fractionation. The resulting data set analyzed more than 74,000 peptides, corresponding to similar to 5000 proteins, from nuclear, cytosolic, membrane, and cytoskeletal compartments. These data identified rapidly degraded proteasome targets, such as PRR11 and high-lighted a feedback mechanism resulting in translation inhibition, induced by blocking the proteasome. We show this is mediated by activation of the unfolded protein response. We observed compartment-specific differences in protein degradation, including proteins that would not have been characterized as rapidly degraded through analysis of whole cell lysates. Bioinformatic analysis of the entire data set is presented in the Encyclopedia of Proteome Dynamics, a web-based resource, with proteins annotated for stability and subcellular distribution. Molecular & Cellular Proteomics 12: 10.1074/mcp.M112.024547, 638-650, 2013.

AB -

Protein degradation provides an important regulatory mechanism used to control cell cycle progression and many other cellular pathways. To comprehensively analyze the spatial control of protein degradation in U2OS osteosarcoma cells, we have combined drug treatment and SILAC-based quantitative mass spectrometry with subcellular and protein fractionation. The resulting data set analyzed more than 74,000 peptides, corresponding to similar to 5000 proteins, from nuclear, cytosolic, membrane, and cytoskeletal compartments. These data identified rapidly degraded proteasome targets, such as PRR11 and high-lighted a feedback mechanism resulting in translation inhibition, induced by blocking the proteasome. We show this is mediated by activation of the unfolded protein response. We observed compartment-specific differences in protein degradation, including proteins that would not have been characterized as rapidly degraded through analysis of whole cell lysates. Bioinformatic analysis of the entire data set is presented in the Encyclopedia of Proteome Dynamics, a web-based resource, with proteins annotated for stability and subcellular distribution. Molecular & Cellular Proteomics 12: 10.1074/mcp.M112.024547, 638-650, 2013.

KW - UBIQUITIN KW - LOCALIZATION KW - AMINO-ACIDS KW - QUANTIFICATION KW - PHOSPHORYLATION KW - STABILITY KW - EXPRESSION KW - TURNOVER KW - PROTEASOME KW - SPECTROMETRY-BASED PROTEOMICS U2 - 10.1074/mcp.M112.024547 DO - 10.1074/mcp.M112.024547 M1 - Article JO - Molecular & Cellular Proteomics JF - Molecular & Cellular Proteomics SN - 1535-9476 IS - 3 VL - 12 SP - 638 EP - 650 ER - TY - JOUR T1 - Hormonal regulation of the Salt-inducible Kinase (SIK), a key mediator that controls hepatic gluconeogenesis A1 - Patel,K. A1 - Goransson,O. A1 - Sutherland,C. A1 - Sakamoto,K. AU - Patel,K. AU - Goransson,O. AU - Sutherland,C. AU - Sakamoto,K. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12170 DO - 10.1111/dme.12170 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - E2-E2 ER - TY - CONF T1 - Hormonal regulation of the Salt-inducible Kinase (SIK), a key mediator that controls hepatic gluconeogenesis A1 - Patel,K. A1 - Goransson,O. A1 - Sutherland,C. A1 - Sakamoto,K. AU - Patel,K. AU - Goransson,O. AU - Sutherland,C. AU - Sakamoto,K. PY - 2013/3 Y1 - 2013/3 UR - http://www.diabetes.org.uk/Diabetes-UK-Professional-Conference/ M1 - Poster ER - TY - JOUR T1 - How does glucophage (metformin) work? Investigation of the cellular action of chemical analogues A1 - Logie,L. A1 - Bacon,S. A1 - Middleton,P. A1 - Harthill,J. A1 - Coats,J. A1 - Stewart,D. A1 - Sakamoto,K. A1 - McDougall,G. A1 - Rena,G. AU - Logie,L. AU - Bacon,S. AU - Middleton,P. AU - Harthill,J. AU - Coats,J. AU - Stewart,D. AU - Sakamoto,K. AU - McDougall,G. AU - Rena,G. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_1 DO - 10.1111/dme.12091_1 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 41 EP - 41 ER - TY - JOUR T1 - Identification and functional characterization of FMN2 T2 - a regulator of the cyclin-dependent kinase Inhibitor p21 A1 - Yamada,Kayo A1 - Ono,Motoharu A1 - Perkins,Neil D. A1 - Rocha,Sonia A1 - Lamond,Angus I. AU - Yamada,Kayo AU - Ono,Motoharu AU - Perkins,Neil D. AU - Rocha,Sonia AU - Lamond,Angus I. PY - 2013/3 Y1 - 2013/3 N2 - The ARF tumor suppressor is a central component of the cellular defense against oncogene activation in mammals. p14ARF activates p53 by binding and inhibiting HDM2, resulting, inter alia, in increased transcription and expression of the cyclin-dependent kinase inhibitor p21 and consequent cell-cycle arrest. We analyzed the effect of p14ARF induction on nucleolar protein dynamics using SILAC mass spectrometry and have identified the human Formin-2 (FMN2) protein as a component of the p14ARF tumor suppressor pathway. We show that FMN2 is increased upon p14ARF induction at both the mRNA and the protein level via a NF-?B-dependent mechanism that is independent of p53. FMN2 enhances expression of the cell-cycle inhibitor p21 by preventing its degradation. FMN2 is also induced by activation of other oncogenes, hypoxia, and DNA damage. These results identify FMN2 as a crucial component in the regulation of p21 and consequent oncogene/stress-induced cell-cycle arrest in human cells. AB - The ARF tumor suppressor is a central component of the cellular defense against oncogene activation in mammals. p14ARF activates p53 by binding and inhibiting HDM2, resulting, inter alia, in increased transcription and expression of the cyclin-dependent kinase inhibitor p21 and consequent cell-cycle arrest. We analyzed the effect of p14ARF induction on nucleolar protein dynamics using SILAC mass spectrometry and have identified the human Formin-2 (FMN2) protein as a component of the p14ARF tumor suppressor pathway. We show that FMN2 is increased upon p14ARF induction at both the mRNA and the protein level via a NF-?B-dependent mechanism that is independent of p53. FMN2 enhances expression of the cell-cycle inhibitor p21 by preventing its degradation. FMN2 is also induced by activation of other oncogenes, hypoxia, and DNA damage. These results identify FMN2 as a crucial component in the regulation of p21 and consequent oncogene/stress-induced cell-cycle arrest in human cells. U2 - 10.1016/j.molcel.2012.12.023 DO - 10.1016/j.molcel.2012.12.023 M1 - Article JO - Molecular Cell JF - Molecular Cell IS - 5 VL - 49 SP - 922 EP - 933 ER - TY - JOUR T1 - Influence of β2-adrenergic receptor polymorphism on methacholine hyperresponsiveness in asthmatic patients A1 - Manoharan,Arvind A1 - Anderson,William J. A1 - Lipworth,Brian J AU - Manoharan,Arvind AU - Anderson,William J. AU - Lipworth,Brian J PY - 2013/3 Y1 - 2013/3 N2 - Background
We previously reported that the ß2-adrenergic receptor (ADRB2) polymorphism had no effect on bronchial hyperresponsiveness (BHR) to methacholine in asthmatic patients. We have now replicated this analysis in a different and larger cohort of patients.

Objective
To assess the effect of the ADRB2 polymorphism in methacholine-responsive patients with asthma.

Methods
We conducted a retrospective analysis of the effects of ADRB2 haplotypes at position 16 (Gly/Arg) and 27(Gln/Glu) in 449 patients with a physician diagnosis of asthma who were responsive to methacholine (ie, provocation concentration that caused a decrease in forced expiratory volume in 1 second [FEV1] of 20% [PC20], <8 mg/mL).

Results
No differences were found in age, FEV1, or inhaled corticosteroid dose among the genotypes or haplotypes. No significant differences were found in methacholine PC20 (ie, <8 mg/mL) between the separate genotypes at position 16 or 27 or between the haplotypes at positions 16/27 combined. In addition, no significant differences were found among individual genotypes when stratified according to severity of BHR using different doubling dilution cutoff points for methacholine PC20 (ie, <4 mg/mL, <2 mg/mL, and <1 mg/mL).

Conclusion
We have confirmed in this replication study that common ADRB2 genotypes or haplotypes at positions 16/27 do not influence BHR in methacholine-responsive patients with asthma. AB - Background
We previously reported that the ß2-adrenergic receptor (ADRB2) polymorphism had no effect on bronchial hyperresponsiveness (BHR) to methacholine in asthmatic patients. We have now replicated this analysis in a different and larger cohort of patients.

Objective
To assess the effect of the ADRB2 polymorphism in methacholine-responsive patients with asthma.

Methods
We conducted a retrospective analysis of the effects of ADRB2 haplotypes at position 16 (Gly/Arg) and 27(Gln/Glu) in 449 patients with a physician diagnosis of asthma who were responsive to methacholine (ie, provocation concentration that caused a decrease in forced expiratory volume in 1 second [FEV1] of 20% [PC20], <8 mg/mL).

Results
No differences were found in age, FEV1, or inhaled corticosteroid dose among the genotypes or haplotypes. No significant differences were found in methacholine PC20 (ie, <8 mg/mL) between the separate genotypes at position 16 or 27 or between the haplotypes at positions 16/27 combined. In addition, no significant differences were found among individual genotypes when stratified according to severity of BHR using different doubling dilution cutoff points for methacholine PC20 (ie, <4 mg/mL, <2 mg/mL, and <1 mg/mL).

Conclusion
We have confirmed in this replication study that common ADRB2 genotypes or haplotypes at positions 16/27 do not influence BHR in methacholine-responsive patients with asthma. U2 - 10.1016/j.anai.2012.12.019 DO - 10.1016/j.anai.2012.12.019 M1 - Article JO - Annals of Allergy, Asthma & Immunology JF - Annals of Allergy, Asthma & Immunology SN - 1081-1206 IS - 3 VL - 110 SP - 161 EP - 164 ER - TY - JOUR T1 - Insulin sensitising effects of monounsaturated and polyunsaturated fatty acids in skeletal muscle cells A1 - Nardi,F. A1 - Lipina,C. A1 - Magill,D. A1 - Hundal,H. S. AU - Nardi,F. AU - Lipina,C. AU - Magill,D. AU - Hundal,H. S. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_1 DO - 10.1111/dme.12091_1 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 49 EP - 49 ER - TY - JOUR T1 - Is thiazolidinedione treatment an important cause of oedema? A1 - Vella,S. A1 - Donnelly,L. A1 - Lang,C. C. A1 - Pearson,E. R. A1 - Petrie,J. R. AU - Vella,S. AU - Donnelly,L. AU - Lang,C. C. AU - Pearson,E. R. AU - Petrie,J. R. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_2 DO - 10.1111/dme.12091_2 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 197 EP - 197 ER - TY - JOUR T1 - Kelvin-Helmholtz instability in a current-vortex sheet at a 3D magnetic null A1 - Wyper,P.F. A1 - Pontin,D.I. AU - Wyper,P.F. AU - Pontin,D.I. PY - 2013/3 Y1 - 2013/3 N2 - We report here, for the first time, an observed instability of a Kelvin-Helmholtz nature occurring in a fully three-dimensional (3D) current-vortex sheet at the fan plane of a 3D magnetic null point. The current-vortex layer forms self-consistently in response to foot point driving around the spine lines of the null. The layer first becomes unstable at an intermediate distance from the null point, with the instability being characterized by a rippling of the fan surface and a filamentation of the current density and vorticity in the shear layer. Owing to the 3D geometry of the shear layer, a branching of the current filaments and vortices is observed. The instability results in a mixing of plasma between the two topologically distinct regions of magnetic flux on either side of the fan separatrix surface, as flux is reconnected across this surface. We make a preliminary investigation of the scaling of the system with the dissipation parameters. Our results indicate that the fan plane separatrix surface is an ideal candidate for the formation of current-vortex sheets in complex magnetic fields and, therefore, the enhanced heating and connectivity change associated with the instabilities of such layers. © 2013 American Institute of Physics. AB - We report here, for the first time, an observed instability of a Kelvin-Helmholtz nature occurring in a fully three-dimensional (3D) current-vortex sheet at the fan plane of a 3D magnetic null point. The current-vortex layer forms self-consistently in response to foot point driving around the spine lines of the null. The layer first becomes unstable at an intermediate distance from the null point, with the instability being characterized by a rippling of the fan surface and a filamentation of the current density and vorticity in the shear layer. Owing to the 3D geometry of the shear layer, a branching of the current filaments and vortices is observed. The instability results in a mixing of plasma between the two topologically distinct regions of magnetic flux on either side of the fan separatrix surface, as flux is reconnected across this surface. We make a preliminary investigation of the scaling of the system with the dissipation parameters. Our results indicate that the fan plane separatrix surface is an ideal candidate for the formation of current-vortex sheets in complex magnetic fields and, therefore, the enhanced heating and connectivity change associated with the instabilities of such layers. © 2013 American Institute of Physics. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875789287&md5=4b52f7a9b16f4b78e1f1604c35a09793 U2 - 10.1063/1.4798516 DO - 10.1063/1.4798516 M1 - Article JO - Physics of Plasmas JF - Physics of Plasmas SN - 1070-664X IS - 3 VL - 20 ER - TY - JOUR T1 - Lessons from Mackenzie that still resonate A1 - Van Hecke,Oliver A1 - Smith,Blair H. A1 - Sullivan,Frank M. AU - Van Hecke,Oliver AU - Smith,Blair H. AU - Sullivan,Frank M. PY - 2013/3 Y1 - 2013/3 N2 - On 4 June 1921 Sir James Mackenzie defended his thesis, The Opportunities of the General Practitioner are Essential for the Investigation of Disease and the Progress of Medicine, in the British Medical Journal. Just under a century later, there is still a message for all researchers in primary care which resonates. A short précis of a full commentary from the International Journal of Epidemiology is given below. © British Journal of General Practice. AB - On 4 June 1921 Sir James Mackenzie defended his thesis, The Opportunities of the General Practitioner are Essential for the Investigation of Disease and the Progress of Medicine, in the British Medical Journal. Just under a century later, there is still a message for all researchers in primary care which resonates. A short précis of a full commentary from the International Journal of Epidemiology is given below. © British Journal of General Practice. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875796087&md5=f33706c6d4e332992faf88f6f552e15b U2 - 10.3399/bjgp13X664423 DO - 10.3399/bjgp13X664423 M1 - Comment/debate JO - British Journal of General Practice JF - British Journal of General Practice SN - 0960-1643 IS - 608 VL - 63 SP - 158 EP - 159 ER - TY - JOUR T1 - Measuring endogenous insulin secretion in type 1 diabetes is life changing A1 - Connelly,P. J. A1 - Gellatly,E. A1 - Bell,L. A1 - Shepherd,M. A1 - Hattersley,A. T. A1 - Pearson,E. AU - Connelly,P. J. AU - Gellatly,E. AU - Bell,L. AU - Shepherd,M. AU - Hattersley,A. T. AU - Pearson,E. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_2 DO - 10.1111/dme.12091_2 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 94 EP - 95 ER - TY - JOUR T1 - Mechanical and durability studies on concrete containing wollastonite-fly ash combination A1 - Kalla,Pawan A1 - Misra,Anurag A1 - Gupta,Ramesh Chandra A1 - Csetenyi,Laszlo A1 - Gahlot,Vimal A1 - Arora,Amarnath AU - Kalla,Pawan AU - Misra,Anurag AU - Gupta,Ramesh Chandra AU - Csetenyi,Laszlo AU - Gahlot,Vimal AU - Arora,Amarnath PY - 2013/3 Y1 - 2013/3 N2 -

Several materials including fly ash, silica fume, metakaoline, wollastonite etc. which are either industrial wastes or naturally occurring minerals, have been investigated for making durable concrete material. Fly ash, silica fume, marble slurry etc. have been used in combination with wollastonite in cement concrete mixes for property enhancement. Huge amount of fly ash is being produced in India every year. It is expected to reach 225 million tons by 2017, creating its disposal problem which can be minimized by utilizing it in useful applications. The present investigation has been aimed to determine the influence of wollastonite-fly ash (W-FA) combination on properties of concrete such as strength, permeability, and durability over a range of water-binder (w/b) ratios and cement replacement. The microstructure and mercury intrusion porosity results of concrete mixes indicated that increased replacement levels of cement by W-FA combination (45-55%) causes some densification resulting into their enhanced mechanical and durability properties. (C) 2012 Elsevier Ltd. All rights reserved.

AB -

Several materials including fly ash, silica fume, metakaoline, wollastonite etc. which are either industrial wastes or naturally occurring minerals, have been investigated for making durable concrete material. Fly ash, silica fume, marble slurry etc. have been used in combination with wollastonite in cement concrete mixes for property enhancement. Huge amount of fly ash is being produced in India every year. It is expected to reach 225 million tons by 2017, creating its disposal problem which can be minimized by utilizing it in useful applications. The present investigation has been aimed to determine the influence of wollastonite-fly ash (W-FA) combination on properties of concrete such as strength, permeability, and durability over a range of water-binder (w/b) ratios and cement replacement. The microstructure and mercury intrusion porosity results of concrete mixes indicated that increased replacement levels of cement by W-FA combination (45-55%) causes some densification resulting into their enhanced mechanical and durability properties. (C) 2012 Elsevier Ltd. All rights reserved.

KW - Water-binder ratio KW - Durability KW - Fly ash KW - MICROSILICA KW - Concrete U2 - 10.1016/j.conbuildmat.2012.09.102 DO - 10.1016/j.conbuildmat.2012.09.102 M1 - Article JO - Construction and Building Materials JF - Construction and Building Materials SN - 0950-0618 VL - 40 SP - 1142 EP - 1150 ER - TY - JOUR T1 - Metformin pharmacogenetics and SLC2A2 T2 - genome-wide association study and 2-stage replication in GoDARTS and UKPDS A1 - Zhou,K. A1 - Bennett,A. A1 - Coleman,R. A1 - Groves,R. A1 - Holman,R. A1 - McCarthy,M. A1 - Palmer,C. A1 - Pearson,E. AU - Zhou,K. AU - Bennett,A. AU - Coleman,R. AU - Groves,R. AU - Holman,R. AU - McCarthy,M. AU - Palmer,C. AU - Pearson,E. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_1 DO - 10.1111/dme.12091_1 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 52 EP - 52 ER - TY - JOUR T1 - Nine out of 10 sunbeds in England emit ultraviolet radiation levels that exceed current safety limits A1 - Tierney,P. A1 - Ferguson,J. A1 - Ibbotson,S. A1 - Dawe,R. A1 - Eadie,E. A1 - Moseley,H. AU - Tierney,P. AU - Ferguson,J. AU - Ibbotson,S. AU - Dawe,R. AU - Eadie,E. AU - Moseley,H. PY - 2013/3 Y1 - 2013/3 N2 - Background Exposure to ultraviolet (UV) radiation from sunlight is recognized as the principal cause of skin cancer. Moreover, sunbeds have been classified as carcinogenic by the International Agency for Research on Cancer. Despite this, there is a shortage of objective data on UV exposure levels in sunbeds in England.

Objectives We set out to measure UV emission levels in sunbeds at sites around England, and to compare these levels with both current standards and natural sunlight.

Methods Between October 2010 and February 2011, UV spectra were measured on site from a total of 402 artificial tanning units in England. Measurement instrumentation was calibrated, traceable to the National Physical Laboratory. Compliance with the relevant British and European standard was determined, and a skin-cancer weighting factor was used to compare the carcinogenic potential of sunbeds with that of sunlight.

Results For compliance with the European standard, erythemal-effective irradiance should not exceed 0·3 W m-2. The values that we measured ranged between 0·10 and 1·32 W m-2 with a mean of 0·56 ± 0·21 W m-2. Only 10% of sunbeds surveyed were within the recommended limit. Application of the skin-cancer weighting factor produced values that varied from 0·17 to 2·52 W m-2 with a mean of 0·99 ± 0·41 W m-2. The comparable value for Mediterranean noonday sun was 0·43 W m-2.

Conclusions Nine out of 10 sunbeds surveyed throughout England emitted levels of UV radiation that exceed the maximum levels contained within the European standard. Moreover, the skin cancer risk for comparable times of exposure was up to six times higher than that for Mediterranean sunlight. This situation is unacceptable and stricter control measures must be put in place. AB - Background Exposure to ultraviolet (UV) radiation from sunlight is recognized as the principal cause of skin cancer. Moreover, sunbeds have been classified as carcinogenic by the International Agency for Research on Cancer. Despite this, there is a shortage of objective data on UV exposure levels in sunbeds in England.

Objectives We set out to measure UV emission levels in sunbeds at sites around England, and to compare these levels with both current standards and natural sunlight.

Methods Between October 2010 and February 2011, UV spectra were measured on site from a total of 402 artificial tanning units in England. Measurement instrumentation was calibrated, traceable to the National Physical Laboratory. Compliance with the relevant British and European standard was determined, and a skin-cancer weighting factor was used to compare the carcinogenic potential of sunbeds with that of sunlight.

Results For compliance with the European standard, erythemal-effective irradiance should not exceed 0·3 W m-2. The values that we measured ranged between 0·10 and 1·32 W m-2 with a mean of 0·56 ± 0·21 W m-2. Only 10% of sunbeds surveyed were within the recommended limit. Application of the skin-cancer weighting factor produced values that varied from 0·17 to 2·52 W m-2 with a mean of 0·99 ± 0·41 W m-2. The comparable value for Mediterranean noonday sun was 0·43 W m-2.

Conclusions Nine out of 10 sunbeds surveyed throughout England emitted levels of UV radiation that exceed the maximum levels contained within the European standard. Moreover, the skin cancer risk for comparable times of exposure was up to six times higher than that for Mediterranean sunlight. This situation is unacceptable and stricter control measures must be put in place. U2 - 10.1111/bjd.12181 DO - 10.1111/bjd.12181 M1 - Article JO - British Journal of Dermatology JF - British Journal of Dermatology SN - 0007-0963 IS - 3 VL - 168 SP - 602 EP - 608 ER - TY - JOUR T1 - Out of hours ophthalmic surgery T2 - a UK national survey A1 - O'Colmain,U. A1 - Wright,M. A1 - Bennett,H. A1 - MacEwen,C. J. AU - O'Colmain,U. AU - Wright,M. AU - Bennett,H. AU - MacEwen,C. J. PY - 2013/3 Y1 - 2013/3 N2 -

Aims There have been significant changes in the management of out of hours services in ophthalmology recently. The European Working Time Directive (EWTD) and economic measures have anecdotally reduced the availability of staff and facilities outside normal working hours, and there have been various responses to the provision of emergency surgical care. There are disparate attitudes to the optimum management of the emergency surgical case. We sought to establish a nationwide picture of the management of out of hours surgery.

Methods A questionnaire was distributed to every consultant ophthalmologist working in the NHS and registered with the Royal College of Ophthalmologists (n = 947). Information was requested regarding departmental and personal policies, local facilities, and personal beliefs regarding emergency surgery.

Results A total of 440 (46.5%) questionnaires were returned from 155 units; 18.7% of the units had no out of hours services or no operating facilities. Sixty-three percent of units reported a local policy regarding a time after which patients should not be taken to theatre. For 57%, this time began between 2100 hours and midnight. The most common reasons for not operating after a certain time were 'belief that delay does not significantly affect the outcome' (41.6%), 'delayed access to theatre due to competition with other surgical specialities' (40%), and 'no specialist ophthalmic-theatre nursing input' (32.7%).

Conclusion We report the first nationwide study on out of hours ophthalmological surgical working practices. This demonstrates variation in work patterns. It is significant to patients and ophthalmologists that there should be units in United Kingdom without full local facilities and staff. Eye (2013) 27, 363-366; doi:10.1038/eye.2012.280; published online 1 February 2013

AB -

Aims There have been significant changes in the management of out of hours services in ophthalmology recently. The European Working Time Directive (EWTD) and economic measures have anecdotally reduced the availability of staff and facilities outside normal working hours, and there have been various responses to the provision of emergency surgical care. There are disparate attitudes to the optimum management of the emergency surgical case. We sought to establish a nationwide picture of the management of out of hours surgery.

Methods A questionnaire was distributed to every consultant ophthalmologist working in the NHS and registered with the Royal College of Ophthalmologists (n = 947). Information was requested regarding departmental and personal policies, local facilities, and personal beliefs regarding emergency surgery.

Results A total of 440 (46.5%) questionnaires were returned from 155 units; 18.7% of the units had no out of hours services or no operating facilities. Sixty-three percent of units reported a local policy regarding a time after which patients should not be taken to theatre. For 57%, this time began between 2100 hours and midnight. The most common reasons for not operating after a certain time were 'belief that delay does not significantly affect the outcome' (41.6%), 'delayed access to theatre due to competition with other surgical specialities' (40%), and 'no specialist ophthalmic-theatre nursing input' (32.7%).

Conclusion We report the first nationwide study on out of hours ophthalmological surgical working practices. This demonstrates variation in work patterns. It is significant to patients and ophthalmologists that there should be units in United Kingdom without full local facilities and staff. Eye (2013) 27, 363-366; doi:10.1038/eye.2012.280; published online 1 February 2013

KW - training KW - INJURIES KW - ophthalmologic surgical procedures KW - after-hours care KW - IRAQI FREEDOM KW - policy KW - GLOBE U2 - 10.1038/eye.2012.280 DO - 10.1038/eye.2012.280 M1 - Article JO - Eye JF - Eye SN - 0950-222X IS - 3 VL - 27 SP - 363 EP - 366 ER - TY - JOUR T1 - Phase IIa randomized, placebo-controlled study of antimicrobial photodynamic therapy in bacterially colonized, chronic leg ulcers and diabetic foot ulcers: a new approach to antimicrobial therapy A1 - Morley,S. A1 - Griffiths,J. A1 - Philips,G. A1 - Moseley,H. A1 - O'Grady,C. A1 - Mellish,K. A1 - Lankester,C. L. A1 - Faris,B. A1 - Young,R. J. A1 - Brown,S. B. A1 - Rhodes,L. E. AU - Morley,S. AU - Griffiths,J. AU - Philips,G. AU - Moseley,H. AU - O'Grady,C. AU - Mellish,K. AU - Lankester,C. L. AU - Faris,B. AU - Young,R. J. AU - Brown,S. B. AU - Rhodes,L. E. PY - 2013/3 Y1 - 2013/3 N2 - Background With increasing problems of antibiotic resistance, photodynamic therapy (PDT) is being developed as a novel antimicrobial treatment. Following light activation, cationic photosensitizer PPA904 [3,7-bis(N,N-dibutylamino) phenothiazin-5-ium bromide] kills a broad spectrum of bacteria in vitro and this has a variety of potential clinical applications. Objectives To determine if PDT in bacterially colonized chronic leg ulcers and chronic diabetic foot ulcers can reduce bacterial load, and potentially lead to accelerated wound healing. Methods Sixteen patients with chronic leg ulcers and 16 patients with diabetic foot ulcers (each eight active treatment/eight placebo) were recruited into a blinded, randomized, placebo-controlled, single-treatment, Phase IIa trial. All patients had ulcer duration > 3 months, bacterially colonized with > 10 colony-forming units cm . After quantitatively assessing pretreatment bacterial load via swabbing, PPA904 or placebo was applied topically to wounds for 15 min, followed immediately by 50 J cm of red light and the wound again sampled for quantitative microbiology. The wound area was measured for up to 3 months following treatment. Results Treatment was well tolerated with no reports of pain or other safety issues. In contrast to placebo, patients on active treatment showed a reduction in bacterial load immediately post-treatment (P AB - Background With increasing problems of antibiotic resistance, photodynamic therapy (PDT) is being developed as a novel antimicrobial treatment. Following light activation, cationic photosensitizer PPA904 [3,7-bis(N,N-dibutylamino) phenothiazin-5-ium bromide] kills a broad spectrum of bacteria in vitro and this has a variety of potential clinical applications. Objectives To determine if PDT in bacterially colonized chronic leg ulcers and chronic diabetic foot ulcers can reduce bacterial load, and potentially lead to accelerated wound healing. Methods Sixteen patients with chronic leg ulcers and 16 patients with diabetic foot ulcers (each eight active treatment/eight placebo) were recruited into a blinded, randomized, placebo-controlled, single-treatment, Phase IIa trial. All patients had ulcer duration > 3 months, bacterially colonized with > 10 colony-forming units cm . After quantitatively assessing pretreatment bacterial load via swabbing, PPA904 or placebo was applied topically to wounds for 15 min, followed immediately by 50 J cm of red light and the wound again sampled for quantitative microbiology. The wound area was measured for up to 3 months following treatment. Results Treatment was well tolerated with no reports of pain or other safety issues. In contrast to placebo, patients on active treatment showed a reduction in bacterial load immediately post-treatment (P UR - http://europepmc.org/abstract/MED/23066973 U2 - 10.1111/bjd.12098 DO - 10.1111/bjd.12098 M1 - Article JO - British Journal of Dermatology JF - British Journal of Dermatology SN - 0007-0963 IS - 3 VL - 168 SP - 617 EP - 624 ER - TY - JOUR T1 - Possibilities for human skin characterization based on strongly reduced Raman spectroscopic information A1 - Baclig,A.C. A1 - Bakker Schut,T.C. A1 - O'Regan,G.M. A1 - Irvine,A.D. A1 - McLean,W.H.I. A1 - Puppels,G.J. A1 - Caspers,P.J. AU - Baclig,A.C. AU - Bakker Schut,T.C. AU - O'Regan,G.M. AU - Irvine,A.D. AU - McLean,W.H.I. AU - Puppels,G.J. AU - Caspers,P.J. PY - 2013/3 Y1 - 2013/3 N2 - Loss-of-function mutations in the gene coding for filaggrin are the single most important risk factor for development of atopic dermatitis and associated allergic rhinitis and asthma. Filaggrin is enzymatically degraded to natural moisturizing factor (NMF) in the stratum corneum (SC). In vivo Raman spectra of human skin can be used to quantify the NMF concentration in SC and thereby identify carriers of a loss-of-function mutation in the gene coding for filaggrin, which results in decreased NMF content. Here, we demonstrate that strongly reduced Raman spectral information is sufficient to make this differentiation. This is an important step towards development of a dedicated diagnostic device of reduced complexity, size and cost as compared to current state-of-the-art Raman equipment. A genetic algorithm was used to select the spectral regions needed to classify skin based on normal or reduced NMF content in SC. Using the NMF content based on full spectral information as gold standard, only four Raman regions were required to create a linear discriminant analysis model that can differentiate between skin with low NMF and skin with normal NMF with a prediction accuracy of 93 %. Copyright © 2013 John Wiley & Sons, Ltd. AB - Loss-of-function mutations in the gene coding for filaggrin are the single most important risk factor for development of atopic dermatitis and associated allergic rhinitis and asthma. Filaggrin is enzymatically degraded to natural moisturizing factor (NMF) in the stratum corneum (SC). In vivo Raman spectra of human skin can be used to quantify the NMF concentration in SC and thereby identify carriers of a loss-of-function mutation in the gene coding for filaggrin, which results in decreased NMF content. Here, we demonstrate that strongly reduced Raman spectral information is sufficient to make this differentiation. This is an important step towards development of a dedicated diagnostic device of reduced complexity, size and cost as compared to current state-of-the-art Raman equipment. A genetic algorithm was used to select the spectral regions needed to classify skin based on normal or reduced NMF content in SC. Using the NMF content based on full spectral information as gold standard, only four Raman regions were required to create a linear discriminant analysis model that can differentiate between skin with low NMF and skin with normal NMF with a prediction accuracy of 93 %. Copyright © 2013 John Wiley & Sons, Ltd. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875699125&md5=32b6299dccb4dceddbeda91a05b3d09a U2 - 10.1002/jrs.4198 DO - 10.1002/jrs.4198 M1 - Article JO - Journal of Raman Spectroscopy JF - Journal of Raman Spectroscopy SN - 0377-0486 IS - 3 VL - 44 SP - 340 EP - 345 ER - TY - JOUR T1 - Progress on website accessibility? A1 - Hanson,Vicki L. A1 - Richards,John T. AU - Hanson,Vicki L. AU - Richards,John T. PY - 2013/3 Y1 - 2013/3 N2 - Over 100 top-traffic and government websites from the United States and United Kingdom were examined for evidence of changes on accessibility indicators over the 14-year period from 1999 to 2012, the longest period studied to date. Automated analyses of WCAG 2.0 Level A Success Criteria found high percentages of violations overall. Unlike more circumscribed studies, however, these sites exhibited improvements over the years on a number of accessibility indicators, with government sites being less likely than topsites to have accessibility violations. Examination of the causes of success and failure suggests that improving accessibility may be due, in part, to changes in website technologies and coding practices rather than a focus on accessibility per se. AB - Over 100 top-traffic and government websites from the United States and United Kingdom were examined for evidence of changes on accessibility indicators over the 14-year period from 1999 to 2012, the longest period studied to date. Automated analyses of WCAG 2.0 Level A Success Criteria found high percentages of violations overall. Unlike more circumscribed studies, however, these sites exhibited improvements over the years on a number of accessibility indicators, with government sites being less likely than topsites to have accessibility violations. Examination of the causes of success and failure suggests that improving accessibility may be due, in part, to changes in website technologies and coding practices rather than a focus on accessibility per se. U2 - 10.1145/2435215.2435217 DO - 10.1145/2435215.2435217 M1 - Article JO - ACM Transactions on the Web JF - ACM Transactions on the Web SN - 1559-1131 IS - 1 VL - 7 ER - TY - JOUR T1 - Serial and parallel processes in eye movement control T2 - Current controversies and future directions A1 - Murray,Wayne S A1 - Fischer,Martin H A1 - Tatler,Benjamin W AU - Murray,Wayne S AU - Fischer,Martin H AU - Tatler,Benjamin W PY - 2013/3 Y1 - 2013/3 N2 - In this editorial for the Special Issue on Serial and Parallel Processing in Reading we explore the background to the current debate concerning whether the word recognition processes in reading are strictly serial-sequential or take place in an overlapping parallel fashion. We consider the history of the controversy and some of the underlying assumptions, together with an analysis of the types of evidence and arguments that have been adduced to both sides of the debate, concluding that both accounts necessarily presuppose some weakening of, or elasticity in, the eye-mind assumption. We then consider future directions, both for reading research and for scene viewing, and wrap up the editorial with a brief overview of the following articles and their conclusions. AB - In this editorial for the Special Issue on Serial and Parallel Processing in Reading we explore the background to the current debate concerning whether the word recognition processes in reading are strictly serial-sequential or take place in an overlapping parallel fashion. We consider the history of the controversy and some of the underlying assumptions, together with an analysis of the types of evidence and arguments that have been adduced to both sides of the debate, concluding that both accounts necessarily presuppose some weakening of, or elasticity in, the eye-mind assumption. We then consider future directions, both for reading research and for scene viewing, and wrap up the editorial with a brief overview of the following articles and their conclusions. U2 - 10.1080/17470218.2012.759979 DO - 10.1080/17470218.2012.759979 M1 - Article JO - Quarterly Journal of Experimental Psychology JF - Quarterly Journal of Experimental Psychology SN - 1747-0218 IS - 3 VL - 66 SP - 417 EP - 428 ER - TY - JOUR T1 - Sleep and sleep-wake disturbances in care recipient-caregiver dyads in the context of a chronic illness T2 - a critical review of the literature A1 - Kotronoulas,Grigorios A1 - Wengström,Yvonne A1 - Kearney,Nora AU - Kotronoulas,Grigorios AU - Wengström,Yvonne AU - Kearney,Nora PY - 2013/3 Y1 - 2013/3 N2 -

Context. Alterations in sleep-wake patterns of care recipients and their informal caregivers are common in the context of a chronic illness. Given the current notion that sleep may be regulated within and affected by close human relationships, concurrent and interrelated sleep problems may be present in care recipient-caregiver dyads.

Objectives. To critically analyze evidence regarding concurrent sleep patterns or changes in care recipient-caregiver dyads in the context of a chronic illness and address methodological and research gaps.

Methods. Using a wide range of key terms and synonyms, three electronic databases (Medline, CINAHL, and Embase) were systematically searched for the period between January 1990 and July 2011.

Results. Ten studies met prespecified selection criteria and were included for analysis. Study quality was fair to good on average. Seven studies were conducted in the context of dementia or Parkinson's disease, two in the context of cancer, and one study included a group of community elders with mixed related comorbidities and their informal caregivers. Bidirectional associations in the sleep of care recipient-caregiver dyads seem to exist. Concurrent and comparable nocturnal sleep disruptions also may be evident. Yet, inconsistencies in the methods implemented, and the samples included, as well as uncertainty regarding factors coaffecting sleep, still preclude safe conclusions to be drawn on.

Conclusion. The dyadic investigation of sleep is a promising approach to the development of truly effective interventions to improve sleep quality of care recipients and their caregivers. Nevertheless, more systematic, longitudinal dyadic research is warranted to augment our understanding of co-occurrence and over time changes of sleep problems in care recipient-caregiver dyads, as well as to clarify covariates/factors that appear to contribute to these problems within the dyad and across time and context of illness. J Pain Symptom Manage 2013;45:579-594. (C) 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

AB -

Context. Alterations in sleep-wake patterns of care recipients and their informal caregivers are common in the context of a chronic illness. Given the current notion that sleep may be regulated within and affected by close human relationships, concurrent and interrelated sleep problems may be present in care recipient-caregiver dyads.

Objectives. To critically analyze evidence regarding concurrent sleep patterns or changes in care recipient-caregiver dyads in the context of a chronic illness and address methodological and research gaps.

Methods. Using a wide range of key terms and synonyms, three electronic databases (Medline, CINAHL, and Embase) were systematically searched for the period between January 1990 and July 2011.

Results. Ten studies met prespecified selection criteria and were included for analysis. Study quality was fair to good on average. Seven studies were conducted in the context of dementia or Parkinson's disease, two in the context of cancer, and one study included a group of community elders with mixed related comorbidities and their informal caregivers. Bidirectional associations in the sleep of care recipient-caregiver dyads seem to exist. Concurrent and comparable nocturnal sleep disruptions also may be evident. Yet, inconsistencies in the methods implemented, and the samples included, as well as uncertainty regarding factors coaffecting sleep, still preclude safe conclusions to be drawn on.

Conclusion. The dyadic investigation of sleep is a promising approach to the development of truly effective interventions to improve sleep quality of care recipients and their caregivers. Nevertheless, more systematic, longitudinal dyadic research is warranted to augment our understanding of co-occurrence and over time changes of sleep problems in care recipient-caregiver dyads, as well as to clarify covariates/factors that appear to contribute to these problems within the dyad and across time and context of illness. J Pain Symptom Manage 2013;45:579-594. (C) 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

KW - PATIENT KW - critical review KW - RANDOMIZED-TRIAL KW - DEMENTIA KW - QUALITY-OF-LIFE KW - sleep-wake disturbances KW - PARKINSONS-DISEASE KW - INSTRUMENTS KW - patient-caregiver dyad KW - FAMILY CAREGIVERS KW - chronic illness KW - Sleep KW - COUPLES KW - informal caregiving KW - dyadic approach KW - DEPRESSIVE SYMPTOMS KW - CANCER-PATIENTS U2 - 10.1016/j.jpainsymman.2012.03.013 DO - 10.1016/j.jpainsymman.2012.03.013 M1 - Scientific review JO - Journal of Pain and Symptom Management JF - Journal of Pain and Symptom Management SN - 0885-3924 IS - 3 VL - 45 SP - 579 EP - 594 ER - TY - JOUR T1 - Subcutaneous insulin administration in hospital T2 - a framework for self-management A1 - Hodgson,A. D. A1 - Voigt,D. J. AU - Hodgson,A. D. AU - Voigt,D. J. PY - 2013/3 Y1 - 2013/3 U2 - 10.1111/dme.12091_2 DO - 10.1111/dme.12091_2 M1 - Meeting abstract JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - Suppl. 1 VL - 30 SP - 135 EP - 136 ER - TY - JOUR T1 - Targeting the renin-angiotensin-aldosterone system in heart failure A1 - Lang,Chim C. A1 - Struthers,Allan D. AU - Lang,Chim C. AU - Struthers,Allan D. PY - 2013/3 Y1 - 2013/3 N2 - The renin-angiotensin-aldosterone system is a well-established therapeutic target in the treatment of heart failure (HF). Substantial advances have been made with existing agents-angiotensin-converting enzyme (ACE) inhibitors, angiotensin II-receptor blockers (ARBs), and mineralocorticoid-receptor antagonists (MRAs)-and new data continue to emerge. The indication for the use of MRAs has been broadened to include potentially all patients who have HF with reduced ejection fraction (HFrEF), and ACE inhibitors might have a novel application in patients who are at risk of left ventricular dysfunction (those with aortic valvular disease or pacing-induced heart disease). ARBs have been shown to be a beneficial alternative to ACE inhibitors in HFrEF, but their value when added to ACE inhibitors has been questioned. Upstream, direct renin blockade with aliskiren is being pursued in two large trials of HF, despite the premature halting of a third study. A substantial, unmet need remains in patients who have HF with preserved ejection fraction (HFpEF). New data on spironolactone and LCZ696 (a combined ARB and neprilysin inhibitor) show promise for these patients. Results of the TOPCAT study of spironolactone in patients with HFpEF are awaited, and LCZ696 is now being tested in a large trial in patients with HFrEF. AB - The renin-angiotensin-aldosterone system is a well-established therapeutic target in the treatment of heart failure (HF). Substantial advances have been made with existing agents-angiotensin-converting enzyme (ACE) inhibitors, angiotensin II-receptor blockers (ARBs), and mineralocorticoid-receptor antagonists (MRAs)-and new data continue to emerge. The indication for the use of MRAs has been broadened to include potentially all patients who have HF with reduced ejection fraction (HFrEF), and ACE inhibitors might have a novel application in patients who are at risk of left ventricular dysfunction (those with aortic valvular disease or pacing-induced heart disease). ARBs have been shown to be a beneficial alternative to ACE inhibitors in HFrEF, but their value when added to ACE inhibitors has been questioned. Upstream, direct renin blockade with aliskiren is being pursued in two large trials of HF, despite the premature halting of a third study. A substantial, unmet need remains in patients who have HF with preserved ejection fraction (HFpEF). New data on spironolactone and LCZ696 (a combined ARB and neprilysin inhibitor) show promise for these patients. Results of the TOPCAT study of spironolactone in patients with HFpEF are awaited, and LCZ696 is now being tested in a large trial in patients with HFrEF. U2 - 10.1038/nrcardio.2012.196 DO - 10.1038/nrcardio.2012.196 M1 - Article JO - Nature reviews. Cardiology JF - Nature reviews. Cardiology SN - 1759-5002 VL - 10 SP - 125 EP - 134 ER - TY - JOUR T1 - The functional exchangeability of pk- and k-turns in RNA structure A1 - Daldrop,Peter A1 - Masquida,Benoit A1 - Lilley,David M. J. AU - Daldrop,Peter AU - Masquida,Benoit AU - Lilley,David M. J. PY - 2013/3 Y1 - 2013/3 N2 -

Ribonuclease P RNA requires a sharply kinked RNA helix to make a loop-receptor interaction that creates the binding site for the substrate. In some forms of the ribozyme, this is accomplished by a k-turn, while others have a different element called the pk-turn. The structure of the pk-turn in RNase P of Thermotoga maritima is globally very similar to a k-turn, but lacks all the standard features of that structure, including long-range hydrogen bonds between the two helical arms. We show here that in an isolated RNA duplex, the pk-turn fails to adopt a tightly kinked structure, but rather is a flexible element. This suggests that the tertiary contacts of RNase P assist its folding into the required kinked structure. We find that we can replace the k-turn of the SAM-I riboswitch with the pk-turn, such that the resulting RNA retains its ability to bind SAM, although with lower affinity. We also find that we can replace the pk-turn of T. maritima RNase P with a standard k-turn (in either orientation) with retention of ribozyme activity. Thus, although the pk-turn cannot intrinsically fold into the kinked structure, it can be induced to fold correctly in context. And the pk-turn and k-turns can substitute functionally for one another.

AB -

Ribonuclease P RNA requires a sharply kinked RNA helix to make a loop-receptor interaction that creates the binding site for the substrate. In some forms of the ribozyme, this is accomplished by a k-turn, while others have a different element called the pk-turn. The structure of the pk-turn in RNase P of Thermotoga maritima is globally very similar to a k-turn, but lacks all the standard features of that structure, including long-range hydrogen bonds between the two helical arms. We show here that in an isolated RNA duplex, the pk-turn fails to adopt a tightly kinked structure, but rather is a flexible element. This suggests that the tertiary contacts of RNase P assist its folding into the required kinked structure. We find that we can replace the k-turn of the SAM-I riboswitch with the pk-turn, such that the resulting RNA retains its ability to bind SAM, although with lower affinity. We also find that we can replace the pk-turn of T. maritima RNase P with a standard k-turn (in either orientation) with retention of ribozyme activity. Thus, although the pk-turn cannot intrinsically fold into the kinked structure, it can be induced to fold correctly in context. And the pk-turn and k-turns can substitute functionally for one another.

KW - RNase P KW - BINDING KW - SAM-I riboswitch KW - MOTIF KW - RNA folding KW - CRYSTAL-STRUCTURE KW - LYSINE RIBOSWITCH KW - L7AE PROTEIN KW - ELEMENT KW - RNA structure KW - HELICAL JUNCTIONS KW - INDUCED FIT KW - SNRNA KW - NUCLEIC-ACIDS KW - kink turn U2 - 10.4161/rna.23673 DO - 10.4161/rna.23673 M1 - Article JO - RNA Biology JF - RNA Biology SN - 1547-6286 IS - 3 VL - 10 SP - 445 EP - 452 ER - TY - JOUR T1 - The utility of the proximal epiphysis of the fifth metatarsal in age estimation A1 - Davies,Catriona M. A1 - Hackman,Lucina A1 - Black,Sue AU - Davies,Catriona M. AU - Hackman,Lucina AU - Black,Sue PY - 2013/3 Y1 - 2013/3 N2 - Radiographs of 277 living individuals were assessed via a numerical scoring system to determine the timing of appearance and degree of fusion between the proximal epiphysis of the fifth metatarsal and its diaphysis. The epiphysis was observed to first appear in females at 8 years and 10 years in males and fuse by 14 years in females and 15 years in males. When assessing the level of agreement of category assignment, inter-observer agreement was 78% for females and 64% for males whereas intra-observer agreement was 77% for females and 86.1% for males. These results suggest that the maturation of the proximal epiphysis of the fifth metatarsal may be of value in age estimation in the child and that the scoring system is sufficiently robust to merit continued investigation. Previously this epiphysis has been considered an inconstant feature, but this research confirmed its presence in all individuals studied. AB - Radiographs of 277 living individuals were assessed via a numerical scoring system to determine the timing of appearance and degree of fusion between the proximal epiphysis of the fifth metatarsal and its diaphysis. The epiphysis was observed to first appear in females at 8 years and 10 years in males and fuse by 14 years in females and 15 years in males. When assessing the level of agreement of category assignment, inter-observer agreement was 78% for females and 64% for males whereas intra-observer agreement was 77% for females and 86.1% for males. These results suggest that the maturation of the proximal epiphysis of the fifth metatarsal may be of value in age estimation in the child and that the scoring system is sufficiently robust to merit continued investigation. Previously this epiphysis has been considered an inconstant feature, but this research confirmed its presence in all individuals studied. KW - Forensic science KW - Forensic anthropology KW - Age estimation KW - Epiphyseal union KW - Foot KW - Fifth metatarsal U2 - 10.1111/1556-4029.12069 DO - 10.1111/1556-4029.12069 M1 - Article JO - Journal of Forensic Sciences JF - Journal of Forensic Sciences SN - 0022-1198 IS - 2 VL - 58 SP - 436 EP - 442 ER - TY - JOUR T1 - Thyroid testing in pregnant women with thyroid dysfunction in Tayside, Scotland T2 - the thyroid epidemiology, audit and research study (TEARS) A1 - Vadiveloo,Thenmalar A1 - Mires,Gary J A1 - Donnan,Peter T A1 - Leese,Graham P AU - Vadiveloo,Thenmalar AU - Mires,Gary J AU - Donnan,Peter T AU - Leese,Graham P PY - 2013/3 Y1 - 2013/3 N2 - Objective
To investigate the rate of thyroid testing during pregnancy.

Design
Population-based, retrospective record-linkage study.

Setting
Health care data on pregnant women in Tayside, Scotland.

Participants
All pregnant women who were 18 years and above and who delivered between 1 January 1993 and 31 March 2011 in Tayside were identified. Patients were included in the study if they have had at least three thyroxine prescriptions prior to pregnancy of which at least one prescription was within 6 months prior to pregnancy.

Main outcome measures
Number of thyroid-stimulating hormone (TSH) assays performed during pregnancy and the changes in dosage of thyroxine prescribed during pregnancy.

Results
We identified 950 pregnancies that had thyroxine prescribed prior to pregnancy. Overall, 96·9% (95% CI: 96–98) of these pregnancies had at least one TSH assay performed during or just prior to pregnancy, with 81·2% (95% CI: 79–84) in the first trimester. The prescription of thyroxine was increased in 60·0% (95% CI: 57–63) at any time during pregnancy and in 34·0% (95% CI: 31–37) of pregnancies during the first trimester. Overall, 60% (95% CI: 57–63) of pregnancies had at least one elevated serum TSH during pregnancy with 55% (95% CI: 51–58) in the first trimester.

Conclusion
The TSH concentration is raised in many pregnancies in women taking long-term thyroxine. AB - Objective
To investigate the rate of thyroid testing during pregnancy.

Design
Population-based, retrospective record-linkage study.

Setting
Health care data on pregnant women in Tayside, Scotland.

Participants
All pregnant women who were 18 years and above and who delivered between 1 January 1993 and 31 March 2011 in Tayside were identified. Patients were included in the study if they have had at least three thyroxine prescriptions prior to pregnancy of which at least one prescription was within 6 months prior to pregnancy.

Main outcome measures
Number of thyroid-stimulating hormone (TSH) assays performed during pregnancy and the changes in dosage of thyroxine prescribed during pregnancy.

Results
We identified 950 pregnancies that had thyroxine prescribed prior to pregnancy. Overall, 96·9% (95% CI: 96–98) of these pregnancies had at least one TSH assay performed during or just prior to pregnancy, with 81·2% (95% CI: 79–84) in the first trimester. The prescription of thyroxine was increased in 60·0% (95% CI: 57–63) at any time during pregnancy and in 34·0% (95% CI: 31–37) of pregnancies during the first trimester. Overall, 60% (95% CI: 57–63) of pregnancies had at least one elevated serum TSH during pregnancy with 55% (95% CI: 51–58) in the first trimester.

Conclusion
The TSH concentration is raised in many pregnancies in women taking long-term thyroxine. U2 - 10.1111/j.1365-2265.2012.04426.x DO - 10.1111/j.1365-2265.2012.04426.x M1 - Article JO - Clinical Endocrinology JF - Clinical Endocrinology IS - 3 VL - 78 SP - 466 EP - 471 ER - TY - JOUR T1 - Transrectal quantitative shear wave elastography in the detection and characterisation of prostate cancer A1 - Ahmad,Sarfraz A1 - Cao,Rui A1 - Varghese,Tomy A1 - Bidaut,Luc A1 - Nabi,Ghulam AU - Ahmad,Sarfraz AU - Cao,Rui AU - Varghese,Tomy AU - Bidaut,Luc AU - Nabi,Ghulam PY - 2013/3 Y1 - 2013/3 N2 - Background: Shear wave imaging (SWI) is a new ultrasound technique whose application facilitates quantitative tissue elasticity assessment during transrectal ultrasound biopsies of the prostate gland. The aim of this study was to determine whether SWI quantitative data can differentiate between benign and malignant areas within prostate glands in men suspected of prostate cancer (PCa). Methods: We conducted a protocol-based, prospective, prebiopsy quantitative SWI of prostate glands in 50 unscreened men suspected of prostate cancer between July 2011 and May 2012. The ultrasound image of whole prostate gland was arbitrarily divided into 12 zones for sampling biopsies, as is carried out in routine clinical practice. Each region was imaged by grey scale and SWI imaging techniques. Each region was further biopsied irrespective of findings of grey scale or SWI on ultrasound. Additional biopsies were taken if SWI abnormal area was felt to be outside of these 12 zones. Quantitative assessment of SWI abnormal areas was obtained in kilopascals (kPa) from abnormal regions shown by SWI and compared with histopathology. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios were calculated for SWI (histopathology was a reference standard). Results: Fifty patients, with a mean age of 69 ± 6.2 years, were recruited into the study. Thirty-three (66 %) patients were diagnosed with PCa, while an additional 4 (8 %) had atypia in at least one of the 12 prostate biopsies. Thirteen (26 %) patients had a benign biopsy. Data analysed per core for SWI findings showed that for patients with PSA 20 µg/L, the sensitivity and specificity were 0.93 and 0.93, respectively. In addition, PCa had significantly higher stiffness values compared to benign tissues (p AB - Background: Shear wave imaging (SWI) is a new ultrasound technique whose application facilitates quantitative tissue elasticity assessment during transrectal ultrasound biopsies of the prostate gland. The aim of this study was to determine whether SWI quantitative data can differentiate between benign and malignant areas within prostate glands in men suspected of prostate cancer (PCa). Methods: We conducted a protocol-based, prospective, prebiopsy quantitative SWI of prostate glands in 50 unscreened men suspected of prostate cancer between July 2011 and May 2012. The ultrasound image of whole prostate gland was arbitrarily divided into 12 zones for sampling biopsies, as is carried out in routine clinical practice. Each region was imaged by grey scale and SWI imaging techniques. Each region was further biopsied irrespective of findings of grey scale or SWI on ultrasound. Additional biopsies were taken if SWI abnormal area was felt to be outside of these 12 zones. Quantitative assessment of SWI abnormal areas was obtained in kilopascals (kPa) from abnormal regions shown by SWI and compared with histopathology. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios were calculated for SWI (histopathology was a reference standard). Results: Fifty patients, with a mean age of 69 ± 6.2 years, were recruited into the study. Thirty-three (66 %) patients were diagnosed with PCa, while an additional 4 (8 %) had atypia in at least one of the 12 prostate biopsies. Thirteen (26 %) patients had a benign biopsy. Data analysed per core for SWI findings showed that for patients with PSA 20 µg/L, the sensitivity and specificity were 0.93 and 0.93, respectively. In addition, PCa had significantly higher stiffness values compared to benign tissues (p UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875205626&md5=b1bc77bd57ca34f1c7ceaa060e0b2908 U2 - 10.1007/s00464-013-2906-7 DO - 10.1007/s00464-013-2906-7 M1 - Article JO - Surgical Endoscopy JF - Surgical Endoscopy SN - 0930-2794 SP - 1 EP - 8 ER - TY - JOUR T1 - Use of aspirin post-diagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality A1 - McCowan,C. A1 - Munro,A. J. A1 - Donnan,P. T. A1 - Steele,R. J. C. AU - McCowan,C. AU - Munro,A. J. AU - Donnan,P. T. AU - Steele,R. J. C. PY - 2013/3 Y1 - 2013/3 N2 -

Objective: Aspirin is associated with a reduced risk of developing colorectal cancer. This study examined whether patients with colorectal cancer prescribed aspirin had improved survival.

Design: An observational population cohort study was undertaken using data linkage of cancer registry, dispensed prescriptions and death certificate records in Tayside, Scotland. All community prescribed aspirin pre- and post-diagnosis was extracted and periods of aspirin use post-diagnosis for each individual were analysed using Cox proportional hazard models. Main outcome measures were all-cause and colorectal mortality from death certificates.

Results: Two thousand nine hundred ninety patients were identified with colorectal cancer between 1st January 1997 and 30th December 2006 and followed up until 28th February 2010. Median age at diagnosis was 73 (interquartile range [IQR] 65-80) with 52% male. One thousand nine hundred ninety-eight (67%) deaths were recorded with 1021 (34%) attributed to colorectal cancer. One thousand three hundred forty (45%) patients used aspirin at some stage of the study period.

Aspirin use post-diagnosis was associated with lower risk of all cause mortality (hazard ratio [HR] = 0.67, 95% confidence interval [CI] = 0.57-0.79, p <0.001) and colorectal cancer specific mortality after allowing for age, Dukes' stage, gender, socio-economic status and aspirin use pre-diagnosis. Increasing age and stage at diagnosis were associated with increased risk, with more affluent patients at reduced risk.

Conclusions: Our study suggests that aspirin use post-diagnosis of colorectal cancer may reduce both all cause and colorectal cancer specific mortality. However further work is required to ensure this is a causal relationship and to identify whether it is best used in specific groups of patients. (C) 2012 Elsevier Ltd. All rights reserved.

AB -

Objective: Aspirin is associated with a reduced risk of developing colorectal cancer. This study examined whether patients with colorectal cancer prescribed aspirin had improved survival.

Design: An observational population cohort study was undertaken using data linkage of cancer registry, dispensed prescriptions and death certificate records in Tayside, Scotland. All community prescribed aspirin pre- and post-diagnosis was extracted and periods of aspirin use post-diagnosis for each individual were analysed using Cox proportional hazard models. Main outcome measures were all-cause and colorectal mortality from death certificates.

Results: Two thousand nine hundred ninety patients were identified with colorectal cancer between 1st January 1997 and 30th December 2006 and followed up until 28th February 2010. Median age at diagnosis was 73 (interquartile range [IQR] 65-80) with 52% male. One thousand nine hundred ninety-eight (67%) deaths were recorded with 1021 (34%) attributed to colorectal cancer. One thousand three hundred forty (45%) patients used aspirin at some stage of the study period.

Aspirin use post-diagnosis was associated with lower risk of all cause mortality (hazard ratio [HR] = 0.67, 95% confidence interval [CI] = 0.57-0.79, p <0.001) and colorectal cancer specific mortality after allowing for age, Dukes' stage, gender, socio-economic status and aspirin use pre-diagnosis. Increasing age and stage at diagnosis were associated with increased risk, with more affluent patients at reduced risk.

Conclusions: Our study suggests that aspirin use post-diagnosis of colorectal cancer may reduce both all cause and colorectal cancer specific mortality. However further work is required to ensure this is a causal relationship and to identify whether it is best used in specific groups of patients. (C) 2012 Elsevier Ltd. All rights reserved.

KW - RISK KW - COLON-CANCER KW - Colorectal cancer KW - SURVIVAL KW - Survival KW - ADENOMAS KW - CYCLOOXYGENASE-2 INHIBITOR KW - ROFECOXIB KW - RANDOMIZED-TRIALS KW - Aspirin KW - PREVENTION KW - TUMOR-GROWTH KW - LIVER METASTASIS U2 - 10.1016/j.ejca.2012.10.024 DO - 10.1016/j.ejca.2012.10.024 M1 - Article JO - European Journal of Cancer JF - European Journal of Cancer SN - 0959-8049 IS - 5 VL - 49 SP - 1049 EP - 1057 ER - TY - JOUR T1 - Utility of prognostic genomic tests in breast cancer practice T2 - The IMPAKT 2012 Working Group Consensus Statement A1 - Azim,H. A. A1 - Michiels,S. A1 - Zagouri,F. A1 - Delaloge,S. A1 - Filipits,M. A1 - Namer,M. A1 - Neven,P. A1 - Symmans,W. F. A1 - Thompson,A. A1 - Andre,F. A1 - Loi,S. A1 - Swanton,C. AU - Azim,H. A. AU - Michiels,S. AU - Zagouri,F. AU - Delaloge,S. AU - Filipits,M. AU - Namer,M. AU - Neven,P. AU - Symmans,W. F. AU - Thompson,A. AU - Andre,F. AU - Loi,S. AU - Swanton,C. PY - 2013/3 Y1 - 2013/3 N2 -

Background: We critically evaluated the available evidence on genomic tests in breast cancer to define their prognostic ability and likelihood to determine treatment benefit.

Design: Independent evaluation of six genomic tests [Oncotype Dx (TM), MammaPrint (R), Genomic Grade Index, PAM50 (ROR-S), Breast Cancer Index, and EndoPredict] was carried out by a panel of experts in three parameters: analytical validity, clinical validity, and clinical utility based on the principles of the EGAPP criteria.

Panel statements: The majority of the working group members found the available evidence on the analytical and clinical validity of Oncotype Dx (TM) and MammaPrint (R) to be convincing. None of the genomic tests demonstrated robust evidence of clinical utility: it was not clear from the current evidence that modifying treatment decisions based on the results of a given genomic test could result in improving clinical outcome.

Conclusions: The IMPAKT 2012 Working Group proposed the following recommendations: (I) a need to develop models that integrate clinicopathologic factors along with genomic tests; (ii) demonstration of clinical utility should be made in the context of a prospective randomized trial; and (ii) the creation of registries for patients who are subjected to genomic testing in the daily practice.

AB -

Background: We critically evaluated the available evidence on genomic tests in breast cancer to define their prognostic ability and likelihood to determine treatment benefit.

Design: Independent evaluation of six genomic tests [Oncotype Dx (TM), MammaPrint (R), Genomic Grade Index, PAM50 (ROR-S), Breast Cancer Index, and EndoPredict] was carried out by a panel of experts in three parameters: analytical validity, clinical validity, and clinical utility based on the principles of the EGAPP criteria.

Panel statements: The majority of the working group members found the available evidence on the analytical and clinical validity of Oncotype Dx (TM) and MammaPrint (R) to be convincing. None of the genomic tests demonstrated robust evidence of clinical utility: it was not clear from the current evidence that modifying treatment decisions based on the results of a given genomic test could result in improving clinical outcome.

Conclusions: The IMPAKT 2012 Working Group proposed the following recommendations: (I) a need to develop models that integrate clinicopathologic factors along with genomic tests; (ii) demonstration of clinical utility should be made in the context of a prospective randomized trial; and (ii) the creation of registries for patients who are subjected to genomic testing in the daily practice.

KW - RISK KW - METASTATIC COLORECTAL-CANCER KW - VALIDATION KW - ASSAY KW - GRADE KW - PREDICTOR KW - SUBTYPES KW - prediction KW - prognosis KW - GENE-EXPRESSION SIGNATURE KW - ADJUVANT KW - breast cancer KW - genomic signatures KW - RECURRENCE SCORE U2 - 10.1093/annonc/mds645 DO - 10.1093/annonc/mds645 M1 - Article JO - Annals of Oncology JF - Annals of Oncology SN - 0923-7534 IS - 3 VL - 24 SP - 647 EP - 654 ER - TY - JOUR T1 - Validation of conventional 2D lateral cephalometry using 3D cone beam CT A1 - Shaw,Karen A1 - McIntyre,Grant A1 - Mossey,Peter A. A1 - Menhinick,Alison A1 - Thomson,Donald AU - Shaw,Karen AU - McIntyre,Grant AU - Mossey,Peter A. AU - Menhinick,Alison AU - Thomson,Donald PY - 2013/3 Y1 - 2013/3 N2 - Objective: To determine if two-dimensional (2D) measurements from conventional cephalometric lateral skull radiographs are comparable to those derived from three-dimensional (3D) cone beam computed tomography (CBCT) images.

Design: In vitro laboratory study.

Setting: University Dental Hospital.

Method: A sample size calculation determined that 14 dried skulls were required to detect a 2° difference in angular measurements. The skulls were scanned at 0·3 mm3 voxel size. Maximum intensity projection (MIP) views were uploaded into OPAL cephalometric software (British Orthodontic Society, London, UK) for 2D analysis. CBCT data was uploaded into Mimics (Materialise, Leuven, Belgium) with 3D reconstructed and sagittal slice views being used. An Eastman analysis was carried out for the 2D and 3D images with the data compared using two-sample t-tests at P<0·05. Measurements greater than 2° between the 2D and 3D data were considered clinically significantly different. Intra-observer reproducibility was assessed by calculating random and systematic error using the Dahlberg formula and a two-sample t-test (P<0·05).

Results: The random error was below 0·5° and the systematic error was acceptable (P<0·05). There were no statistically significant differences between the measurements from the 2D and 3D images for any variable (P<0·05). However, the mean SNB value and the mean value for the angle between the lower incisor and mandibular plane differed by greater than 2° between the 2D and 3D data. The latter was thought to be due to limitations of the definition of Gonion for 3D images and the precision of locating the lower incisor apex in 2D.

Conclusion: Measurements used in the Eastman cephalometric analysis derived from 2D cephalometric lateral skull images are comparable to those derived from 3D CBCT images. AB - Objective: To determine if two-dimensional (2D) measurements from conventional cephalometric lateral skull radiographs are comparable to those derived from three-dimensional (3D) cone beam computed tomography (CBCT) images.

Design: In vitro laboratory study.

Setting: University Dental Hospital.

Method: A sample size calculation determined that 14 dried skulls were required to detect a 2° difference in angular measurements. The skulls were scanned at 0·3 mm3 voxel size. Maximum intensity projection (MIP) views were uploaded into OPAL cephalometric software (British Orthodontic Society, London, UK) for 2D analysis. CBCT data was uploaded into Mimics (Materialise, Leuven, Belgium) with 3D reconstructed and sagittal slice views being used. An Eastman analysis was carried out for the 2D and 3D images with the data compared using two-sample t-tests at P<0·05. Measurements greater than 2° between the 2D and 3D data were considered clinically significantly different. Intra-observer reproducibility was assessed by calculating random and systematic error using the Dahlberg formula and a two-sample t-test (P<0·05).

Results: The random error was below 0·5° and the systematic error was acceptable (P<0·05). There were no statistically significant differences between the measurements from the 2D and 3D images for any variable (P<0·05). However, the mean SNB value and the mean value for the angle between the lower incisor and mandibular plane differed by greater than 2° between the 2D and 3D data. The latter was thought to be due to limitations of the definition of Gonion for 3D images and the precision of locating the lower incisor apex in 2D.

Conclusion: Measurements used in the Eastman cephalometric analysis derived from 2D cephalometric lateral skull images are comparable to those derived from 3D CBCT images. U2 - 10.1179/1465313312Y.0000000009 DO - 10.1179/1465313312Y.0000000009 M1 - Article JO - Journal of Orthodontics JF - Journal of Orthodontics SN - 1465-3125 IS - 1 VL - 40 SP - 22 EP - 28 ER - TY - JOUR T1 - Avoiding hypoglycemia during protracted physical exercise by utilizing modern technology A1 - George,Priya A1 - McCrimmon,Rory AU - George,Priya AU - McCrimmon,Rory PY - 2013/2/28 Y1 - 2013/2/28 N2 - This case study describes a 40-year-old lady with long-standing type 1 diabetes for 37 years. Despite a history of recurrent hypoglycemia, impaired hypoglycemia awareness and an eating disorder, by changing to continuous subcutaneous insulin infusion therapy with an insulin pump, in combination with carbohydrate counting, she restored her hypoglycemia awareness and reduced blood glucose variability. This gave her the confidence to register to run in a marathon but during training experienced wide fluctuations in blood glucose with frequent hypoglycemia. With continuous glucose monitoring using a glucose sensor, she was able to undertake a strenuous training programme and subsequently manage her glucose to avoid hypoglycemia and maintain good control for the duration of the marathon. For some people with type 1 diabetes, technological advances have provided the capacity to reduce hypoglycemia risk, improve their quality of life, and enable them to participate in demanding physical activities. AB - This case study describes a 40-year-old lady with long-standing type 1 diabetes for 37 years. Despite a history of recurrent hypoglycemia, impaired hypoglycemia awareness and an eating disorder, by changing to continuous subcutaneous insulin infusion therapy with an insulin pump, in combination with carbohydrate counting, she restored her hypoglycemia awareness and reduced blood glucose variability. This gave her the confidence to register to run in a marathon but during training experienced wide fluctuations in blood glucose with frequent hypoglycemia. With continuous glucose monitoring using a glucose sensor, she was able to undertake a strenuous training programme and subsequently manage her glucose to avoid hypoglycemia and maintain good control for the duration of the marathon. For some people with type 1 diabetes, technological advances have provided the capacity to reduce hypoglycemia risk, improve their quality of life, and enable them to participate in demanding physical activities. UR - http://www.hypodiab.com/article.aspx?volumeID=15&issueID=24&articleID=128 M1 - Article JO - Diabetic Hypoglycemia JF - Diabetic Hypoglycemia SN - 1757-2428 IS - 3 VL - 5 SP - 12 EP - 14 ER - TY - JOUR T1 - Broadly tunable quantum-dot based ultra-short pulse laser system with different diffraction grating orders A1 - Alhazime,A. A1 - Ding,Y. A1 - Nikitichev,D. I. A1 - Fedorova,K. A. A1 - Krestnikov,I. L. A1 - Krakowski,M. A1 - Rafailov,E. U. AU - Alhazime,A. AU - Ding,Y. AU - Nikitichev,D. I. AU - Fedorova,K. A. AU - Krestnikov,I. L. AU - Krakowski,M. AU - Rafailov,E. U. PY - 2013/2/28 Y1 - 2013/2/28 N2 - A broadly tunable quantum-dot based ultra-short pulse master oscillator power amplifier with different diffraction grating orders as an external-cavity resonance feedback is studied. A broader tuning range, narrower optical spectra as well as higher peak power spectal density (maximun of 1.37 W/nm) from the second-order diffraction beam are achieved compared to those from the first-order diffraction beam in spite of slightly broader pulse duration from the second-order diffraction. AB - A broadly tunable quantum-dot based ultra-short pulse master oscillator power amplifier with different diffraction grating orders as an external-cavity resonance feedback is studied. A broader tuning range, narrower optical spectra as well as higher peak power spectal density (maximun of 1.37 W/nm) from the second-order diffraction beam are achieved compared to those from the first-order diffraction beam in spite of slightly broader pulse duration from the second-order diffraction. KW - quantum dot lasers KW - SEMICONDUCTOR OPTICAL AMPLIFIER KW - diffraction grating KW - laser tuning KW - High-speed optical techniques UR - http://ieeexplore.ieee.org/xpl/articleDetails.jsp?tp=&arnumber=6473961&contentType=Journals+%26+Magazines&sortType%3Dasc_p_Sequence%26filter%3DAND%28p_IS_Number%3A6473925%29%26rowsPerPage%3D50 U2 - 10.1049/el.2012.3761 DO - 10.1049/el.2012.3761 M1 - Article JO - Electronics Letters JF - Electronics Letters SN - 0013-5194 IS - 5 VL - 49 SP - 364 EP - 366 ER - TY - JOUR T1 - Obesity-Induced Insulin Resistance in Human Skeletal Muscle Is Characterised by Defective Activation of p42/p44 MAP Kinase A1 - Ruiz-Alcaraz,Antonio J. A1 - Lipina,Christopher A1 - Petrie,John R. A1 - Murphy,Michael J. A1 - Morris,Andrew D. A1 - Sutherland,Calum A1 - Cuthbertson,Daniel J. AU - Ruiz-Alcaraz,Antonio J. AU - Lipina,Christopher AU - Petrie,John R. AU - Murphy,Michael J. AU - Morris,Andrew D. AU - Sutherland,Calum AU - Cuthbertson,Daniel J. PY - 2013/2/28 Y1 - 2013/2/28 N2 -

Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20-37 kg/m). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min-1.m-2.), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR.

AB -

Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20-37 kg/m). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min-1.m-2.), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR.

U2 - 10.1371/journal.pone.0056928 DO - 10.1371/journal.pone.0056928 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 2 VL - 8 ER - TY - JOUR T1 - Poxvirus targeting of E3 ligase β-TrCP by molecular mimicry T2 - a mechanism to inhibit NF-κB activation and promote immune evasion and virulence A1 - Mansur,Daniel S. A1 - Maluquer de Motes,Carlos A1 - Unterholzner,Leonie A1 - Sumner,Rebecca P. A1 - Ferguson,Brian J. A1 - Ren,Hongwei A1 - Strnadova,Pavla A1 - Bowie,Andrew G. A1 - Smith,Geoffrey L. AU - Mansur,Daniel S. AU - Maluquer de Motes,Carlos AU - Unterholzner,Leonie AU - Sumner,Rebecca P. AU - Ferguson,Brian J. AU - Ren,Hongwei AU - Strnadova,Pavla AU - Bowie,Andrew G. AU - Smith,Geoffrey L. PY - 2013/2/28 Y1 - 2013/2/28 N2 - The transcription factor NF-?B is essential for immune responses against pathogens and its activation requires the phosphorylation, ubiquitination and proteasomal degradation of I?Ba. Here we describe an inhibitor of NF-?B from vaccinia virus that has a closely related counterpart in variola virus, the cause of smallpox, and mechanistic similarity with the HIV protein Vpu. Protein A49 blocks NF-?B activation by molecular mimicry and contains a motif conserved in I?Ba which, in I?Ba, is phosphorylated by IKKß causing ubiquitination and degradation. Like I?Ba, A49 binds the E3 ligase ß-TrCP, thereby preventing ubiquitination and degradation of I?Ba. Consequently, A49 stabilised phosphorylated I?Ba (p-I?Ba) and its interaction with p65, so preventing p65 nuclear translocation. Serine-to-alanine mutagenesis within the I?Ba-like motif of A49 abolished ß-TrCP binding, stabilisation of p-I?Ba and inhibition of NF-?B activation. Remarkably, despite encoding nine other inhibitors of NF-?B, a VACV lacking A49 showed reduced virulence in vivo. AB - The transcription factor NF-?B is essential for immune responses against pathogens and its activation requires the phosphorylation, ubiquitination and proteasomal degradation of I?Ba. Here we describe an inhibitor of NF-?B from vaccinia virus that has a closely related counterpart in variola virus, the cause of smallpox, and mechanistic similarity with the HIV protein Vpu. Protein A49 blocks NF-?B activation by molecular mimicry and contains a motif conserved in I?Ba which, in I?Ba, is phosphorylated by IKKß causing ubiquitination and degradation. Like I?Ba, A49 binds the E3 ligase ß-TrCP, thereby preventing ubiquitination and degradation of I?Ba. Consequently, A49 stabilised phosphorylated I?Ba (p-I?Ba) and its interaction with p65, so preventing p65 nuclear translocation. Serine-to-alanine mutagenesis within the I?Ba-like motif of A49 abolished ß-TrCP binding, stabilisation of p-I?Ba and inhibition of NF-?B activation. Remarkably, despite encoding nine other inhibitors of NF-?B, a VACV lacking A49 showed reduced virulence in vivo. U2 - 10.1371/journal.ppat.1003183 DO - 10.1371/journal.ppat.1003183 M1 - Article JO - PLoS Pathogens JF - PLoS Pathogens SN - 1553-7366 IS - 2 VL - 9 ER - TY - JOUR T1 - Salience network-midbrain dysconnectivity and blunted reward signals in schizophrenia A1 - Gradin,Victoria B. A1 - Waiter,Gordon A1 - O'Connor,Akira A1 - Romaniuk,Liana A1 - Stickle,Catriona A1 - Matthews,Keith A1 - Hall,Jeremy A1 - Steele,J. Douglas AU - Gradin,Victoria B. AU - Waiter,Gordon AU - O'Connor,Akira AU - Romaniuk,Liana AU - Stickle,Catriona AU - Matthews,Keith AU - Hall,Jeremy AU - Steele,J. Douglas PY - 2013/2/28 Y1 - 2013/2/28 N2 -

Theories of schizophrenia propose that abnormal functioning of the neural reward system is linked to negative and psychotic symptoms, by disruption of reward processing and promotion of context-independent false associations. Recently, it has been argued that an insula-anterior cingulate cortex (ACC) salience network system enables switching of brain states from the default mode to a task-related activity mode. Abnormal interaction between the insula-ACC system and reward processing regions may help explain abnormal reinforcer processing and symptoms. Here we use functional magnetic resonance imaging to assess the neural correlates of reward processing in schizophrenia. Furthermore, we investigated functional connectivity between the dopaminergic midbrain, a key region for the processing of reinforcers, and other brain regions. In response to rewards, controls activated task related regions (striatum, amygdala/hippocampus and midbrain) and the insula-ACC salience network. Patients similarly activated the insula-ACC salience network system but failed to activate task related regions. Reduced functional connectivity between the midbrain and the insula was found in schizophrenia, with the extent of this abnormality correlating with increased psychotic symptoms. The findings support the notion that reward processing is abnormal in schizophrenia and highlight the potential role of abnormal interactions between the insula-ACC salience network and reward regions. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

AB -

Theories of schizophrenia propose that abnormal functioning of the neural reward system is linked to negative and psychotic symptoms, by disruption of reward processing and promotion of context-independent false associations. Recently, it has been argued that an insula-anterior cingulate cortex (ACC) salience network system enables switching of brain states from the default mode to a task-related activity mode. Abnormal interaction between the insula-ACC system and reward processing regions may help explain abnormal reinforcer processing and symptoms. Here we use functional magnetic resonance imaging to assess the neural correlates of reward processing in schizophrenia. Furthermore, we investigated functional connectivity between the dopaminergic midbrain, a key region for the processing of reinforcers, and other brain regions. In response to rewards, controls activated task related regions (striatum, amygdala/hippocampus and midbrain) and the insula-ACC salience network. Patients similarly activated the insula-ACC salience network system but failed to activate task related regions. Reduced functional connectivity between the midbrain and the insula was found in schizophrenia, with the extent of this abnormality correlating with increased psychotic symptoms. The findings support the notion that reward processing is abnormal in schizophrenia and highlight the potential role of abnormal interactions between the insula-ACC salience network and reward regions. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

KW - BIOLOGY KW - FRAMEWORK KW - Salience network KW - PREDICTION KW - DELUSIONS KW - Midbrain KW - Connectivity KW - FUNCTIONAL CONNECTIVITY KW - Schizophrenia KW - ACTIVATION KW - Functional magnetic resonance imaging (fMRI) KW - MEMORY KW - DOPAMINE KW - PSYCHOSIS KW - DYSFUNCTION KW - Reward processing U2 - 10.1016/j.pscychresns.2012.06.003 DO - 10.1016/j.pscychresns.2012.06.003 M1 - Article JO - Psychiatry Research: Neuroimaging JF - Psychiatry Research: Neuroimaging SN - 0925-4927 IS - 2 VL - 211 SP - 104 EP - 111 ER - TY - JOUR T1 - On terminal alkynes that can react with active-site cysteine nucleophiles in proteases A1 - Ekkebus,Reggy A1 - van Kasteren,Sander I A1 - Kulathu,Yogesh A1 - Scholten,Arjen A1 - Berlin,Ilana A1 - Geurink,Paul P A1 - de Jong,Annemieke A1 - Goerdayal,Soenita A1 - Neefjes,Jacques A1 - Heck,Albert J R A1 - Komander,David A1 - Ovaa,Huib AU - Ekkebus,Reggy AU - van Kasteren,Sander I AU - Kulathu,Yogesh AU - Scholten,Arjen AU - Berlin,Ilana AU - Geurink,Paul P AU - de Jong,Annemieke AU - Goerdayal,Soenita AU - Neefjes,Jacques AU - Heck,Albert J R AU - Komander,David AU - Ovaa,Huib PY - 2013/2/27 Y1 - 2013/2/27 N2 - Active-site directed probes are powerful in studies of enzymatic function. We report an active-site directed probe based on a warhead so far considered unreactive. By replacing the C-terminal carboxylate of ubiquitin (Ub) with an alkyne functionality, a selective reaction with the active-site cysteine residue of de-ubiquitinating enzymes was observed. The resulting product was shown to be a quaternary vinyl thioether, as determined by X-ray crystallography. Proteomic analysis of proteins bound to an immobilized Ub alkyne probe confirmed the selectivity toward de-ubiquitinating enzymes. The observed reactivity is not just restricted to propargylated Ub, as highlighted by the selective reaction between caspase-1 (interleukin converting enzyme) and a propargylated peptide derived from IL-1ß, a caspase-1 substrate. AB - Active-site directed probes are powerful in studies of enzymatic function. We report an active-site directed probe based on a warhead so far considered unreactive. By replacing the C-terminal carboxylate of ubiquitin (Ub) with an alkyne functionality, a selective reaction with the active-site cysteine residue of de-ubiquitinating enzymes was observed. The resulting product was shown to be a quaternary vinyl thioether, as determined by X-ray crystallography. Proteomic analysis of proteins bound to an immobilized Ub alkyne probe confirmed the selectivity toward de-ubiquitinating enzymes. The observed reactivity is not just restricted to propargylated Ub, as highlighted by the selective reaction between caspase-1 (interleukin converting enzyme) and a propargylated peptide derived from IL-1ß, a caspase-1 substrate. U2 - 10.1021/ja309802n DO - 10.1021/ja309802n M1 - Article JO - Journal of the American Chemical Society JF - Journal of the American Chemical Society SN - 0002-7863 IS - 8 VL - 135 SP - 2867 EP - 2870 ER - TY - JOUR T1 - Should I eXtract Every Six dental trial (SIXES) T2 - study protocol for a randomized controlled trial A1 - Innes,Nicola A1 - Borrie,Felicity A1 - Bearn,David A1 - Evans,Dafydd A1 - Rauchhaus,Petra A1 - McSwiggan,Steve A1 - Page,Lyndie F. A1 - Hogarth,Fiona AU - Innes,Nicola AU - Borrie,Felicity AU - Bearn,David AU - Evans,Dafydd AU - Rauchhaus,Petra AU - McSwiggan,Steve AU - Page,Lyndie F. AU - Hogarth,Fiona PY - 2013/2/27 Y1 - 2013/2/27 N2 - Extraction of lower first permanent molars in children is common. There is uncertainty among clinicians as to whether a 'compensating extraction' (removal of the upper first permanent molar to prevent it over erupting) is necessary despite current guidelines recommending this. As a result, unnecessary dental extractions may be carried out or children may be failing to receive extractions required to achieve optimal long-term oral health. In addition, the decision to extract fewer or more teeth affects management options (local anesthetic injections alone, inhalation sedation or general anesthesia) needed to support the child with the surgical procedure(s).The SIXES (Should I eXtract Every Six) dental trial investigates clinical effectiveness and quality of life for conventional treatment (following the guideline of compensation extraction of the upper first permanent molar) compared with the alternative intervention (removal of lower first permanent molars but no extraction of the upper). AB - Extraction of lower first permanent molars in children is common. There is uncertainty among clinicians as to whether a 'compensating extraction' (removal of the upper first permanent molar to prevent it over erupting) is necessary despite current guidelines recommending this. As a result, unnecessary dental extractions may be carried out or children may be failing to receive extractions required to achieve optimal long-term oral health. In addition, the decision to extract fewer or more teeth affects management options (local anesthetic injections alone, inhalation sedation or general anesthesia) needed to support the child with the surgical procedure(s).The SIXES (Should I eXtract Every Six) dental trial investigates clinical effectiveness and quality of life for conventional treatment (following the guideline of compensation extraction of the upper first permanent molar) compared with the alternative intervention (removal of lower first permanent molars but no extraction of the upper). UR - http://www.trialsjournal.com/content/14/1/59/abstract# U2 - 10.1186/1745-6215-14-59 DO - 10.1186/1745-6215-14-59 M1 - Article JO - Trials JF - Trials SN - 1745-6215 VL - 14 ER - TY - JOUR T1 - Variational assimilation of land surface temperature and the estimation of surface energy balance components A1 - Bateni,S.M. A1 - Entekhabi,D. A1 - Jeng,D.-S. AU - Bateni,S.M. AU - Entekhabi,D. AU - Jeng,D.-S. PY - 2013/2/25 Y1 - 2013/2/25 N2 - Recently, numerous studies have focused on the estimation of surface energy flux components, based on the assimilation of land surface temperature (LST) within a variational data assimilation (VDA) framework. Unlike the previous investigations based on the force-restore equation, in this study, the full heat diffusion equation is employed in the VDA scheme as an adjoint (constraint). In addition, a model error term is added to the surface energy balance (SEB) equation and the VDA scheme to include the model uncertainty. Both VDA schemes (with and without the model uncertainty) are tested over the First International Satellite Land Surface Climatology Project Field Experiment (FIFE) site. The comprehensive comparisons between the present model (with heat diffusion equation) and previous model (with the force-restore equation) demonstrate that the present model will decrease the phase error associated with the ground heat flux diurnal cycle, and improve the evaporative fraction and heat fluxes estimation. The numerical examples also conclude that the errors caused by model structures and noisy data in the SEB equation can be detected and quantified in the present model (with model uncertainty). © 2013 Elsevier B.V. All rights reserved. AB - Recently, numerous studies have focused on the estimation of surface energy flux components, based on the assimilation of land surface temperature (LST) within a variational data assimilation (VDA) framework. Unlike the previous investigations based on the force-restore equation, in this study, the full heat diffusion equation is employed in the VDA scheme as an adjoint (constraint). In addition, a model error term is added to the surface energy balance (SEB) equation and the VDA scheme to include the model uncertainty. Both VDA schemes (with and without the model uncertainty) are tested over the First International Satellite Land Surface Climatology Project Field Experiment (FIFE) site. The comprehensive comparisons between the present model (with heat diffusion equation) and previous model (with the force-restore equation) demonstrate that the present model will decrease the phase error associated with the ground heat flux diurnal cycle, and improve the evaporative fraction and heat fluxes estimation. The numerical examples also conclude that the errors caused by model structures and noisy data in the SEB equation can be detected and quantified in the present model (with model uncertainty). © 2013 Elsevier B.V. All rights reserved. KW - Land surface temperature KW - Variational data assimilaton KW - Model uncertainty KW - Energy balance UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872262480&md5=af73c8dd03447b67f9e403921b4d23b0 U2 - 10.1016/j.jhydrol.2012.12.039 DO - 10.1016/j.jhydrol.2012.12.039 M1 - Article JO - Journal of Hydrology JF - Journal of Hydrology SN - 0022-1694 VL - 481 SP - 143 EP - 156 ER - TY - JOUR T1 - CNP/cGMP signaling regulates axon branching and growth by modulating microtubule polymerization A1 - Xia,Caihong A1 - Nguyen,Minh A1 - Garrison,Amy K A1 - Zhao,Zhen A1 - Wang,Zheng A1 - Sutherland,Calum A1 - Ma,Le AU - Xia,Caihong AU - Nguyen,Minh AU - Garrison,Amy K AU - Zhao,Zhen AU - Wang,Zheng AU - Sutherland,Calum AU - Ma,Le PY - 2013/2/18 Y1 - 2013/2/18 N2 - The peptide hormone CNP has recently been found to positively regulate axon branching and growth via activation of cGMP signaling in embryonic dorsal root ganglion (DRG) neurons, but the cellular mechanisms mediating the regulation of these developmental processes have not been established. In this study, we provide evidence linking CNP/cGMP signaling to microtubule dynamics via the microtubule regulator CRMP2. First, phosphorylation of CRMP2 can be suppressed by cGMP activation in embryonic DRG neurons, and non-phosphorylated CRMP2 promotes axon branching and growth. In addition, real time analysis of growing microtubule ends indicates a similar correlation of CRMP2 phosphorylation and its activity in promoting microtubule polymerization rates and durations in COS cells and DRG growth cones. Moreover, direct activation of cGMP signaling leads to increased assembly of dynamic microtubules in DRG growth cones. Finally, low doses of a microtubule depolymerization drug nocodazole block CNP/cGMP-dependent axon branching and growth. Taken together, our results support a critical role of microtubule dynamics in mediating CNP/cGMP regulation of axonal development. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013. AB - The peptide hormone CNP has recently been found to positively regulate axon branching and growth via activation of cGMP signaling in embryonic dorsal root ganglion (DRG) neurons, but the cellular mechanisms mediating the regulation of these developmental processes have not been established. In this study, we provide evidence linking CNP/cGMP signaling to microtubule dynamics via the microtubule regulator CRMP2. First, phosphorylation of CRMP2 can be suppressed by cGMP activation in embryonic DRG neurons, and non-phosphorylated CRMP2 promotes axon branching and growth. In addition, real time analysis of growing microtubule ends indicates a similar correlation of CRMP2 phosphorylation and its activity in promoting microtubule polymerization rates and durations in COS cells and DRG growth cones. Moreover, direct activation of cGMP signaling leads to increased assembly of dynamic microtubules in DRG growth cones. Finally, low doses of a microtubule depolymerization drug nocodazole block CNP/cGMP-dependent axon branching and growth. Taken together, our results support a critical role of microtubule dynamics in mediating CNP/cGMP regulation of axonal development. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013. U2 - 10.1002/dneu.22078 DO - 10.1002/dneu.22078 M1 - Article JO - Developmental Neurobiology JF - Developmental Neurobiology ER - TY - JOUR T1 - Temporary brittle bone disease T2 - association with intracranial bleeding A1 - Monk,Elizabeth A1 - Paterson,Colin R AU - Monk,Elizabeth AU - Paterson,Colin R PY - 2013/2/15 Y1 - 2013/2/15 N2 - Abstract We report 20 infants aged between 1 month and 6 months found to have subdural bleeding and also multiple unexplained fractures in a pattern similar to that described earlier as temporary brittle bone disease. Child abuse seemed unlikely as a cause of the fractures as in no case was there clinical evidence of injury commensurate with the fracturing, as some patients had fractures while in hospital and as metaphyseal lesions, when present, were often symmetrical in distribution. Abuse seemed unlikely to have been the cause of the subdural bleeding in several patients; three had clear histories of accidental injury and five had evidence that the initial bleeding was likely to have taken place at birth. Abuse also seemed unlikely as the cause of the syndrome; the nine patients who were returned to their parents had no subsequent allegations of abuse with a mean follow-up period of 15.8 years. The finding of hypermobile joints in the parents of eight of the children is an additional pointer to a natural cause for this condition. The cause of this combination of fractures and subdural bleeding is not yet clear but it is important to be aware that it can result from natural disease. AB - Abstract We report 20 infants aged between 1 month and 6 months found to have subdural bleeding and also multiple unexplained fractures in a pattern similar to that described earlier as temporary brittle bone disease. Child abuse seemed unlikely as a cause of the fractures as in no case was there clinical evidence of injury commensurate with the fracturing, as some patients had fractures while in hospital and as metaphyseal lesions, when present, were often symmetrical in distribution. Abuse seemed unlikely to have been the cause of the subdural bleeding in several patients; three had clear histories of accidental injury and five had evidence that the initial bleeding was likely to have taken place at birth. Abuse also seemed unlikely as the cause of the syndrome; the nine patients who were returned to their parents had no subsequent allegations of abuse with a mean follow-up period of 15.8 years. The finding of hypermobile joints in the parents of eight of the children is an additional pointer to a natural cause for this condition. The cause of this combination of fractures and subdural bleeding is not yet clear but it is important to be aware that it can result from natural disease. U2 - 10.1515/jpem-2012-0272 DO - 10.1515/jpem-2012-0272 M1 - Article JO - Journal of Pediatric Endocrinology & Metabolism JF - Journal of Pediatric Endocrinology & Metabolism SN - 0334-018X SP - 1 EP - 10 ER - TY - CHAP T1 - British students in the United States T2 - International students and scholars in the United States A1 - King,Russell A1 - Findlay,Allan A1 - Ahrens,Jill A1 - Geddes,Alistair AU - King,Russell AU - Findlay,Allan AU - Ahrens,Jill AU - Geddes,Alistair PB - Palgrave Macmillan CY - New York PY - 2013/2/13 Y1 - 2013/2/13 UR - http://www.palgrave.com/products/title.aspx?pid=575936 M1 - Chapter SN - 9781137024466 BT - International students and scholars in the United States A2 - Alberts,Heike ED - Alberts,Heike SP - 25 ER - TY - JOUR T1 - The effects of sustained forest use on hillslope soil hydraulic conductivity in the Middle Mountains of Central Nepal A1 - Ghimire,Chandra Prasad A1 - Bruijnzeel ,L. Adrian A1 - Bonell,Mike A1 - Coles,Neil A1 - Lubczynski,Maciek W. A1 - Gilmour,Don A. AU - Ghimire,Chandra Prasad AU - Bruijnzeel ,L. Adrian AU - Bonell,Mike AU - Coles,Neil AU - Lubczynski,Maciek W. AU - Gilmour,Don A. PY - 2013/2/11 Y1 - 2013/2/11 N2 -

This work investigated the multi-decadal changes in field saturated hydraulic conductivity, Kfs, beneath severely degraded pasture, natural forest and two mature planted Pinus roxburghii stands between two sets of measurements made in 1986 and 2011 at the same locations in the Middle Mountains of Central Nepal.Multiple measurements of Kfs were made at the four sites, both at
the surface and at depths of 005–015, 015–025 and 025–050 m. The Kfs results were subsequently combined with rainfall intensities associated with different time intervals to infer multi-decadal changes in dominant hillslope stormflow pathways.
The widely assumed hydrological benefits of reforesting degraded land through the enhancement of near-surface permeability due to such factors as the incorporation of a greater amount of organic matter, formation of macropores, as well as root development were not observed in this study. Continued heavy use of the natural and planted forests of the Middle Mountains, particularly the removal of understory vegetation and leaf litter, and cattle grazing, are considered to be the chief causal factors of the presently observed deterioration in forest hydrological functioning. This situation is typical not only of the Middle Mountain
Zone across the Himalaya but is also observed in other densely populated parts of South and South-East Asia.
The key conclusion of this work is that simply planting trees in degraded landscapes is not sufficient in itself to restore watershed hydrological functioning. Attention also needs to be given to on-going management of the reforested areas to balance product usage with watershed functions.

AB -

This work investigated the multi-decadal changes in field saturated hydraulic conductivity, Kfs, beneath severely degraded pasture, natural forest and two mature planted Pinus roxburghii stands between two sets of measurements made in 1986 and 2011 at the same locations in the Middle Mountains of Central Nepal.Multiple measurements of Kfs were made at the four sites, both at
the surface and at depths of 005–015, 015–025 and 025–050 m. The Kfs results were subsequently combined with rainfall intensities associated with different time intervals to infer multi-decadal changes in dominant hillslope stormflow pathways.
The widely assumed hydrological benefits of reforesting degraded land through the enhancement of near-surface permeability due to such factors as the incorporation of a greater amount of organic matter, formation of macropores, as well as root development were not observed in this study. Continued heavy use of the natural and planted forests of the Middle Mountains, particularly the removal of understory vegetation and leaf litter, and cattle grazing, are considered to be the chief causal factors of the presently observed deterioration in forest hydrological functioning. This situation is typical not only of the Middle Mountain
Zone across the Himalaya but is also observed in other densely populated parts of South and South-East Asia.
The key conclusion of this work is that simply planting trees in degraded landscapes is not sufficient in itself to restore watershed hydrological functioning. Attention also needs to be given to on-going management of the reforested areas to balance product usage with watershed functions.

KW - Forest degradation KW - Hillslope hydrological response KW - Himalaya KW - Reforestation KW - Field, saturated hydraulic conductivity U2 - 10.1002/eco.1367 DO - 10.1002/eco.1367 M1 - Article JO - Ecohydrology JF - Ecohydrology SN - 1936-0584 ER - TY - JOUR T1 - West Cork and the Writing of History A1 - Regan,John M. AU - Regan,John M. PY - 2013/2/11 Y1 - 2013/2/11 KW - historiography UR - http://www.drb.ie/reviews/west-cork-and-the-writing-of-history M1 - Comment/debate JO - Dublin Review of Books JF - Dublin Review of Books IS - 29 ER - TY - ADVS T1 - Looking back on Modern Living A1 - Dunlop,Gair AU - Dunlop,Gair PY - 2013/2/9 Y1 - 2013/2/9 N2 - Visual archive material from the heyday of one of the UK's greatest megastructures: Cumbernauld Town Centre. Interviews with architects, planners and the town artists are interwoven with personal recollections. Visual material comes from the North Lanarkshire Archive, RCAHMS, Brian Miller(town artist). AB - Visual archive material from the heyday of one of the UK's greatest megastructures: Cumbernauld Town Centre. Interviews with architects, planners and the town artists are interwoven with personal recollections. Visual material comes from the North Lanarkshire Archive, RCAHMS, Brian Miller(town artist). UR - http://bookleteer.com/book.html?id=2749#page/1/mode/2up M1 - Web publication/site ER - TY - JOUR T1 - The influence of instructions on object memory in a real world setting A1 - Tatler,Benjamin W. A1 - Tatler,Sarah AU - Tatler,Benjamin W. AU - Tatler,Sarah PY - 2013/2/6 Y1 - 2013/2/6 N2 - The representations that are formed as we view real environments are still not well characterized. We studied the influence of task instructions on memory performance and fixation allocation in a real-world setting, in which participants were free to move around. Object memories were found to be task sensitive, as was the allocation of foveal vision. However, changes in the number of fixations directed at objects could not fully explain the changes in object memory performance that were found between task instruction conditions. Our data suggest that the manner in which information is extracted and retained from fixations varies with the instructions given to participants, with strategic prioritization of information retention from fixations made to task-relevant objects and strategic deprioritization of information retention from fixations directed to task-irrelevant objects. AB - The representations that are formed as we view real environments are still not well characterized. We studied the influence of task instructions on memory performance and fixation allocation in a real-world setting, in which participants were free to move around. Object memories were found to be task sensitive, as was the allocation of foveal vision. However, changes in the number of fixations directed at objects could not fully explain the changes in object memory performance that were found between task instruction conditions. Our data suggest that the manner in which information is extracted and retained from fixations varies with the instructions given to participants, with strategic prioritization of information retention from fixations made to task-relevant objects and strategic deprioritization of information retention from fixations directed to task-irrelevant objects. KW - Task KW - INSTRUCTION KW - object memory KW - representation KW - real world KW - natural KW - prioritization U2 - 10.1167/13.2.5 DO - 10.1167/13.2.5 M1 - Article JO - Journal of Vision JF - Journal of Vision SN - 1534-7362 IS - 2 VL - 13 SP - 5 ER - TY - JOUR T1 - Exposure to acetylcholinesterase inhibitors alters the physiology and motor function of honeybees A1 - Williamson,Sally M. A1 - Moffat,Christopher A1 - Gomersall,Martha A. E. A1 - Saranzewa,Nastja A1 - Connolly,Christopher N. A1 - Wright,Geraldine A. AU - Williamson,Sally M. AU - Moffat,Christopher AU - Gomersall,Martha A. E. AU - Saranzewa,Nastja AU - Connolly,Christopher N. AU - Wright,Geraldine A. PY - 2013/2/5 Y1 - 2013/2/5 N2 - Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15min. At a 10nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1µM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival. AB - Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15min. At a 10nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1µM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival. U2 - 10.3389/fphys.2013.00013 DO - 10.3389/fphys.2013.00013 M1 - Article JO - Frontiers in Physiology JF - Frontiers in Physiology VL - 4 ER - TY - JOUR T1 - DNA-binding regulates site-specific ubiquitination of IRF-1 A1 - Landré,Vivien A1 - Pion,Emmanuelle A1 - Narayan,Vikram A1 - Xirodimas,Dimitris P A1 - Ball,Kathryn L AU - Landré,Vivien AU - Pion,Emmanuelle AU - Narayan,Vikram AU - Xirodimas,Dimitris P AU - Ball,Kathryn L PY - 2013/2/1 Y1 - 2013/2/1 N2 - Understanding the determinants for site-specific ubiquitination by E3 ligase components of the ubiquitin machinery is proving to be a challenge. In the present study we investigate the role of an E3 ligase docking site (Mf2 domain) in an intrinsically disordered domain of IRF-1 [IFN (interferon) regulatory factor-1], a short-lived IFN?-regulated transcription factor, in ubiquitination of the protein. Ubiquitin modification of full-length IRF-1 by E3 ligases such as CHIP [C-terminus of the Hsc (heat-shock cognate) 70-interacting protein] and MDM2 (murine double minute 2), which dock to the Mf2 domain, was specific for lysine residues found predominantly in loop structures that extend from the DNA-binding domain, whereas no modification was detected in the more conformationally flexible C-terminal half of the protein. The E3 docking site was not available when IRF-1 was in its DNA-bound conformation and cognate DNA-binding sequences strongly suppressed ubiquitination, highlighting a strict relationship between ligase binding and site-specific modification at residues in the DNA-binding domain. Hyperubiquitination of a non-DNA-binding mutant supports a mechanism where an active DNA-bound pool of IRF-1 is protected from polyubiquitination and degradation. AB - Understanding the determinants for site-specific ubiquitination by E3 ligase components of the ubiquitin machinery is proving to be a challenge. In the present study we investigate the role of an E3 ligase docking site (Mf2 domain) in an intrinsically disordered domain of IRF-1 [IFN (interferon) regulatory factor-1], a short-lived IFN?-regulated transcription factor, in ubiquitination of the protein. Ubiquitin modification of full-length IRF-1 by E3 ligases such as CHIP [C-terminus of the Hsc (heat-shock cognate) 70-interacting protein] and MDM2 (murine double minute 2), which dock to the Mf2 domain, was specific for lysine residues found predominantly in loop structures that extend from the DNA-binding domain, whereas no modification was detected in the more conformationally flexible C-terminal half of the protein. The E3 docking site was not available when IRF-1 was in its DNA-bound conformation and cognate DNA-binding sequences strongly suppressed ubiquitination, highlighting a strict relationship between ligase binding and site-specific modification at residues in the DNA-binding domain. Hyperubiquitination of a non-DNA-binding mutant supports a mechanism where an active DNA-bound pool of IRF-1 is protected from polyubiquitination and degradation. U2 - 10.1042/BJ20121076 DO - 10.1042/BJ20121076 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 IS - 3 VL - 449 SP - 707 EP - 717 ER - TY - JOUR T1 - Long-acting β-agonist prescribing in people with asthma in primary care A1 - Morales,Daniel R A1 - Jackson,Cathy A1 - Fielding,Shona A1 - Guthrie,Bruce AU - Morales,Daniel R AU - Jackson,Cathy AU - Fielding,Shona AU - Guthrie,Bruce PY - 2013/2/1 Y1 - 2013/2/1 N2 - Long-acting ß2-agonist (LABA) monotherapy is contraindicated in asthma following reports of serious adverse events. Anonymised Scottish health data were used to determine the prevalence of LABA prescribing and LABA monotherapy (sustained and episodic) in asthma during 2006. Of 73 486 asthma patients identified, 5592 (7.6%; 95% CI 7.4% to 7.8%) were prescribed LABAs as a separate inhaler of which 991 patients had LABA monotherapy (17.7% (95% CI 16.7% to 18.7%) of patients at risk). Asthma reviews were associated with reductions in sustained (OR 0.44; 95% CI 0.32 to 0.61) but not episodic monotherapy (OR 1.16; 95% CI 0.85 to 1.57). These findings support recent changes in UK asthma guidelines recommending LABAs in fixed-dose combination inhalers. AB - Long-acting ß2-agonist (LABA) monotherapy is contraindicated in asthma following reports of serious adverse events. Anonymised Scottish health data were used to determine the prevalence of LABA prescribing and LABA monotherapy (sustained and episodic) in asthma during 2006. Of 73 486 asthma patients identified, 5592 (7.6%; 95% CI 7.4% to 7.8%) were prescribed LABAs as a separate inhaler of which 991 patients had LABA monotherapy (17.7% (95% CI 16.7% to 18.7%) of patients at risk). Asthma reviews were associated with reductions in sustained (OR 0.44; 95% CI 0.32 to 0.61) but not episodic monotherapy (OR 1.16; 95% CI 0.85 to 1.57). These findings support recent changes in UK asthma guidelines recommending LABAs in fixed-dose combination inhalers. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872686039&md5=8e65ca2e00ffa3bb6fea75784d77485a U2 - 10.1136/thoraxjnl-2012-202071 DO - 10.1136/thoraxjnl-2012-202071 M1 - Article JO - Thorax JF - Thorax IS - 2 VL - 68 SP - 192 EP - 194 ER - TY - JOUR T1 - Maternal and umbilical cord levels of T4, TSH, TPOAb and TGAb in term infants and neurodevelopmental outcome at 5.5 years. A1 - Williams,Fiona L. R. A1 - Watson,Jennifer A1 - Ogston,Simon A. A1 - Visser,Theo J. A1 - Hume,Robert A1 - Willatts,Peter AU - Williams,Fiona L. R. AU - Watson,Jennifer AU - Ogston,Simon A. AU - Visser,Theo J. AU - Hume,Robert AU - Willatts,Peter PY - 2013/2/1 Y1 - 2013/2/1 U2 - 10.1210/jc.2012-3572 DO - 10.1210/jc.2012-3572 M1 - Article JO - Journal of Clinical Endocrinology and Metabolism JF - Journal of Clinical Endocrinology and Metabolism SP - 829 EP - 838 ER - TY - JOUR T1 - Potential role of non-insulin adjunct therapy in Type 1 diabetes A1 - George,P. A1 - McCrimmon,R J AU - George,P. AU - McCrimmon,R J PY - 2013/2/1 Y1 - 2013/2/1 N2 - Despite improvements in the pharmacodynamics of injectable insulin and better insulin delivery systems, glucose control remains suboptimal in the majority of individuals with Type 1 diabetes. Profound defects in the physiological processes that normally maintain glucose homeostasis contribute to the difficulty in achieving glycaemic targets. Non-insulin-based adjunct treatments offer a potential means of complementing intensive insulin therapy in Type 1 diabetes through addressing some of the physiological disturbances that result from endogenous ß-cell destruction, particularly through preservation of ß-cell mass and prevention of apoptosis, and suppression of a-cell glucagon release in the postprandial state. The former approach applies most readily to newly diagnosed C-peptide-positive Type 1 diabetes, while the latter to established C-peptide-negative Type 1 diabetes. This review focuses primarily on the clinical trial data available on the use of non-insulin-based therapies in longer-duration Type 1 diabetes. We conclude that metformin may prove useful in macrovascular disease reduction, while pramlintide, glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors and leptin co-therapies may reduce HbA(1c) , glucose variability, postprandial glucose excursions and body weight. These early studies are encouraging and offer novel and potentially very effective approaches to the treatment of Type 1 diabetes, but the evidence is largely restricted to small, often uncontrolled trials. As such, these therapies cannot be currently recommended for routine clinical practice. There is a clear need to support large, multi-centre randomized controlled trials designed to establish whether adjunct insulin therapy has a place in the modern management of Type 1 diabetes. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK. AB - Despite improvements in the pharmacodynamics of injectable insulin and better insulin delivery systems, glucose control remains suboptimal in the majority of individuals with Type 1 diabetes. Profound defects in the physiological processes that normally maintain glucose homeostasis contribute to the difficulty in achieving glycaemic targets. Non-insulin-based adjunct treatments offer a potential means of complementing intensive insulin therapy in Type 1 diabetes through addressing some of the physiological disturbances that result from endogenous ß-cell destruction, particularly through preservation of ß-cell mass and prevention of apoptosis, and suppression of a-cell glucagon release in the postprandial state. The former approach applies most readily to newly diagnosed C-peptide-positive Type 1 diabetes, while the latter to established C-peptide-negative Type 1 diabetes. This review focuses primarily on the clinical trial data available on the use of non-insulin-based therapies in longer-duration Type 1 diabetes. We conclude that metformin may prove useful in macrovascular disease reduction, while pramlintide, glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors and leptin co-therapies may reduce HbA(1c) , glucose variability, postprandial glucose excursions and body weight. These early studies are encouraging and offer novel and potentially very effective approaches to the treatment of Type 1 diabetes, but the evidence is largely restricted to small, often uncontrolled trials. As such, these therapies cannot be currently recommended for routine clinical practice. There is a clear need to support large, multi-centre randomized controlled trials designed to establish whether adjunct insulin therapy has a place in the modern management of Type 1 diabetes. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872714268&md5=92f7559ed6d59bd627aa74710acf8b01 U2 - 10.1111/j.1464-5491.2012.03744.x DO - 10.1111/j.1464-5491.2012.03744.x M1 - Article JO - Diabetic Medicine JF - Diabetic Medicine IS - 2 VL - 30 SP - 179 EP - 188 ER - TY - CHAP T1 - ‘Auden and the Cinema’ A1 - Williams,Keith AU - Williams,Keith PB - Cambridge University Press CY - Cambridge PY - 2013/2 Y1 - 2013/2 UR - http://www.cambridge.org/gb/knowledge/isbn/item6857809/?site_locale=en_GB UR - http://library.dundee.ac.uk/F/?func=direct&local_base=DUN01&doc_number=000818890 M1 - Chapter SN - 9780521196574 BT - W.H. Auden in Context T2 - W.H. Auden in Context A2 - Sharpe,Tony ED - Sharpe,Tony SP - 205 EP - 216 ER - TY - JOUR T1 - A proteomic approach identifies many novel palmitoylated proteins in Arabidopsis A1 - Hemsley,Piers A A1 - Weimar,Thilo A1 - Lilley,Kathryn S A1 - Dupree,Paul A1 - Grierson,Claire S AU - Hemsley,Piers A AU - Weimar,Thilo AU - Lilley,Kathryn S AU - Dupree,Paul AU - Grierson,Claire S PY - 2013/2 Y1 - 2013/2 N2 - S-acylation (palmitoylation) is a poorly understood post-translational modification of proteins involving the addition of acyl lipids to cysteine residues. S-acylation promotes the association of proteins with membranes and influences protein stability, microdomain partitioning, membrane targeting and activation state. No consensus motif for S-acylation exists and it therefore requires empirical identification. Here, we describe a biotin switch isobaric tagging for relative and absolute quantification (iTRAQ)-based method to identify S-acylated proteins from Arabidopsis. We use these data to predict and confirm S-acylation of proteins not in our dataset. We identified c. 600 putative S-acylated proteins affecting diverse cellular processes. These included proteins involved in pathogen perception and response, mitogen-activated protein kinases (MAPKs), leucine-rich repeat receptor-like kinases (LRR-RLKs) and RLK superfamily members, integral membrane transporters, ATPases, soluble N-ethylmaleimide-sensitive factor-activating protein receptors (SNAREs) and heterotrimeric G-proteins. The prediction of S-acylation of related proteins was demonstrated by the identification and confirmation of S-acylation sites within the SNARE and LRR-RLK families. We showed that S-acylation of the LRR-RLK FLS2 is required for a full response to elicitation by the flagellin derived peptide flg22, but is not required for localization to the plasma membrane. Arabidopsis contains many more S-acylated proteins than previously thought. These data can be used to identify S-acylation sites in related proteins. We also demonstrated that S-acylation is required for full LRR-RLK function. AB - S-acylation (palmitoylation) is a poorly understood post-translational modification of proteins involving the addition of acyl lipids to cysteine residues. S-acylation promotes the association of proteins with membranes and influences protein stability, microdomain partitioning, membrane targeting and activation state. No consensus motif for S-acylation exists and it therefore requires empirical identification. Here, we describe a biotin switch isobaric tagging for relative and absolute quantification (iTRAQ)-based method to identify S-acylated proteins from Arabidopsis. We use these data to predict and confirm S-acylation of proteins not in our dataset. We identified c. 600 putative S-acylated proteins affecting diverse cellular processes. These included proteins involved in pathogen perception and response, mitogen-activated protein kinases (MAPKs), leucine-rich repeat receptor-like kinases (LRR-RLKs) and RLK superfamily members, integral membrane transporters, ATPases, soluble N-ethylmaleimide-sensitive factor-activating protein receptors (SNAREs) and heterotrimeric G-proteins. The prediction of S-acylation of related proteins was demonstrated by the identification and confirmation of S-acylation sites within the SNARE and LRR-RLK families. We showed that S-acylation of the LRR-RLK FLS2 is required for a full response to elicitation by the flagellin derived peptide flg22, but is not required for localization to the plasma membrane. Arabidopsis contains many more S-acylated proteins than previously thought. These data can be used to identify S-acylation sites in related proteins. We also demonstrated that S-acylation is required for full LRR-RLK function. U2 - 10.1111/nph.12077 DO - 10.1111/nph.12077 M1 - Article JO - New Phytologist JF - New Phytologist SN - 0028-646X IS - 3 VL - 197 SP - 805 EP - 814 ER - TY - JOUR T1 - A review of mobile bearing unicompartmental knee in patients aged 80 years or older and comparison with younger groups A1 - Ingale,Pradeep A. A1 - Hadden,William A. AU - Ingale,Pradeep A. AU - Hadden,William A. PY - 2013/2 Y1 - 2013/2 N2 - The Knee Society scores and other outcome measures in patients aged 80 years or older (n = 51) who had mobile bearing unicompartmental knee arthroplasty performed in Tayside, Scotland, were reviewed retrospectively. The results were compared with those in younger age groups: "younger than 60 years" (n = 110), "60 to 69 years" (n = 164), and "70 to 79" years (n = 145). In the study group, the mean Knee Society knee score (objective) at 1-year follow-up was 85.21, compared with a mean of 77.82 for younger-than-60-years age group, 81.28 for 60-to-69-years age group, and 87.33 for 70-to-79-years age group. The differences between the knee scores in the study group and the other groups were not statistically significant. Revision rate and survival of implant were not different between the groups. We conclude that patients aged 80 or older should be considered for mobile bearing unicompartmental knee arthroplasty if they fulfill the described criteria. © 2012 Elsevier Inc. All rights reserved. AB - The Knee Society scores and other outcome measures in patients aged 80 years or older (n = 51) who had mobile bearing unicompartmental knee arthroplasty performed in Tayside, Scotland, were reviewed retrospectively. The results were compared with those in younger age groups: "younger than 60 years" (n = 110), "60 to 69 years" (n = 164), and "70 to 79" years (n = 145). In the study group, the mean Knee Society knee score (objective) at 1-year follow-up was 85.21, compared with a mean of 77.82 for younger-than-60-years age group, 81.28 for 60-to-69-years age group, and 87.33 for 70-to-79-years age group. The differences between the knee scores in the study group and the other groups were not statistically significant. Revision rate and survival of implant were not different between the groups. We conclude that patients aged 80 or older should be considered for mobile bearing unicompartmental knee arthroplasty if they fulfill the described criteria. © 2012 Elsevier Inc. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84863960175&md5=b58b39b7b15a345c671cf15270c127a6 U2 - 10.1016/j.arth.2012.05.002 DO - 10.1016/j.arth.2012.05.002 M1 - Article JO - Journal of Arthroplasty JF - Journal of Arthroplasty SN - 0883-5403 IS - 2 VL - 28 SP - 262 EP - 267 ER - TY - JOUR T1 - Beyond Bartleby and Bad Faith T2 - Thinking Critically with Sartre and Deleuze A1 - Smith,Dominic AU - Smith,Dominic PY - 2013/2 Y1 - 2013/2 N2 - This essay argues that important critical and political perspective can be gained on Deleuze's famous essay, ‘Bartleby; or, The Formula’ by viewing it as an attempt to move beyond the Sartrean framework of ‘bad faith’. The argument comprises four sections. In section one, I contextualise Deleuze's essay in terms of contrasting readings of Bartleby, from a prior account by Georges Perec, to contemporary accounts indebted to Deleuze, from Hardt and Negri's Empire to Gisèle Berkman's recent L'Effet Bartleby. The argument of this section is that a problematically reductive image of Bartleby has emerged in the wake of Deleuze's essay, but that this can be challenged in favour of a more nuanced and politically significant reading by contextualising the essay as an attempt to overcome bad faith. In section two, I develop this by drawing out the nature and relevance of the threat posed by bad faith through a focus on Sartrean, Deleuzian and Badioucan critiques of Bartleby, before arguing, in section three, that attention to the concept of a ‘logic of presuppositions’ developed in Deleuze's essay shows how bad faith can be overcome. These sections all build towards the fourth and longest section, which draws out the wider political significance of what it means to overcome bad faith. To do so, I pay attention to how logics of presupposition function in Bartleby's story, and consider Deleuze's essay in relation to his work on ‘control societies’ and ‘collective assemblages of enunciation’.
AB - This essay argues that important critical and political perspective can be gained on Deleuze's famous essay, ‘Bartleby; or, The Formula’ by viewing it as an attempt to move beyond the Sartrean framework of ‘bad faith’. The argument comprises four sections. In section one, I contextualise Deleuze's essay in terms of contrasting readings of Bartleby, from a prior account by Georges Perec, to contemporary accounts indebted to Deleuze, from Hardt and Negri's Empire to Gisèle Berkman's recent L'Effet Bartleby. The argument of this section is that a problematically reductive image of Bartleby has emerged in the wake of Deleuze's essay, but that this can be challenged in favour of a more nuanced and politically significant reading by contextualising the essay as an attempt to overcome bad faith. In section two, I develop this by drawing out the nature and relevance of the threat posed by bad faith through a focus on Sartrean, Deleuzian and Badioucan critiques of Bartleby, before arguing, in section three, that attention to the concept of a ‘logic of presuppositions’ developed in Deleuze's essay shows how bad faith can be overcome. These sections all build towards the fourth and longest section, which draws out the wider political significance of what it means to overcome bad faith. To do so, I pay attention to how logics of presupposition function in Bartleby's story, and consider Deleuze's essay in relation to his work on ‘control societies’ and ‘collective assemblages of enunciation’.
KW - Deleuze, Gilles, 1925-1995 KW - Badiou, Alain KW - Sartre, Jean-Paul KW - Perec, Georges KW - Logic of Presuppositions KW - Bad Faith KW - Image of Thought UR - http://www.euppublishing.com/doi/pdfplus/10.3366/dls.2013.0095 U2 - 10.3366/dls.2013.0095 DO - 10.3366/dls.2013.0095 M1 - Article JO - Deleuze Studies JF - Deleuze Studies SN - 1750-2241 IS - 1 VL - 7 SP - 83 EP - 105 ER - TY - CHAP T1 - Climate Law in the United Kingdom A1 - Reid,Colin T. AU - Reid,Colin T. PB - Springer CY - Dordrecht PY - 2013/2 Y1 - 2013/2 N2 - There is no single legislative source for the United Kingdom’s legal response to climate change. Initial measures to tax large energy users, enable participation in the EU ETS and encourage renewable electricity generation have subsequently been joined by the Climate Change Acts operating at UK and Scottish levels. These Acts set demanding targets for reductions in greenhouse gas emissions and break new and uncertain legal ground in making these legally binding on Ministers. The targets are supported by detailed reporting mechanisms, to Parliament and the public, that are intended to be the main route to enforcement and by provisions enabling many detailed changes to the law to allow progress towards the targets. The separate legislation in Scotland highlights the difficulties that dealing with pervasive issues, especially those with an EU and international dimension, pose for by sub-national governments with distinct political ambitions but limited jurisdiction. AB - There is no single legislative source for the United Kingdom’s legal response to climate change. Initial measures to tax large energy users, enable participation in the EU ETS and encourage renewable electricity generation have subsequently been joined by the Climate Change Acts operating at UK and Scottish levels. These Acts set demanding targets for reductions in greenhouse gas emissions and break new and uncertain legal ground in making these legally binding on Ministers. The targets are supported by detailed reporting mechanisms, to Parliament and the public, that are intended to be the main route to enforcement and by provisions enabling many detailed changes to the law to allow progress towards the targets. The separate legislation in Scotland highlights the difficulties that dealing with pervasive issues, especially those with an EU and international dimension, pose for by sub-national governments with distinct political ambitions but limited jurisdiction. KW - "Climate Change" Law M1 - Chapter (peer-reviewed) SN - 9789400754393 BT - Climate Change and the Law T2 - Climate Change and the Law A2 - Mehling,Michael ED - Mehling,Michael T3 - Ius Gentium: Comparative Perspectives on Law and Justice T3 - en_GB SP - 537 EP - 549 ER - TY - JOUR T1 - Experimental demonstration of optical transport, sorting and self-arrangement using a 'tractor beam' A1 - Brzobohaty,O. A1 - Karasek,V. A1 - Siler,M. A1 - Chvatal,L. A1 - Cizmar,T. A1 - Zemanek,P. AU - Brzobohaty,O. AU - Karasek,V. AU - Siler,M. AU - Chvatal,L. AU - Cizmar,T. AU - Zemanek,P. PY - 2013/2 Y1 - 2013/2 N2 -

Following the Keplerian idea of optical forces, one would intuitively expect that an object illuminated by sunlight radiation or a laser beam will be accelerated along the direction of photon flow. Recent theoretical studies(1-5) have shown that small particles can be pulled by light beams against the photon stream, even in beams with uniform optical intensity along the propagation axis. Here, we present a geometry to generate such a 'tractor beam', and experimentally demonstrate its functionality using spherical microparticles of various sizes, as well as its enhancement with optically self-arranged structures of microparticles. In addition to the pulling of the particles, we also demonstrate that their two-dimensional motion and one-dimensional sorting may be controlled conveniently by rotation of the polarization of the linearly polarized incident beam. The relative simplicity of this geometry could serve to encourage its widespread application, and ongoing investigations will broaden the understanding of the light-matter interaction through studies combining more interacting micro-objects with various properties.

AB -

Following the Keplerian idea of optical forces, one would intuitively expect that an object illuminated by sunlight radiation or a laser beam will be accelerated along the direction of photon flow. Recent theoretical studies(1-5) have shown that small particles can be pulled by light beams against the photon stream, even in beams with uniform optical intensity along the propagation axis. Here, we present a geometry to generate such a 'tractor beam', and experimentally demonstrate its functionality using spherical microparticles of various sizes, as well as its enhancement with optically self-arranged structures of microparticles. In addition to the pulling of the particles, we also demonstrate that their two-dimensional motion and one-dimensional sorting may be controlled conveniently by rotation of the polarization of the linearly polarized incident beam. The relative simplicity of this geometry could serve to encourage its widespread application, and ongoing investigations will broaden the understanding of the light-matter interaction through studies combining more interacting micro-objects with various properties.

KW - RADIATION FORCE KW - BINDING KW - TWEEZERS KW - THEORETICAL DETERMINATION U2 - 10.1038/NPHOTON.2012.332 DO - 10.1038/NPHOTON.2012.332 M1 - Article JO - Nature Photonics JF - Nature Photonics SN - 1749-4885 IS - 2 VL - 7 SP - 123 EP - 127 ER - TY - JOUR T1 - Improved short term surgical outcomes in Scotland for oesophageal cancer A1 - Young,J.A. A1 - Shimi,S.M. A1 - Waugh,L. A1 - McPhillips,G. A1 - Thompson,A.M. AU - Young,J.A. AU - Shimi,S.M. AU - Waugh,L. AU - McPhillips,G. AU - Thompson,A.M. PY - 2013/2 Y1 - 2013/2 N2 - Aim: This study examined the trends in mortality and contributing adverse events associated with death under surgical care for patients with oesophageal cancer. Methods: Adverse events in surgical care were prospectively audited in patients who died with cancer of the oesophagus or oesophago-gastric junction under surgical care in Scotland from 1994 to 2005 through the Scottish Audit of Surgical Mortality (SASM). Results: Between 1994 and 2005 (inclusive), 1424 patients with oesophageal cancer (median age 72, 62% male) died. The proportion of oesophageal cancer patients dying on a surgical ward fell significantly from 17% to 13% (p = 0.005). There has been a significant decrease in the annual number of major surgical resections for oesophageal cancer in Scotland from 324 in 1994 to 193 in 2005 (p <0.001). The proportion of patients operated on in specialist cancer centres increased since 2000. In the period 1996 to 2005, 1157 patients died under surgical care with oesophageal cancer and were audited by SASM. One hundred and thirty five patients (12%) had 239 adverse events. Overall, the number of adverse events decreased over time with 65/130 of those who died following a cancer resection had adverse events. An anastomotic leak was a factor in 25 of these patients. There was a significant decrease in the proportion of deaths following therapeutic endoscopy (p = 0.011). Conclusion: There has been a significant decrease in the number of cancer resections, adverse events and mortality associated with oesophageal cancer surgery at a time of increasing surgical specialisation. © 2012 Elsevier Ltd. All rights reserved. AB - Aim: This study examined the trends in mortality and contributing adverse events associated with death under surgical care for patients with oesophageal cancer. Methods: Adverse events in surgical care were prospectively audited in patients who died with cancer of the oesophagus or oesophago-gastric junction under surgical care in Scotland from 1994 to 2005 through the Scottish Audit of Surgical Mortality (SASM). Results: Between 1994 and 2005 (inclusive), 1424 patients with oesophageal cancer (median age 72, 62% male) died. The proportion of oesophageal cancer patients dying on a surgical ward fell significantly from 17% to 13% (p = 0.005). There has been a significant decrease in the annual number of major surgical resections for oesophageal cancer in Scotland from 324 in 1994 to 193 in 2005 (p <0.001). The proportion of patients operated on in specialist cancer centres increased since 2000. In the period 1996 to 2005, 1157 patients died under surgical care with oesophageal cancer and were audited by SASM. One hundred and thirty five patients (12%) had 239 adverse events. Overall, the number of adverse events decreased over time with 65/130 of those who died following a cancer resection had adverse events. An anastomotic leak was a factor in 25 of these patients. There was a significant decrease in the proportion of deaths following therapeutic endoscopy (p = 0.011). Conclusion: There has been a significant decrease in the number of cancer resections, adverse events and mortality associated with oesophageal cancer surgery at a time of increasing surgical specialisation. © 2012 Elsevier Ltd. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872122718&md5=ea5bdaf398d48761f1a6916c6843078f U2 - 10.1016/j.ejso.2012.10.006 DO - 10.1016/j.ejso.2012.10.006 M1 - Article JO - European Journal of Surgical Oncology JF - European Journal of Surgical Oncology SN - 0748-7983 IS - 2 VL - 39 SP - 131 EP - 135 ER - TY - JOUR T1 - Interactions of Apoptotic Cells with Macrophages in Radiation-Induced Bystander Signaling A1 - Rastogi,Shubhra A1 - Boylan,Michael A1 - Wright,Eric G A1 - Coates,Philip J AU - Rastogi,Shubhra AU - Boylan,Michael AU - Wright,Eric G AU - Coates,Philip J PY - 2013/2 Y1 - 2013/2 N2 - Nontargeted effects that result in ongoing cellular and tissue damage show genotype-dependency in murine models with CBA/Ca, but not C57BL/6, exhibiting sensitivity to induced genomic instability. In vivo, radiation exposure is associated with genotype-dependent macrophage activation, and these cells are a source of bystander signaling involving cytokines and reactive oxygen and nitrogen species. The mechanisms responsible for macrophage activation and production of damaging bystander signals after irradiation are unclear. Macrophages from CBA/Ca exhibit an M1 (proinflammatory) phenotype compared to the M2 (anti-inflammatory) phenotype of C57BL/6 macrophages. Using the murine RAW264.7 macrophage-like cell line, we show that the ability of macrophages to interact with apoptotic cells and their responses to interaction varies significantly according to macrophage phenotype. Nonstimulated and M2 macrophages induce anti-inflammatory markers arginase and TGFß after engulfment of apoptotic cells. In contrast, M1 macrophages do not induce anti-inflammatory responses, but express the proinflammatory markers NOS2, IL-6, TNFa, superoxide and NO, able to contribute to a damaging microenvironment. Macrophages stimulated with both inflammatory and anti-inflammatory agents prior to exposure to apoptotic cells induce a mixed response. The results indicate a complex cross-talk between macrophages and apoptotic cells and demonstrate that phagocytic clearance of apoptotic cells induced by genotoxic stress can produce microenvironmental responses consistent with the induction of a chromosomal instability phenotype in sensitive CBA/Ca mice with M1 macrophage activation, but not in resistant C57BL/6 mice with M2 macrophage activation. Modulation of macrophage phenotypes may represent a novel approach for reducing the nontargeted effects of radiation. AB - Nontargeted effects that result in ongoing cellular and tissue damage show genotype-dependency in murine models with CBA/Ca, but not C57BL/6, exhibiting sensitivity to induced genomic instability. In vivo, radiation exposure is associated with genotype-dependent macrophage activation, and these cells are a source of bystander signaling involving cytokines and reactive oxygen and nitrogen species. The mechanisms responsible for macrophage activation and production of damaging bystander signals after irradiation are unclear. Macrophages from CBA/Ca exhibit an M1 (proinflammatory) phenotype compared to the M2 (anti-inflammatory) phenotype of C57BL/6 macrophages. Using the murine RAW264.7 macrophage-like cell line, we show that the ability of macrophages to interact with apoptotic cells and their responses to interaction varies significantly according to macrophage phenotype. Nonstimulated and M2 macrophages induce anti-inflammatory markers arginase and TGFß after engulfment of apoptotic cells. In contrast, M1 macrophages do not induce anti-inflammatory responses, but express the proinflammatory markers NOS2, IL-6, TNFa, superoxide and NO, able to contribute to a damaging microenvironment. Macrophages stimulated with both inflammatory and anti-inflammatory agents prior to exposure to apoptotic cells induce a mixed response. The results indicate a complex cross-talk between macrophages and apoptotic cells and demonstrate that phagocytic clearance of apoptotic cells induced by genotoxic stress can produce microenvironmental responses consistent with the induction of a chromosomal instability phenotype in sensitive CBA/Ca mice with M1 macrophage activation, but not in resistant C57BL/6 mice with M2 macrophage activation. Modulation of macrophage phenotypes may represent a novel approach for reducing the nontargeted effects of radiation. U2 - 10.1667/RR2969.1 DO - 10.1667/RR2969.1 M1 - Article JO - Radiation Research JF - Radiation Research IS - 2 VL - 179 SP - 135 EP - 145 ER - TY - JOUR T1 - Italian fascism and the political mobilisation of working-class women 1937-43 A1 - Willson,Perry AU - Willson,Perry PY - 2013/2 Y1 - 2013/2 N2 - The Sezione Operaie e Lavoranti a Domicilio dei Fasci Femminili (Section of the Fascist Women's Groups for Female Workers and Outworkers) is the only one of the three Italian Fascist Party organisations for adult women that has never been studied. Founded in 1937 and recruiting factory workers, outworkers and domestic servants, it achieved a membership of almost a million by the fall of the regime in 1943. A top-down organisation, run by the largely middle-class Fasci Femminili, it offered its membership a mix of social, educational and professional opportunities. This article explores its activities, its organisational structure, the messages it attempted to convey to its membership and the reasons why such large numbers of women joined. © 2012 Cambridge University Press. AB - The Sezione Operaie e Lavoranti a Domicilio dei Fasci Femminili (Section of the Fascist Women's Groups for Female Workers and Outworkers) is the only one of the three Italian Fascist Party organisations for adult women that has never been studied. Founded in 1937 and recruiting factory workers, outworkers and domestic servants, it achieved a membership of almost a million by the fall of the regime in 1943. A top-down organisation, run by the largely middle-class Fasci Femminili, it offered its membership a mix of social, educational and professional opportunities. This article explores its activities, its organisational structure, the messages it attempted to convey to its membership and the reasons why such large numbers of women joined. © 2012 Cambridge University Press. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871266353&md5=2014c62f35b9eb8b91ebbdbf982ef120 U2 - 10.1017/S0960777312000483 DO - 10.1017/S0960777312000483 M1 - Article JO - Contemporary European History JF - Contemporary European History SN - 0960-7773 IS - 1 VL - 22 SP - 65 EP - 86 ER - TY - JOUR T1 - Making and gifting belonging T2 - creative arts and people with learning disabilities A1 - Hall,Edward AU - Hall,Edward PY - 2013/2 Y1 - 2013/2 N2 - Creative arts are understood to be a mediator between positions of social exclusion and inclusion for marginalised people and places, building self-confidence and strengthening social networks. Whilst there are undoubted benefits from involvement in creative arts, the paper critiques the assumed shift from excluded to included positions. Instead, the paper adopts the nuanced notion of ‘belonging’ to reflect the desires and experiences of one marginal group, people with learning disabilities. Drawing on case-studies of two creative arts organisations in Edinburgh, Scotland, the paper argues: first, the making of arts objects and performances provides opportunities for embodied and emotional expression; second, the act of ‘gifting’ objects and performances to people in wider society transmits emotions and creativity into non-disabled spaces with possible outcomes of connection and recognition; third, the intimate communities and safe spaces where creative art is made provide bases for ventures into public spaces for gifting, and the generation of senses of belonging. The paper concludes hopefully, arguing that through the doing of creative arts people with learning disabilities can transcend the exclusionary landscape (albeit temporarily) and begin to reimagine and transform understandings of learning disability and difference in society. AB - Creative arts are understood to be a mediator between positions of social exclusion and inclusion for marginalised people and places, building self-confidence and strengthening social networks. Whilst there are undoubted benefits from involvement in creative arts, the paper critiques the assumed shift from excluded to included positions. Instead, the paper adopts the nuanced notion of ‘belonging’ to reflect the desires and experiences of one marginal group, people with learning disabilities. Drawing on case-studies of two creative arts organisations in Edinburgh, Scotland, the paper argues: first, the making of arts objects and performances provides opportunities for embodied and emotional expression; second, the act of ‘gifting’ objects and performances to people in wider society transmits emotions and creativity into non-disabled spaces with possible outcomes of connection and recognition; third, the intimate communities and safe spaces where creative art is made provide bases for ventures into public spaces for gifting, and the generation of senses of belonging. The paper concludes hopefully, arguing that through the doing of creative arts people with learning disabilities can transcend the exclusionary landscape (albeit temporarily) and begin to reimagine and transform understandings of learning disability and difference in society. KW - Creative arts KW - Social inclusion KW - Belonging KW - Learning disability U2 - 10.1068/a44629 DO - 10.1068/a44629 M1 - Article JO - Environment and Planning A JF - Environment and Planning A SN - 0308-518X IS - 2 VL - 45 SP - 244 EP - 262 ER - TY - JOUR T1 - Occupational issues of adults with ADHD A1 - Adamou,Marios A1 - Arif,Muhammad A1 - Asherson,Philip A1 - Aw,Tar-Ching A1 - Bolea,Blanca A1 - Coghill,David A1 - Guðjónsson,Gísli A1 - Halmøy,Anne A1 - Hodgkins,Paul A1 - Müller,Ulrich A1 - Pitts,Mark A1 - Trakoli,Anna A1 - Williams,Nerys A1 - Young,Susan AU - Adamou,Marios AU - Arif,Muhammad AU - Asherson,Philip AU - Aw,Tar-Ching AU - Bolea,Blanca AU - Coghill,David AU - Guðjónsson,Gísli AU - Halmøy,Anne AU - Hodgkins,Paul AU - Müller,Ulrich AU - Pitts,Mark AU - Trakoli,Anna AU - Williams,Nerys AU - Young,Susan PY - 2013/2 Y1 - 2013/2 N2 - ABSTRACT: BACKGROUND: ADHD is a common neurodevelopmental disorder that persists into adulthood. Its symptoms cause impairments in a number of social domains, one of which is employment. We wish to produce a consensus statement on how ADHD affects employment. METHODS: This consensus development conference statement was developed as a result of a joint international meeting held in July 2010. The consensus committee was international in scope (United Kingdom, mainland Europe, United Arab Emirates) and consisted of individuals from a broad range of backgrounds (Psychiatry, Occupational Medicine, Health Economists, Disability Advisors). The objectives of the conference were to discuss some of the occupational impairments adults with ADHD may face and how to address these problems from an inclusive perspective. Furthermore the conference looked at influencing policy and decision making at a political level to address impaired occupational functioning in adults with ADHD and fears around employing people with disabilities in general. RESULTS: The consensus was that there were clear weaknesses in the current arrangements in the UK and internationally to address occupational difficulties. More so, Occupational Health was not wholly integrated and used as a means of making positive changes to the workplace, but rather as a superfluous last resort that employers tried to avoid. Furthermore the lack of cross professional collaboration on occupational functioning in adults with ADHD was a significant problem. CONCLUSIONS: Future research needs to concentrate on further investigating occupational functioning in adults with ADHD and pilot exploratory initiatives and tools, leading to a better and more informed understanding of possible barriers to employment and potential schemes to put in place to address these problems. AB - ABSTRACT: BACKGROUND: ADHD is a common neurodevelopmental disorder that persists into adulthood. Its symptoms cause impairments in a number of social domains, one of which is employment. We wish to produce a consensus statement on how ADHD affects employment. METHODS: This consensus development conference statement was developed as a result of a joint international meeting held in July 2010. The consensus committee was international in scope (United Kingdom, mainland Europe, United Arab Emirates) and consisted of individuals from a broad range of backgrounds (Psychiatry, Occupational Medicine, Health Economists, Disability Advisors). The objectives of the conference were to discuss some of the occupational impairments adults with ADHD may face and how to address these problems from an inclusive perspective. Furthermore the conference looked at influencing policy and decision making at a political level to address impaired occupational functioning in adults with ADHD and fears around employing people with disabilities in general. RESULTS: The consensus was that there were clear weaknesses in the current arrangements in the UK and internationally to address occupational difficulties. More so, Occupational Health was not wholly integrated and used as a means of making positive changes to the workplace, but rather as a superfluous last resort that employers tried to avoid. Furthermore the lack of cross professional collaboration on occupational functioning in adults with ADHD was a significant problem. CONCLUSIONS: Future research needs to concentrate on further investigating occupational functioning in adults with ADHD and pilot exploratory initiatives and tools, leading to a better and more informed understanding of possible barriers to employment and potential schemes to put in place to address these problems. U2 - 10.1186/1471-244X-13-59 DO - 10.1186/1471-244X-13-59 M1 - Article JO - BMC Psychiatry JF - BMC Psychiatry VL - 13 ER - TY - JOUR T1 - Oral 5-aminolevulinic acid induced photodynamic diagnostic ureterorenoscopy - does the blood pressure require monitoring? A1 - Bondad,J. A1 - Aboumarzouk,O. M. A1 - Moseley,H. A1 - Kata,S. G. AU - Bondad,J. AU - Aboumarzouk,O. M. AU - Moseley,H. AU - Kata,S. G. PY - 2013/2 Y1 - 2013/2 N2 - Background: Photodynamic Diagnosis has been proven to improve detection of superficial bladder cancer and improve visualisation of resection margins. The use of 5-aminolevulinic acid as the photosensitising agent has been associated with side effects, specifically hypotension. We aimed to evaluate the effect of oral 5-ALA on the blood pressure in a group of patient who underwent Photodynamic Diagnostic Ureterorenoscopy. Methods: We carried out an observational study on all patients who underwent PDD-Ureterorenoscopy with oral 5-ALA between July 2009 and September 2011. Pre-administration, hourly post-administration and hourly post-operative blood pressures were noted. Mean arterial blood pressure and the threshold for cerebral ischaemia were calculated as well. Results: The study includes thirty-eight procedures which involved twenty-four patients with a mean age of 74 (SD ± 16.95). Hypotension was defined as AB - Background: Photodynamic Diagnosis has been proven to improve detection of superficial bladder cancer and improve visualisation of resection margins. The use of 5-aminolevulinic acid as the photosensitising agent has been associated with side effects, specifically hypotension. We aimed to evaluate the effect of oral 5-ALA on the blood pressure in a group of patient who underwent Photodynamic Diagnostic Ureterorenoscopy. Methods: We carried out an observational study on all patients who underwent PDD-Ureterorenoscopy with oral 5-ALA between July 2009 and September 2011. Pre-administration, hourly post-administration and hourly post-operative blood pressures were noted. Mean arterial blood pressure and the threshold for cerebral ischaemia were calculated as well. Results: The study includes thirty-eight procedures which involved twenty-four patients with a mean age of 74 (SD ± 16.95). Hypotension was defined as UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84864134240&md5=452b60d4cba1e80b55f962438d37da43 U2 - 10.1016/j.pdpdt.2012.06.004 DO - 10.1016/j.pdpdt.2012.06.004 M1 - Article JO - Photodiagnosis and Photodynamic Therapy JF - Photodiagnosis and Photodynamic Therapy SN - 1572-1000 IS - 1 VL - 10 SP - 39 EP - 41 ER - TY - JOUR T1 - Quantifying the fraction of cirrhosis attributable to alcohol among chronic hepatitis C virus patients T2 - implications for treatment cost-effectiveness A1 - Innes,Hamish A. A1 - Hutchinson,Sharon J. A1 - Barclay,Stephen A1 - Cadzow,Elaine A1 - Dillon,John F. A1 - Fraser,Andrew A1 - Goldberg,David J. A1 - Mills,Peter R. A1 - McDonald,Scott A. A1 - Morris,Judith A1 - Stanley,Adrian A1 - Hayes,Peter A1 - Hepatitis C Clinical Database Monitoring Committee AU - Innes,Hamish A. AU - Hutchinson,Sharon J. AU - Barclay,Stephen AU - Cadzow,Elaine AU - Dillon,John F. AU - Fraser,Andrew AU - Goldberg,David J. AU - Mills,Peter R. AU - McDonald,Scott A. AU - Morris,Judith AU - Stanley,Adrian AU - Hayes,Peter AU - Hepatitis C Clinical Database Monitoring Committee PY - 2013/2 Y1 - 2013/2 N2 - A substantial baseline risk of liver cirrhosis exists for patients with chronic hepatitis C virus (HCV) infection. However, the extent to which this could be driven by heavy alcohol use is unclear. Therefore, our principal aim was to determine the fraction of cirrhosis attributable to heavy alcohol use among chronic HCV patients attending a liver clinic. The study population comprised chronic HCV patients who had attended one of five liver clinics in Scotland during 1996-2010 and had (1) remained in follow-up for at least 6 months, (2) acquired HCV through either injecting drugs or blood transfusion, and (3) an estimated date of acquiring infection. Predictors of cirrhosis were determined from multivariate logistic regression. Regression parameters were used to determine the fraction of cirrhosis attributable to heavy alcohol use. Among 1,620 patients, 9% were diagnosed with cirrhosis, and 34% had ever engaged in heavy alcohol use (>50 units/week for a sustained period). Significant predictors of cirrhosis were age, duration of infection, and ever heavy alcohol use. The fraction of cirrhosis attributable to ever heavy alcohol use was 36.1% (95% confidence interval [CI]: 24.4-47.4). Moreover, among patients who had ever engaged in heavy alcohol use specifically, this attributable fraction exceeded 50% (61.6%; 95% CI: 47.0-72.2). Conclusions: A substantial proportion of patients with chronic HCV develop liver cirrhosis as a consequence of heavy alcohol use. This has not been adequately acknowledged by cost utility analyses (CUAs). As such, estimates of cost-effectiveness may be exaggerated. Thus, these data are important to guide forthcoming CUAs in terms of taking better account of the factors leading to cirrhosis among patients with chronic HCV. (HEPATOLOGY 2013). AB - A substantial baseline risk of liver cirrhosis exists for patients with chronic hepatitis C virus (HCV) infection. However, the extent to which this could be driven by heavy alcohol use is unclear. Therefore, our principal aim was to determine the fraction of cirrhosis attributable to heavy alcohol use among chronic HCV patients attending a liver clinic. The study population comprised chronic HCV patients who had attended one of five liver clinics in Scotland during 1996-2010 and had (1) remained in follow-up for at least 6 months, (2) acquired HCV through either injecting drugs or blood transfusion, and (3) an estimated date of acquiring infection. Predictors of cirrhosis were determined from multivariate logistic regression. Regression parameters were used to determine the fraction of cirrhosis attributable to heavy alcohol use. Among 1,620 patients, 9% were diagnosed with cirrhosis, and 34% had ever engaged in heavy alcohol use (>50 units/week for a sustained period). Significant predictors of cirrhosis were age, duration of infection, and ever heavy alcohol use. The fraction of cirrhosis attributable to ever heavy alcohol use was 36.1% (95% confidence interval [CI]: 24.4-47.4). Moreover, among patients who had ever engaged in heavy alcohol use specifically, this attributable fraction exceeded 50% (61.6%; 95% CI: 47.0-72.2). Conclusions: A substantial proportion of patients with chronic HCV develop liver cirrhosis as a consequence of heavy alcohol use. This has not been adequately acknowledged by cost utility analyses (CUAs). As such, estimates of cost-effectiveness may be exaggerated. Thus, these data are important to guide forthcoming CUAs in terms of taking better account of the factors leading to cirrhosis among patients with chronic HCV. (HEPATOLOGY 2013). U2 - 10.1002/hep.26051 DO - 10.1002/hep.26051 M1 - Article JO - Hepatology JF - Hepatology IS - 2 VL - 57 SP - 451 EP - 460 ER - TY - JOUR T1 - Review T2 - Freedom of Information in Scotland in Practice by Kevin Dunion A1 - Reid,Colin T. AU - Reid,Colin T. PY - 2013/2 Y1 - 2013/2 M1 - Book/Film/Article review JO - SCOLAG Legal Journal JF - SCOLAG Legal Journal SN - 0264-8717 IS - 424 VL - 2013 SP - 40 ER - TY - JOUR T1 - Risk Aversion and Anxiety in Scottish Criminal Justice Social Work T2 - Can Desistance and Human Rights Agendas Have an Impact? A1 - Fenton,Jane AU - Fenton,Jane PY - 2013/2 Y1 - 2013/2 N2 - This article explores the difficulty that criminal justice social work (CJSW) might have in implementing a desistance approach to work with offenders. Supporting desistance requires responsive, autonomous social workers and this article questions whether criminal justice agencies, characterised by risk aversion and managerialism, would be able to tolerate the anxiety this would inevitably, and properly, generate. Suggestions are made regarding the place of desistance work within a positive human rights framework, which might provide a force against the corrosive progression of popular punitivism - a major factor in the persistence of risk averse, managerial practice. © 2012 The Author. The Howard Journal of Criminal Justice © 2012 The Howard League and Blackwell Publishing Ltd. AB - This article explores the difficulty that criminal justice social work (CJSW) might have in implementing a desistance approach to work with offenders. Supporting desistance requires responsive, autonomous social workers and this article questions whether criminal justice agencies, characterised by risk aversion and managerialism, would be able to tolerate the anxiety this would inevitably, and properly, generate. Suggestions are made regarding the place of desistance work within a positive human rights framework, which might provide a force against the corrosive progression of popular punitivism - a major factor in the persistence of risk averse, managerial practice. © 2012 The Author. The Howard Journal of Criminal Justice © 2012 The Howard League and Blackwell Publishing Ltd. KW - disjuncture KW - Desistance KW - ontological anxiety KW - risk KW - Human Rights UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872406314&md5=3d8b11c5fe20b29fdd05b5765ae80e10 U2 - 10.1111/j.1468-2311.2012.00716.x DO - 10.1111/j.1468-2311.2012.00716.x M1 - Article JO - Howard Journal of Criminal Justice JF - Howard Journal of Criminal Justice SN - 0265-5527 IS - 1 VL - 52 SP - 77 EP - 90 ER - TY - JOUR T1 - Semantic consistency versus perceptual salience in visual scenes T2 - Findings from change detection A1 - Spotorno,Sara A1 - Tatler,Benjamin W. A1 - Faure,S. AU - Spotorno,Sara AU - Tatler,Benjamin W. AU - Faure,S. PY - 2013/2 Y1 - 2013/2 N2 - In a one-shot change detection task, we investigated the relationship between semantic properties (high consistency, i.e., diagnosticity, versus inconsistency with regard to gist) and perceptual properties (high versus low salience) of objects in guiding attention in visual scenes and in constructing scene representations. To produce the change an object was added or deleted in either the right or left half of coloured drawings of daily-life events. Diagnostic object deletions were more accurately detected than inconsistent ones, indicating rapid inclusion into early scene representation for the most predictable objects. Detection was faster and more accurate for high salience than for low salience changes. An advantage was found for diagnostic object changes in the high salience condition, although it was limited to additions when considering response speed. For inconsistent objects of high salience, deletions were detected faster than additions. These findings may indicate that objects are primarily selected on a perceptual basis with subsequent and supplementary effect of semantic consistency, in the sense of facilitation due to object diagnosticity or lengthening of processing time due to inconsistency. © 2012. AB - In a one-shot change detection task, we investigated the relationship between semantic properties (high consistency, i.e., diagnosticity, versus inconsistency with regard to gist) and perceptual properties (high versus low salience) of objects in guiding attention in visual scenes and in constructing scene representations. To produce the change an object was added or deleted in either the right or left half of coloured drawings of daily-life events. Diagnostic object deletions were more accurately detected than inconsistent ones, indicating rapid inclusion into early scene representation for the most predictable objects. Detection was faster and more accurate for high salience than for low salience changes. An advantage was found for diagnostic object changes in the high salience condition, although it was limited to additions when considering response speed. For inconsistent objects of high salience, deletions were detected faster than additions. These findings may indicate that objects are primarily selected on a perceptual basis with subsequent and supplementary effect of semantic consistency, in the sense of facilitation due to object diagnosticity or lengthening of processing time due to inconsistency. © 2012. KW - Change detection KW - Diagnosticity KW - Semantic inconsistency KW - Probability of occurance KW - Perceptual salience UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872508698&md5=9878b7e93db6cfa71a937d48cd397149 U2 - 10.1016/j.actpsy.2012.12.009 DO - 10.1016/j.actpsy.2012.12.009 M1 - Article JO - Acta Psychologica JF - Acta Psychologica SN - 0001-6918 IS - 2 VL - 142 SP - 168 EP - 176 ER - TY - JOUR T1 - Testosterone protects female embryonic heart H9c2 cells against severe metabolic stress by activating estrogen receptors and up-regulating IES SUR2B A1 - Ballantyne,Thomas A1 - Du,Qingyou A1 - Jovanovic,Sofija A1 - Neemo,Andrew A1 - Holmes,Robert A1 - Sinha,Sharabh A1 - Jovanovic,Aleksandar AU - Ballantyne,Thomas AU - Du,Qingyou AU - Jovanovic,Sofija AU - Neemo,Andrew AU - Holmes,Robert AU - Sinha,Sharabh AU - Jovanovic,Aleksandar PY - 2013/2 Y1 - 2013/2 N2 -

A recent clinical study demonstrated that a testosterone supplementation improves functional capacity in elderly female patients suffering from heart failure. These findings prompted us to consider possible mechanisms of testosterone-induced cardioprotection in females. To address this question we have used a pure female population of rat heart embryonic H9c2 cells. Pre-treatment of cells with testosterone for 24 h significantly increased survival of H9c2 cells exposed to 2,4-dinitrophenol (DNP), an inhibitor of oxidative phosphorylation. These cells expressed low level of androgen receptors and the effect of testosterone was not modified by hydroxyflutamide, an antagonist of androgen receptor. In contrast, cyclohexamide, an inhibitor of protein biosynthesis, and tamoxifene, a partial agonist of estrogen receptors, abolished cardioprotection afforded by testosterone. In addition, finasteride, an inhibitor of 5a-reductase, and anastrazole, an inhibitor of a-aromatase, also blocked testosterone-induced cytoprotection. Real time RT-PCR revealed that testosterone did not regulate the expression of nine subunits and accessory proteins of sarcolemmal ATP-sensitive K+ (KATP) channels. On the other hand, testosterone, as well as 17ß-estradiol, up-regulated a putative mitochondrial KATP channel subunit, mitochondrial sulfonylurea receptor 2B intraexonics splice variant (IES SUR2B), without affecting expression of IES SUR2A. Tamoxifene inhibited testosterone-induced up-regulation of IES SUR2B without affecting IES SUR2A. In conclusion, this study has shown that testosterone protect female embryonic heart H9c2 cells against severe metabolic stress by its conversion into metabolites that activate estrogen receptors and up-regulate IES SUR2B.

AB -

A recent clinical study demonstrated that a testosterone supplementation improves functional capacity in elderly female patients suffering from heart failure. These findings prompted us to consider possible mechanisms of testosterone-induced cardioprotection in females. To address this question we have used a pure female population of rat heart embryonic H9c2 cells. Pre-treatment of cells with testosterone for 24 h significantly increased survival of H9c2 cells exposed to 2,4-dinitrophenol (DNP), an inhibitor of oxidative phosphorylation. These cells expressed low level of androgen receptors and the effect of testosterone was not modified by hydroxyflutamide, an antagonist of androgen receptor. In contrast, cyclohexamide, an inhibitor of protein biosynthesis, and tamoxifene, a partial agonist of estrogen receptors, abolished cardioprotection afforded by testosterone. In addition, finasteride, an inhibitor of 5a-reductase, and anastrazole, an inhibitor of a-aromatase, also blocked testosterone-induced cytoprotection. Real time RT-PCR revealed that testosterone did not regulate the expression of nine subunits and accessory proteins of sarcolemmal ATP-sensitive K+ (KATP) channels. On the other hand, testosterone, as well as 17ß-estradiol, up-regulated a putative mitochondrial KATP channel subunit, mitochondrial sulfonylurea receptor 2B intraexonics splice variant (IES SUR2B), without affecting expression of IES SUR2A. Tamoxifene inhibited testosterone-induced up-regulation of IES SUR2B without affecting IES SUR2A. In conclusion, this study has shown that testosterone protect female embryonic heart H9c2 cells against severe metabolic stress by its conversion into metabolites that activate estrogen receptors and up-regulate IES SUR2B.

U2 - 10.1016/j.biocel.2012.10.005 DO - 10.1016/j.biocel.2012.10.005 M1 - Article JO - International Journal of Biochemistry & Cell Biology JF - International Journal of Biochemistry & Cell Biology SN - 1357-2725 IS - 2 VL - 45 SP - 283 EP - 291 ER - TY - JOUR T1 - The Escherichia coli SLC26 homologue YchM (DauA) is a C(4) -dicarboxylic acid transporter A1 - Karinou,Eleni A1 - Compton,Emma L R A1 - Morel,Mélanie A1 - Javelle,Arnaud AU - Karinou,Eleni AU - Compton,Emma L R AU - Morel,Mélanie AU - Javelle,Arnaud PY - 2013/2 Y1 - 2013/2 N2 - The SLC26/SulP (solute carrier/sulphate transporter) proteins are a ubiquitous superfamily of secondary anion transporters. Prior studies have focused almost exclusively on eukaryotic members and bacterial members are frequently classified as sulphate transporters based on their homology with SulP proteins from plants and fungi. In this study we have examined the function and physiological role of the Escherichia coli Slc26 homologue, YchM. We show that there is a clear YchM-dependent growth defect when succinate is used as the sole carbon source. Using an in vivo succinate transport assay, we show that YchM is the sole aerobic succinate transporter active at acidic pH. We demonstrate that YchM can also transport other C(4) -dicarboxylic acids and that its substrate specificity differs from the well-characterized succinate transporter, DctA. Accordingly ychM was re-designated dauA (dicarboxylic acid uptake system A). Finally, our data suggest that DauA is a protein with transport and regulation activities. This is the first report that a SLC26/SulP protein acts as a C(4) -dicarboxylic acid transporter and an unexpected new function for a prokaryotic member of this transporter family. AB - The SLC26/SulP (solute carrier/sulphate transporter) proteins are a ubiquitous superfamily of secondary anion transporters. Prior studies have focused almost exclusively on eukaryotic members and bacterial members are frequently classified as sulphate transporters based on their homology with SulP proteins from plants and fungi. In this study we have examined the function and physiological role of the Escherichia coli Slc26 homologue, YchM. We show that there is a clear YchM-dependent growth defect when succinate is used as the sole carbon source. Using an in vivo succinate transport assay, we show that YchM is the sole aerobic succinate transporter active at acidic pH. We demonstrate that YchM can also transport other C(4) -dicarboxylic acids and that its substrate specificity differs from the well-characterized succinate transporter, DctA. Accordingly ychM was re-designated dauA (dicarboxylic acid uptake system A). Finally, our data suggest that DauA is a protein with transport and regulation activities. This is the first report that a SLC26/SulP protein acts as a C(4) -dicarboxylic acid transporter and an unexpected new function for a prokaryotic member of this transporter family. KW - c4-dicarboxylic acid transporter U2 - 10.1111/mmi.12120 DO - 10.1111/mmi.12120 M1 - Article JO - Molecular Microbiology JF - Molecular Microbiology SN - 0950-382x IS - 3 VL - 87 SP - 623 EP - 640 ER - TY - JOUR T1 - The construction of power in family medicine bedside teaching T2 - A video observation study A1 - Rees,Charlotte E. A1 - Ajjawi,Rola A1 - Monrouxe,Lynn V. AU - Rees,Charlotte E. AU - Ajjawi,Rola AU - Monrouxe,Lynn V. PY - 2013/2 Y1 - 2013/2 N2 - Introduction Bedside teaching is essential for helping students develop skills, reasoning and professionalism, and involves the learning triad of student, patient and clinical teacher. Although current rhetoric espouses the sharing of power, the medical workplace is imbued with power asymmetries. Power is context-specific and although previous research has explored some elements of the enactment and resistance of power within bedside teaching, this exploration has been conducted within hospital rather than general practice settings. Furthermore, previous research has employed audio-recorded rather than video-recorded observation and has therefore focused on language and para-language at the expense of non-verbal communication and human-material interaction. Methods A qualitative design was adopted employing video- and audio-recorded observations of seven bedside teaching encounters (BTEs), followed by short individual interviews with students, patients and clinical teachers. Thematic and discourse analyses of BTEs were conducted. Results Power is constructed by students, patients and clinical teachers throughout different BTE activities through the use of linguistic, para-linguistic and non-verbal communication. In terms of language, participants construct power through the use of questions, orders, advice, pronouns and medical/health belief talk. With reference to para-language, participants construct power through the use of interruption and laughter. In terms of non-verbal communication, participants construct power through physical positioning and the possession or control of medical materials such as the stethoscope. Conclusions Using this paper as a trigger for discussion, we encourage students and clinical teachers to reflect critically on how their verbal and non-verbal communication constructs power in bedside teaching. Students and clinical teachers need to develop their awareness of what power is, how it can be constructed and shared, and what it means for the student-patient-doctor relationship within bedside teaching. Discuss ideas arising from this article at 'discuss' © Blackwell Publishing Ltd 2013. AB - Introduction Bedside teaching is essential for helping students develop skills, reasoning and professionalism, and involves the learning triad of student, patient and clinical teacher. Although current rhetoric espouses the sharing of power, the medical workplace is imbued with power asymmetries. Power is context-specific and although previous research has explored some elements of the enactment and resistance of power within bedside teaching, this exploration has been conducted within hospital rather than general practice settings. Furthermore, previous research has employed audio-recorded rather than video-recorded observation and has therefore focused on language and para-language at the expense of non-verbal communication and human-material interaction. Methods A qualitative design was adopted employing video- and audio-recorded observations of seven bedside teaching encounters (BTEs), followed by short individual interviews with students, patients and clinical teachers. Thematic and discourse analyses of BTEs were conducted. Results Power is constructed by students, patients and clinical teachers throughout different BTE activities through the use of linguistic, para-linguistic and non-verbal communication. In terms of language, participants construct power through the use of questions, orders, advice, pronouns and medical/health belief talk. With reference to para-language, participants construct power through the use of interruption and laughter. In terms of non-verbal communication, participants construct power through physical positioning and the possession or control of medical materials such as the stethoscope. Conclusions Using this paper as a trigger for discussion, we encourage students and clinical teachers to reflect critically on how their verbal and non-verbal communication constructs power in bedside teaching. Students and clinical teachers need to develop their awareness of what power is, how it can be constructed and shared, and what it means for the student-patient-doctor relationship within bedside teaching. Discuss ideas arising from this article at 'discuss' © Blackwell Publishing Ltd 2013. KW - bedside teaching KW - Power KW - family practice, education KW - CLINICAL TEACHERS UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84870002762&md5=303bfe50bdda9aa31b8dd7f2be5e5162 U2 - 10.1111/medu.12055 DO - 10.1111/medu.12055 M1 - Article JO - Medical Education JF - Medical Education SN - 0308-0110 IS - 2 VL - 47 SP - 154 EP - 165 ER - TY - JOUR T1 - The microsporidian parasites Nosema ceranae and Nosema apis are widespread in honeybee (Apis mellifera) colonies across Scotland A1 - Bollan,Karen A. A1 - Hothersall,J. Daniel A1 - Moffat,Christopher A1 - Durkacz,John A1 - Saranzewa,Nastja A1 - Wright,Geraldine A. A1 - Raine,Nigel E. A1 - Highet,Fiona A1 - Connolly,Christopher N. AU - Bollan,Karen A. AU - Hothersall,J. Daniel AU - Moffat,Christopher AU - Durkacz,John AU - Saranzewa,Nastja AU - Wright,Geraldine A. AU - Raine,Nigel E. AU - Highet,Fiona AU - Connolly,Christopher N. PY - 2013/2 Y1 - 2013/2 N2 - Nosema ceranae is spreading into areas where Nosema apis already exists. N. ceranae has been reported to cause an asymptomatic infection that may lead, ultimately, to colony collapse. It is thought that there may be a temperature barrier to its infiltration into countries in colder climates. In this study, 71 colonies from Scottish Beekeeper's Association members have been screened for the presence of N. apis and N. ceranae across Scotland. We find that only 11 of the 71 colonies tested positive for spores by microscopy. However, 70.4 % of colonies screened by PCR revealed the presence of both N. ceranae and N. apis, with only 4.2 or 7 % having either strain alone and 18.3 % being Nosema free. A range of geographically separated colonies testing positive for N. ceranae were sequenced to confirm their identity. All nine sequences confirmed the presence of N. ceranae and indicated the presence of a single new variant. Furthermore, two of the spore-containing colonies had only N. ceranae present, and these exhibited the presence of smaller spores that could be distinguished from N. apis by the analysis of average spore size. Differential quantification of the PCR product revealed N. ceranae to be the dominant species in all seven samples tested. In conclusion, N. ceranae is widespread in Scotland where it exists in combination with the endemic N. apis. A single variant, identical to that found in France (DQ374655) except for the addition of a single nucleotide polymorphism, is present in Scotland. © 2012 Springer-Verlag Berlin Heidelberg. AB - Nosema ceranae is spreading into areas where Nosema apis already exists. N. ceranae has been reported to cause an asymptomatic infection that may lead, ultimately, to colony collapse. It is thought that there may be a temperature barrier to its infiltration into countries in colder climates. In this study, 71 colonies from Scottish Beekeeper's Association members have been screened for the presence of N. apis and N. ceranae across Scotland. We find that only 11 of the 71 colonies tested positive for spores by microscopy. However, 70.4 % of colonies screened by PCR revealed the presence of both N. ceranae and N. apis, with only 4.2 or 7 % having either strain alone and 18.3 % being Nosema free. A range of geographically separated colonies testing positive for N. ceranae were sequenced to confirm their identity. All nine sequences confirmed the presence of N. ceranae and indicated the presence of a single new variant. Furthermore, two of the spore-containing colonies had only N. ceranae present, and these exhibited the presence of smaller spores that could be distinguished from N. apis by the analysis of average spore size. Differential quantification of the PCR product revealed N. ceranae to be the dominant species in all seven samples tested. In conclusion, N. ceranae is widespread in Scotland where it exists in combination with the endemic N. apis. A single variant, identical to that found in France (DQ374655) except for the addition of a single nucleotide polymorphism, is present in Scotland. © 2012 Springer-Verlag Berlin Heidelberg. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84869473197&md5=0dbffca8f6feacea99a8cf8d030b3d7f U2 - 10.1007/s00436-012-3195-0 DO - 10.1007/s00436-012-3195-0 M1 - Article JO - Parasitology Research JF - Parasitology Research SN - 0932-0113 IS - 2 VL - 112 SP - 751 EP - 759 ER - TY - JOUR T1 - The microsporidian parasites Nosema ceranae and Nosema apis are widespread in honeybee (Apis mellifera) colonies across Scotland A1 - Bollan,Karen A. A1 - Hothersall,J. Daniel A1 - Moffat,Christopher A1 - Durkacz,John A1 - Saranzewa,Nastja A1 - Wright,Geraldine A. A1 - Raine,Nigel E. A1 - Highet,Fiona A1 - Connolly,Christopher N. AU - Bollan,Karen A. AU - Hothersall,J. Daniel AU - Moffat,Christopher AU - Durkacz,John AU - Saranzewa,Nastja AU - Wright,Geraldine A. AU - Raine,Nigel E. AU - Highet,Fiona AU - Connolly,Christopher N. PY - 2013/2 Y1 - 2013/2 N2 - Nosema ceranae is spreading into areas where Nosema apis already exists. N. ceranae has been reported to cause an asymptomatic infection that may lead, ultimately, to colony collapse. It is thought that there may be a temperature barrier to its infiltration into countries in colder climates. In this study, 71 colonies from Scottish Beekeeper's Association members have been screened for the presence of N. apis and N. ceranae across Scotland. We find that only 11 of the 71 colonies tested positive for spores by microscopy. However, 70.4 % of colonies screened by PCR revealed the presence of both N. ceranae and N. apis, with only 4.2 or 7 % having either strain alone and 18.3 % being Nosema free. A range of geographically separated colonies testing positive for N. ceranae were sequenced to confirm their identity. All nine sequences confirmed the presence of N. ceranae and indicated the presence of a single new variant. Furthermore, two of the spore-containing colonies had only N. ceranae present, and these exhibited the presence of smaller spores that could be distinguished from N. apis by the analysis of average spore size. Differential quantification of the PCR product revealed N. ceranae to be the dominant species in all seven samples tested. In conclusion, N. ceranae is widespread in Scotland where it exists in combination with the endemic N. apis. A single variant, identical to that found in France (DQ374655) except for the addition of a single nucleotide polymorphism, is present in Scotland. AB - Nosema ceranae is spreading into areas where Nosema apis already exists. N. ceranae has been reported to cause an asymptomatic infection that may lead, ultimately, to colony collapse. It is thought that there may be a temperature barrier to its infiltration into countries in colder climates. In this study, 71 colonies from Scottish Beekeeper's Association members have been screened for the presence of N. apis and N. ceranae across Scotland. We find that only 11 of the 71 colonies tested positive for spores by microscopy. However, 70.4 % of colonies screened by PCR revealed the presence of both N. ceranae and N. apis, with only 4.2 or 7 % having either strain alone and 18.3 % being Nosema free. A range of geographically separated colonies testing positive for N. ceranae were sequenced to confirm their identity. All nine sequences confirmed the presence of N. ceranae and indicated the presence of a single new variant. Furthermore, two of the spore-containing colonies had only N. ceranae present, and these exhibited the presence of smaller spores that could be distinguished from N. apis by the analysis of average spore size. Differential quantification of the PCR product revealed N. ceranae to be the dominant species in all seven samples tested. In conclusion, N. ceranae is widespread in Scotland where it exists in combination with the endemic N. apis. A single variant, identical to that found in France (DQ374655) except for the addition of a single nucleotide polymorphism, is present in Scotland. KW - DISPERSAL KW - APIARIES KW - BEES KW - HYMENOPTERA KW - INFECTION KW - APIDAE KW - EUROPE KW - PATHOGEN KW - COLLAPSE DISORDER KW - TEMPERATURE U2 - 10.1007/s00436-012-3195-0 DO - 10.1007/s00436-012-3195-0 M1 - Article JO - Parasitology Research JF - Parasitology Research IS - 2 VL - 112 SP - 751 EP - 759 ER - TY - JOUR T1 - There's a hole in my symphysis - a review of disorders causing widening, erosion, and destruction of the symphysis pubis A1 - Budak,M. J. A1 - Oliver,T. B. AU - Budak,M. J. AU - Oliver,T. B. PY - 2013/2 Y1 - 2013/2 N2 - The symphysis pubis is demonstrated on many conventional radiographic and cross-sectional examinations and abnormality of the symphysis pubis is a common imaging finding with numerous possible causes. Many significant disorders that affect the symphysis pubis cause it to appear widened, eroded, or destroyed on imaging studies. It is useful for radiologists to have a working differential diagnosis for these appearances, to use when reporting such studies. This review briefly describes the anatomy of the symphysis pubis and presents examples of the various developmental, inflammatory, infectious, neoplastic, traumatic, and metabolic disorders that may cause it to become widened, eroded, or destroyed. Some disorders have pathognomonic imaging features. Others give rise to similar findings that depend more on overall disease activity, rather than the specific diagnosis itself. In such cases, correlation with clinical and laboratory findings will help narrow the differential diagnosis. © 2012. AB - The symphysis pubis is demonstrated on many conventional radiographic and cross-sectional examinations and abnormality of the symphysis pubis is a common imaging finding with numerous possible causes. Many significant disorders that affect the symphysis pubis cause it to appear widened, eroded, or destroyed on imaging studies. It is useful for radiologists to have a working differential diagnosis for these appearances, to use when reporting such studies. This review briefly describes the anatomy of the symphysis pubis and presents examples of the various developmental, inflammatory, infectious, neoplastic, traumatic, and metabolic disorders that may cause it to become widened, eroded, or destroyed. Some disorders have pathognomonic imaging features. Others give rise to similar findings that depend more on overall disease activity, rather than the specific diagnosis itself. In such cases, correlation with clinical and laboratory findings will help narrow the differential diagnosis. © 2012. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84862772212&md5=860513402fde63f1f259bcfff7d739f5 U2 - 10.1016/j.crad.2012.03.021 DO - 10.1016/j.crad.2012.03.021 M1 - Article JO - Clinical Radiology JF - Clinical Radiology SN - 0009-9260 IS - 2 VL - 68 SP - 173 EP - 180 ER - TY - JOUR T1 - Understanding social learning relations of international students in a large classroom using social network analysis A1 - Rienties,Bart A1 - Héliot,YingFei A1 - Jindal-Snape,Divya AU - Rienties,Bart AU - Héliot,YingFei AU - Jindal-Snape,Divya PY - 2013/2 Y1 - 2013/2 N2 - A common assumption in higher education is that international students find it difficult to develop learning and friendship relations with host students. When students are placed in a student-centred environment, international students from different cultural backgrounds are "forced" to work together with other students, which allows students to learn from different perspectives. However, large lecture rooms may provide fewer opportunities for students to work together in small groups. The purpose of this article is to understand how 191 international students from 34 cultural backgrounds and 16 host students build learning and friendship relations in a large classroom of 207 students. We have used an innovative mixed-method design of social network analysis in a pre- and post-test manner combined with two sets of focus groups. Using multiple regression quadratic assignment procedures, the results indicate that learning ties after 11 weeks were significantly predicted by the friendship and learning ties established at the beginning of the module, (sub)specialisation, and whether students were Chinese or not. Contrary to previous findings, team divisions played only a marginal role in building (new) learning relations. A substantial segregation between Confucian Asian, European international and UK students was present. Follow-up qualitative data highlighted that international students made a conscious effort to build friendship and learning relations primarily outside the formal team, which for some were along co-national lines, while others were pro-actively looking for new perspectives from multi-national students. These results indicate that the instructional design might have a strong influence on how international and host students work and learn together. We believe that this study is the first to provide an in-depth and unique understanding of how international students from different cultural backgrounds build friendship and learning-relationships with other students in- and outside their classroom over time in a large classroom of 200+ students. © 2013 Springer Science+Business Media Dordrecht. AB - A common assumption in higher education is that international students find it difficult to develop learning and friendship relations with host students. When students are placed in a student-centred environment, international students from different cultural backgrounds are "forced" to work together with other students, which allows students to learn from different perspectives. However, large lecture rooms may provide fewer opportunities for students to work together in small groups. The purpose of this article is to understand how 191 international students from 34 cultural backgrounds and 16 host students build learning and friendship relations in a large classroom of 207 students. We have used an innovative mixed-method design of social network analysis in a pre- and post-test manner combined with two sets of focus groups. Using multiple regression quadratic assignment procedures, the results indicate that learning ties after 11 weeks were significantly predicted by the friendship and learning ties established at the beginning of the module, (sub)specialisation, and whether students were Chinese or not. Contrary to previous findings, team divisions played only a marginal role in building (new) learning relations. A substantial segregation between Confucian Asian, European international and UK students was present. Follow-up qualitative data highlighted that international students made a conscious effort to build friendship and learning relations primarily outside the formal team, which for some were along co-national lines, while others were pro-actively looking for new perspectives from multi-national students. These results indicate that the instructional design might have a strong influence on how international and host students work and learn together. We believe that this study is the first to provide an in-depth and unique understanding of how international students from different cultural backgrounds build friendship and learning-relationships with other students in- and outside their classroom over time in a large classroom of 200+ students. © 2013 Springer Science+Business Media Dordrecht. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84873347411&md5=f71bfa4e889b0fa2cf33a0c2b994d8c6 U2 - 10.1007/s10734-013-9617-9 DO - 10.1007/s10734-013-9617-9 M1 - Article JO - Studies in Higher Education JF - Studies in Higher Education SN - 0018-1560 SP - 1 EP - 16 ER - TY - JOUR T1 - Unionization, international integration, and selection A1 - Montagna,Catia A1 - Nocco,Antonella AU - Montagna,Catia AU - Nocco,Antonella PY - 2013/2 Y1 - 2013/2 N2 - We study how unionization affects competitive selection between heterogeneous firms when wage negotiations can occur at the firm or at the profit-centre level. With productivity specific wages, an increase in union power has: (i) a selection-softening; (ii) a counter-competitive; (iii) a wage-inequality; and (iv) a variety effect. In a two-country asymmetric setting, stronger unions soften competition for domestic firms and toughen it for exporters. With profit-centre bargaining, we show how trade liberalization can affect wage inequality among identical workers both across firms (via its effects on competitive selection) and within firms (via wage discrimination across destination markets). ©Canadian Economics Association. AB - We study how unionization affects competitive selection between heterogeneous firms when wage negotiations can occur at the firm or at the profit-centre level. With productivity specific wages, an increase in union power has: (i) a selection-softening; (ii) a counter-competitive; (iii) a wage-inequality; and (iv) a variety effect. In a two-country asymmetric setting, stronger unions soften competition for domestic firms and toughen it for exporters. With profit-centre bargaining, we show how trade liberalization can affect wage inequality among identical workers both across firms (via its effects on competitive selection) and within firms (via wage discrimination across destination markets). ©Canadian Economics Association. KW - UNEMPLOYMENT KW - F12 KW - UNIONS KW - TRADE LIBERALIZATION KW - J51 KW - R13 KW - HETEROGENEITY KW - F16 KW - MARKET KW - JOBS KW - WAGE INEQUALITY KW - PRODUCTIVITY KW - COMPETITION UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84874184557&md5=e6c61826974b42648c8cd120e9fab44e U2 - 10.1111/caje.12005 DO - 10.1111/caje.12005 M1 - Article JO - Canadian Journal of Economics JF - Canadian Journal of Economics SN - 0008-4085 IS - 1 VL - 46 SP - 23 EP - 45 ER - TY - JOUR T1 - Why developing countries have failed to increase their exports of agricultural processed products A1 - Mohan,Sushil A1 - Khorana,Sangeeta A1 - Choudhury,Homagni AU - Mohan,Sushil AU - Khorana,Sangeeta AU - Choudhury,Homagni PY - 2013/2 Y1 - 2013/2 N2 - The article uses the case study of coffee, tea and cocoa to analyse whether tariff escalation constitutes a barrier to market access that thwarts diversification efforts of developing countries into exports of value-added agricultural processed products. It also examines the extent to which non-tariff barriers act as market access barriers that constrain developing countries from developing their exports of agricultural processed products. Our analysis shows that tariff escalation is not the main barrier; rather it is the prevalence of non-tariff barriers (including domestic non-tariff barriers) that limits the ability of developing countries to increase their agricultural processed exports. This has important policy implications in terms of the emphasis that trade negotiators and policy planners should place on addressing non-tariff barriers. AB - The article uses the case study of coffee, tea and cocoa to analyse whether tariff escalation constitutes a barrier to market access that thwarts diversification efforts of developing countries into exports of value-added agricultural processed products. It also examines the extent to which non-tariff barriers act as market access barriers that constrain developing countries from developing their exports of agricultural processed products. Our analysis shows that tariff escalation is not the main barrier; rather it is the prevalence of non-tariff barriers (including domestic non-tariff barriers) that limits the ability of developing countries to increase their agricultural processed exports. This has important policy implications in terms of the emphasis that trade negotiators and policy planners should place on addressing non-tariff barriers. KW - agricultural processed products KW - cocoa KW - coffee KW - developing countries KW - non-tariff barriers KW - tariff escalation KW - tea KW - tropical beverages KW - value addition U2 - 10.1111/ecaf.12000 DO - 10.1111/ecaf.12000 M1 - Article JO - Economic Affairs JF - Economic Affairs SN - 0265-0665 IS - 1 VL - 33 SP - 48 EP - 64 ER - TY - JOUR T1 - Competing interests declared T2 - early interventions and long-term psychological outcomes A1 - Hull,Alastair M. A1 - Rattray,Janice AU - Hull,Alastair M. AU - Rattray,Janice PY - 2013/1/31 Y1 - 2013/1/31 N2 - Survivors of motor vehicle accidents and/or survivors of critical care unit admission are at increased risk of developing post-traumatic reactions such as post-traumatic stress disorder, depression and anxiety. Examining the possible risk factors for the development of these disorders must consider pre-traumatic, peri-traumatic and post-traumatic factors and must do so across domains relating to the trauma, the person and their circumstances. The present study has found propofol administration in the first 72 hours post motor vehicle accident to confer a higher risk for full or partial post-traumatic stress disorder at 6 months. This study highlights concerns that treatment needed acutely post injury may impact adversely on long-term outcome, albeit in a different domain-the psychological. © 2013 BioMed Central Ltd. AB - Survivors of motor vehicle accidents and/or survivors of critical care unit admission are at increased risk of developing post-traumatic reactions such as post-traumatic stress disorder, depression and anxiety. Examining the possible risk factors for the development of these disorders must consider pre-traumatic, peri-traumatic and post-traumatic factors and must do so across domains relating to the trauma, the person and their circumstances. The present study has found propofol administration in the first 72 hours post motor vehicle accident to confer a higher risk for full or partial post-traumatic stress disorder at 6 months. This study highlights concerns that treatment needed acutely post injury may impact adversely on long-term outcome, albeit in a different domain-the psychological. © 2013 BioMed Central Ltd. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84873525428&md5=bec9a77ed8d02d4745e0f609366f6842 U2 - 10.1186/cc11916 DO - 10.1186/cc11916 M1 - Comment/debate JO - Nursing in Critical Care JF - Nursing in Critical Care SN - 1364-8535 IS - 1 VL - 17 ER - TY - JOUR T1 - Genetic and environmental effects on Tannin composition in strawberry (Fragaria x ananassa) cultivars grown in different European locations A1 - Josuttis,Melanie A1 - Verrall,Susan A1 - Stewart,Derek A1 - Krueger,Erika A1 - McDougall,Gordon J. AU - Josuttis,Melanie AU - Verrall,Susan AU - Stewart,Derek AU - Krueger,Erika AU - McDougall,Gordon J. PY - 2013/1/30 Y1 - 2013/1/30 N2 -

Strawberry cultivars grown at different locations in Europe showed genotype- and environment-dependent variation in total phenol and anthocyanin contents. This study focused on the compositional diversity of tannins from these cultivars using a high-throughput liquid chromatography-mass spectrometric (LC-MS) technique. Cultivars grown in Germany showed differences in the relative amounts of proanthocyanidins (PACs) and ellagitannins (ETs). Cultivars grown at three different European locations showed differences in their PAC/ET balance. 'Elsanta' grown in Switzerland had higher levels of ET-derived than PAC-derived signals compared to 'Elsanta' grown in Germany and Denmark. The trend to increased ET-derived signals was also noted for 'Clery' grown in Switzerland over Germany and was apparent for 'Korona' grown in Denmark over Germany. The altered ET/PAC balance was confirmed by conventional LC-MS analysis, which highlighted specific changes in composition rather than a general increase in ET components. These findings are discussed with respect to the environmental conditions at the different European locations.

AB -

Strawberry cultivars grown at different locations in Europe showed genotype- and environment-dependent variation in total phenol and anthocyanin contents. This study focused on the compositional diversity of tannins from these cultivars using a high-throughput liquid chromatography-mass spectrometric (LC-MS) technique. Cultivars grown in Germany showed differences in the relative amounts of proanthocyanidins (PACs) and ellagitannins (ETs). Cultivars grown at three different European locations showed differences in their PAC/ET balance. 'Elsanta' grown in Switzerland had higher levels of ET-derived than PAC-derived signals compared to 'Elsanta' grown in Germany and Denmark. The trend to increased ET-derived signals was also noted for 'Clery' grown in Switzerland over Germany and was apparent for 'Korona' grown in Denmark over Germany. The altered ET/PAC balance was confirmed by conventional LC-MS analysis, which highlighted specific changes in composition rather than a general increase in ET components. These findings are discussed with respect to the environmental conditions at the different European locations.

KW - proanthocyanidins KW - ellagitannins KW - origin KW - POLYPHENOL COMPOSITION KW - HUMAN HEALTH KW - PLANT-GROWTH KW - TOTAL ANTIOXIDANT CAPACITY KW - IN-VITRO KW - strawberries KW - polyphenols KW - FRUIT-QUALITY KW - cultivars KW - ELLAGIC ACID KW - latitude KW - ELLAGITANNINS KW - PHENOLIC-COMPOUNDS KW - MASS-SPECTROMETRY U2 - 10.1021/jf303725g DO - 10.1021/jf303725g M1 - Article JO - Journal of Agricultural and Food Chemistry JF - Journal of Agricultural and Food Chemistry SN - 0021-8561 IS - 4 VL - 61 SP - 790 EP - 800 ER - TY - JOUR T1 - Respiratory system part 1 T2 - pulmonary ventilation. A1 - McLafferty,Ella A1 - Johnstone,Carolyn A1 - Hendry,Charles A1 - Farley,Alistair AU - McLafferty,Ella AU - Johnstone,Carolyn AU - Hendry,Charles AU - Farley,Alistair PY - 2013/1/30 Y1 - 2013/1/30 N2 - This article, which forms part of the life sciences series and is the first of two articles on the respiratory system, describes the anatomy of the respiratory system and explains the mechanics of respiration. It provides a brief overview of three common respiratory disorders: pneumonia, pulmonary embolism and pulmonary tuberculosis. The second article discusses gaseous exchange and the control of ventilation in more detail. AB - This article, which forms part of the life sciences series and is the first of two articles on the respiratory system, describes the anatomy of the respiratory system and explains the mechanics of respiration. It provides a brief overview of three common respiratory disorders: pneumonia, pulmonary embolism and pulmonary tuberculosis. The second article discusses gaseous exchange and the control of ventilation in more detail. UR - http://nursingstandard.rcnpublishing.co.uk/archive/article-respiratory-system-part-1-pulmonary-ventilation UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875777462&md5=ec43673e5e15be9f15a65a420c238346 M1 - Article JO - Nursing Standard JF - Nursing Standard SN - 0029-6570 IS - 22 VL - 27 SP - 40 EP - 47 ER - TY - CHAP T1 - Selling Blackwood’s Magazine, 1817-1834 A1 - Finkelstein,David AU - Finkelstein,David PB - Palgrave Macmillan CY - Basingstoke PY - 2013/1/25 Y1 - 2013/1/25 N2 - Examines Blackwood's Magazine at its peak, when it published many leading writers of the day & commented on all major literary, political, economic & cultural forces that shaped Romanticism AB - Examines Blackwood's Magazine at its peak, when it published many leading writers of the day & commented on all major literary, political, economic & cultural forces that shaped Romanticism UR - http://library.dundee.ac.uk/F/?func=direct&local_base=DUN01&doc_number=000818361 M1 - Chapter SN - 9780230304413 BT - Romanticism and Blackwood’s Magazine T2 - Romanticism and Blackwood’s Magazine A2 - Roberts,Daniel S. ED - Roberts,Daniel S. T3 - Palgrave Studies in the Enlightenment, Romanticism and the Cultures of Print T3 - en_GB SP - 69 EP - 86 ER - TY - JOUR T1 - The importance of the N-terminus of T7 endonuclease I in the interaction with DNA junctions A1 - Freeman,Alasdair D. J. A1 - Déclais,Anne-Cécile A1 - Lilley,David M. J. AU - Freeman,Alasdair D. J. AU - Déclais,Anne-Cécile AU - Lilley,David M. J. PY - 2013/1/23 Y1 - 2013/1/23 N2 -

T7 endonuclease I is a dimeric nuclease that is selective for four-way DNA junctions. Previous crystallographic studies have found that the N-terminal 16 amino acids are not visible, neither in the presence nor in the absence of DNA. We have now investigated the effect of deleting the N-terminus completely or partially. N-terminal deleted enzyme binds more tightly to DNA junctions but cleaves them more slowly. While deletion of the N-terminus does not measurably affect the global structure of the complex, the presence of the peptide is required to generate a local opening at the center of the DNA junction that is observed by 2-aminopurine fluorescence. Complete deletion of the peptide leads to a cleavage rate that is 3 orders of magnitude slower and an activation enthalpy that is 3-fold higher, suggesting that the most important interaction of the peptide is with the reaction transition state. Taken together, these data point to an important role of the N-terminus in generating a central opening of the junction that is required for the cleavage reaction to proceed properly. In the absence of this, we find that a cruciform junction is no longer subject to bilateral cleavage, but instead, just one strand is cleaved. Thus, the N-terminus is required for a productive resolution of the junction. (C) 2012 Elsevier Ltd. All rights reserved.

AB -

T7 endonuclease I is a dimeric nuclease that is selective for four-way DNA junctions. Previous crystallographic studies have found that the N-terminal 16 amino acids are not visible, neither in the presence nor in the absence of DNA. We have now investigated the effect of deleting the N-terminus completely or partially. N-terminal deleted enzyme binds more tightly to DNA junctions but cleaves them more slowly. While deletion of the N-terminus does not measurably affect the global structure of the complex, the presence of the peptide is required to generate a local opening at the center of the DNA junction that is observed by 2-aminopurine fluorescence. Complete deletion of the peptide leads to a cleavage rate that is 3 orders of magnitude slower and an activation enthalpy that is 3-fold higher, suggesting that the most important interaction of the peptide is with the reaction transition state. Taken together, these data point to an important role of the N-terminus in generating a central opening of the junction that is required for the cleavage reaction to proceed properly. In the absence of this, we find that a cruciform junction is no longer subject to bilateral cleavage, but instead, just one strand is cleaved. Thus, the N-terminus is required for a productive resolution of the junction. (C) 2012 Elsevier Ltd. All rights reserved.

KW - BACTERIOPHAGE T7 KW - ESCHERICHIA-COLI KW - RESOLVING ENZYME CCE1 KW - STRUCTURAL RECOGNITION KW - REPLICATION FORKS KW - HOMOLOGOUS RECOMBINATION KW - GENETIC-RECOMBINATION KW - HOLLIDAY JUNCTION KW - SULFOLOBUS-SOLFATARICUS KW - SACCHAROMYCES-CEREVISIAE U2 - 10.1016/j.jmb.2012.11.029 DO - 10.1016/j.jmb.2012.11.029 M1 - Article JO - Journal of Molecular Biology JF - Journal of Molecular Biology SN - 0022-2836 IS - 2 VL - 425 SP - 395 EP - 410 ER - TY - JOUR T1 - Adiposity, compared with masculinity, serves as a more valid cue to immunocompetence in human mate choice A1 - Rantala,Markus J. A1 - Coetzee,Vinet A1 - Moore,Fhionna R. A1 - Skrinda,Ilona A1 - Kecko,Sanita A1 - Krama,Tatjana A1 - Kivleniece,Inese A1 - Krams,Indrikis AU - Rantala,Markus J. AU - Coetzee,Vinet AU - Moore,Fhionna R. AU - Skrinda,Ilona AU - Kecko,Sanita AU - Krama,Tatjana AU - Kivleniece,Inese AU - Krams,Indrikis PY - 2013/1/22 Y1 - 2013/1/22 N2 - According to the ‘good genes’ hypothesis, females choose males based on traits that indicate the male's genetic quality in terms of disease resistance. The ‘immunocompetence handicap hypothesis’ proposed that secondary sexual traits serve as indicators of male genetic quality, because they indicate that males can contend with the immunosuppressive effects of testosterone. Masculinity is commonly assumed to serve as such a secondary sexual trait. Yet, women do not consistently prefer masculine looking men, nor is masculinity consistently related to health across studies. Here, we show that adiposity, but not masculinity, significantly mediates the relationship between a direct measure of immune response (hepatitis B antibody response) and attractiveness for both body and facial measurements. In addition, we show that circulating testosterone is more closely associated with adiposity than masculinity. These findings indicate that adiposity, compared with masculinity, serves as a more important cue to immunocompetence in female mate choice. AB - According to the ‘good genes’ hypothesis, females choose males based on traits that indicate the male's genetic quality in terms of disease resistance. The ‘immunocompetence handicap hypothesis’ proposed that secondary sexual traits serve as indicators of male genetic quality, because they indicate that males can contend with the immunosuppressive effects of testosterone. Masculinity is commonly assumed to serve as such a secondary sexual trait. Yet, women do not consistently prefer masculine looking men, nor is masculinity consistently related to health across studies. Here, we show that adiposity, but not masculinity, significantly mediates the relationship between a direct measure of immune response (hepatitis B antibody response) and attractiveness for both body and facial measurements. In addition, we show that circulating testosterone is more closely associated with adiposity than masculinity. These findings indicate that adiposity, compared with masculinity, serves as a more important cue to immunocompetence in female mate choice. U2 - 10.1098/rspb.2012.2495 DO - 10.1098/rspb.2012.2495 M1 - Article JO - Proceedings of the Royal Society B JF - Proceedings of the Royal Society B SN - 0962-8452 IS - 1751 VL - 280 ER - TY - JOUR T1 - Temporal instability analysis of inviscid compound jets falling under gravity A1 - Mohsin,Muhammad A1 - Uddin,Jamal A1 - Decent,Stephen P. A1 - Afzaal,Muhammad F. AU - Mohsin,Muhammad AU - Uddin,Jamal AU - Decent,Stephen P. AU - Afzaal,Muhammad F. PY - 2013/1/18 Y1 - 2013/1/18 N2 -

Compound liquid jets can be used in a variety of industrial applications ranging from capsule production in pharmaceutics to enhance printing methods in ink-jet printing. An appreciation of how instability along compound jets can lead to breakup and droplet formation is thus critical in many fields in science and engineering. In this paper, we perform a theoretical analysis to examine the instability of an axisymmetric inviscid compound liquid jet which falls vertically under the influence of gravity. We use a long-wavelength, slender-jet asymptotic expansion to reduce the governing equations of the problem into a set of one-dimensional partial differential equations, which describe the evolution of the leading-order axial velocity of the jet as well as the radii of both the inner and the outer interfaces. We first determine the steady-state solutions of the one-dimensional model equations and then we perform a linear temporal instability analysis to obtain a dispersion relation, which gives us useful information about the maximum growth rate and the maximum wavenumber of the imposed wave-like disturbance. We use our results to estimate the location and qualitative nature of breakup and then compare our results with numerical simulations.

AB -

Compound liquid jets can be used in a variety of industrial applications ranging from capsule production in pharmaceutics to enhance printing methods in ink-jet printing. An appreciation of how instability along compound jets can lead to breakup and droplet formation is thus critical in many fields in science and engineering. In this paper, we perform a theoretical analysis to examine the instability of an axisymmetric inviscid compound liquid jet which falls vertically under the influence of gravity. We use a long-wavelength, slender-jet asymptotic expansion to reduce the governing equations of the problem into a set of one-dimensional partial differential equations, which describe the evolution of the leading-order axial velocity of the jet as well as the radii of both the inner and the outer interfaces. We first determine the steady-state solutions of the one-dimensional model equations and then we perform a linear temporal instability analysis to obtain a dispersion relation, which gives us useful information about the maximum growth rate and the maximum wavenumber of the imposed wave-like disturbance. We use our results to estimate the location and qualitative nature of breakup and then compare our results with numerical simulations.

KW - Liquid jets KW - Flows KW - Spacial instability KW - Microcapsules U2 - 10.1063/1.4775792 DO - 10.1063/1.4775792 M1 - Article JO - Physics of Fluids JF - Physics of Fluids SN - 1070-6631 IS - 1 VL - 25 SP - 1 EP - 16 ER - TY - JOUR T1 - Metabolism of inflammation limited by AMPK and pseudo-starvation A1 - O'Neill,L.A.J. A1 - Hardie,D. Grahame AU - O'Neill,L.A.J. AU - Hardie,D. Grahame PY - 2013/1/17 Y1 - 2013/1/17 N2 - Metabolic changes in cells that participate in inflammation, such as activated macrophages and T-helper 17 cells, include a shift towards enhanced glucose uptake, glycolysis and increased activity of the pentose phosphate pathway. Opposing roles in these changes for hypoxia-inducible factor 1ß and AMP-activated protein kinase have been proposed. By contrast, anti-inflammatory cells, such as M2 macrophages, regulatory T cells and quiescent memory T cells, have lower glycolytic rates and higher levels of oxidative metabolism. Some anti-inflammatory agents might act by inducing, through activation of AMP-activated protein kinase, a state akin to pseudo-starvation. Altered metabolism may thus participate in the signal-directed programs that promote or inhibit inflammation. © 2013 Macmillan Publishers Limited. All rights reserved. AB - Metabolic changes in cells that participate in inflammation, such as activated macrophages and T-helper 17 cells, include a shift towards enhanced glucose uptake, glycolysis and increased activity of the pentose phosphate pathway. Opposing roles in these changes for hypoxia-inducible factor 1ß and AMP-activated protein kinase have been proposed. By contrast, anti-inflammatory cells, such as M2 macrophages, regulatory T cells and quiescent memory T cells, have lower glycolytic rates and higher levels of oxidative metabolism. Some anti-inflammatory agents might act by inducing, through activation of AMP-activated protein kinase, a state akin to pseudo-starvation. Altered metabolism may thus participate in the signal-directed programs that promote or inhibit inflammation. © 2013 Macmillan Publishers Limited. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872576236&md5=8e10774e98c9b00ed4d6c5d0adbc2b73 U2 - 10.1038/nature11862 DO - 10.1038/nature11862 M1 - Article JO - Nature JF - Nature SN - 0028-0836 IS - 7432 VL - 493 SP - 346 EP - 355 ER - TY - JOUR T1 - p68/DdX5 supports β-Catenin & RNAP II during androgen receptor mediated transcription in prostate cancer A1 - Clark,Emma L. A1 - Hadjimichael,Christiana A1 - Temperley,Richard A1 - Barnard,Amy A1 - Fuller-Pace,Frances V. A1 - Robson,Craig N. AU - Clark,Emma L. AU - Hadjimichael,Christiana AU - Temperley,Richard AU - Barnard,Amy AU - Fuller-Pace,Frances V. AU - Robson,Craig N. PY - 2013/1/17 Y1 - 2013/1/17 N2 -

The DEAD box RNA helicase p68 (Ddx5) is an important androgen receptor (AR) transcriptional co-activator in prostate cancer (PCa) and is over-expressed in late stage disease. beta-Catenin is a multifunctional protein with important structural and signalling functions which is up-regulated in PCa and similar to p68, interacts with the AR to co-activate expression of AR target genes. Importantly, p68 forms complexes with nuclear beta-Catenin and promotes gene transcription in colon cancer indicating a functional interplay between these two proteins in cancer progression. In this study, we explore the relationship of p68 and beta-Catenin in PCa to assess their potential co-operation in AR-dependent gene expression, which may be of importance in the development of castrate resistant prostate cancer (CRPCa). We use immunoprecipitation to demonstrate a novel interaction between p68 and beta-Catenin in the nucleus of PCa cells, which is androgen dependent in LNCaP cells but androgen independent in a hormone refractory derivative of the same cell line (representative of the CRPCa disease type). Enhanced AR activity is seen in androgen-dependent luciferase reporter assays upon transient co-transfection of p68 and beta-Catenin as an additive effect, and p68-depleted Chromatin-Immunoprecipitation (ChIP) showed a decrease in the recruitment of the AR and beta-Catenin to androgen responsive promoter regions. In addition, we found p68 immunoprecipitated with the processive and non-processive form of RNA polymerase II (RNAP II) and show p68 recruited to elongating regions of the AR mediated PSA gene, suggesting a role for p68 in facilitating RNAP II transcription of AR mediated genes. These results suggest p68 is important in facilitating beta-Catenin and AR transcriptional activity in PCa cells.

AB -

The DEAD box RNA helicase p68 (Ddx5) is an important androgen receptor (AR) transcriptional co-activator in prostate cancer (PCa) and is over-expressed in late stage disease. beta-Catenin is a multifunctional protein with important structural and signalling functions which is up-regulated in PCa and similar to p68, interacts with the AR to co-activate expression of AR target genes. Importantly, p68 forms complexes with nuclear beta-Catenin and promotes gene transcription in colon cancer indicating a functional interplay between these two proteins in cancer progression. In this study, we explore the relationship of p68 and beta-Catenin in PCa to assess their potential co-operation in AR-dependent gene expression, which may be of importance in the development of castrate resistant prostate cancer (CRPCa). We use immunoprecipitation to demonstrate a novel interaction between p68 and beta-Catenin in the nucleus of PCa cells, which is androgen dependent in LNCaP cells but androgen independent in a hormone refractory derivative of the same cell line (representative of the CRPCa disease type). Enhanced AR activity is seen in androgen-dependent luciferase reporter assays upon transient co-transfection of p68 and beta-Catenin as an additive effect, and p68-depleted Chromatin-Immunoprecipitation (ChIP) showed a decrease in the recruitment of the AR and beta-Catenin to androgen responsive promoter regions. In addition, we found p68 immunoprecipitated with the processive and non-processive form of RNA polymerase II (RNAP II) and show p68 recruited to elongating regions of the AR mediated PSA gene, suggesting a role for p68 in facilitating RNAP II transcription of AR mediated genes. These results suggest p68 is important in facilitating beta-Catenin and AR transcriptional activity in PCa cells.

KW - COLON-CANCER KW - WNT/BETA-CATENIN KW - GROWTH KW - WNT SIGNALING PATHWAYS KW - COACTIVATOR KW - HISTONE DEACETYLASE-1 KW - EXPRESSION KW - MULTIFUNCTIONAL PROTEINS KW - NUCLEAR TRANSLOCATION KW - HELICASE P68 U2 - 10.1371/journal.pone.0054150 DO - 10.1371/journal.pone.0054150 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 1 VL - 8 ER - TY - JOUR T1 - AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues. A1 - Chen,Hong-Yu A1 - Ducommun,Serge A1 - Quan,Chao A1 - Xie,Bingxian A1 - Li,Min A1 - Wasserman,David H A1 - Sakamoto,Kei A1 - MacKintosh,Carol A1 - Chen,Shuai AU - Chen,Hong-Yu AU - Ducommun,Serge AU - Quan,Chao AU - Xie,Bingxian AU - Li,Min AU - Wasserman,David H AU - Sakamoto,Kei AU - MacKintosh,Carol AU - Chen,Shuai PY - 2013/1/15 Y1 - 2013/1/15 N2 - AS160 (Akt substrate of 160 kDa) is a Rab GTPase-activating protein implicated in insulin control of GLUT4 (glucose transporter 4) trafficking. In humans, a truncation mutation (R363X) in one allele of AS160 decreased the expression of the protein and caused severe postprandial hyperinsulinaemia during puberty. To complement the limited studies possible in humans, we generated an AS160-knockout mouse. In wild-type mice, AS160 expression is relatively high in adipose tissue and soleus muscle, low in EDL (extensor digitorum longus) muscle and detectable in liver only after enrichment. Despite having lower blood glucose levels under both fasted and random-fed conditions, the AS160-knockout mice exhibited insulin resistance in both muscle and liver in a euglycaemic clamp study. Consistent with this paradoxical phenotype, basal glucose uptake was higher in AS160-knockout primary adipocytes and normal in isolated soleus muscle, but their insulin-stimulated glucose uptake and overall GLUT4 levels were markedly decreased. In contrast, insulin-stimulated glucose uptake and GLUT4 levels were normal in EDL muscle. The liver also contributes to the AS160-knockout phenotype via hepatic insulin resistance, elevated hepatic expression of phosphoenolpyruvate carboxykinase isoforms and pyruvate intolerance, which are indicative of increased gluconeogenesis. Overall, as well as its catalytic function, AS160 influences expression of other proteins, and its loss deregulates basal and insulin-regulated glucose homoeostasis, not only in tissues that normally express AS160, but also by influencing liver function. AB - AS160 (Akt substrate of 160 kDa) is a Rab GTPase-activating protein implicated in insulin control of GLUT4 (glucose transporter 4) trafficking. In humans, a truncation mutation (R363X) in one allele of AS160 decreased the expression of the protein and caused severe postprandial hyperinsulinaemia during puberty. To complement the limited studies possible in humans, we generated an AS160-knockout mouse. In wild-type mice, AS160 expression is relatively high in adipose tissue and soleus muscle, low in EDL (extensor digitorum longus) muscle and detectable in liver only after enrichment. Despite having lower blood glucose levels under both fasted and random-fed conditions, the AS160-knockout mice exhibited insulin resistance in both muscle and liver in a euglycaemic clamp study. Consistent with this paradoxical phenotype, basal glucose uptake was higher in AS160-knockout primary adipocytes and normal in isolated soleus muscle, but their insulin-stimulated glucose uptake and overall GLUT4 levels were markedly decreased. In contrast, insulin-stimulated glucose uptake and GLUT4 levels were normal in EDL muscle. The liver also contributes to the AS160-knockout phenotype via hepatic insulin resistance, elevated hepatic expression of phosphoenolpyruvate carboxykinase isoforms and pyruvate intolerance, which are indicative of increased gluconeogenesis. Overall, as well as its catalytic function, AS160 influences expression of other proteins, and its loss deregulates basal and insulin-regulated glucose homoeostasis, not only in tissues that normally express AS160, but also by influencing liver function. KW - Akt substrate of 160 kDa (AS160) KW - glucose transport KW - Insulin Resistance KW - LIVER KW - MUSCLE U2 - 10.1042/BJ20120702 DO - 10.1042/BJ20120702 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 IS - 2 VL - 449 SP - 479 EP - 489 ER - TY - JOUR T1 - Characterization of Staphylococcus aureus EssB, an integral membrane component of the Type VII secretion system T2 - atomic resolution crystal structure of the cytoplasmic segment A1 - Zoltner,Martin A1 - Fyfe,Paul K. A1 - Palmer,Tracy A1 - Hunter,William N. AU - Zoltner,Martin AU - Fyfe,Paul K. AU - Palmer,Tracy AU - Hunter,William N. PY - 2013/1/15 Y1 - 2013/1/15 N2 - The Type VII protein translocation/secretion system, unique to Gram-positive bacteria, is a key virulence determinant in Staphylococcus aureus. We aim to characterize the architecture of this secretion machinery and now describe the present study of S. aureus EssB, a 52 kDa bitopic membrane protein essential for secretion of the ESAT-6 (early secretory antigenic target of 6 kDa) family of proteins, the prototypic substrate of Type VII secretion. Full-length EssB was heterologously expressed in Escherichia coli, solubilized from the bacterial membrane, purified to homogeneity and shown to be dimeric. A C-terminal truncation, EssB?C, and two soluble fragments termed EssB-N and EssB-C, predicted to occur on either side of the cytoplasmic membrane, have been successfully purified in a recombinant form, characterized and, together with the full-length protein, used in crystallization trials. EssB-N, the 25 kDa N-terminal cytoplasmic fragment, gave well-ordered crystals and we report the structure, determined by SAD (single-wavelength anomalous diffraction) targeting an SeMet (selenomethionine) derivative, refined to atomic (1.05 Å; 1 Å = 0.1 nm) resolution. EssB-N is dimeric in solution, but crystallizes as a monomer and displays a fold comprised of two globular domains separated by a cleft. The structure is related to that of serine/threonine protein kinases and the present study identifies that the Type VII secretion system exploits and re-uses a stable modular entity and fold that has evolved to participate in protein-protein interactions in a similar fashion to the catalytically inert pseudokinases. © The Authors Journal compilation © 2013 Biochemical Society. AB - The Type VII protein translocation/secretion system, unique to Gram-positive bacteria, is a key virulence determinant in Staphylococcus aureus. We aim to characterize the architecture of this secretion machinery and now describe the present study of S. aureus EssB, a 52 kDa bitopic membrane protein essential for secretion of the ESAT-6 (early secretory antigenic target of 6 kDa) family of proteins, the prototypic substrate of Type VII secretion. Full-length EssB was heterologously expressed in Escherichia coli, solubilized from the bacterial membrane, purified to homogeneity and shown to be dimeric. A C-terminal truncation, EssB?C, and two soluble fragments termed EssB-N and EssB-C, predicted to occur on either side of the cytoplasmic membrane, have been successfully purified in a recombinant form, characterized and, together with the full-length protein, used in crystallization trials. EssB-N, the 25 kDa N-terminal cytoplasmic fragment, gave well-ordered crystals and we report the structure, determined by SAD (single-wavelength anomalous diffraction) targeting an SeMet (selenomethionine) derivative, refined to atomic (1.05 Å; 1 Å = 0.1 nm) resolution. EssB-N is dimeric in solution, but crystallizes as a monomer and displays a fold comprised of two globular domains separated by a cleft. The structure is related to that of serine/threonine protein kinases and the present study identifies that the Type VII secretion system exploits and re-uses a stable modular entity and fold that has evolved to participate in protein-protein interactions in a similar fashion to the catalytically inert pseudokinases. © The Authors Journal compilation © 2013 Biochemical Society. KW - early secretory antigenic target of 6 kDa system 1 (ESX-1) KW - Gram-positive bacterium KW - protein kinase KW - PROTEIN SECRETION KW - pseudokinase KW - X-ray crystallography UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871446545&md5=00973a3de28a524adbdff0f746325c46 U2 - 10.1042/BJ20121209 DO - 10.1042/BJ20121209 M1 - Article JO - Biochemical Journal JF - Biochemical Journal SN - 0264-6021 IS - 2 VL - 449 SP - 469 EP - 477 ER - TY - JOUR T1 - Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity A1 - Yao,Chen A1 - Johnson,William M. A1 - Gao,Yue A1 - Wang,Wen A1 - Zhang,Jinwei A1 - Deak,Maria A1 - Alessi,Dario R. A1 - Zhu,Xiongwei A1 - Mieyal,John J. A1 - Roder,Hanno A1 - Wilson-Delfosse,Amy L. A1 - Chen,Shu G. AU - Yao,Chen AU - Johnson,William M. AU - Gao,Yue AU - Wang,Wen AU - Zhang,Jinwei AU - Deak,Maria AU - Alessi,Dario R. AU - Zhu,Xiongwei AU - Mieyal,John J. AU - Roder,Hanno AU - Wilson-Delfosse,Amy L. AU - Chen,Shu G. PY - 2013/1/15 Y1 - 2013/1/15 N2 -

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent known cause of late-onset Parkinson’s disease (PD). To explore the therapeutic potential of small molecules targeting the LRRK2 kinase domain, we characterized two LRRK2 kinase inhibitors, TTT-3002 and LRRK2-IN1, for their effects against LRRK2 activity in vitro and in Caenorhabditis elegans models of LRRK2-linked neurodegeneration. TTT-3002 and LRRK2-IN1 potently inhibited in vitro kinase activity of LRRK2 wild-type and mutant proteins, attenuated phosphorylation of cellular LRRK2 and rescued neurotoxicity of mutant LRRK2 in transfected cells. To establish whether LRRK2 kinase inhibitors can mitigate pathogenesis caused by different mutations including G2019S and R1441C located within and outside of the LRRK2 kinase domain, respectively, we evaluated effects of TTT-3002 and
LRRK2-IN1 against R1441C- and G2019S-induced neurodegeneration in C. elegans models. TTT-3002 and LRRK2-IN1 rescued the behavioral deficit characteristic of dopaminergic impairment in transgenic C. elegans expressing human R1441C- and G2019S-LRRK2. The inhibitors displayed nanomolar to low micromolar rescue potency when administered either pre-symptomatically or post-symptomatically, indicating both prevention and reversal of the dopaminergic deficit. The same treatments also led to long-lasting prevention and
rescue of neurodegeneration. In contrast, TTT-3002 and LRRK2-IN1 were ineffective against the neurodegenerative phenotype in transgenic worms carrying the inhibitor-resistant A2016T mutation ofLRRK2, suggesting that they elicit neuroprotective effects in vivo by targeting LRRK2 specifically. Our findings indicate that the LRRK2 kinase activity is critical for neurodegeneration caused by R1441C and G2019S mutations, suggesting that kinase inhibition of LRRK2 may represent a promising therapeutic strategy for PD.

AB -

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent known cause of late-onset Parkinson’s disease (PD). To explore the therapeutic potential of small molecules targeting the LRRK2 kinase domain, we characterized two LRRK2 kinase inhibitors, TTT-3002 and LRRK2-IN1, for their effects against LRRK2 activity in vitro and in Caenorhabditis elegans models of LRRK2-linked neurodegeneration. TTT-3002 and LRRK2-IN1 potently inhibited in vitro kinase activity of LRRK2 wild-type and mutant proteins, attenuated phosphorylation of cellular LRRK2 and rescued neurotoxicity of mutant LRRK2 in transfected cells. To establish whether LRRK2 kinase inhibitors can mitigate pathogenesis caused by different mutations including G2019S and R1441C located within and outside of the LRRK2 kinase domain, respectively, we evaluated effects of TTT-3002 and
LRRK2-IN1 against R1441C- and G2019S-induced neurodegeneration in C. elegans models. TTT-3002 and LRRK2-IN1 rescued the behavioral deficit characteristic of dopaminergic impairment in transgenic C. elegans expressing human R1441C- and G2019S-LRRK2. The inhibitors displayed nanomolar to low micromolar rescue potency when administered either pre-symptomatically or post-symptomatically, indicating both prevention and reversal of the dopaminergic deficit. The same treatments also led to long-lasting prevention and
rescue of neurodegeneration. In contrast, TTT-3002 and LRRK2-IN1 were ineffective against the neurodegenerative phenotype in transgenic worms carrying the inhibitor-resistant A2016T mutation ofLRRK2, suggesting that they elicit neuroprotective effects in vivo by targeting LRRK2 specifically. Our findings indicate that the LRRK2 kinase activity is critical for neurodegeneration caused by R1441C and G2019S mutations, suggesting that kinase inhibition of LRRK2 may represent a promising therapeutic strategy for PD.

U2 - 10.1093/hmg/dds431 DO - 10.1093/hmg/dds431 M1 - Article JO - Human Molecular Genetics JF - Human Molecular Genetics SN - 0964-6906 IS - 2 VL - 22 SP - 328 EP - 344 ER - TY - JOUR T1 - Long-term, intermittent, insulin-induced hypoglycemia produces marked obesity without hyperphagia or insulin resistance T2 - a model for weight gain with intensive insulin therapy A1 - McNay,Ewan C A1 - Teske,Jennifer A A1 - Kotz,Catherine M A1 - Dunn-Meynell,Ambrose A1 - Levin,Barry E A1 - McCrimmon,Rory J A1 - Sherwin,Robert S AU - McNay,Ewan C AU - Teske,Jennifer A AU - Kotz,Catherine M AU - Dunn-Meynell,Ambrose AU - Levin,Barry E AU - McCrimmon,Rory J AU - Sherwin,Robert S PY - 2013/1/15 Y1 - 2013/1/15 N2 - A major side effect of insulin treatment of diabetes is weight gain, which limits patient compliance and may pose additional health risks. Although the mechanisms responsible for this weight gain are poorly understood, it has been suggested that there may be a link to the incidence of recurrent episodes of hypoglycemia. Here we present a rodent model of marked weight gain associated with weekly insulin-induced hypoglycemic episodes in the absence of diabetes. Insulin treatment caused a significant increase in both body weight and fat mass, accompanied by reduced motor activity, lowered thermogenesis in response to a cold challenge, and reduced brown fat uncoupling protein mRNA. However, there was no effect of insulin treatment on total food intake nor on hypothalamic neuropeptide Y or proopiomelanocortin mRNA expression, and insulin-treated animals did not become insulin-resistant. Our results suggest that repeated iatrogenic hypoglycemia leads to weight gain, and that such weight gain is associated with a multifaceted deficit in metabolic regulation rather than to a chronic increase in caloric intake. AB - A major side effect of insulin treatment of diabetes is weight gain, which limits patient compliance and may pose additional health risks. Although the mechanisms responsible for this weight gain are poorly understood, it has been suggested that there may be a link to the incidence of recurrent episodes of hypoglycemia. Here we present a rodent model of marked weight gain associated with weekly insulin-induced hypoglycemic episodes in the absence of diabetes. Insulin treatment caused a significant increase in both body weight and fat mass, accompanied by reduced motor activity, lowered thermogenesis in response to a cold challenge, and reduced brown fat uncoupling protein mRNA. However, there was no effect of insulin treatment on total food intake nor on hypothalamic neuropeptide Y or proopiomelanocortin mRNA expression, and insulin-treated animals did not become insulin-resistant. Our results suggest that repeated iatrogenic hypoglycemia leads to weight gain, and that such weight gain is associated with a multifaceted deficit in metabolic regulation rather than to a chronic increase in caloric intake. U2 - 10.1152/ajpendo.00262.2012 DO - 10.1152/ajpendo.00262.2012 M1 - Article JO - American Journal of Physiology, Endocrinology and Metabolism JF - American Journal of Physiology, Endocrinology and Metabolism SN - 0193-1849 IS - 2 VL - 304 SP - E131-E138 ER - TY - JOUR T1 - PGE2 Induces Macrophage IL-10 Production and a Regulatory-like Phenotype via a Protein Kinase A-SIK-CRTC3 Pathway A1 - Mackenzie,Kirsty F A1 - Clark,Kristopher A1 - Naqvi,Shaista A1 - McGuire,Victoria A A1 - Nöehren,Gesa A1 - Kristariyanto,Yosua A1 - van den Bosch,Mirjam A1 - Mudaliar,Manikhandan A1 - McCarthy,Pierre C A1 - Pattison,Michael J A1 - Pedrioli,Patrick G A A1 - Barton,Geoff J A1 - Toth,Rachel A1 - Prescott,Alan A1 - Arthur,J Simon C. AU - Mackenzie,Kirsty F AU - Clark,Kristopher AU - Naqvi,Shaista AU - McGuire,Victoria A AU - Nöehren,Gesa AU - Kristariyanto,Yosua AU - van den Bosch,Mirjam AU - Mudaliar,Manikhandan AU - McCarthy,Pierre C AU - Pattison,Michael J AU - Pedrioli,Patrick G A AU - Barton,Geoff J AU - Toth,Rachel AU - Prescott,Alan AU - Arthur,J Simon C. PY - 2013/1/15 Y1 - 2013/1/15 N2 - The polarization of macrophages into a regulatory-like phenotype and the production of IL-10 plays an important role in the resolution of inflammation. We show in this study that PGE(2), in combination with LPS, is able to promote an anti-inflammatory phenotype in macrophages characterized by high expression of IL-10 and the regulatory markers SPHK1 and LIGHT via a protein kinase A-dependent pathway. Both TLR agonists and PGE(2) promote the phosphorylation of the transcription factor CREB on Ser(133). However, although CREB regulates IL-10 transcription, the mutation of Ser(133) to Ala in the endogenous CREB gene did not prevent the ability of PGE(2) to promote IL-10 transcription. Instead, we demonstrate that protein kinase A regulates the phosphorylation of salt-inducible kinase 2 on Ser(343), inhibiting its ability to phosphorylate CREB-regulated transcription coactivator 3 in cells. This in turn allows CREB-regulated transcription coactivator 3 to translocate to the nucleus where it serves as a coactivator with the transcription factor CREB to induce IL-10 transcription. In line with this, we find that either genetic or pharmacological inhibition of salt-inducible kinases mimics the effect of PGE(2) on IL-10 production. AB - The polarization of macrophages into a regulatory-like phenotype and the production of IL-10 plays an important role in the resolution of inflammation. We show in this study that PGE(2), in combination with LPS, is able to promote an anti-inflammatory phenotype in macrophages characterized by high expression of IL-10 and the regulatory markers SPHK1 and LIGHT via a protein kinase A-dependent pathway. Both TLR agonists and PGE(2) promote the phosphorylation of the transcription factor CREB on Ser(133). However, although CREB regulates IL-10 transcription, the mutation of Ser(133) to Ala in the endogenous CREB gene did not prevent the ability of PGE(2) to promote IL-10 transcription. Instead, we demonstrate that protein kinase A regulates the phosphorylation of salt-inducible kinase 2 on Ser(343), inhibiting its ability to phosphorylate CREB-regulated transcription coactivator 3 in cells. This in turn allows CREB-regulated transcription coactivator 3 to translocate to the nucleus where it serves as a coactivator with the transcription factor CREB to induce IL-10 transcription. In line with this, we find that either genetic or pharmacological inhibition of salt-inducible kinases mimics the effect of PGE(2) on IL-10 production. U2 - 10.4049/jimmunol.1202462 DO - 10.4049/jimmunol.1202462 M1 - Article JO - Journal of Immunology JF - Journal of Immunology IS - 2 VL - 190 SP - 565 EP - 577 ER - TY - JOUR T1 - Structural basis for cooperativity of CRM1 export complex formation A1 - Monecke,T. A1 - Haselbach,D. A1 - Voß,B. A1 - Russek,A. A1 - Neumann,P. A1 - Thomson,E. A1 - Hurt,E. A1 - Zachariae,Ulrich A1 - Stark,H. A1 - Grubmul̈ler,H. A1 - Dickmanns,A. A1 - Ficner,R. AU - Monecke,T. AU - Haselbach,D. AU - Voß,B. AU - Russek,A. AU - Neumann,P. AU - Thomson,E. AU - Hurt,E. AU - Zachariae,Ulrich AU - Stark,H. AU - Grubmul̈ler,H. AU - Dickmanns,A. AU - Ficner,R. PY - 2013/1/15 Y1 - 2013/1/15 N2 - In eukaryotes, the nucleocytoplasmic transport of macromolecules is mainly mediated by soluble nuclear transport receptors of the karyopherin-ß superfamily termed importins and exportins. The highly versatile exportin chromosome region maintenance 1 (CRM1) is essential for nuclear depletion of numerous structurally and functionally unrelated protein and ribonucleoprotein cargoes. CRM1 has been shown to adopt a toroidal structure in several functional transport complexes and was thought to maintain this conformation throughout the entire nucleocytoplasmic transport cycle. We solved crystal structures of free CRM1 from the thermophilic eukaryote Chaetomium thermophilum. Surprisingly, unbound CRM1 exhibits an overall extended and pitched superhelical conformation. The two regulatory regions, namely the acidic loop and the C-terminal a-helix, are dramatically repositioned in free CRM1 in comparison with the ternary CRM1-Ran-Snurportin1 export complex. Single-particle EM analysis demonstrates that, in a noncrystalline environment, free CRM1 exists in equilibrium between extended, superhelical and compact, ring-like conformations. Molecular dynamics simulations show that the C-terminal helix plays an important role in regulating the transition from an extended to a compact conformation and reveal how the binding site for nuclear export signals of cargoes is modulated by different CRM1 conformations. Combining these results, we propose a model for the cooperativity of CRM1 export complex assembly involving the long-range allosteric communication between the distant binding sites of GTP-bound Ran and cargo. AB - In eukaryotes, the nucleocytoplasmic transport of macromolecules is mainly mediated by soluble nuclear transport receptors of the karyopherin-ß superfamily termed importins and exportins. The highly versatile exportin chromosome region maintenance 1 (CRM1) is essential for nuclear depletion of numerous structurally and functionally unrelated protein and ribonucleoprotein cargoes. CRM1 has been shown to adopt a toroidal structure in several functional transport complexes and was thought to maintain this conformation throughout the entire nucleocytoplasmic transport cycle. We solved crystal structures of free CRM1 from the thermophilic eukaryote Chaetomium thermophilum. Surprisingly, unbound CRM1 exhibits an overall extended and pitched superhelical conformation. The two regulatory regions, namely the acidic loop and the C-terminal a-helix, are dramatically repositioned in free CRM1 in comparison with the ternary CRM1-Ran-Snurportin1 export complex. Single-particle EM analysis demonstrates that, in a noncrystalline environment, free CRM1 exists in equilibrium between extended, superhelical and compact, ring-like conformations. Molecular dynamics simulations show that the C-terminal helix plays an important role in regulating the transition from an extended to a compact conformation and reveal how the binding site for nuclear export signals of cargoes is modulated by different CRM1 conformations. Combining these results, we propose a model for the cooperativity of CRM1 export complex assembly involving the long-range allosteric communication between the distant binding sites of GTP-bound Ran and cargo. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872581560&md5=c21860b7db428a0c467e22391d5be7c9 U2 - 10.1073/pnas.1215214110 DO - 10.1073/pnas.1215214110 M1 - Article JO - Proceedings of the National Academy of Sciences of the United States of America JF - Proceedings of the National Academy of Sciences of the United States of America SN - 0027-8424 IS - 3 VL - 110 SP - 960 EP - 965 ER - TY - GEN T1 - Canada and Denmark reach agreement on the Lincoln Sea boundary A1 - Hartmann,Jacques AU - Hartmann,Jacques PB - EjilTalk PY - 2013/1/10 Y1 - 2013/1/10 UR - http://www.ejiltalk.org/canada-and-denmark-reach-agreement-on-the-lincoln-sea-boundary/ M1 - Other contribution ER - TY - JOUR T1 - The diversity and management of chronic Hepatitis B virus infections in the United Kingdom T2 - a wake-up call A1 - Tedder,Richard S. A1 - Rodger,Alison J. A1 - Fries,Lori A1 - Ijaz,Samreen A1 - Thursz,Mark A1 - Rosenberg,William A1 - Naoumov,Nikolai A1 - Banatvala,Jangu A1 - Williams,Roger A1 - Dusheiko,Geoffrey A1 - Chokshi,Shilpa A1 - Wong,Terry A1 - Rosenberg,Gillian A1 - Moreea,Sulleman A1 - Bassendine,Margaret A1 - Jacobs,Michael A1 - Mills,Peter R. A1 - Mutimer,David A1 - Ryder,Stephen D. A1 - Bathgate,Andrew A1 - Hussaini,Hyder A1 - Dillon,John F. A1 - Wright,Mark A1 - Bird,George A1 - Collier,Jane A1 - Anderson,Michael A1 - Johnson,Anne M. A1 - for the Collaborative UK Study of Chronic Hepatitis B Infection (CUSHI-B) Study Group AU - Tedder,Richard S. AU - Rodger,Alison J. AU - Fries,Lori AU - Ijaz,Samreen AU - Thursz,Mark AU - Rosenberg,William AU - Naoumov,Nikolai AU - Banatvala,Jangu AU - Williams,Roger AU - Dusheiko,Geoffrey AU - Chokshi,Shilpa AU - Wong,Terry AU - Rosenberg,Gillian AU - Moreea,Sulleman AU - Bassendine,Margaret AU - Jacobs,Michael AU - Mills,Peter R. AU - Mutimer,David AU - Ryder,Stephen D. AU - Bathgate,Andrew AU - Hussaini,Hyder AU - Dillon,John F. AU - Wright,Mark AU - Bird,George AU - Collier,Jane AU - Anderson,Michael AU - Johnson,Anne M. AU - for the Collaborative UK Study of Chronic Hepatitis B Infection (CUSHI-B) Study Group PY - 2013/1/10 Y1 - 2013/1/10 N2 - Background. Through migration, diversity of chronic hepatitis B virus (HBV) infection has changed, affecting disease burden and control. We describe clinical and viral characteristics of chronic HBV in the United Kingdom.Methods. A total of 698 individuals with chronic HBV infection were recruited from referral liver centers. Demographic, clinical, and laboratory data were collected.Results. Sixty-one percent of patients were male, 80% were not born in the United Kingdom, and the largest ethnicity was East/Southeast Asian (36%). Twenty-two percent were hepatitis B e antigen (HBeAg) seropositive; 20.4% (59/289) had cirrhosis and 10 (1.7%) had hepatocellular carcinoma. Genotype D was most common (31%) followed by A, C, B, and E (20%, 20%, 19%, and 9%, respectively). Genotype was significantly associated with country of birth, length of time in the United Kingdom, HBeAg status, and precore and basal core promoter mutations. One-third were on treatment, with men independently more likely to be treated. Only 18% of those on treatment were on recommended first-line therapies, and 30% were on lamivudine monotherapy. Among treated individuals, 27% had antiviral drug resistance. Testing rates for human immunodeficiency virus, hepatitis C virus, and delta coinfections were low.Conclusions. We demonstrated diversity of chronic HBV infections in UK patients, suggesting that optimal management requires awareness of the variable patterns of chronic HBV in countries of origin. We also found less-than-optimal clinical management practices, possible gender-based treatment bias, and the need to improve testing for coinfections. AB - Background. Through migration, diversity of chronic hepatitis B virus (HBV) infection has changed, affecting disease burden and control. We describe clinical and viral characteristics of chronic HBV in the United Kingdom.Methods. A total of 698 individuals with chronic HBV infection were recruited from referral liver centers. Demographic, clinical, and laboratory data were collected.Results. Sixty-one percent of patients were male, 80% were not born in the United Kingdom, and the largest ethnicity was East/Southeast Asian (36%). Twenty-two percent were hepatitis B e antigen (HBeAg) seropositive; 20.4% (59/289) had cirrhosis and 10 (1.7%) had hepatocellular carcinoma. Genotype D was most common (31%) followed by A, C, B, and E (20%, 20%, 19%, and 9%, respectively). Genotype was significantly associated with country of birth, length of time in the United Kingdom, HBeAg status, and precore and basal core promoter mutations. One-third were on treatment, with men independently more likely to be treated. Only 18% of those on treatment were on recommended first-line therapies, and 30% were on lamivudine monotherapy. Among treated individuals, 27% had antiviral drug resistance. Testing rates for human immunodeficiency virus, hepatitis C virus, and delta coinfections were low.Conclusions. We demonstrated diversity of chronic HBV infections in UK patients, suggesting that optimal management requires awareness of the variable patterns of chronic HBV in countries of origin. We also found less-than-optimal clinical management practices, possible gender-based treatment bias, and the need to improve testing for coinfections. U2 - 10.1093/cid/cis1013 DO - 10.1093/cid/cis1013 M1 - Article JO - Clinical Infectious Diseases JF - Clinical Infectious Diseases SN - 1058-4838 IS - 7 VL - 56 SP - 951 EP - 960 ER - TY - JOUR T1 - p53 is activated in response to disruption of the pre-mRNA splicing machinery A1 - Allende-Vega,N. A1 - Dayal,S. A1 - Agarwala,U. A1 - Sparks,A. A1 - Bourdon,J.-C. A1 - Saville,M. K. AU - Allende-Vega,N. AU - Dayal,S. AU - Agarwala,U. AU - Sparks,A. AU - Bourdon,J.-C. AU - Saville,M. K. PY - 2013/1/3 Y1 - 2013/1/3 N2 - In this study, we show that interfering with the splicing machinery results in activation of the tumour-suppressor p53. The spliceosome was targeted by small interfering RNA-mediated knockdown of proteins associated with different small nuclear ribonucleoprotein complexes and by using the small-molecule splicing modulator TG003. These interventions cause: the accumulation of p53, an increase in p53 transcriptional activity and can result in p53-dependent G 1 cell cycle arrest. Mdm2 and MdmX are two key repressors of p53. We show that a decrease in MdmX protein level contributes to p53 activation in response to targeting the spliceosome. Interfering with the spliceosome also causes an increase in the rate of degradation of Mdm2. Alterations in splicing are linked with tumour development. There are frequently global changes in splicing in cancer. Our study suggests that p53 activation could participate in protection against potential tumour-promoting defects in the spliceosome. A number of known p53-activating agents affect the splicing machinery and this could contribute to their ability to upregulate p53. Preclinical studies indicate that tumours can be more sensitive than normal cells to small-molecule spliceosome inhibitors. Activation of p53 could influence the selective anti-tumour activity of this therapeutic approach. © 2013 Macmillan Publishers Limited. AB - In this study, we show that interfering with the splicing machinery results in activation of the tumour-suppressor p53. The spliceosome was targeted by small interfering RNA-mediated knockdown of proteins associated with different small nuclear ribonucleoprotein complexes and by using the small-molecule splicing modulator TG003. These interventions cause: the accumulation of p53, an increase in p53 transcriptional activity and can result in p53-dependent G 1 cell cycle arrest. Mdm2 and MdmX are two key repressors of p53. We show that a decrease in MdmX protein level contributes to p53 activation in response to targeting the spliceosome. Interfering with the spliceosome also causes an increase in the rate of degradation of Mdm2. Alterations in splicing are linked with tumour development. There are frequently global changes in splicing in cancer. Our study suggests that p53 activation could participate in protection against potential tumour-promoting defects in the spliceosome. A number of known p53-activating agents affect the splicing machinery and this could contribute to their ability to upregulate p53. Preclinical studies indicate that tumours can be more sensitive than normal cells to small-molecule spliceosome inhibitors. Activation of p53 could influence the selective anti-tumour activity of this therapeutic approach. © 2013 Macmillan Publishers Limited. KW - PROTEIN KW - Mdm2 KW - DNA-DAMAGE KW - GENOTOXIC STRESS KW - IN-VIVO KW - FACTOR SF3B KW - spliceosome KW - splicing KW - p53 KW - DEUBIQUITINATING ENZYME USP2A KW - EMERGING ROLE KW - TRANSCRIPTION KW - TG003 KW - MDM2 KW - MdmX KW - CANCER-CELLS UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871985001&md5=ba94c0e1910b39efad29cb86f6e00f61 U2 - 10.1038/onc.2012.38 DO - 10.1038/onc.2012.38 M1 - Article JO - Oncogene JF - Oncogene SN - 0950-9232 IS - 1 VL - 32 SP - 1 EP - 14 ER - TY - JOUR T1 - Age estimation using foot radiographs from a modern Scottish population A1 - Hackman,Lucina A1 - Davies,Catriona M. A1 - Black,Sue AU - Hackman,Lucina AU - Davies,Catriona M. AU - Black,Sue PY - 2013/1/1 Y1 - 2013/1/1 N2 - The Hoerr et al. atlas was published in 1962 and provides a standard for the age estimation of juveniles through radiographs of the feet. This study examines the accuracy of this atlas when used as an age estimation method on a modern Scottish population. A total of 403 left foot/ankle radiographs (175 female, 228 male) were age assessed using the Hoerr et al. atlas method. Analysis showed that there was a strong correlation between chronological age and estimated age (female R² = 0.952, male R² = 0.962). The atlas had a tendency to underage all ages of females and to underage males up to the age of 10 years after which point the pattern is one of both over and underaging. This study showed that the Hoerr et al. atlas method can be applied to a modern population. AB - The Hoerr et al. atlas was published in 1962 and provides a standard for the age estimation of juveniles through radiographs of the feet. This study examines the accuracy of this atlas when used as an age estimation method on a modern Scottish population. A total of 403 left foot/ankle radiographs (175 female, 228 male) were age assessed using the Hoerr et al. atlas method. Analysis showed that there was a strong correlation between chronological age and estimated age (female R² = 0.952, male R² = 0.962). The atlas had a tendency to underage all ages of females and to underage males up to the age of 10 years after which point the pattern is one of both over and underaging. This study showed that the Hoerr et al. atlas method can be applied to a modern population. KW - Forensic science KW - Forensic anthropology KW - Age estimation KW - Radiographs KW - Hoerr et al. atlas KW - Age-assessment KW - Foot-ankle UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872290146&md5=02ac04964a8bdc14c4992d91c7538458 U2 - 10.1111/1556-4029.12004 DO - 10.1111/1556-4029.12004 M1 - Article JO - Journal of Forensic Sciences JF - Journal of Forensic Sciences IS - S1 VL - 58 SP - S146-S150 ER - TY - JOUR T1 - An analytical solution for response of a porous seabed to combined wave and current loading A1 - Zhang,Y. A1 - Jeng,D. -S. A1 - Gao,F. P. A1 - Zhang,J. -S. AU - Zhang,Y. AU - Jeng,D. -S. AU - Gao,F. P. AU - Zhang,J. -S. PY - 2013/1/1 Y1 - 2013/1/1 N2 -

In this paper, an analytical approximation for the evaluation of the pore pressure and effective stresses in marine sediments under combined wave and current loadings is derived. Unlike previous investigations, non-linear interactions between waves and currents are considered in this study. An analytical solution for the wave-current induced oscillatory soil response in marine sediment is presented first. Based on the proposed analytical solution, a parametric study for the liquefaction potential will be carried out. Parametric study results indicate that the influence of current and non-linear waves on the maximum liquefaction depth is significant. (C) 2012 Elsevier Ltd. All rights reserved.

AB -

In this paper, an analytical approximation for the evaluation of the pore pressure and effective stresses in marine sediments under combined wave and current loadings is derived. Unlike previous investigations, non-linear interactions between waves and currents are considered in this study. An analytical solution for the wave-current induced oscillatory soil response in marine sediment is presented first. Based on the proposed analytical solution, a parametric study for the liquefaction potential will be carried out. Parametric study results indicate that the influence of current and non-linear waves on the maximum liquefaction depth is significant. (C) 2012 Elsevier Ltd. All rights reserved.

KW - EFFECTIVE STRESSES KW - Porous seabed KW - WATER-WAVES KW - BED KW - Wave-current interactions KW - Effective stresses KW - Pore pressure KW - INDUCED PORE PRESSURE U2 - 10.1016/j.oceaneng.2012.09.001 DO - 10.1016/j.oceaneng.2012.09.001 M1 - Article JO - Ocean Engineering JF - Ocean Engineering SN - 0029-8018 VL - 57 SP - 240 EP - 247 ER - TY - JOUR T1 - An observational study of psychotropic drug use and initiation in older patients resident in their own home or in care A1 - McCowan,Colin A1 - Magin,Parker A1 - Clark,Stella A1 - Guthrie,Bruce AU - McCowan,Colin AU - Magin,Parker AU - Clark,Stella AU - Guthrie,Bruce PY - 2013/1/1 Y1 - 2013/1/1 N2 - Objective: to compare the prescription of psychotropic medications for patients living in care homes with that for patients living at home.

Design and setting: retrospective population database study in the Tayside region of Scotland.

Subjects: 70,297 patients aged =65 and followed until death or the end of the study.

Methods: examining registered addresses for all people aged 65–99 identified those in care. The prescriptions for a 12-week period was examined and psychotropic drug use compared by their place of residence. Comparisons of prescriptions pre- and post-admission were performed for people admitted to a care home from Jan 2005 to Dec 2006.

Results: people living in care (4.1%) received 9.80 more prescribed items (P < 0.001) from 1.63 more British National Formulary (BNF) categories (P < 0.001) than people living at home over a 12-week period. They were more likely to receive any psychotropic medication (42 versus 16%, odds ratio (OR) 3.09, 95% CI: 2.79–3.41).

Over 70% of 1,715 people admitted to care homes during the study who received psychotropic medication commenced the medication prior to admission. Patients who started anti-psychotics in the 30 days prior to admission were less likely to have stopped them (OR: 0.53, 95% CI: 0.30–0.94).

Conclusion: prolonged prescription of psychotropic medications is commonplace in care home residents. Almost half of the people prescribed antipsychotic drugs received them for a minimum of 6 months. Systematic medication reviews must be established in all care homes to promote safe and effective prescription to this at-risk population. AB - Objective: to compare the prescription of psychotropic medications for patients living in care homes with that for patients living at home.

Design and setting: retrospective population database study in the Tayside region of Scotland.

Subjects: 70,297 patients aged =65 and followed until death or the end of the study.

Methods: examining registered addresses for all people aged 65–99 identified those in care. The prescriptions for a 12-week period was examined and psychotropic drug use compared by their place of residence. Comparisons of prescriptions pre- and post-admission were performed for people admitted to a care home from Jan 2005 to Dec 2006.

Results: people living in care (4.1%) received 9.80 more prescribed items (P < 0.001) from 1.63 more British National Formulary (BNF) categories (P < 0.001) than people living at home over a 12-week period. They were more likely to receive any psychotropic medication (42 versus 16%, odds ratio (OR) 3.09, 95% CI: 2.79–3.41).

Over 70% of 1,715 people admitted to care homes during the study who received psychotropic medication commenced the medication prior to admission. Patients who started anti-psychotics in the 30 days prior to admission were less likely to have stopped them (OR: 0.53, 95% CI: 0.30–0.94).

Conclusion: prolonged prescription of psychotropic medications is commonplace in care home residents. Almost half of the people prescribed antipsychotic drugs received them for a minimum of 6 months. Systematic medication reviews must be established in all care homes to promote safe and effective prescription to this at-risk population. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871348849&md5=bae69f9d24ce277bade7316780c90dec U2 - 10.1093/ageing/afs117 DO - 10.1093/ageing/afs117 M1 - Article JO - Age and Ageing JF - Age and Ageing SN - 0002-0729 IS - 1 VL - 42 SP - 51 EP - 56 ER - TY - JOUR T1 - Commentary T2 - assessment of non-alcoholic fatty liver disease using serum total cell death and apoptosis markers A1 - Miller,M.H. A1 - Dillon,J.F. AU - Miller,M.H. AU - Dillon,J.F. PY - 2013/1/1 Y1 - 2013/1/1 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872857061&md5=4210a6e7fb45e8b2d3e8c33691202470 U2 - 10.1111/apt.12134 DO - 10.1111/apt.12134 M1 - Article JO - Alimentary Pharmacology & Therapeutics JF - Alimentary Pharmacology & Therapeutics SN - 0269-2813 IS - 2 VL - 37 SP - 275 ER - TY - JOUR T1 - Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6 A1 - MacCallum,Stephanie F. A1 - Groves,M.J. A1 - James,J. A1 - Murray,K. A1 - Appleyard,Virginia A1 - Prescott,Alan R. A1 - Drbal,A.A. A1 - Nicolaou,A. A1 - Cunningham,Joan A1 - Haydock,S. A1 - Ganley,Ian G. A1 - Westwood,N.J. A1 - Coates,Philip J. A1 - Lain,Sonia A1 - Tauro,Sudhir AU - MacCallum,Stephanie F. AU - Groves,M.J. AU - James,J. AU - Murray,K. AU - Appleyard,Virginia AU - Prescott,Alan R. AU - Drbal,A.A. AU - Nicolaou,A. AU - Cunningham,Joan AU - Haydock,S. AU - Ganley,Ian G. AU - Westwood,N.J. AU - Coates,Philip J. AU - Lain,Sonia AU - Tauro,Sudhir PY - 2013/1/1 Y1 - 2013/1/1 N2 - Tenovin-6 (Tnv-6) is a bioactive small molecule with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways. AB - Tenovin-6 (Tnv-6) is a bioactive small molecule with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84874339014&md5=86afd7561c85e4085692667c91d7b378 U2 - 10.1038/srep01275 DO - 10.1038/srep01275 M1 - Article JO - Scientific Reports JF - Scientific Reports VL - 3 ER - TY - JOUR T1 - Inhomogeneous bimolecular recombination in partially crystallised tri-methylphenyl diamine glasses A1 - Goldie,D.M. AU - Goldie,D.M. PY - 2013/1/1 Y1 - 2013/1/1 N2 - The rise and fall dynamics of transient photocurrents induced by exposure to ultraviolet radiation have been analysed for a series of glassy tri-methylphenyl diamine films that have been partially crystallised by ageing under ambient conditions following vapour deposition. An inhomogeneous bimolecular recombination model that uses coupled rate equations is found to provide a consistent fit for the observed photocurrent dynamics provided the recombination rate of holes in the crystallised regions of the films is lower compared to the amorphous regions. Parameters returned by the bimolecular model are investigated as a function of the film age but are observed to be highly sensitive to the initial experimental estimates that are supplied for the effective hole recombination time. The effective hole recombination time generated by the model is found to be relatively independent of film age, however, and has a value of around 0.16 s for a carrier generation rate of 7 × 10 cm s. The effective recombination time and steady-state photoconductivity magnitudes are found to be consistent with experimental hole mobility and photo-carrier generation efficiency values that are obtained using complementary time-of-flight and charge collection experiments. © 2012 Elsevier B.V. All rights reserved. AB - The rise and fall dynamics of transient photocurrents induced by exposure to ultraviolet radiation have been analysed for a series of glassy tri-methylphenyl diamine films that have been partially crystallised by ageing under ambient conditions following vapour deposition. An inhomogeneous bimolecular recombination model that uses coupled rate equations is found to provide a consistent fit for the observed photocurrent dynamics provided the recombination rate of holes in the crystallised regions of the films is lower compared to the amorphous regions. Parameters returned by the bimolecular model are investigated as a function of the film age but are observed to be highly sensitive to the initial experimental estimates that are supplied for the effective hole recombination time. The effective hole recombination time generated by the model is found to be relatively independent of film age, however, and has a value of around 0.16 s for a carrier generation rate of 7 × 10 cm s. The effective recombination time and steady-state photoconductivity magnitudes are found to be consistent with experimental hole mobility and photo-carrier generation efficiency values that are obtained using complementary time-of-flight and charge collection experiments. © 2012 Elsevier B.V. All rights reserved. KW - organic glass KW - inhomogeneous KW - RECOMBINATION KW - effective lifetime UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871531734&md5=0e541fe9dd85141f0f071c0dc6ea94de U2 - 10.1016/j.tsf.2012.12.008 DO - 10.1016/j.tsf.2012.12.008 M1 - Article JO - Thin Solid Films JF - Thin Solid Films SN - 0040-6090 VL - 527 SP - 377 EP - 382 ER - TY - JOUR T1 - The reliability of the Greulich and Pyle Atlas when applied to a modern Scottish population A1 - Hackman,Lucina A1 - Black,Sue AU - Hackman,Lucina AU - Black,Sue PY - 2013/1/1 Y1 - 2013/1/1 N2 - This study examines the reliability of age estimation utilizing the Greulich and Pyle atlas in relation to a modern Scottish population. A total of 406 left-hand/wrist radiographs (157 females and 249 males) were age-assessed using the Greulich and Pyle atlas. Analysis showed that there was a strong correlation between chronological age and estimated age (females R(2)  = 0.939, males R(2)  = 0.940). When age groups were broken down into year cohorts, the atlas over-aged females from birth until 13 years of age. The pattern for males showed that the atlas under-estimated age until 13 years of age after which point it consistently over-aged boys between 13 and 17 years of age. This study showed that the Greulich and Pyle atlas can be applied to a modern population but would recommend that any analysis takes into account the potential for over- and under-aging shown in this study. AB - This study examines the reliability of age estimation utilizing the Greulich and Pyle atlas in relation to a modern Scottish population. A total of 406 left-hand/wrist radiographs (157 females and 249 males) were age-assessed using the Greulich and Pyle atlas. Analysis showed that there was a strong correlation between chronological age and estimated age (females R(2)  = 0.939, males R(2)  = 0.940). When age groups were broken down into year cohorts, the atlas over-aged females from birth until 13 years of age. The pattern for males showed that the atlas under-estimated age until 13 years of age after which point it consistently over-aged boys between 13 and 17 years of age. This study showed that the Greulich and Pyle atlas can be applied to a modern population but would recommend that any analysis takes into account the potential for over- and under-aging shown in this study. KW - Forensic science KW - Forensic anthropology KW - age estimation KW - radiographs KW - Greulich and Pyle atlas KW - Age assessment living UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872410140&md5=587cbf947e2a45e5f7a76848dc3bf98f U2 - 10.1111/j.1556-4029.2012.02294.x DO - 10.1111/j.1556-4029.2012.02294.x M1 - Article JO - Journal of Forensic Sciences JF - Journal of Forensic Sciences IS - 1 VL - 58 SP - 114 EP - 119 ER - TY - JOUR T1 - You say you want a revolution? T2 - transforming education and capacity building in response to global change A1 - O'Brien,Karen A1 - Reams,Jonathan A1 - Caspari,Anne A1 - Dugmore,Andrew A1 - Faghihimani,Maryam A1 - Fazey,Ioan A1 - Hackmann,Heide A1 - Manuel-Navarrete,David A1 - Marks,John A1 - Miller,Riel A1 - Raivio,Kari A1 - Romero-Lankao,Patricia A1 - Virji,Hassan A1 - Vogel,Coleen A1 - Winiwarter,Verena AU - O'Brien,Karen AU - Reams,Jonathan AU - Caspari,Anne AU - Dugmore,Andrew AU - Faghihimani,Maryam AU - Fazey,Ioan AU - Hackmann,Heide AU - Manuel-Navarrete,David AU - Marks,John AU - Miller,Riel AU - Raivio,Kari AU - Romero-Lankao,Patricia AU - Virji,Hassan AU - Vogel,Coleen AU - Winiwarter,Verena PY - 2013/1/1 Y1 - 2013/1/1 N2 - This paper considers the changes in education and capacity building that are needed in response to environmental and social challenges of the 21st Century. We argue that such changes will require more than adjustments in current educational systems, research funding strategies, and interdisciplinary collaborations. Instead, it calls for a deeper questioning of the assumptions and beliefs that frame both problems and solutions. We first discuss the challenges of transforming education and capacity building within five key arenas: interdisciplinary research; university education systems; primary and secondary education systems; researchers from the developing world; and the public at large and politicians. Our starting point is that any type of revolution that is proposed in response to global change is likely to reflect the educational perspectives and paradigms of those calling for the revolution. We differentiate between a circular revolution (as in the "plan-do-check-act cycle" often used in change management) versus an axial revolution (moving to a different way of thinking about the issues), arguing that the latter is a more appropriate response to the complex transdisciplinary challenges posed by global environmental change. We present some potential tools to promote an axial revolution, and consider the limits to this approach. We conclude that rather than promoting one large and ideologically homogenous revolution in education and capacity building, there is a need for a revolution in the way that leaders working with education and capacity building look at systems and processes of change. From this perspective, transformative learning may not only be desirable, but critical in responding to the challenges posed by global environmental change. © 2012 Elsevier Ltd. All rights reserved. AB - This paper considers the changes in education and capacity building that are needed in response to environmental and social challenges of the 21st Century. We argue that such changes will require more than adjustments in current educational systems, research funding strategies, and interdisciplinary collaborations. Instead, it calls for a deeper questioning of the assumptions and beliefs that frame both problems and solutions. We first discuss the challenges of transforming education and capacity building within five key arenas: interdisciplinary research; university education systems; primary and secondary education systems; researchers from the developing world; and the public at large and politicians. Our starting point is that any type of revolution that is proposed in response to global change is likely to reflect the educational perspectives and paradigms of those calling for the revolution. We differentiate between a circular revolution (as in the "plan-do-check-act cycle" often used in change management) versus an axial revolution (moving to a different way of thinking about the issues), arguing that the latter is a more appropriate response to the complex transdisciplinary challenges posed by global environmental change. We present some potential tools to promote an axial revolution, and consider the limits to this approach. We conclude that rather than promoting one large and ideologically homogenous revolution in education and capacity building, there is a need for a revolution in the way that leaders working with education and capacity building look at systems and processes of change. From this perspective, transformative learning may not only be desirable, but critical in responding to the challenges posed by global environmental change. © 2012 Elsevier Ltd. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872071827&md5=681bcdf2ea3c80a6b60736d1d435ce18 U2 - 10.1016/j.envsci.2012.11.011 DO - 10.1016/j.envsci.2012.11.011 M1 - Article JO - Environmental Science and Policy JF - Environmental Science and Policy SN - 1462-9011 ER - TY - JOUR T1 - ‘A Documentary History of African Politics in South Africa, 1882-1990: From Protest to Challenge (Vol. 6, 1980-1990)’, by Gail M. Gerhart and Clive L. Glaser A1 - Graham,Matthew AU - Graham,Matthew PY - 2013/1 Y1 - 2013/1 U2 - 10.1111/1478-9302.12000_115 DO - 10.1111/1478-9302.12000_115 M1 - Book/Film/Article review JO - Political Studies Review JF - Political Studies Review SN - 1478-9299 IS - 1 VL - 11 SP - 145 EP - 146 ER - TY - JOUR T1 - Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation A1 - Dichtel-Danjoy,M.-L. A1 - Ma,D. A1 - Dourlen,P. A1 - Chatelain,G. A1 - Napoletano,F. A1 - Robin,M. A1 - Corbet,M. A1 - Levet,C. A1 - Hafsi,H. A1 - Hainaut,P. A1 - Ryoo,H.D. A1 - Bourdon,J.-C. A1 - Mollereau,B. AU - Dichtel-Danjoy,M.-L. AU - Ma,D. AU - Dourlen,P. AU - Chatelain,G. AU - Napoletano,F. AU - Robin,M. AU - Corbet,M. AU - Levet,C. AU - Hafsi,H. AU - Hainaut,P. AU - Ryoo,H.D. AU - Bourdon,J.-C. AU - Mollereau,B. PY - 2013/1 Y1 - 2013/1 N2 - Irradiated or injured cells enter apoptosis, and in turn, promote proliferation of surrounding unaffected cells. In Drosophila, apoptotic cells have an active role in proliferation, where the caspase Dronc and p53 induce mitogen expression and growth in the surrounding tissues. The Drosophila p53 gene structure is conserved and encodes at least two protein isoforms: a full-length isoform (Dp53) and an N-terminally truncated isoform (D?Np53). Historically, D?Np53 was the first p53 isoform identified and was thought to be responsible for all p53 biological activities. It was shown that D?Np53 induces apoptosis by inducing the expression of IAP antagonists, such as Reaper. Here we investigated the roles of Dp53 and D?Np53 in apoptosis and apoptosis-induced proliferation. We found that both isoforms were capable of activating apoptosis, but that they each induced distinct IAP antagonists. Expression of D?Np53 induced Wingless (Wg) expression and enhanced proliferation in both 'undead cells' and in 'genuine' apoptotic cells. In contrast to D?Np53, Dp53 did not induce Wg expression in the absence of the endogenous p53 gene. Thus, we propose that D?Np53 is the main isoform that regulates apoptosis-induced proliferation. Understanding the roles of Drosophila p53 isoforms in apoptosis and in apoptosis-induced proliferation may shed new light on the roles of p53 isoforms in humans, with important implications in cancer biology. © 2013 Macmillan Publishers Limited All rights reserved. AB - Irradiated or injured cells enter apoptosis, and in turn, promote proliferation of surrounding unaffected cells. In Drosophila, apoptotic cells have an active role in proliferation, where the caspase Dronc and p53 induce mitogen expression and growth in the surrounding tissues. The Drosophila p53 gene structure is conserved and encodes at least two protein isoforms: a full-length isoform (Dp53) and an N-terminally truncated isoform (D?Np53). Historically, D?Np53 was the first p53 isoform identified and was thought to be responsible for all p53 biological activities. It was shown that D?Np53 induces apoptosis by inducing the expression of IAP antagonists, such as Reaper. Here we investigated the roles of Dp53 and D?Np53 in apoptosis and apoptosis-induced proliferation. We found that both isoforms were capable of activating apoptosis, but that they each induced distinct IAP antagonists. Expression of D?Np53 induced Wingless (Wg) expression and enhanced proliferation in both 'undead cells' and in 'genuine' apoptotic cells. In contrast to D?Np53, Dp53 did not induce Wg expression in the absence of the endogenous p53 gene. Thus, we propose that D?Np53 is the main isoform that regulates apoptosis-induced proliferation. Understanding the roles of Drosophila p53 isoforms in apoptosis and in apoptosis-induced proliferation may shed new light on the roles of p53 isoforms in humans, with important implications in cancer biology. © 2013 Macmillan Publishers Limited All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84870990619&md5=82143d6d9c274cc8be1826dac6ae1393 U2 - 10.1038/cdd.2012.100 DO - 10.1038/cdd.2012.100 M1 - Article JO - Cell Death & Differentiation JF - Cell Death & Differentiation SN - 1350-9047 IS - 1 VL - 20 SP - 108 EP - 116 ER - TY - JOUR T1 - A surveillance model for skin cancer in organ transplant recipients T2 - A 22-year prospective study in an ethnically diverse population A1 - Harwood,C.A. A1 - Mesher,D. A1 - McGregor,J.M. A1 - Mitchell,L. A1 - Leedham-Green,M. A1 - Raftery,M. A1 - Cerio,R. A1 - Leigh,I.M. A1 - Sasieni,P. A1 - Proby,C.M. AU - Harwood,C.A. AU - Mesher,D. AU - McGregor,J.M. AU - Mitchell,L. AU - Leedham-Green,M. AU - Raftery,M. AU - Cerio,R. AU - Leigh,I.M. AU - Sasieni,P. AU - Proby,C.M. PY - 2013/1 Y1 - 2013/1 N2 - Skin cancer is a frequent complication of organ transplantation. Current guidelines advise specialist skin surveillance but there are limited data on how these should be implemented. This study determines overall burden of cancer and relevant intervals for strategic surveillance in an ethnically diverse transplant population. Prospective data on time to first and subsequent cancers and cumulative burden with respect to defined risk factors were analyzed in a cohort of 1010 patients in a UK center over 22 years. Among 931 individuals transplanted >6 months (mean 10.3 years), 1820 skin cancers occurred in 267 (29%) individuals and were multiple in 66%. Cumulative incidence at 5, 10, 20 and 30 years was 11%, 25%, 54% and 74%, with median time to second, third and fourth cancers of 24, 14.7 and 8.4 months, respectively. Tumors were overwhelmingly squamous and basal cell carcinomas (73% and 24%, respectively). Skin phototype, ultraviolet radiation exposure, age at transplant and duration of transplant were significant risk predictors and were used to construct clinically relevant surveillance intervals. This study provides a comprehensive, prospective analysis of skin cancer morbidity and risk in an ethnically diverse transplant population from which we derive an evidence-based skin cancer surveillance program. The authors employ an evidence-based approach to skin cancer surveillance in renal transplant recipients in a singlecentre prospective study. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons. AB - Skin cancer is a frequent complication of organ transplantation. Current guidelines advise specialist skin surveillance but there are limited data on how these should be implemented. This study determines overall burden of cancer and relevant intervals for strategic surveillance in an ethnically diverse transplant population. Prospective data on time to first and subsequent cancers and cumulative burden with respect to defined risk factors were analyzed in a cohort of 1010 patients in a UK center over 22 years. Among 931 individuals transplanted >6 months (mean 10.3 years), 1820 skin cancers occurred in 267 (29%) individuals and were multiple in 66%. Cumulative incidence at 5, 10, 20 and 30 years was 11%, 25%, 54% and 74%, with median time to second, third and fourth cancers of 24, 14.7 and 8.4 months, respectively. Tumors were overwhelmingly squamous and basal cell carcinomas (73% and 24%, respectively). Skin phototype, ultraviolet radiation exposure, age at transplant and duration of transplant were significant risk predictors and were used to construct clinically relevant surveillance intervals. This study provides a comprehensive, prospective analysis of skin cancer morbidity and risk in an ethnically diverse transplant population from which we derive an evidence-based skin cancer surveillance program. The authors employ an evidence-based approach to skin cancer surveillance in renal transplant recipients in a singlecentre prospective study. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871719483&md5=520a5d18c843f769db634e5a21399e04 U2 - 10.1111/j.1600-6143.2012.04292.x DO - 10.1111/j.1600-6143.2012.04292.x M1 - Article JO - American Journal of Transplantation JF - American Journal of Transplantation SN - 1600-6135 IS - 1 VL - 13 SP - 119 EP - 129 ER - TY - JOUR T1 - Aortic valvular heart disease T2 - is there a place for angiotensin-converting-enzyme inhibitors? A1 - Elder,Douglas H J A1 - McAlpine-Scott,Victoria A1 - Choy,Anna Maria A1 - Struthers,Allan D A1 - Lang,Chim C AU - Elder,Douglas H J AU - McAlpine-Scott,Victoria AU - Choy,Anna Maria AU - Struthers,Allan D AU - Lang,Chim C PY - 2013/1 Y1 - 2013/1 N2 - Aortic valve disease (AVD) is the most common form of valvular heart disease in the western world. The only proven therapy for severe AVD is open aortic valve replacement, with trans-catheter aortic valve implantation emerging as a promising modality to treat severe aortic stenosis in a selected group of patients. AVD has a long asymptomatic phase with symptoms occurring late in the disease and once symptoms develop, prognosis is poor. There is a growing appreciation that aortic valvular heart disease incorporates a disease process that extends beyond the valve itself leading to an aortic valvular 'heart' disease. The renin-angiotensin system is known to modulate adverse left ventricular remodeling and myocardial fibrosis, which could be caused by increased load caused by the AVD. In this review, the authors explore evidence that suggest that drugs that target the renin-angiotensin system may have a potential therapeutic role in AVD. AB - Aortic valve disease (AVD) is the most common form of valvular heart disease in the western world. The only proven therapy for severe AVD is open aortic valve replacement, with trans-catheter aortic valve implantation emerging as a promising modality to treat severe aortic stenosis in a selected group of patients. AVD has a long asymptomatic phase with symptoms occurring late in the disease and once symptoms develop, prognosis is poor. There is a growing appreciation that aortic valvular heart disease incorporates a disease process that extends beyond the valve itself leading to an aortic valvular 'heart' disease. The renin-angiotensin system is known to modulate adverse left ventricular remodeling and myocardial fibrosis, which could be caused by increased load caused by the AVD. In this review, the authors explore evidence that suggest that drugs that target the renin-angiotensin system may have a potential therapeutic role in AVD. U2 - 10.1586/erc.12.143 DO - 10.1586/erc.12.143 M1 - Article JO - Expert Review of Cardiovascular Therapy JF - Expert Review of Cardiovascular Therapy IS - 1 VL - 11 SP - 107 EP - 114 ER - TY - JOUR T1 - Are we discussing SUDEP?-A retrospective case note analysis A1 - Waddell,B. A1 - McColl,K. A1 - Turner,C. A1 - Norman,A. A1 - Coker,A. A1 - White,K. A1 - Roberts,R. A1 - Heath,C. A. AU - Waddell,B. AU - McColl,K. AU - Turner,C. AU - Norman,A. AU - Coker,A. AU - White,K. AU - Roberts,R. AU - Heath,C. A. PY - 2013/1 Y1 - 2013/1 N2 -

Purpose: Sudden unexplained death in epilepsy (SUDEP) is uncommon. Discussing the risk of SUDEP can be difficult, particularly in those where the risk is considered low, and previous studies have suggested that clinical practice varies widely. The Scottish Intercollegiate Guidelines Network (SIGN) suggest information on SUDEP is "essential" and National Institute of Clinical Excellence (NICE) recommend that "tailored information on the person's relative risk of SUDEP should be part of the counselling process ...". The study aimed to evaluate if discussion of SUDEP risk is being documented in clinical records and to determine if there is an association between documented discussion and risk factors for SUDEP.

Methods: A retrospective case note review was undertaken in those with an established diagnosis of epilepsy attending clinic between 1st January 2009 and 30th June 2009.

Results: Overall, a documented SUDEP discussion was noted in 14/345 (4%) cases. Patients were statistically more likely to have a documented SUDEP discussion if they had ongoing generalised tonic-clonic seizures, with a trend also towards informing those non-compliant with medication.

Conclusion: Patients were more likely to be informed of SUDEP if they had potentially modifiable risk factors identified. There was, however, no documented evidence to suggest that SUDEP is being discussed in the majority of cases. (C) 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

AB -

Purpose: Sudden unexplained death in epilepsy (SUDEP) is uncommon. Discussing the risk of SUDEP can be difficult, particularly in those where the risk is considered low, and previous studies have suggested that clinical practice varies widely. The Scottish Intercollegiate Guidelines Network (SIGN) suggest information on SUDEP is "essential" and National Institute of Clinical Excellence (NICE) recommend that "tailored information on the person's relative risk of SUDEP should be part of the counselling process ...". The study aimed to evaluate if discussion of SUDEP risk is being documented in clinical records and to determine if there is an association between documented discussion and risk factors for SUDEP.

Methods: A retrospective case note review was undertaken in those with an established diagnosis of epilepsy attending clinic between 1st January 2009 and 30th June 2009.

Results: Overall, a documented SUDEP discussion was noted in 14/345 (4%) cases. Patients were statistically more likely to have a documented SUDEP discussion if they had ongoing generalised tonic-clonic seizures, with a trend also towards informing those non-compliant with medication.

Conclusion: Patients were more likely to be informed of SUDEP if they had potentially modifiable risk factors identified. There was, however, no documented evidence to suggest that SUDEP is being discussed in the majority of cases. (C) 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

KW - SUDDEN UNEXPECTED DEATH KW - Epilepsy KW - EPILEPSY SUDEP KW - SUDEP U2 - 10.1016/j.seizure.2012.09.017 DO - 10.1016/j.seizure.2012.09.017 M1 - Article JO - Seizure JF - Seizure SN - 1059-1311 IS - 1 VL - 22 SP - 74 EP - 76 ER - TY - JOUR T1 - Assessment of long term function following hypospadias reconstruction T2 - do flow rates, flow quality and cosmesis improve with time? Results from the modified Bretteville technique A1 - Robinson,A. J. A1 - Harry,L. E. A1 - Stevenson,J. H. AU - Robinson,A. J. AU - Harry,L. E. AU - Stevenson,J. H. PY - 2013/1 Y1 - 2013/1 N2 - Background: Very few studies on long term evaluation of functional outcome following hypospadias reconstruction are available. Results from the modified Bretteville method have shown excellent cosmesis with a low risk of fistula and stenosis. This study addresses the question; do flow rates, quality of urinary stream and cosmesis change over time? Methods: A sample of 18 patients who had undergone the 2 stage modified Bretteville technique between 1998 and 2004 were reviewed. Following a mean interval of 10 years and 5 months from initial functional assessment, repeat evaluation was performed using the "HOSE" questionnaire, flowmetry, and spray analysis. Results: Improvement in mean flow rate (15.3 vs 10.1 ml/s; p value = 0.0036), reduced spraying (3.2 g vs 4.4 g; p value = 0.2927), with a mean increase in the "HOSE" score (from 13.8 (maximum score 16) to 15.4 (maximum score 16); p value = 0.0440) was observed over the follow up time. Conclusion: Improvement in flow rates, flow quality, and cosmesis over a mean interval of 10 years 5 months has been demonstrated in a random cohort of patients undergoing the modified Bretteville method of hypospadias reconstruction. © 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. AB - Background: Very few studies on long term evaluation of functional outcome following hypospadias reconstruction are available. Results from the modified Bretteville method have shown excellent cosmesis with a low risk of fistula and stenosis. This study addresses the question; do flow rates, quality of urinary stream and cosmesis change over time? Methods: A sample of 18 patients who had undergone the 2 stage modified Bretteville technique between 1998 and 2004 were reviewed. Following a mean interval of 10 years and 5 months from initial functional assessment, repeat evaluation was performed using the "HOSE" questionnaire, flowmetry, and spray analysis. Results: Improvement in mean flow rate (15.3 vs 10.1 ml/s; p value = 0.0036), reduced spraying (3.2 g vs 4.4 g; p value = 0.2927), with a mean increase in the "HOSE" score (from 13.8 (maximum score 16) to 15.4 (maximum score 16); p value = 0.0440) was observed over the follow up time. Conclusion: Improvement in flow rates, flow quality, and cosmesis over a mean interval of 10 years 5 months has been demonstrated in a random cohort of patients undergoing the modified Bretteville method of hypospadias reconstruction. © 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84864502298&md5=3d8b473d7bf9b0b4ea9e248c6d0fa527 U2 - 10.1016/j.bjps.2012.07.011 DO - 10.1016/j.bjps.2012.07.011 M1 - Article JO - Journal of Plastic, Reconstructive and Aesthetic Surgery JF - Journal of Plastic, Reconstructive and Aesthetic Surgery SN - 1748-6815 IS - 1 VL - 66 SP - 120 EP - 126 ER - TY - JOUR T1 - Avoiding tokenism in health professional education A1 - Bearman,Margaret A1 - Ajjawi,Rola AU - Bearman,Margaret AU - Ajjawi,Rola PY - 2013/1 Y1 - 2013/1 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871562220&md5=28f428e6708fb34d8919414e1072b833 U2 - 10.1111/medu.12109 DO - 10.1111/medu.12109 M1 - Article JO - Medical Education JF - Medical Education SN - 0308-0110 IS - 1 VL - 47 SP - 9 EP - 11 ER - TY - JOUR T1 - Comparison of Rapid Load Test Analysis Techniques in Clay Soils A1 - Brown,Michael J. A1 - Powell,John J. M. AU - Brown,Michael J. AU - Powell,John J. M. PY - 2013/1 Y1 - 2013/1 N2 -

Rapid load pile testing (RLT) techniques such as Statnamic were developed as an alternative to more frequently adopted static and dynamic tests. The existing unloading point method (UPM) for deriving equivalent static load-settlement behavior from rapid load tests seems to be adequate in coarse-grained soils but may result in poor prediction in clays and silts. To address these shortcomings, the UPM has been improved to reflect soil type, and new analysis techniques have been developed. To test the performance of the improved UPM and new analysis techniques, pile tests from two clay sites were analyzed. The first case study site was underlain by very to extremely high-plasticity Quaternary London clay, and the second site was underlain by low-to intermediate-plasticity matrix dominant glacial till. The best predictions of static equivalent load-settlement behavior for very-high-plasticity clay were obtained from a new analysis technique that incorporated a soil-specific rate effect parameter (selected on the basis of the clays' plasticity index) that varied with pile settlement. In general, the UPM performed better for tests undertaken in the low-to intermediate-plasticity glacial till, as there is greater experience of RLT in these soils. The results of the study suggest that the development of analysis techniques would benefit greatly from tests in a wider variety of soil types. On the basis of the findings of this study, improvements to the UPM and Schmuker techniques are presented, which include pile settlement-dependent variation of the damping and rate effect parameters. DOI: 10.1061/(ASCE)GT.1943-5606.0000733. (C) 2013 American Society of Civil Engineers.

AB -

Rapid load pile testing (RLT) techniques such as Statnamic were developed as an alternative to more frequently adopted static and dynamic tests. The existing unloading point method (UPM) for deriving equivalent static load-settlement behavior from rapid load tests seems to be adequate in coarse-grained soils but may result in poor prediction in clays and silts. To address these shortcomings, the UPM has been improved to reflect soil type, and new analysis techniques have been developed. To test the performance of the improved UPM and new analysis techniques, pile tests from two clay sites were analyzed. The first case study site was underlain by very to extremely high-plasticity Quaternary London clay, and the second site was underlain by low-to intermediate-plasticity matrix dominant glacial till. The best predictions of static equivalent load-settlement behavior for very-high-plasticity clay were obtained from a new analysis technique that incorporated a soil-specific rate effect parameter (selected on the basis of the clays' plasticity index) that varied with pile settlement. In general, the UPM performed better for tests undertaken in the low-to intermediate-plasticity glacial till, as there is greater experience of RLT in these soils. The results of the study suggest that the development of analysis techniques would benefit greatly from tests in a wider variety of soil types. On the basis of the findings of this study, improvements to the UPM and Schmuker techniques are presented, which include pile settlement-dependent variation of the damping and rate effect parameters. DOI: 10.1061/(ASCE)GT.1943-5606.0000733. (C) 2013 American Society of Civil Engineers.

KW - Static tests KW - Soil-pile interaction KW - PILE KW - Glacial till KW - Fine-grained soils KW - Pile load tests KW - STATIC CAPACITY KW - Damping KW - Clays U2 - 10.1061/(ASCE)GT.1943-5606.0000733 DO - 10.1061/(ASCE)GT.1943-5606.0000733 M1 - Article JO - Journal of Geotechnical and Geoenvironmental Engineering JF - Journal of Geotechnical and Geoenvironmental Engineering SN - 1090-0241 IS - 1 VL - 139 SP - 152 EP - 161 ER - TY - JOUR T1 - Crystal structure of the O2-tolerant membrane-bound hydrogenase 1 from Escherichia coli in complex with its cognate cytochrome b A1 - Volbeda,Anne A1 - Darnault,Claudine A1 - Parkin,Alison A1 - Sargent,Frank A1 - Armstrong,Fraser A. A1 - Fontecilla-Camps,Juan C. AU - Volbeda,Anne AU - Darnault,Claudine AU - Parkin,Alison AU - Sargent,Frank AU - Armstrong,Fraser A. AU - Fontecilla-Camps,Juan C. PY - 2013/1 Y1 - 2013/1 N2 -

We report the 3.3 Å resolution structure of dimeric membrane-bound O2-tolerant hydrogenase 1 from Escherichia coli in a 2:1 complex with its physiological partner, cytochrome b. From the short distance between distal [Fe4S4] clusters, we predict rapid transfer of H2-derived electrons between hydrogenase heterodimers. Thus, under low O2 levels, a functional active site in one heterodimer can reductively reactivate its O2-exposed counterpart in the other. Hydrogenase 1 is maximally expressed during fermentation, when electron acceptors are scarce. These conditions are achieved in the lower part of the host's intestinal tract when E. coli is soon to be excreted and undergo an anaerobic-to-aerobic metabolic transition. The apparent paradox of having an O2-tolerant hydrogenase expressed under anoxia makes sense if the enzyme functions to keep intracellular O2 levels low by reducing it to water, protecting O2-sensitive enzymes during the transition. Cytochrome b's main role may be anchoring the hydrogenase to the membrane.

AB -

We report the 3.3 Å resolution structure of dimeric membrane-bound O2-tolerant hydrogenase 1 from Escherichia coli in a 2:1 complex with its physiological partner, cytochrome b. From the short distance between distal [Fe4S4] clusters, we predict rapid transfer of H2-derived electrons between hydrogenase heterodimers. Thus, under low O2 levels, a functional active site in one heterodimer can reductively reactivate its O2-exposed counterpart in the other. Hydrogenase 1 is maximally expressed during fermentation, when electron acceptors are scarce. These conditions are achieved in the lower part of the host's intestinal tract when E. coli is soon to be excreted and undergo an anaerobic-to-aerobic metabolic transition. The apparent paradox of having an O2-tolerant hydrogenase expressed under anoxia makes sense if the enzyme functions to keep intracellular O2 levels low by reducing it to water, protecting O2-sensitive enzymes during the transition. Cytochrome b's main role may be anchoring the hydrogenase to the membrane.

U2 - 10.1016/j.str.2012.11.010 DO - 10.1016/j.str.2012.11.010 M1 - Article JO - Structure JF - Structure IS - 1 VL - 21 SP - 184 EP - 190 ER - TY - JOUR T1 - Erlotinib - how does it fare in an unselected population? An NHS Tayside experience A1 - Johnstone,J. A1 - Brown,E. A1 - Lord,H. AU - Johnstone,J. AU - Brown,E. AU - Lord,H. PY - 2013/1 Y1 - 2013/1 UR - http://www.lungcancerjournal.info/supplements M1 - Meeting abstract JO - Lung Cancer JF - Lung Cancer SN - 0169-5002 VL - 79 SP - S9-S9 ER - TY - JOUR T1 - Frequency dependence of laser ultrasonic SAW phase velocities measurements A1 - Li,Chunhui A1 - Song,Shaozhen A1 - Guan,Guangying A1 - Wang,Ruikang K A1 - Huang,Zhihong AU - Li,Chunhui AU - Song,Shaozhen AU - Guan,Guangying AU - Wang,Ruikang K AU - Huang,Zhihong PY - 2013/1 Y1 - 2013/1 N2 - Advances in the field of laser ultrasonics have opened up new possibilities in applications in many areas. This paper verifies the relationship between phase velocities of different materials, including hard solid and soft solid, and the frequency range of SAW signal. We propose a novel approach that utilizes a low coherence interferometer to detect the laser-induced surface acoustic waves (SAWs). A Nd:YAG focused laser line-source is applied to steel, iron, plastic plates and a 3.5% agar-agar phantom. The generated SAW signals are detected by a time domain low coherence interferometry system. SAW phase velocity dispersion curves were calculated, from which the elasticity of the specimens was evaluated. The relationship between frequency content and phase velocities was analyzed. We show that the experimental results agreed well with those of the theoretical expectations. AB - Advances in the field of laser ultrasonics have opened up new possibilities in applications in many areas. This paper verifies the relationship between phase velocities of different materials, including hard solid and soft solid, and the frequency range of SAW signal. We propose a novel approach that utilizes a low coherence interferometer to detect the laser-induced surface acoustic waves (SAWs). A Nd:YAG focused laser line-source is applied to steel, iron, plastic plates and a 3.5% agar-agar phantom. The generated SAW signals are detected by a time domain low coherence interferometry system. SAW phase velocity dispersion curves were calculated, from which the elasticity of the specimens was evaluated. The relationship between frequency content and phase velocities was analyzed. We show that the experimental results agreed well with those of the theoretical expectations. KW - Surface acoustic wave (SAW) KW - Frequency content KW - Laser ultrasonics KW - GENERATION KW - ELASTIC PROPERTIES KW - LINE SOURCE KW - WAVES KW - CONSTANTS KW - Phase velocity KW - Young's modulus UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84869118392&md5=dad6f66028894ba62e1d542541950f99 U2 - 10.1016/j.ultras.2012.05.009 DO - 10.1016/j.ultras.2012.05.009 M1 - Article JO - Ultrasonics JF - Ultrasonics IS - 1 VL - 53 SP - 191 EP - 195 ER - TY - JOUR T1 - Healthcare and the politics of austerity A1 - Drummond,John S. AU - Drummond,John S. PY - 2013/1 Y1 - 2013/1 UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871660703&md5=1399834cde130f366a43c841a4b2e9ba U2 - 10.1111/nup.12003 DO - 10.1111/nup.12003 M1 - Editorial JO - Nursing Philosophy JF - Nursing Philosophy SN - 1466-7681 IS - 1 VL - 14 SP - 1 ER - TY - JOUR T1 - How are we doing? Clinical audit of patient survival and toxicities following adjuvant chemotherapy for non-small cell lung cancer in NHS Tayside 2005-2010 A1 - Costantino,S. A1 - Lord,H. AU - Costantino,S. AU - Lord,H. PY - 2013/1 Y1 - 2013/1 UR - http://www.lungcancerjournal.info/supplements M1 - Meeting abstract JO - Lung Cancer JF - Lung Cancer SN - 0169-5002 VL - 79 SP - S16-S16 ER - TY - JOUR T1 - Inhaled and Systemic Corticosteroid Response in Severe Asthma Assessed by Alveolar Nitric Oxide T2 - a randomised crossover pilot study of add-on therapy A1 - Williamson,Peter A A1 - Short,Philip M A1 - Vaidyanathan,Sriram A1 - Lipworth,Brian J AU - Williamson,Peter A AU - Short,Philip M AU - Vaidyanathan,Sriram AU - Lipworth,Brian J PY - 2013/1 Y1 - 2013/1 N2 - Aims: Alveolar nitric oxide (CA(NO) ) is a potential biomarker of small airway inflammation. We investigated effects on CA(NO) of the addition of coarse and fine particle inhaled corticosteroids to standard therapy in severe asthma. Methods: Severe asthmatics taking =1600µg/day budesonide or equivalent performed a randomised open-label crossover study. Subjects with FEV(1) AB - Aims: Alveolar nitric oxide (CA(NO) ) is a potential biomarker of small airway inflammation. We investigated effects on CA(NO) of the addition of coarse and fine particle inhaled corticosteroids to standard therapy in severe asthma. Methods: Severe asthmatics taking =1600µg/day budesonide or equivalent performed a randomised open-label crossover study. Subjects with FEV(1) U2 - 10.1111/j.1365-2125.2012.04319.x DO - 10.1111/j.1365-2125.2012.04319.x M1 - Article JO - British Journal of Clinical Pharmacology JF - British Journal of Clinical Pharmacology IS - 1 VL - 75 SP - 93 EP - 102 ER - TY - JOUR T1 - Left Ventricular Hypertrophy in Chronic Obstructive Pulmonary Disease without Hypoxaemia T2 - The Elephant in the Room? A1 - Anderson,William J. A1 - Lipworth,Brian J. A1 - Rekhraj,Sushma A1 - Struthers,Allan D. A1 - George,Jacob AU - Anderson,William J. AU - Lipworth,Brian J. AU - Rekhraj,Sushma AU - Struthers,Allan D. AU - George,Jacob PY - 2013/1 Y1 - 2013/1 N2 - ABSTRACT BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with significant cardiovascular mortality. Left ventricular hypertrophy (LVH) is a pivotal cardiovascular risk factor. The prevalence of LVH in COPD is currently unknown. METHODS: We performed a pilot study of 93 normoxaemic COPD patients and 34 controls. Patients underwent echocardiography to measure left ventricular (LV) dimensions; electrocardiography; 24-hour blood pressure (BP) recording; and serum B-type natriuretic peptide (BNP) levels, along with spirometry and oxygen saturations. RESULTS: COPD patients' oxygen saturations were normal at 96.5% (95%CI: 96.1-97.0%), with a mean FEV1 of 70.0% predicted (95% CI: 65.2-74.8%). 30.1% of COPD patients met echocardiographic criteria for LVH based on LV mass index, with more LVH in females than males (43.2% vs. 21.4%, p=0.02). LV mass index in COPD was 96.2g/m2 (95%CI: 90.1-102.7g/m2) vs. controls 82.9g/m2 (95%CI: 75.8-90.6g/m2), p=0.017. LV mass index remained high in COPD patients in the absence of hypertension history (94.5g/m2 vs. 79.9g/m2, p=0.015) and with 24-hr systolic BP<135mmHg (96.7g/m2 vs. 82.5g/m2, p=0.024). LV ejection fraction (mean=63.4%) and BNP (mean=28.7pg/ml) were normal in COPD patients. Mean 24hr BP was normal in COPD patients at 125/72mmHg. Electrocardiography was less sensitive for detecting LVH than echocardiography. CONCLUSION: LVH was present in a significant proportion of normotensive, normoxaemic COPD patients, especially in females, along with normal LV ejection fraction and BNP levels. Clinical trials are therefore indicated to evaluate treatments to regress LVH in patients with COPD. AB - ABSTRACT BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with significant cardiovascular mortality. Left ventricular hypertrophy (LVH) is a pivotal cardiovascular risk factor. The prevalence of LVH in COPD is currently unknown. METHODS: We performed a pilot study of 93 normoxaemic COPD patients and 34 controls. Patients underwent echocardiography to measure left ventricular (LV) dimensions; electrocardiography; 24-hour blood pressure (BP) recording; and serum B-type natriuretic peptide (BNP) levels, along with spirometry and oxygen saturations. RESULTS: COPD patients' oxygen saturations were normal at 96.5% (95%CI: 96.1-97.0%), with a mean FEV1 of 70.0% predicted (95% CI: 65.2-74.8%). 30.1% of COPD patients met echocardiographic criteria for LVH based on LV mass index, with more LVH in females than males (43.2% vs. 21.4%, p=0.02). LV mass index in COPD was 96.2g/m2 (95%CI: 90.1-102.7g/m2) vs. controls 82.9g/m2 (95%CI: 75.8-90.6g/m2), p=0.017. LV mass index remained high in COPD patients in the absence of hypertension history (94.5g/m2 vs. 79.9g/m2, p=0.015) and with 24-hr systolic BP<135mmHg (96.7g/m2 vs. 82.5g/m2, p=0.024). LV ejection fraction (mean=63.4%) and BNP (mean=28.7pg/ml) were normal in COPD patients. Mean 24hr BP was normal in COPD patients at 125/72mmHg. Electrocardiography was less sensitive for detecting LVH than echocardiography. CONCLUSION: LVH was present in a significant proportion of normotensive, normoxaemic COPD patients, especially in females, along with normal LV ejection fraction and BNP levels. Clinical trials are therefore indicated to evaluate treatments to regress LVH in patients with COPD. UR - http://journal.publications.chestnet.org/article.aspx?articleid=1216512 M1 - Article JO - CHEST JF - CHEST IS - 1 VL - 143 SP - 91 EP - 97 ER - TY - JOUR T1 - Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β. A1 - Doherty,Gayle H. A1 - Beccano-Kelly,Dayne A1 - Yan,Shi-Du A1 - Gunn-Moore,Frank A1 - Harvey,Jenni AU - Doherty,Gayle H. AU - Beccano-Kelly,Dayne AU - Yan,Shi-Du AU - Gunn-Moore,Frank AU - Harvey,Jenni PY - 2013/1 Y1 - 2013/1 N2 - Accumulation of amyloid-ß (Aß) is a key event mediating the cognitive deficits in Alzheimer's disease (AD) as Aß promotes synaptic dysfunction and triggers neuronal death. Recent evidence has linked the hormone leptin to AD as leptin levels are markedly attenuated in AD patients. Leptin is also a potential cognitive enhancer as it facilitates the cellular events underlying hippocampal learning and memory. Here we show that leptin prevents the detrimental effects of Aß1–42 on hippocampal long-term potentiation. Moreover leptin inhibits Aß1–42-driven facilitation of long-term depression and internalization of the 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid (AMPA) receptor subunit, GluR1, via activation of PI3-kinase. Leptin also protects cortical neurons from Aß1–42-induced cell death by a signal transducer and activator of transcription-3 (STAT-3)-dependent mechanism. Furthermore, leptin inhibits Aß1–42-mediated upregulation of endophilin I and phosphorylated tau in vitro, whereas cortical levels of endophilin I and phosphorylated tau are enhanced in leptin-insensitive Zucker fa/fa rats. Thus leptin benefits the functional characteristics and viability of neurons that degenerate in AD. These novel findings establish that the leptin system is an important therapeutic target in neurodegenerative conditions. AB - Accumulation of amyloid-ß (Aß) is a key event mediating the cognitive deficits in Alzheimer's disease (AD) as Aß promotes synaptic dysfunction and triggers neuronal death. Recent evidence has linked the hormone leptin to AD as leptin levels are markedly attenuated in AD patients. Leptin is also a potential cognitive enhancer as it facilitates the cellular events underlying hippocampal learning and memory. Here we show that leptin prevents the detrimental effects of Aß1–42 on hippocampal long-term potentiation. Moreover leptin inhibits Aß1–42-driven facilitation of long-term depression and internalization of the 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid (AMPA) receptor subunit, GluR1, via activation of PI3-kinase. Leptin also protects cortical neurons from Aß1–42-induced cell death by a signal transducer and activator of transcription-3 (STAT-3)-dependent mechanism. Furthermore, leptin inhibits Aß1–42-mediated upregulation of endophilin I and phosphorylated tau in vitro, whereas cortical levels of endophilin I and phosphorylated tau are enhanced in leptin-insensitive Zucker fa/fa rats. Thus leptin benefits the functional characteristics and viability of neurons that degenerate in AD. These novel findings establish that the leptin system is an important therapeutic target in neurodegenerative conditions. KW - Leptin KW - SYNAPTIC PLASTICITY KW - AMPA receptor trafficking KW - Amyloid beta KW - Endophilin U2 - 10.1016/j.neurobiolaging.2012.08.003 DO - 10.1016/j.neurobiolaging.2012.08.003 M1 - Article JO - Neurobiology of Aging JF - Neurobiology of Aging SN - 0197-4580 IS - 1 VL - 34 SP - 226 EP - 237 ER - TY - JOUR T1 - Longitudinal assessment of endothelial function in the microvasculature of mice in-vivo A1 - Belch,Jill J.F. A1 - Akbar,Naveed A1 - Alapati,Venkateswara A1 - Petrie,John A1 - Arthur,Simon A1 - Khan,Faisel AU - Belch,Jill J.F. AU - Akbar,Naveed AU - Alapati,Venkateswara AU - Petrie,John AU - Arthur,Simon AU - Khan,Faisel PY - 2013/1 Y1 - 2013/1 N2 - Endothelial dysfunction is associated with early development of cardiovascular disease, making longitudinal measurements desirable. We devised a protocol using laser Doppler imaging (LDI) and iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) to assess the skin microcirculation longitudinally in mice every 4 weeks for 24 weeks in two groups of C57BL/6 mice, chow versus high-cholesterol diet(known to induce endothelial dysfunction). LDI measurements were compared with vascular function (isometric tension) measured using wire myography in the tail artery in response to ACh and SNP. Microvascular responses to ACh were significantly reduced in cholesterol-fed versus chow-fed mice from week 4 onwards (P <0.005, ANOVA). Pre-treatment with N(G)-nitro-l-arginine methyl-ester-hydrochloride (L-NAME) showed a significant reduction in ACh response compared with vehicle-treated animals (P <0.05) at baseline and at 12 weeks. In cholesterol-fed mice, ACh responses were 226 ± 21 and 180 ± 21 AU (P = 0.03) before and after L-NAME, respectively. A reduction in ex-vivo ACh response was detected in the tail artery in cholesterol-fed mice, and a significant correlation found between peak microvascular ACh response and maximum ACh response in the tail artery (r = 0.699, P = 0.017). No changes were found in SNP responses in the microvasculature or tail artery. Using this protocol, we have shown longitudinal decreases in microvascular endothelial function to cholesterol feeding. L-NAME studies confirm that the reduced vasodilatation to ACh in cholesterol-fed mice was mediated partly through reduced NO bioavailability. Wire myography of tail arteries confirmed that in-vivo measurements of microvascular function reflect ex-vivo vascular function in other beds. Longitudinal assessments of skin microvascular function in mice could provide a useful translatable model for assessing early endothelial dysfunction. © 2012 Elsevier Inc. All rights reserved. AB - Endothelial dysfunction is associated with early development of cardiovascular disease, making longitudinal measurements desirable. We devised a protocol using laser Doppler imaging (LDI) and iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) to assess the skin microcirculation longitudinally in mice every 4 weeks for 24 weeks in two groups of C57BL/6 mice, chow versus high-cholesterol diet(known to induce endothelial dysfunction). LDI measurements were compared with vascular function (isometric tension) measured using wire myography in the tail artery in response to ACh and SNP. Microvascular responses to ACh were significantly reduced in cholesterol-fed versus chow-fed mice from week 4 onwards (P <0.005, ANOVA). Pre-treatment with N(G)-nitro-l-arginine methyl-ester-hydrochloride (L-NAME) showed a significant reduction in ACh response compared with vehicle-treated animals (P <0.05) at baseline and at 12 weeks. In cholesterol-fed mice, ACh responses were 226 ± 21 and 180 ± 21 AU (P = 0.03) before and after L-NAME, respectively. A reduction in ex-vivo ACh response was detected in the tail artery in cholesterol-fed mice, and a significant correlation found between peak microvascular ACh response and maximum ACh response in the tail artery (r = 0.699, P = 0.017). No changes were found in SNP responses in the microvasculature or tail artery. Using this protocol, we have shown longitudinal decreases in microvascular endothelial function to cholesterol feeding. L-NAME studies confirm that the reduced vasodilatation to ACh in cholesterol-fed mice was mediated partly through reduced NO bioavailability. Wire myography of tail arteries confirmed that in-vivo measurements of microvascular function reflect ex-vivo vascular function in other beds. Longitudinal assessments of skin microvascular function in mice could provide a useful translatable model for assessing early endothelial dysfunction. © 2012 Elsevier Inc. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84868677337&md5=17cb446e59ecf84e75eb8961dad7c3bb U2 - 10.1016/j.mvr.2012.10.008 DO - 10.1016/j.mvr.2012.10.008 M1 - Article JO - Microvascular Research JF - Microvascular Research SN - 0026-2862 VL - 85 SP - 86 EP - 92 ER - TY - JOUR T1 - Narrative, emotion and action T2 - analysing 'most memorable' professionalism dilemmas A1 - Rees,Charlotte E. A1 - Monrouxe,Lynn V. A1 - McDonald,Laura A. AU - Rees,Charlotte E. AU - Monrouxe,Lynn V. AU - McDonald,Laura A. PY - 2013/1 Y1 - 2013/1 N2 -

OBJECTIVES Although previous studies have explored medical learners' 'most memorable' experiences, these have typically focused on patient deaths or mistakes. Drawing on multiple theoretical perspectives to understand the interplay between narrative, emotion and action, this paper aims to explore the whats and hows of written narratives of most memorable professionalism dilemmas: what types of dilemma are most memorable? When and where do they take place? How do students act? What characteristics relate to these dilemmas? How are dilemmas narrated?

METHODS A total of 680 students from 29 of 32 UK medical schools provided a written narrative of their most memorable dilemma as part of their responses to an online questionnaire exploring the impact of professionalism dilemmas on moral distress. We employed quantitative thematic and discourse analysis of all narratives using Linguistic Inquiry Word Count software (LIWC) and conducted a narrative analysis of one exemplar.

RESULTS The most common themes across all narratives concerned dilemmas that related to issues of patient care with reference to the actions of health care professionals or students, student abuse, and consent and intimate examination. A total of 41.1% of experiences had occurred over 6 months previously and 80.1% had taken place in hospital settings. Overall, 54.9% of narrators reported having done something in the face of their dilemma, although only 13.2% described taking obvious or direct action. Numerous characteristics were related to most memorable dilemmas (e. g. narratives citing intimate examinations were more likely to take place in surgical settings). A total of 92.6% of narratives included negative emotion talk and numerous significant relationships emerged between types of emotion talk and most memorable dilemmas (e. g. more anger talk in abuse narratives). Our narrative analysis of one exemplar illustrates the richness of emotion talk and more subtle devices to establish emotional tone.

DISCUSSION Findings extend previous research into issues related to professionalism by exploring relationships between narrative, emotion and action in the context of written narratives of most memorable dilemmas. We encourage medical educators to help students construct coherent and emotionally integrated narratives to make sense of negative professionalism dilemmas.

AB -

OBJECTIVES Although previous studies have explored medical learners' 'most memorable' experiences, these have typically focused on patient deaths or mistakes. Drawing on multiple theoretical perspectives to understand the interplay between narrative, emotion and action, this paper aims to explore the whats and hows of written narratives of most memorable professionalism dilemmas: what types of dilemma are most memorable? When and where do they take place? How do students act? What characteristics relate to these dilemmas? How are dilemmas narrated?

METHODS A total of 680 students from 29 of 32 UK medical schools provided a written narrative of their most memorable dilemma as part of their responses to an online questionnaire exploring the impact of professionalism dilemmas on moral distress. We employed quantitative thematic and discourse analysis of all narratives using Linguistic Inquiry Word Count software (LIWC) and conducted a narrative analysis of one exemplar.

RESULTS The most common themes across all narratives concerned dilemmas that related to issues of patient care with reference to the actions of health care professionals or students, student abuse, and consent and intimate examination. A total of 41.1% of experiences had occurred over 6 months previously and 80.1% had taken place in hospital settings. Overall, 54.9% of narrators reported having done something in the face of their dilemma, although only 13.2% described taking obvious or direct action. Numerous characteristics were related to most memorable dilemmas (e. g. narratives citing intimate examinations were more likely to take place in surgical settings). A total of 92.6% of narratives included negative emotion talk and numerous significant relationships emerged between types of emotion talk and most memorable dilemmas (e. g. more anger talk in abuse narratives). Our narrative analysis of one exemplar illustrates the richness of emotion talk and more subtle devices to establish emotional tone.

DISCUSSION Findings extend previous research into issues related to professionalism by exploring relationships between narrative, emotion and action in the context of written narratives of most memorable dilemmas. We encourage medical educators to help students construct coherent and emotionally integrated narratives to make sense of negative professionalism dilemmas.

KW - CURRICULUM KW - WHITE COAT KW - ETHICAL DILEMMAS KW - MEDICAL-EDUCATION RESEARCH KW - DOCTORS KW - IMPACT KW - IDENTIFICATION KW - PERSPECTIVES KW - EVENTS KW - STUDENTS PERCEPTIONS U2 - 10.1111/j.1365-2923.2012.04302.x DO - 10.1111/j.1365-2923.2012.04302.x M1 - Article JO - Medical Education JF - Medical Education SN - 0308-0110 IS - 1 VL - 47 SP - 80 EP - 96 ER - TY - JOUR T1 - Pioglitazone and bladder cancer T2 - A propensity score matched cohort study A1 - Wei,Li A1 - Macdonald,Thomas M. A1 - Mackenzie,Isla S. AU - Wei,Li AU - Macdonald,Thomas M. AU - Mackenzie,Isla S. PY - 2013/1 Y1 - 2013/1 N2 - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT •Pioglitazone is mainly used in combination with diet and exercise and other anti-diabetic medications to treat type 2 diabetes mellitus. •Long term use of pioglitazone (>24 months of therapy) may be associated with an increased risk of bladder cancer. WHAT THIS STUDY ADDS •In this study population, pioglitazone does not appear to be significantly associated with an increased risk of bladder cancer in patients with type 2 diabetes. AIM To examine whether exposure to pioglitazone use is associated with increased incidence of bladder cancer in patients with type 2 diabetes mellitus. METHOD A cohort study was done in the General Practice Research Database (GPRD) between 2001 and 2010. Two hundred and seven thousand seven hundred and fourteen patients aged =40years with type 2 diabetes were studied (23548 exposed to pioglitazone and 184166 exposed to other antidiabetic medications but not pioglitazone). The association between pioglitazone and risk of bladder cancer was assessed by a Cox regression model. A propensity score matched analysis was done in a group of patients without missing baseline characteristics data. RESULTS Sixty-six and 803 new cases of bladder cancer occurred in the pioglitazone and other group, respectively (rates of 80.2 (95% CI 60.8, 99.5) and 81.8 (95% CI 76.2, 87.5) per 100000 person-years respectively). Pioglitazone did not increase the risk of bladder cancer significantly compared with the other antidiabetic drugs treatment group, (adjusted hazard ratio (HR), 1.16, 95% CI 0.83, 1.62). In a matched propensity score analysis in which both groups had similar baseline characteristics (17249 patients in each group), the adjusted HR was 1.22 (95% CI 0.80, 1.84). CONCLUSION The results suggest that pioglitazone may not be significantly associated with an increased risk of bladder cancer in patients with type 2 diabetes. © 2012 The British Pharmacological Society. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT •Pioglitazone is mainly used in combination with diet and exercise and other anti-diabetic medications to treat type 2 diabetes mellitus. •Long term use of pioglitazone (>24 months of therapy) may be associated with an increased risk of bladder cancer. WHAT THIS STUDY ADDS •In this study population, pioglitazone does not appear to be significantly associated with an increased risk of bladder cancer in patients with type 2 diabetes. AIM To examine whether exposure to pioglitazone use is associated with increased incidence of bladder cancer in patients with type 2 diabetes mellitus. METHOD A cohort study was done in the General Practice Research Database (GPRD) between 2001 and 2010. Two hundred and seven thousand seven hundred and fourteen patients aged =40years with type 2 diabetes were studied (23548 exposed to pioglitazone and 184166 exposed to other antidiabetic medications but not pioglitazone). The association between pioglitazone and risk of bladder cancer was assessed by a Cox regression model. A propensity score matched analysis was done in a group of patients without missing baseline characteristics data. RESULTS Sixty-six and 803 new cases of bladder cancer occurred in the pioglitazone and other group, respectively (rates of 80.2 (95% CI 60.8, 99.5) and 81.8 (95% CI 76.2, 87.5) per 100000 person-years respectively). Pioglitazone did not increase the risk of bladder cancer significantly compared with the other antidiabetic drugs treatment group, (adjusted hazard ratio (HR), 1.16, 95% CI 0.83, 1.62). In a matched propensity score analysis in which both groups had similar baseline characteristics (17249 patients in each group), the adjusted HR was 1.22 (95% CI 0.80, 1.84). CONCLUSION The results suggest that pioglitazone may not be significantly associated with an increased risk of bladder cancer in patients with type 2 diabetes. © 2012 The British Pharmacological Society. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871113059&md5=fba652b4254a34dbca10ec1234f04982 U2 - 10.1111/j.1365-2125.2012.04325.x DO - 10.1111/j.1365-2125.2012.04325.x M1 - Article JO - British Journal of Clinical Pharmacology JF - British Journal of Clinical Pharmacology SN - 0306-5251 IS - 1 VL - 75 SP - 254 EP - 259 ER - TY - JOUR T1 - Sleep patterns and sleep-impairing factors of persons providing informal care for people with cancer T2 - A critical review of the literature A1 - Kotronoulas,Grigorios A1 - Wengström,Yvonne A1 - Kearney,Nora AU - Kotronoulas,Grigorios AU - Wengström,Yvonne AU - Kearney,Nora PY - 2013/1 Y1 - 2013/1 N2 - Background: Sleep is increasingly recognized as an area of functioning that may be greatly affected in persons who are practically and emotionally involved in the care of patients with cancer. Clinician awareness is required to ensure that effective care for informal caregivers with sleep problems is provided. Objective: A 2-fold critical review of the published literature was conducted, which aimed at summarizing and critically analyzing evidence regarding sleep patterns of informal caregivers of adults with cancer and contributing factors to sleep-wake disturbances. Methods: Using a wide range of key terms and synonyms, 3 electronic databases (MEDLINE, CINAHL, EMBASE) were systematically searched for the period between January 1990 and July 2011. Results: Based on prespecified selection criteria, 44 articles were pooled to provide evidence on sleep-impairing factors in the context of informal caregiving, 17 of which specifically addressed sleep patterns of caregivers of people with cancer. Conclusions: At least 4 of 10 caregivers may report at least 1 sleep problem. Short sleep duration, nocturnal awakenings, wakefulness after sleep onset, and daytime dysfunction seem to be the areas most affected irrespective of stage or type of disease, yet circadian activity remains understudied. In addition, despite a wide spectrum of potential sleep-impairing factors, underlying causal pathways are yet to be explored. Implications for Practice: More longitudinal, mixed-methods, and comparison studies are warranted to explore caregiver sleep disorders in relation to the gravity of the caregiving situation in the context of diverse types of cancer and disease severity. © 2013 Lippincott Williams & Wilkins. AB - Background: Sleep is increasingly recognized as an area of functioning that may be greatly affected in persons who are practically and emotionally involved in the care of patients with cancer. Clinician awareness is required to ensure that effective care for informal caregivers with sleep problems is provided. Objective: A 2-fold critical review of the published literature was conducted, which aimed at summarizing and critically analyzing evidence regarding sleep patterns of informal caregivers of adults with cancer and contributing factors to sleep-wake disturbances. Methods: Using a wide range of key terms and synonyms, 3 electronic databases (MEDLINE, CINAHL, EMBASE) were systematically searched for the period between January 1990 and July 2011. Results: Based on prespecified selection criteria, 44 articles were pooled to provide evidence on sleep-impairing factors in the context of informal caregiving, 17 of which specifically addressed sleep patterns of caregivers of people with cancer. Conclusions: At least 4 of 10 caregivers may report at least 1 sleep problem. Short sleep duration, nocturnal awakenings, wakefulness after sleep onset, and daytime dysfunction seem to be the areas most affected irrespective of stage or type of disease, yet circadian activity remains understudied. In addition, despite a wide spectrum of potential sleep-impairing factors, underlying causal pathways are yet to be explored. Implications for Practice: More longitudinal, mixed-methods, and comparison studies are warranted to explore caregiver sleep disorders in relation to the gravity of the caregiving situation in the context of diverse types of cancer and disease severity. © 2013 Lippincott Williams & Wilkins. KW - Cancer KW - Caregivers KW - Critical review KW - Informal care KW - sleep-impairing factors KW - sleep patterns KW - sleep-wake disturbances UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871623131&md5=c8f7e45ed9a77f814638e472954708ac U2 - 10.1097/NCC.0b013e3182456c38 DO - 10.1097/NCC.0b013e3182456c38 M1 - Article JO - Cancer Nursing JF - Cancer Nursing SN - 0162-220X IS - 1 VL - 36 ER - TY - JOUR T1 - Stress in Nurses T2 - Stress-Related Affect and Its Determinants Examined Over the Nursing Day A1 - Johnston,Derek W A1 - Jones,Martyn C. A1 - Charles,Kathryn A1 - McCann,Sharon K. A1 - McKee,Lorna AU - Johnston,Derek W AU - Jones,Martyn C. AU - Charles,Kathryn AU - McCann,Sharon K. AU - McKee,Lorna PY - 2013/1 Y1 - 2013/1 N2 - Background
Nurses are a stressed group and this may affect their health and work performance. The determinants of occupational stress in nurses and other occupational groups have almost invariably been examined in between subject studies.

Purpose
This study aimed to determine if the main determinants of occupation stress, i.e. demand, control, effort and reward, operate within nurses.

Methods
A real time study using personal digital-assistant-based ecological momentary assessment to measure affect and its hypothesised determinants every 90 min in 254 nurses over three nursing shifts. The measures were negative affect, positive affect, demand/effort, control and reward.

Results
While the effects varied in magnitude between people, in general increased negative affect was predicted by high demand/effort, low control and low reward. Control and reward moderated the effects of demand/effort. High positive affect was predicted by high demand/effort, control and reward.

Conclusions
The same factors are associated with variations in stress-related affect within nurses as between.
AB - Background
Nurses are a stressed group and this may affect their health and work performance. The determinants of occupational stress in nurses and other occupational groups have almost invariably been examined in between subject studies.

Purpose
This study aimed to determine if the main determinants of occupation stress, i.e. demand, control, effort and reward, operate within nurses.

Methods
A real time study using personal digital-assistant-based ecological momentary assessment to measure affect and its hypothesised determinants every 90 min in 254 nurses over three nursing shifts. The measures were negative affect, positive affect, demand/effort, control and reward.

Results
While the effects varied in magnitude between people, in general increased negative affect was predicted by high demand/effort, low control and low reward. Control and reward moderated the effects of demand/effort. High positive affect was predicted by high demand/effort, control and reward.

Conclusions
The same factors are associated with variations in stress-related affect within nurses as between.
KW - Occupational stress KW - Nursing KW - DEMAND KW - Control KW - REWARD KW - Ecological momentary assessment UR - http://link.springer.com/article/10.1007%2Fs12160-012-9458-2 U2 - 10.1007/s12160-012-9458-2 DO - 10.1007/s12160-012-9458-2 M1 - Article JO - Annals of Behavioral Medicine JF - Annals of Behavioral Medicine SN - 0883-6612 ER - TY - JOUR T1 - The influence of incorporating a forecutter on the performance of offshore pipeline ploughs A1 - Lauder,Keith Duncan A1 - Brown,Michael John A1 - Bransby,Mark Fraser A1 - Boyes,Scott AU - Lauder,Keith Duncan AU - Brown,Michael John AU - Bransby,Mark Fraser AU - Boyes,Scott PY - 2013/1 Y1 - 2013/1 N2 - Installation of offshore pipelines in the seabed can be efficiently achieved using pipeline ploughs. Increased efficiency may be achievable through incorporating a smaller forecutter in advance of the main plough share. Currently guidance is limited and conflicting as to the advantages or disadvantages of incorporating a forecutter. To investigate the effect of forecutter inclusion model tests were undertaken at 1/50th scale under laboratory conditions in sand beds prepared at different relative densities in both dry and saturated conditions. Dry sand tests were used to determine the effect of the forecutter on the static or passive components of plough tow force. The currently adopted passive pressure coefficient (C ) did not appear to vary with relative density to the same degree as previously suggested and the forecutter increased the magnitude of the passive or static resistance to ploughing. Saturated tests were used to determine the effects of the forecutter on the rate dependant component of ploughing resistance and allow verification of a dimensionless form of rate effect representation. The forecutter acts to reduce the rate effect component of plough tow force in both fine sand (low permeability) and to a lesser extent in medium sand (higher permeability). In fine and silty sands, however, incorporating a forecutter would seem highly beneficial at all ploughing depths and soil densities but in medium sand (higher permeability) the benefits of incorporation are limited to an operating window at shallower trench depths and lower relative density. © 2012 Elsevier Ltd. AB - Installation of offshore pipelines in the seabed can be efficiently achieved using pipeline ploughs. Increased efficiency may be achievable through incorporating a smaller forecutter in advance of the main plough share. Currently guidance is limited and conflicting as to the advantages or disadvantages of incorporating a forecutter. To investigate the effect of forecutter inclusion model tests were undertaken at 1/50th scale under laboratory conditions in sand beds prepared at different relative densities in both dry and saturated conditions. Dry sand tests were used to determine the effect of the forecutter on the static or passive components of plough tow force. The currently adopted passive pressure coefficient (C ) did not appear to vary with relative density to the same degree as previously suggested and the forecutter increased the magnitude of the passive or static resistance to ploughing. Saturated tests were used to determine the effects of the forecutter on the rate dependant component of ploughing resistance and allow verification of a dimensionless form of rate effect representation. The forecutter acts to reduce the rate effect component of plough tow force in both fine sand (low permeability) and to a lesser extent in medium sand (higher permeability). In fine and silty sands, however, incorporating a forecutter would seem highly beneficial at all ploughing depths and soil densities but in medium sand (higher permeability) the benefits of incorporation are limited to an operating window at shallower trench depths and lower relative density. © 2012 Elsevier Ltd. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84869885376&md5=7850b9a5812b40202d90f379609046a7 U2 - 10.1016/j.apor.2012.11.001 DO - 10.1016/j.apor.2012.11.001 M1 - Article JO - Applied Ocean Research JF - Applied Ocean Research SN - 0141-1187 VL - 39 SP - 121 EP - 130 ER - TY - JOUR T1 - The relationship between organizational culture and performance in acute hospitals A1 - Jacobs,Rowena A1 - Mannion,Russell A1 - Davies,Huw T.O. A1 - Harrison,Stephen A1 - Konteh,Fred A1 - Walshe,Kieran AU - Jacobs,Rowena AU - Mannion,Russell AU - Davies,Huw T.O. AU - Harrison,Stephen AU - Konteh,Fred AU - Walshe,Kieran PY - 2013/1 Y1 - 2013/1 N2 - This paper examines the relationship between senior management team culture and organizational performance in English acute hospitals (NHS Trusts) over three time periods between 2001/2002 and 2007/2008. We use a validated culture rating instrument, the Competing Values Framework, to measure senior management team culture. Organizational performance is assessed using a wide range of routinely collected indicators. We examine the associations between organizational culture and performance using ordered probit and multinomial logit models. We find that organizational culture varies across hospitals and over time, and this variation is at least in part associated in consistent and predictable ways with a variety of organizational characteristics and routine measures of performance. Moreover, hospitals are moving towards more competitive culture archetypes which mirror the current policy context, though with a stronger blend of cultures. The study provides evidence for a relationship between culture and performance in hospital settings. © 2012 Elsevier Ltd. All rights reserved. AB - This paper examines the relationship between senior management team culture and organizational performance in English acute hospitals (NHS Trusts) over three time periods between 2001/2002 and 2007/2008. We use a validated culture rating instrument, the Competing Values Framework, to measure senior management team culture. Organizational performance is assessed using a wide range of routinely collected indicators. We examine the associations between organizational culture and performance using ordered probit and multinomial logit models. We find that organizational culture varies across hospitals and over time, and this variation is at least in part associated in consistent and predictable ways with a variety of organizational characteristics and routine measures of performance. Moreover, hospitals are moving towards more competitive culture archetypes which mirror the current policy context, though with a stronger blend of cultures. The study provides evidence for a relationship between culture and performance in hospital settings. © 2012 Elsevier Ltd. All rights reserved. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84868685396&md5=2d46076e19426e52736bb0ade3c0f1a8 U2 - 10.1016/j.socscimed.2012.10.014 DO - 10.1016/j.socscimed.2012.10.014 M1 - Article JO - Social Science and Medicine JF - Social Science and Medicine SN - 0277-9536 VL - 76 SP - 115 EP - 125 ER - TY - JOUR T1 - The role of amino acid transporters in nutrition A1 - Poncet,Nadege A1 - Taylor,Peter M. AU - Poncet,Nadege AU - Taylor,Peter M. PY - 2013/1 Y1 - 2013/1 N2 -

Purpose of review

We consider recent advances in epithelial amino acid transport physiology and our understanding of the functioning of amino acid transporters as sensors, as well as carriers, of tissue nutrient supplies.

Recent findings

Gut hormones (e. g. leptin) may regulate intestinal amino acid transporter activity by a variety of mechanisms, although the overall functional significance of such regulation is not yet fully understood. Important functional interactions between amino acid transporters and nutrient-signalling pathways which regulate metabolism [e. g. the mammalian target of rapamycin (mTOR) C1 pathway which promotes cell growth] have been revealed in recent studies. Amino acid transporters on endosomal (e. g. lysosomal) membranes may be of unexpected significance as intracellular nutrient sensors. It is also now evident that certain amino acid transporters may have dual receptor-transporter functions and act as 'transceptors' to sense amino acid availability upstream of signal pathways.

Summary

Increased knowledge on the timescale of the amino acid sensor-signal-effector process(es) should help in the optimization of protein-feeding regimes to gain maximum anabolic effect. New opportunities for nutritional therapy include targeting of amino acid transceptors to promote protein-anabolic signals and mechanisms up-regulating amino acid transporter expression to improve absorptive capacity for nutrients.

AB -

Purpose of review

We consider recent advances in epithelial amino acid transport physiology and our understanding of the functioning of amino acid transporters as sensors, as well as carriers, of tissue nutrient supplies.

Recent findings

Gut hormones (e. g. leptin) may regulate intestinal amino acid transporter activity by a variety of mechanisms, although the overall functional significance of such regulation is not yet fully understood. Important functional interactions between amino acid transporters and nutrient-signalling pathways which regulate metabolism [e. g. the mammalian target of rapamycin (mTOR) C1 pathway which promotes cell growth] have been revealed in recent studies. Amino acid transporters on endosomal (e. g. lysosomal) membranes may be of unexpected significance as intracellular nutrient sensors. It is also now evident that certain amino acid transporters may have dual receptor-transporter functions and act as 'transceptors' to sense amino acid availability upstream of signal pathways.

Summary

Increased knowledge on the timescale of the amino acid sensor-signal-effector process(es) should help in the optimization of protein-feeding regimes to gain maximum anabolic effect. New opportunities for nutritional therapy include targeting of amino acid transceptors to promote protein-anabolic signals and mechanisms up-regulating amino acid transporter expression to improve absorptive capacity for nutrients.

KW - absorption KW - mTORC1 pathway KW - nutrient signalling KW - transceptor UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871926120&md5=86280c7b851eef8fb27826447ae0dbfe U2 - 10.1097/MCO.0b013e32835a885c DO - 10.1097/MCO.0b013e32835a885c M1 - Article JO - Current Opinion in Clinical Nutrition and Metabolic Care JF - Current Opinion in Clinical Nutrition and Metabolic Care SN - 1363-1950 IS - 1 VL - 16 SP - 57 EP - 65 ER - TY - JOUR T1 - The safety regulation of small-scale coal mines in China T2 - Analysing the interests and influences of stakeholders A1 - Song,Xiaoqian A1 - Mu,Xiaoyi AU - Song,Xiaoqian AU - Mu,Xiaoyi PY - 2013/1 Y1 - 2013/1 N2 - Small scale coal mines (SCMs) have played an important role in China's energy supply. At the same time, they also suffer from many social, economic, environmental, and safety problems. The Chinese government has made considerable efforts to strengthen the safety regulation of the coal mining industry. Yet, few of these efforts have proven to be very effective. This paper analyzes the interests and influences of key stakeholders in the safety regulation of SCMs, which includes the safety regulator, the local government, the mine owner, and mineworkers. We argue that the effective regulation of coal mine safety must both engage and empower mineworkers. © 2012 Elsevier Ltd. All rights reserved. AB - Small scale coal mines (SCMs) have played an important role in China's energy supply. At the same time, they also suffer from many social, economic, environmental, and safety problems. The Chinese government has made considerable efforts to strengthen the safety regulation of the coal mining industry. Yet, few of these efforts have proven to be very effective. This paper analyzes the interests and influences of key stakeholders in the safety regulation of SCMs, which includes the safety regulator, the local government, the mine owner, and mineworkers. We argue that the effective regulation of coal mine safety must both engage and empower mineworkers. © 2012 Elsevier Ltd. All rights reserved. KW - Small scale mining KW - Safety KW - Stakeholder analysis UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84867465615&md5=5b2d692a2de2bcf4735361cf2108c027 U2 - 10.1016/j.enpol.2012.09.069 DO - 10.1016/j.enpol.2012.09.069 M1 - Article JO - Energy Policy JF - Energy Policy SN - 0301-4215 VL - 52 SP - 472 EP - 481 ER - TY - JOUR T1 - Understanding diagnosis of lung cancer in primary care T2 - qualitative synthesis of significant event audit reports A1 - Mitchell,Elizabeth D. A1 - Rubin,Greg A1 - Macleod,Una AU - Mitchell,Elizabeth D. AU - Rubin,Greg AU - Macleod,Una PY - 2013/1 Y1 - 2013/1 N2 - Background: Most lung cancers present symptomatically, but the pathway to diagnosis in primary care can be complex and is poorly understood. Significant event audit (SEA) is a quality improvement technique widely used in UK general practice. Aim: To gain insights into the diagnostic process for lung cancer, drawn from analysis of SEA documents. Design and setting: Qualitative analysis of SEAs from 92 general practices in the North of England Cancer Network. Method: Participating practices were provided with a standardised electronic template and asked to undertake a significant event audit related to the most recent diagnosis of lung cancer in the practice, even if that patient had since died. Reported accounts for 132 diagnoses were analysed using a modified framework approach. Results: Most SEAs demonstrated timely recognition and referral. Where this had taken longer, there were often reasonable explanations, including: chest X-rays reported as normal or with benign findings; patient-mediated factors, such as delay in re-presenting or declining earlier referral; and presentation complicated by comorbidity. Some opportunities for earlier referral were also found. Lessons drawn from these events included limitations of chest X-ray as a diagnostic tool, the need for vigilance in patients with existing morbidity, and the importance of 'safety-netting'. Conclusion: Qualitative synthesis of SEAs offered considerable value in understanding circumstances surrounding the diagnostic process for lung cancer in primary care. The most common presentation was with cough or other symptoms indicative of infection, and it is by understanding more about these patients in particular that most can be gained. © British Journal of General Practice. AB - Background: Most lung cancers present symptomatically, but the pathway to diagnosis in primary care can be complex and is poorly understood. Significant event audit (SEA) is a quality improvement technique widely used in UK general practice. Aim: To gain insights into the diagnostic process for lung cancer, drawn from analysis of SEA documents. Design and setting: Qualitative analysis of SEAs from 92 general practices in the North of England Cancer Network. Method: Participating practices were provided with a standardised electronic template and asked to undertake a significant event audit related to the most recent diagnosis of lung cancer in the practice, even if that patient had since died. Reported accounts for 132 diagnoses were analysed using a modified framework approach. Results: Most SEAs demonstrated timely recognition and referral. Where this had taken longer, there were often reasonable explanations, including: chest X-rays reported as normal or with benign findings; patient-mediated factors, such as delay in re-presenting or declining earlier referral; and presentation complicated by comorbidity. Some opportunities for earlier referral were also found. Lessons drawn from these events included limitations of chest X-ray as a diagnostic tool, the need for vigilance in patients with existing morbidity, and the importance of 'safety-netting'. Conclusion: Qualitative synthesis of SEAs offered considerable value in understanding circumstances surrounding the diagnostic process for lung cancer in primary care. The most common presentation was with cough or other symptoms indicative of infection, and it is by understanding more about these patients in particular that most can be gained. © British Journal of General Practice. U2 - 10.3399/bjgp13X660760 DO - 10.3399/bjgp13X660760 M1 - Article JO - British Journal of General Practice JF - British Journal of General Practice SN - 0960-1643 IS - 606 VL - 63 SP - e37-346 ER - TY - JOUR T1 - Unique topological characterization of braided magnetic fields A1 - Yeates,A. R. A1 - Hornig,G. AU - Yeates,A. R. AU - Hornig,G. PY - 2013/1 Y1 - 2013/1 N2 - We introduce a topological flux function to quantify the topology of magnetic braids: non-zero, line-tied magnetic fields whose field lines all connect between two boundaries. This scalar function is an ideal invariant defined on a cross-section of the magnetic field, and measures the average poloidal magnetic flux around any given field line, or the average pairwise crossing number between a given field line and all others. Moreover, its integral over the cross-section yields the relative magnetic helicity. Using the fact that the flux function is also an action in the Hamiltonian formulation of the field line equations, we prove that it uniquely characterizes the field line mapping and hence the magnetic topology. AB - We introduce a topological flux function to quantify the topology of magnetic braids: non-zero, line-tied magnetic fields whose field lines all connect between two boundaries. This scalar function is an ideal invariant defined on a cross-section of the magnetic field, and measures the average poloidal magnetic flux around any given field line, or the average pairwise crossing number between a given field line and all others. Moreover, its integral over the cross-section yields the relative magnetic helicity. Using the fact that the flux function is also an action in the Hamiltonian formulation of the field line equations, we prove that it uniquely characterizes the field line mapping and hence the magnetic topology. KW - plasma magnetohydrodynamics KW - topology U2 - 10.1063/1.4773903 DO - 10.1063/1.4773903 M1 - Article JO - Physics of Plasmas JF - Physics of Plasmas SN - 1070-664X IS - 1 VL - 20 ER - TY - JOUR T1 - `Seven Year Itch?' The European Left Party T2 - Struggling to Transform the European Union A1 - Dunphy,Richard A1 - March,Luke AU - Dunphy,Richard AU - March,Luke PY - 2013 Y1 - 2013 N2 - It's an apposite moment to analyze the European Left Party (EL), one of the newest transnational parties (TNPs) founded in 2004, which gathers a large number of radical left parties situating themselves to the left of social democracy. Despite the ostensibly beneficial crisis environment across the EU, radical left parties as a whole have so far failed to make significant gains. The EL's third congress in Paris in 2010 recognized significant future challenges in order to react to the adoption of the Lisbon treaty and to ‘build a Europe of social change’. In this paper we examine this relatively under-analyzed TNP's organizational development and cohesiveness by focussing on the interaction between national parties, the party at European level and the GUE/NGL (European United Left/Nordic Green Left) European parliamentary group. The EL's 2010 congress showed it struggling to combine the ‘deepening’ of its organizational cohesion with the ‘widening’ of its political representation. Although the EL's development to date marks a significant intensification of radical left European co-operation in historical terms, it remains ill-equipped to become an organizationally and strategically effective organization. AB - It's an apposite moment to analyze the European Left Party (EL), one of the newest transnational parties (TNPs) founded in 2004, which gathers a large number of radical left parties situating themselves to the left of social democracy. Despite the ostensibly beneficial crisis environment across the EU, radical left parties as a whole have so far failed to make significant gains. The EL's third congress in Paris in 2010 recognized significant future challenges in order to react to the adoption of the Lisbon treaty and to ‘build a Europe of social change’. In this paper we examine this relatively under-analyzed TNP's organizational development and cohesiveness by focussing on the interaction between national parties, the party at European level and the GUE/NGL (European United Left/Nordic Green Left) European parliamentary group. The EL's 2010 congress showed it struggling to combine the ‘deepening’ of its organizational cohesion with the ‘widening’ of its political representation. Although the EL's development to date marks a significant intensification of radical left European co-operation in historical terms, it remains ill-equipped to become an organizationally and strategically effective organization. U2 - 10.1080/15705854.2013.773653 DO - 10.1080/15705854.2013.773653 M1 - Article JO - Perspectives on European Politics and Society JF - Perspectives on European Politics and Society SN - 1570-5854 ER - TY - JOUR T1 - ‘Dim-conceived glories of the brain’ T2 - On Ambiguity in Literature and Science A1 - Otty,Lisa A1 - Roberts,Andrew Michael AU - Otty,Lisa AU - Roberts,Andrew Michael PY - 2013 Y1 - 2013 N2 - This article explores theoretical issues raised by empirical aesthetics and cognitive literary theory – new fields which attempt to bridge the divide between the humanities and the sciences. The discussion focuses on the concept of ambiguity, which has a rich history in literary studies and has recently attracted attention in neurological and cognitive approaches to literature and art. A shift is proposed from a conception of ambiguity in terms of a relatively passive process of aesthesis to one in which ambiguity plays a role in an active, generative process of poesis. Tracing the influence of ideas of aesthetic autonomy on the historical polarization of science and art, the article draws attention to the role of Romantic aesthetics and the ideologies of modernism in constructing a binary between ambiguous, subjective literary language and rational, objective scientific analysis. It considers how such ideas play out in the literary theory of William Empson and I.A. Richards, the empirical aesthetics of Samir Zeki and Reuven Tsur’s cognitive literary theory. Keats’s famous idea of ‘negative capability’ is deployed, in combination with Andrew Bowie’s distinction between analytic and hermeneutic conceptions of truth, to lead into a discussion of ‘cognitive blending’, conceived by Mark Turner and Gilles Fauconnier as an evolutionary adaptation in the human brain allowing the conceptual integration of huge amounts of information. This theory supports a positive valorization of ambiguity as integral to creative thought in both science and art. AB - This article explores theoretical issues raised by empirical aesthetics and cognitive literary theory – new fields which attempt to bridge the divide between the humanities and the sciences. The discussion focuses on the concept of ambiguity, which has a rich history in literary studies and has recently attracted attention in neurological and cognitive approaches to literature and art. A shift is proposed from a conception of ambiguity in terms of a relatively passive process of aesthesis to one in which ambiguity plays a role in an active, generative process of poesis. Tracing the influence of ideas of aesthetic autonomy on the historical polarization of science and art, the article draws attention to the role of Romantic aesthetics and the ideologies of modernism in constructing a binary between ambiguous, subjective literary language and rational, objective scientific analysis. It considers how such ideas play out in the literary theory of William Empson and I.A. Richards, the empirical aesthetics of Samir Zeki and Reuven Tsur’s cognitive literary theory. Keats’s famous idea of ‘negative capability’ is deployed, in combination with Andrew Bowie’s distinction between analytic and hermeneutic conceptions of truth, to lead into a discussion of ‘cognitive blending’, conceived by Mark Turner and Gilles Fauconnier as an evolutionary adaptation in the human brain allowing the conceptual integration of huge amounts of information. This theory supports a positive valorization of ambiguity as integral to creative thought in both science and art. KW - Literature and science KW - Ambiguity KW - Cognitive literary theory KW - Aesthetics U2 - 10.1080/14735784.2012.752194 DO - 10.1080/14735784.2012.752194 M1 - Article JO - Culture, Theory and Critique JF - Culture, Theory and Critique SN - 1473-5784 IS - 1 VL - 54 SP - 37 EP - 55 ER - TY - JOUR T1 - ‘If a picture paints a thousand words …’ T2 - the development of human identification techniques in forensic anthropology and their implications for human rights in the criminal process A1 - Ferguson,Pamela A1 - Raitt,Fiona AU - Ferguson,Pamela AU - Raitt,Fiona PY - 2013 Y1 - 2013 N2 - Newly developed techniques in forensic anthropology offer great potential to assist in identifying, and ultimately convicting, perpetrators of serious sexual assaults, particularly those involving young children. They can also facilitate the prosecution of those who create and disseminate child pornography. They do, however, require that photographs be taken of suspects' hands, and sometimes their genitals. This article explores the human rights implications which arise from the intrusive procedures needed to obtain the photographs necessary for comparative purposes. It assesses police powers; the rights of suspects to privacy and bodily integrity; the privilege against compelled self-incrimination; and the right to legal advice, and addresses the question: what are the permissible limits of intrusive searches? AB - Newly developed techniques in forensic anthropology offer great potential to assist in identifying, and ultimately convicting, perpetrators of serious sexual assaults, particularly those involving young children. They can also facilitate the prosecution of those who create and disseminate child pornography. They do, however, require that photographs be taken of suspects' hands, and sometimes their genitals. This article explores the human rights implications which arise from the intrusive procedures needed to obtain the photographs necessary for comparative purposes. It assesses police powers; the rights of suspects to privacy and bodily integrity; the privilege against compelled self-incrimination; and the right to legal advice, and addresses the question: what are the permissible limits of intrusive searches? U2 - 10.1350/ijep.2013.17.2.422 DO - 10.1350/ijep.2013.17.2.422 M1 - Article JO - International Journal of Evidence and Proof JF - International Journal of Evidence and Proof SN - 1365-7127 IS - 2 VL - 17 SP - 127 EP - 156 ER - TY - JOUR T1 - A multiscale moving boundary model arising in cancer invasion A1 - Trucu,Dumitru A1 - Lin,Ping A1 - Chaplain,Mark A. J. A1 - Wang,Yangfan AU - Trucu,Dumitru AU - Lin,Ping AU - Chaplain,Mark A. J. AU - Wang,Yangfan PY - 2013 Y1 - 2013 N2 - Cancer invasion of tissue is a key aspect of the growth and spread of cancer and is crucial in the process of metastatic spread, i.e., the growth of secondary cancers. Invasion consists in cancer cells secreting various matrix degrading enzymes (MDEs) which destroy the surrounding tissue or extracellular matrix (ECM). Through a combination of proliferation and migration, the cancer cells then actively spread locally into the surrounding tissue. Thus processes occurring at the level of individual cells eventually give rise to processes occurring at the tissue level. In this paper we introduce a new type of multiscale model describing the process of cancer invasion of tissue. Our multiscale model is a two-scale model which focuses on the macroscopic dynamics of the distributions of cancer cells and of the surrounding extracellular matrix, and on the microscale dynamics of the MDEs, produced at the level of the individual cancer cells. These microscale dynamics take place at the interface of the cancer cells and the ECM and give rise to a moving boundary at the macroscale. On the computational side, in order to approximate the newly proposed model, we have developed a novel computational scheme based on a combination of finite elements at the microscale with a new finite difference technique at the macroscale, linking together in a moving boundary formulation of the problem. This two-scale numerical scheme is organized in such a way that it enables us to accurately model all the key processes of cancer invasion at both the macroscale and microscale. AB - Cancer invasion of tissue is a key aspect of the growth and spread of cancer and is crucial in the process of metastatic spread, i.e., the growth of secondary cancers. Invasion consists in cancer cells secreting various matrix degrading enzymes (MDEs) which destroy the surrounding tissue or extracellular matrix (ECM). Through a combination of proliferation and migration, the cancer cells then actively spread locally into the surrounding tissue. Thus processes occurring at the level of individual cells eventually give rise to processes occurring at the tissue level. In this paper we introduce a new type of multiscale model describing the process of cancer invasion of tissue. Our multiscale model is a two-scale model which focuses on the macroscopic dynamics of the distributions of cancer cells and of the surrounding extracellular matrix, and on the microscale dynamics of the MDEs, produced at the level of the individual cancer cells. These microscale dynamics take place at the interface of the cancer cells and the ECM and give rise to a moving boundary at the macroscale. On the computational side, in order to approximate the newly proposed model, we have developed a novel computational scheme based on a combination of finite elements at the microscale with a new finite difference technique at the macroscale, linking together in a moving boundary formulation of the problem. This two-scale numerical scheme is organized in such a way that it enables us to accurately model all the key processes of cancer invasion at both the macroscale and microscale. U2 - 10.1137/110839011 DO - 10.1137/110839011 M1 - Article JO - Multiscale Modeling and Simulation: A SIAM Interdisciplinary Journal JF - Multiscale Modeling and Simulation: A SIAM Interdisciplinary Journal SN - 1540-3459 IS - 1 VL - 11 SP - 309 EP - 335 ER - TY - JOUR T1 - A nonsense mutation in the mattrin gene causes the matted mouse phenotype and is a predisposing gene for atopic dermatitis in humans A1 - Goh,C. S. A1 - Saunders,S. P. A1 - Cole,Christian A1 - Weidinger,S. A1 - Baurecht,H. A1 - Lee,Y. A1 - Reynolds,N. J. A1 - Barker,J. N. A1 - Cordell,H. J. A1 - Brown,S. J. A1 - Irvine,A. D. A1 - McLean,I. A1 - Sandilands,A. A1 - Fallon,P. G. AU - Goh,C. S. AU - Saunders,S. P. AU - Cole,Christian AU - Weidinger,S. AU - Baurecht,H. AU - Lee,Y. AU - Reynolds,N. J. AU - Barker,J. N. AU - Cordell,H. J. AU - Brown,S. J. AU - Irvine,A. D. AU - McLean,I. AU - Sandilands,A. AU - Fallon,P. G. PY - 2013 Y1 - 2013 U2 - 10.1038/jid.2013.100 DO - 10.1038/jid.2013.100 M1 - Meeting abstract JO - Journal of Investigative Dermatology JF - Journal of Investigative Dermatology SN - 0022-202X IS - S1 VL - 133 SP - S145 ER - TY - JOUR T1 - A novel mutation in COL7A1, G2269R causing nail only DDEB and RDEB, with a presentation similar to TBDN at birth when coinherited with R2814X COL7A1 mutation A1 - Cohn,H. I. A1 - Tran,K. A1 - Chow,C. W. A1 - Palmer,E. A1 - Turner,A. A1 - South,A. P. A1 - Murrell,D. F. AU - Cohn,H. I. AU - Tran,K. AU - Chow,C. W. AU - Palmer,E. AU - Turner,A. AU - South,A. P. AU - Murrell,D. F. PY - 2013 Y1 - 2013 U2 - 10.1038/jid.2013.100 DO - 10.1038/jid.2013.100 M1 - Meeting abstract JO - Journal of Investigative Dermatology JF - Journal of Investigative Dermatology SN - 0022-202X IS - S1 VL - 133 SP - S141 ER - TY - JOUR T1 - A separate pool of cardiac phospholemman that does not regulate or associate with the sodium pump T2 - multimers of phospholemman in ventricular muscle A1 - Wypijewski,Krzysztof J. A1 - Howie,Jacqueline A1 - Reilly,Louise A1 - Tulloch,Lindsay B. A1 - Aughton,Karen L. A1 - McLatchie,Linda M. A1 - Shattock,Michael J. A1 - Calaghan,Sarah C. A1 - Fuller,William AU - Wypijewski,Krzysztof J. AU - Howie,Jacqueline AU - Reilly,Louise AU - Tulloch,Lindsay B. AU - Aughton,Karen L. AU - McLatchie,Linda M. AU - Shattock,Michael J. AU - Calaghan,Sarah C. AU - Fuller,William PY - 2013 Y1 - 2013 N2 - Phospholemman (PLM), the principal quantitative sarcolemmal substrate for protein kinases A and C in the heart, regulates the cardiac sodium pump. Much like phospholamban, which regulates the related ATPase SERCA, PLM is reported to oligomerise. We investigated subpopulations of PLM in adult rat ventricular myocytes based on phosphorylation status. Co-immunoprecipitation identified two pools of PLM: one not associated with the sodium pump phosphorylated at serine 63 (S63), and one, associated with the pump, both phosphorylated at serine 68 and unphosphorylated. Phosphorylation of PLM at S63 following activation of PKC did not abrogate association of PLM with the pump, so its failure to associate with the pump was not due to phosphorylation at this site. All pools of PLM co-localised to cell surface caveolin-enriched microdomains with sodium pump a subunits, despite the lack of caveolin-binding motif in PLM. Mass spectrometry analysis of phosphospecific immunoprecipitation reactions revealed no unique protein interactions for S63-phosphorylated PLM, and crosslinking reagents also failed to identify any partner proteins for this pool. In lysates from hearts of heterozygous transgenic animals expressing wild type and unphosphorylatable PLM, S63-phosphorylated PLM co-immunoprecipitated unphosphorylatable PLM, confirming the existence of PLM multimers. Dephosphorylation of the PLM multimer does not change Na pump activity. Hence like phospholamban, PLM exists as a pump inhibiting monomer and an un-associated oligomer. The distribution of different PLM phosphorylation states to different pools may be explained by their differential proximity to protein phosphatases, rather than a direct effect of phosphorylation on PLM association with the pump.
Copyright © 2013, The American Society for Biochemistry and Molecular Biology AB - Phospholemman (PLM), the principal quantitative sarcolemmal substrate for protein kinases A and C in the heart, regulates the cardiac sodium pump. Much like phospholamban, which regulates the related ATPase SERCA, PLM is reported to oligomerise. We investigated subpopulations of PLM in adult rat ventricular myocytes based on phosphorylation status. Co-immunoprecipitation identified two pools of PLM: one not associated with the sodium pump phosphorylated at serine 63 (S63), and one, associated with the pump, both phosphorylated at serine 68 and unphosphorylated. Phosphorylation of PLM at S63 following activation of PKC did not abrogate association of PLM with the pump, so its failure to associate with the pump was not due to phosphorylation at this site. All pools of PLM co-localised to cell surface caveolin-enriched microdomains with sodium pump a subunits, despite the lack of caveolin-binding motif in PLM. Mass spectrometry analysis of phosphospecific immunoprecipitation reactions revealed no unique protein interactions for S63-phosphorylated PLM, and crosslinking reagents also failed to identify any partner proteins for this pool. In lysates from hearts of heterozygous transgenic animals expressing wild type and unphosphorylatable PLM, S63-phosphorylated PLM co-immunoprecipitated unphosphorylatable PLM, confirming the existence of PLM multimers. Dephosphorylation of the PLM multimer does not change Na pump activity. Hence like phospholamban, PLM exists as a pump inhibiting monomer and an un-associated oligomer. The distribution of different PLM phosphorylation states to different pools may be explained by their differential proximity to protein phosphatases, rather than a direct effect of phosphorylation on PLM association with the pump.
Copyright © 2013, The American Society for Biochemistry and Molecular Biology U2 - 10.1074/jbc.M113.460956 DO - 10.1074/jbc.M113.460956 M1 - Article JO - Journal of Biological Chemistry JF - Journal of Biological Chemistry SN - 0021-9258 ER - TY - JOUR T1 - A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABAA receptors A1 - Jensen,M. L. A1 - Wafford,K. A. A1 - Brown,A. R. A1 - Belelli,D. A1 - Lambert,J. J. A1 - Mirza,N. R. AU - Jensen,M. L. AU - Wafford,K. A. AU - Brown,A. R. AU - Belelli,D. AU - Lambert,J. J. AU - Mirza,N. R. PY - 2013 Y1 - 2013 N2 -

Background and Purpose Most GABAA receptor subtypes comprise 2, 2 and 1 subunit, although for some isoforms, a replaces a -subunit. Extrasynaptic -GABAA receptors are important therapeutic targets, but there are few suitable pharmacological tools. We profiled DS2, the purported positive allosteric modulator (PAM) of -GABAA receptors to better understand subtype selectivity, mechanism/site of action and activity at native -GABAA receptors. Experimental Approach Subunit specificity of DS2 was determined using electrophysiological recordings of Xenopus laevis oocytes expressing human recombinant GABAA receptor isoforms. Effects of DS2 on GABA concentrationresponse curves were assessed to define mechanisms of action. Radioligand binding and electrophysiology utilising mutant receptors and pharmacology were used to define site of action. Using brain-slice electrophysiology, we assessed the influence of DS2 on thalamic inhibition in wild-type and 0/0 mice. Key Results Actions of DS2 were primarily determined by the -subunit but were additionally influenced by the , but not the , subunit (4/6x > 1x >> 2-GABAA receptors > 43). For -GABAA receptors, DS2 enhanced maximum responses to GABA, with minimal influence on GABA potency. (iii) DS2 did not act via the orthosteric, or known modulatory sites on GABAA receptors. (iv) DS2 enhanced tonic currents of thalamocortical neurones from wild-type but not 0/0 mice. Conclusions and Implications DS2 is the first PAM selective for 4/6x receptors, providing a novel tool to investigate extrasynaptic -GABAA receptors. The effects of DS2 are mediated by an unknown site leading to GABAA receptor isoform selectivity.

AB -

Background and Purpose Most GABAA receptor subtypes comprise 2, 2 and 1 subunit, although for some isoforms, a replaces a -subunit. Extrasynaptic -GABAA receptors are important therapeutic targets, but there are few suitable pharmacological tools. We profiled DS2, the purported positive allosteric modulator (PAM) of -GABAA receptors to better understand subtype selectivity, mechanism/site of action and activity at native -GABAA receptors. Experimental Approach Subunit specificity of DS2 was determined using electrophysiological recordings of Xenopus laevis oocytes expressing human recombinant GABAA receptor isoforms. Effects of DS2 on GABA concentrationresponse curves were assessed to define mechanisms of action. Radioligand binding and electrophysiology utilising mutant receptors and pharmacology were used to define site of action. Using brain-slice electrophysiology, we assessed the influence of DS2 on thalamic inhibition in wild-type and 0/0 mice. Key Results Actions of DS2 were primarily determined by the -subunit but were additionally influenced by the , but not the , subunit (4/6x > 1x >> 2-GABAA receptors > 43). For -GABAA receptors, DS2 enhanced maximum responses to GABA, with minimal influence on GABA potency. (iii) DS2 did not act via the orthosteric, or known modulatory sites on GABAA receptors. (iv) DS2 enhanced tonic currents of thalamocortical neurones from wild-type but not 0/0 mice. Conclusions and Implications DS2 is the first PAM selective for 4/6x receptors, providing a novel tool to investigate extrasynaptic -GABAA receptors. The effects of DS2 are mediated by an unknown site leading to GABAA receptor isoform selectivity.

KW - HIPPOCAMPAL PYRAMIDAL NEURONS KW - SUBTYPES KW - MICE LACKING KW - NEUROACTIVE STEROIDS KW - 4-subunit KW - brain-slice electrophysiology KW - TONIC INHIBITION KW - GABA(A)-RECEPTOR KW - ACTIVATION KW - site of interaction KW - DS2 KW - -subunit KW - ADULT-RAT BRAIN KW - PHARMACOLOGICAL CHARACTERIZATION KW - GABAA receptor KW - CEREBELLAR GRANULE CELLS U2 - 10.1111/bph.12001 DO - 10.1111/bph.12001 M1 - Article JO - British Journal of Pharmacology JF - British Journal of Pharmacology SN - 0007-1188 IS - 5 VL - 168 SP - 1118 EP - 1132 ER - TY - JOUR T1 - A survey of photodynamic therapy services in dermatology departments across Scotland A1 - Ibbotson,S.H. A1 - Dawe,R.S. A1 - Morton,C.A. AU - Ibbotson,S.H. AU - Dawe,R.S. AU - Morton,C.A. PY - 2013 Y1 - 2013 N2 - There is good evidence to support the use of topical PDT for superficial nonmelanoma skin cancer and dysplasia; however, there is little information available on the structure, process and outcomes of PDT in clinical practice. We undertook a national survey to determine how PDT was being undertaken in dermatology centres in Scotland. We highlight important information on the practicalities of PDT service delivery and the types of patients and diagnoses treated, and provide preliminary information on the outcomes achieved. These data will be invaluable as a starting point to agree on minimum standards for PDT and criteria to audit against these standards. © 2013 British Association of Dermatologists. AB - There is good evidence to support the use of topical PDT for superficial nonmelanoma skin cancer and dysplasia; however, there is little information available on the structure, process and outcomes of PDT in clinical practice. We undertook a national survey to determine how PDT was being undertaken in dermatology centres in Scotland. We highlight important information on the practicalities of PDT service delivery and the types of patients and diagnoses treated, and provide preliminary information on the outcomes achieved. These data will be invaluable as a starting point to agree on minimum standards for PDT and criteria to audit against these standards. © 2013 British Association of Dermatologists. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84876893974&md5=0592751784f34a51984b584dc3451e06 U2 - 10.1111/ced.12051 DO - 10.1111/ced.12051 M1 - Article JO - Clinical and Experimental Dermatology JF - Clinical and Experimental Dermatology SN - 0307-6938 ER - TY - JOUR T1 - A sweet TET-a-tete-synergy of TET proteins and O-GlcNAc transferase in transcription A1 - Mariappa,Daniel A1 - Pathak,Shalini A1 - van Aalten,Daan M. F. AU - Mariappa,Daniel AU - Pathak,Shalini AU - van Aalten,Daan M. F. PY - 2013 Y1 - 2013 N2 -

5-hydroxy methyl cytosine (5hmC) is a modification identified in vertebrates several decades ago. More recently, a possible role of 5hmC as an epigenetic modifier and/or transcriptional regulator has started to emerge, with altered levels in early embryonic development, embryonic stem (ES) cell differentiation and tumours (Tahiliani et al, 2009; Yang et al, 2012). The balance between 5hmC and 5-methyl cytosine (5mC) at gene promoters and CpG islands in the genome appears to be linked to pluripotency and lineage commitment of a cell (Ito et al, 2010). However, proteins with 5hmC binding capability have not yet been identified, and it has been proposed that 5hmC may only be a reaction intermediate in the process of demethylation (He et al, 2011; Ito et al, 2011). Over the last few years, ten-eleven translocation (Tet) family proteins have been shown to be responsible for the conversion of 5mC to 5hmC (Iyer et al, 2009; Loenarz and Schofield, 2009; Tahiliani et al, 2009). However, how Tet family proteins and 5hmC are linked to transcriptional regulation is currently not clear.

AB -

5-hydroxy methyl cytosine (5hmC) is a modification identified in vertebrates several decades ago. More recently, a possible role of 5hmC as an epigenetic modifier and/or transcriptional regulator has started to emerge, with altered levels in early embryonic development, embryonic stem (ES) cell differentiation and tumours (Tahiliani et al, 2009; Yang et al, 2012). The balance between 5hmC and 5-methyl cytosine (5mC) at gene promoters and CpG islands in the genome appears to be linked to pluripotency and lineage commitment of a cell (Ito et al, 2010). However, proteins with 5hmC binding capability have not yet been identified, and it has been proposed that 5hmC may only be a reaction intermediate in the process of demethylation (He et al, 2011; Ito et al, 2011). Over the last few years, ten-eleven translocation (Tet) family proteins have been shown to be responsible for the conversion of 5mC to 5hmC (Iyer et al, 2009; Loenarz and Schofield, 2009; Tahiliani et al, 2009). However, how Tet family proteins and 5hmC are linked to transcriptional regulation is currently not clear.

KW - 5-METHYLCYTOSINE KW - 5-CARBOXYLCYTOSINE KW - MAMMALIAN DNA KW - CONVERSION U2 - 10.1038/emboj.2013.26 DO - 10.1038/emboj.2013.26 M1 - Editorial JO - EMBO Journal JF - EMBO Journal SN - 0261-4189 IS - 5 VL - 32 SP - 612 EP - 613 ER - TY - JOUR T1 - A test of the Whitaker scoring system for estimating age from the bones of the foot A1 - Davies,Catriona A1 - Black,Sue M. A1 - Hackman,Lucina AU - Davies,Catriona AU - Black,Sue M. AU - Hackman,Lucina PY - 2013 Y1 - 2013 N2 - Within the literature pertaining to skeletal age estimation, there is a paucity of statistically validated methods of age estimation from the foot. Given the prevalence of recovery of pedal elements in isolation, it is critical that methods exist to facilitate the estimation of age from this anatomical region and that those methods be tested to ensure they are reliable, repeatable and statistically robust. A study was carried out to determine the validity of using the Whitaker method of age estimation from the bones of the foot as a tool in forensic age estimation within a modern Scottish population. Two-hundred and sixty radiographs from individuals aged between birth and 18 years were assessed according to the Whitaker method; the results were compared with chronological age. The results of this study suggest that the method of Whitaker et al. is highly unlikely to estimate the age of females below 16 years of age or males below 18 years of age correctly. When the methodology was altered to correspond with best practice principles of age estimation, the estimated age ranges were found to be too wide to be of practical value in forensic age estimation. The results of this study therefore suggest that the Whitaker method for estimating age from the bones of the foot should not be used in forensic age assessment. AB - Within the literature pertaining to skeletal age estimation, there is a paucity of statistically validated methods of age estimation from the foot. Given the prevalence of recovery of pedal elements in isolation, it is critical that methods exist to facilitate the estimation of age from this anatomical region and that those methods be tested to ensure they are reliable, repeatable and statistically robust. A study was carried out to determine the validity of using the Whitaker method of age estimation from the bones of the foot as a tool in forensic age estimation within a modern Scottish population. Two-hundred and sixty radiographs from individuals aged between birth and 18 years were assessed according to the Whitaker method; the results were compared with chronological age. The results of this study suggest that the method of Whitaker et al. is highly unlikely to estimate the age of females below 16 years of age or males below 18 years of age correctly. When the methodology was altered to correspond with best practice principles of age estimation, the estimated age ranges were found to be too wide to be of practical value in forensic age estimation. The results of this study therefore suggest that the Whitaker method for estimating age from the bones of the foot should not be used in forensic age assessment. KW - Forensic anthropology KW - age estimation KW - FOOT KW - skeletal age KW - radiographs U2 - 10.1007/s00414-012-0777-4 DO - 10.1007/s00414-012-0777-4 M1 - Article JO - International Journal of Legal Medicine JF - International Journal of Legal Medicine SN - 0937-9827 IS - 2 VL - 127 SP - 481 EP - 489 ER - TY - JOUR T1 - A two gene serum epigenetic signature detects metastatic melanoma with high sensitivity and specificity A1 - Wang,H. A1 - McHugh,A. A1 - Matin,R. A1 - Fleming,C. A1 - Leigh,I. A1 - Harwood,C. A1 - Inman,G. A1 - Crook,T. A1 - Proby,C. AU - Wang,H. AU - McHugh,A. AU - Matin,R. AU - Fleming,C. AU - Leigh,I. AU - Harwood,C. AU - Inman,G. AU - Crook,T. AU - Proby,C. PY - 2013 Y1 - 2013 U2 - 10.1038/jid.2013.105 DO - 10.1038/jid.2013.105 M1 - Meeting abstract JO - Journal of Investigative Dermatology JF - Journal of Investigative Dermatology SN - 0022-202X IS - S1 VL - 133 SP - S235 ER - TY - JOUR T1 - Adult Dental Health Survey 2009 T2 - relationships between dental attendance patterns, oral health behaviour and the current barriers to dental care A1 - Hill,K B A1 - Chadwick,B A1 - Freeman,R A1 - O'Sullivan,I A1 - Murray,J J AU - Hill,K B AU - Chadwick,B AU - Freeman,R AU - O'Sullivan,I AU - Murray,J J PY - 2013 Y1 - 2013 N2 - The importance of understanding barriers to dental attendance of adults in the UK was acknowledged in the first Adult Dental Health Survey in 1968 and has been investigated in all subsequent ADH surveys. In 1968, approximately 40% of dentate adults said they attended for a regular check-up; by 2009 this was 61%. Attendance patterns were associated with greater frequency of toothbrushing, use of additional dental hygiene products, lower plaque and calculus levels. Just under three-fifths of adults said they had tried to make an NHS dental appointment in the previous five years. The vast majority (92%) successfully received and attended an appointment, while a further 1% received an appointment but did not attend. The remaining 7% of adults were unable to make an appointment with an NHS dentist. The majority of adults were positive about their last visit to the dentist, with 80% of adults giving no negative feedback about their last dentist visit. Cost and anxiety were important barriers to care. Twenty-six percent of adults said the type of treatment they had opted for in the past had been affected by the cost and 19% said they had delayed dental treatment for the same reason. The 2009 survey data demonstrated a relationship between dental anxiety and dental attendance. Adults with extreme dental anxiety were more likely to attend only when they had trouble with their teeth (22%) than for a regular check-up. AB - The importance of understanding barriers to dental attendance of adults in the UK was acknowledged in the first Adult Dental Health Survey in 1968 and has been investigated in all subsequent ADH surveys. In 1968, approximately 40% of dentate adults said they attended for a regular check-up; by 2009 this was 61%. Attendance patterns were associated with greater frequency of toothbrushing, use of additional dental hygiene products, lower plaque and calculus levels. Just under three-fifths of adults said they had tried to make an NHS dental appointment in the previous five years. The vast majority (92%) successfully received and attended an appointment, while a further 1% received an appointment but did not attend. The remaining 7% of adults were unable to make an appointment with an NHS dentist. The majority of adults were positive about their last visit to the dentist, with 80% of adults giving no negative feedback about their last dentist visit. Cost and anxiety were important barriers to care. Twenty-six percent of adults said the type of treatment they had opted for in the past had been affected by the cost and 19% said they had delayed dental treatment for the same reason. The 2009 survey data demonstrated a relationship between dental anxiety and dental attendance. Adults with extreme dental anxiety were more likely to attend only when they had trouble with their teeth (22%) than for a regular check-up. U2 - 10.1038/sj.bdj.2012.1176 DO - 10.1038/sj.bdj.2012.1176 M1 - Article JO - British Dental Journal JF - British Dental Journal IS - 1 VL - 214 SP - 25 EP - 32 ER - TY - JOUR T1 - Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland T2 - the thyroid epidemiology, audit, and research study (TEARS) A1 - Vadiveloo,Thenmalar A1 - Donnan,Peter T. A1 - Murphy,Michael J. A1 - Leese,Graham P. AU - Vadiveloo,Thenmalar AU - Donnan,Peter T. AU - Murphy,Michael J. AU - Leese,Graham P. PY - 2013 Y1 - 2013 N2 - Objective:The aim of the study was to examine the association of tested TSH with age, gender, and diabetes in a large population-based cohort without evidence of thyroid disease.Design:Record-linkage technology was used retrospectively to identify people without evidence of thyroid disease in the general population of Tayside, Scotland, from July 1, 2003, to December 31, 2009.Cohort:All Tayside residents who had thyroid function tests performed were identified. Using a unique patient identifier, data linkage enabled a cohort without thyroid disease to be identified by excluding anyone with thyroid or antithyroid prescription, thyroid-related admission or surgery, treatment with radioactive iodine and/or positive thyroid antibodies. Cases below 18 years of age were also excluded.Outcome Measures:We measured TSH distribution among different age groups and by gender.Results:We identified the latest TSH measurements in 153127 people from the reference population after applying the exclusion criteria. There was a significant increase in median TSH (1.58 mU/L at 31-40 y to 1.86 mU/L at >90 y; P <.001) and 97.5th centile TSH (3.98 to 5.94 mU/L, respectively) with increasing age. The 2.5th centile decreased with age (0.51 to 0.31 mU/L). Patients with diabetes had marginally higher TSH concentration (1.80 vs 1.70 mU/L; P <.001).Conclusion:The use of these age-specific reference intervals for TSH, especially in those over 70 years old, would result in the reclassification of many TSH results from "abnormal" to "normal" (within the 95th centile reference interval) and avoid unnecessary treatment. AB - Objective:The aim of the study was to examine the association of tested TSH with age, gender, and diabetes in a large population-based cohort without evidence of thyroid disease.Design:Record-linkage technology was used retrospectively to identify people without evidence of thyroid disease in the general population of Tayside, Scotland, from July 1, 2003, to December 31, 2009.Cohort:All Tayside residents who had thyroid function tests performed were identified. Using a unique patient identifier, data linkage enabled a cohort without thyroid disease to be identified by excluding anyone with thyroid or antithyroid prescription, thyroid-related admission or surgery, treatment with radioactive iodine and/or positive thyroid antibodies. Cases below 18 years of age were also excluded.Outcome Measures:We measured TSH distribution among different age groups and by gender.Results:We identified the latest TSH measurements in 153127 people from the reference population after applying the exclusion criteria. There was a significant increase in median TSH (1.58 mU/L at 31-40 y to 1.86 mU/L at >90 y; P <.001) and 97.5th centile TSH (3.98 to 5.94 mU/L, respectively) with increasing age. The 2.5th centile decreased with age (0.51 to 0.31 mU/L). Patients with diabetes had marginally higher TSH concentration (1.80 vs 1.70 mU/L; P <.001).Conclusion:The use of these age-specific reference intervals for TSH, especially in those over 70 years old, would result in the reclassification of many TSH results from "abnormal" to "normal" (within the 95th centile reference interval) and avoid unnecessary treatment. U2 - 10.1210/jc.2012-3191 DO - 10.1210/jc.2012-3191 M1 - Article JO - Journal of Clinical Endocrinology & Metabolism JF - Journal of Clinical Endocrinology & Metabolism IS - 3 VL - 98 SP - 1147 EP - 1153 ER - TY - JOUR T1 - Allele-specific siRNA silencing for the common keratin 12 founder mutation in Meesmann epithelial corneal dystrophy A1 - Allen,Edwin H. A. A1 - Atkinson,Sarah D. A1 - Liao,Haihui A1 - Moore,Jonathan E. A1 - Pedrioli,Deena M. Leslie A1 - Smith,Frances J. D. A1 - McLean,William H. Irwin A1 - Moore,C. B. Tara AU - Allen,Edwin H. A. AU - Atkinson,Sarah D. AU - Liao,Haihui AU - Moore,Jonathan E. AU - Pedrioli,Deena M. Leslie AU - Smith,Frances J. D. AU - McLean,William H. Irwin AU - Moore,C. B. Tara PY - 2013 Y1 - 2013 N2 -

PURPOSE. To identify an allele-specific short interfering RNA (siRNA), against the common KRT12 mutation Arg135Thr in Meesmann epithelial corneal dystrophy (MECD) as a personalized approach to treatment.

METHODS. siRNAs against the K12 Arg135Thr mutation were evaluated using a dual luciferase reporter gene assay and the most potent and specific siRNAs were further screened by Western blot. Off-target effects on related keratins were assessed and immunological stimulation of TLR3 was evaluated by RT-PCR. A modified 5' rapid amplification of cDNA ends method was used to confirm siRNA-mediated mutant knockdown. Allele discrimination was confirmed by quantitative infrared immunoblotting.

RESULTS. The lead siRNA, with an IC50 of thirty picomolar, showed no keratin off-target effects or activation of TLR3 in the concentration ranges tested. We confirmed siRNA-mediated knockdown by the presence of K12 mRNA fragments cleaved at the predicted site. A dual tag infrared immunoblot showed knockdown to be allele-specific, with 70% to 80% silencing of the mutant protein.

CONCLUSIONS. A potent allele-specific siRNA against the K12 Arg135Thr mutation was identified. In combination with efficient eyedrop formulation delivery, this would represent a personalized medicine approach, aimed at preventing the pathology associated with MECD and other ocular surface pathologies with dominant-negative or gain-of-function pathomechanisms. (Invest Ophthalmol Vis Sci. 2013;54:494-502) DOI:10.1167/iovs.12-10528

AB -

PURPOSE. To identify an allele-specific short interfering RNA (siRNA), against the common KRT12 mutation Arg135Thr in Meesmann epithelial corneal dystrophy (MECD) as a personalized approach to treatment.

METHODS. siRNAs against the K12 Arg135Thr mutation were evaluated using a dual luciferase reporter gene assay and the most potent and specific siRNAs were further screened by Western blot. Off-target effects on related keratins were assessed and immunological stimulation of TLR3 was evaluated by RT-PCR. A modified 5' rapid amplification of cDNA ends method was used to confirm siRNA-mediated mutant knockdown. Allele discrimination was confirmed by quantitative infrared immunoblotting.

RESULTS. The lead siRNA, with an IC50 of thirty picomolar, showed no keratin off-target effects or activation of TLR3 in the concentration ranges tested. We confirmed siRNA-mediated knockdown by the presence of K12 mRNA fragments cleaved at the predicted site. A dual tag infrared immunoblot showed knockdown to be allele-specific, with 70% to 80% silencing of the mutant protein.

CONCLUSIONS. A potent allele-specific siRNA against the K12 Arg135Thr mutation was identified. In combination with efficient eyedrop formulation delivery, this would represent a personalized medicine approach, aimed at preventing the pathology associated with MECD and other ocular surface pathologies with dominant-negative or gain-of-function pathomechanisms. (Invest Ophthalmol Vis Sci. 2013;54:494-502) DOI:10.1167/iovs.12-10528

KW - DISEASES KW - EPIDERMOLYSIS-BULLOSA SIMPLEX KW - CELL-LINE KW - RNAI THERAPEUTICS KW - GENE-THERAPY KW - KNOCKING KW - INCLUDING PACHYONYCHIA-CONGENITA KW - DISORDERS KW - INTERFERENCE KW - DELIVERY U2 - 10.1167/iovs.12-10528 DO - 10.1167/iovs.12-10528 M1 - Article JO - Investigative Ophthalmology & Visual Science JF - Investigative Ophthalmology & Visual Science SN - 0146-0404 IS - 1 VL - 54 SP - 494 EP - 502 ER - TY - JOUR T1 - Allopurinol reduces left ventricular mass in patients with type ii diabetes and left ventricular hypertrophy A1 - Szwejkowski,Benjamin Robert A1 - Gandy,Stephen A1 - Rekhraj,Sushma A1 - Houston,Graeme A1 - George,Jacob A1 - Lang,Chim C. A1 - Morris,Andrew D. A1 - Struthers,Allan D. AU - Szwejkowski,Benjamin Robert AU - Gandy,Stephen AU - Rekhraj,Sushma AU - Houston,Graeme AU - George,Jacob AU - Lang,Chim C. AU - Morris,Andrew D. AU - Struthers,Allan D. PY - 2013 Y1 - 2013 U2 - 10.1016/S0735-1097(13)61256-5 DO - 10.1016/S0735-1097(13)61256-5 M1 - Meeting abstract JO - Journal of the American College of Cardiology JF - Journal of the American College of Cardiology SN - 0735-1097 IS - 10 Supplement VL - 61 SP - E1256 ER - TY - JOUR T1 - Aminoglycosides and non-aminoglycosides suppress premature stop mutations and restore type VII collagen function in RDEB A1 - Wang,X. Y. A1 - Cogan,J. A1 - Hou,Y. P. A1 - Khilili,M. A1 - Paparisto,E. A1 - South,A. P. A1 - Woodley,D. T. A1 - Chen,M. AU - Wang,X. Y. AU - Cogan,J. AU - Hou,Y. P. AU - Khilili,M. AU - Paparisto,E. AU - South,A. P. AU - Woodley,D. T. AU - Chen,M. PY - 2013 Y1 - 2013 U2 - 10.1038/jid.2013.100 DO - 10.1038/jid.2013.100 M1 - Meeting abstract JO - Journal of Investigative Dermatology JF - Journal of Investigative Dermatology SN - 0022-202X IS - S1 VL - 133 SP - S141 ER - TY - JOUR T1 - An integrated model for the wave-induced seabed response around marine structures T2 - model verifications and applications A1 - Jeng,D. -S. A1 - Ye,J. -H. A1 - Zhang,J-S A1 - Liu,P. L. -F. AU - Jeng,D. -S. AU - Ye,J. -H. AU - Zhang,J-S AU - Liu,P. L. -F. PY - 2013 Y1 - 2013 N2 -

In this study, an integrated model (PORO-WSSI II) for wave-seabed-structure interactions (WSSI) is developed by combining (i) the Volume-Averaged Reynolds-Averaged Navier-Stokes (VARANS) equations for wave motions in a fluid domain and the porous media flows in porous structures, and (ii) the dynamic Blot's equations for a porous elastic seabed. The effects of the porous flow in seabed and marine structures, and the fluid exchange at the interface between the fluid domain and solid domain on wave characteristics are considered. The finite difference two-step projection method and the forward time difference method are adopted to solve the VARANS equations. The volume of fluid (VOF) method is applied to track water free-surface. The finite element method and the Generalized Newmark method are respectively adopted for the space discretization and time discretization of the dynamic Biot's equations. A one-way integrating method is developed to integrate the VARANS equations with the dynamic Biot's equations. Several experimental data available in the literature are used to validate the integrated model. An overall agreement between the numerical results and the experiment data indicates that the integrated model developed for the WSSI problem is highly reliable. The integrated model is then applied to investigate the dynamic response of a large-scale composite breakwater on a seabed, and the mechanism of WSSI. Numerical results indicate that there are intensive fluid exchanges between the water body and the seabed and strong seepage forces in the seabed under the ocean wave loading. The excessive upward seepage force leads to the liquefaction of the seabed in the region under wave trough. There is a liquefaction zone in the seabed close to the bottom corner of the rubble mound, which may lead to foundation instability of the composite breakwater. The parametric study indicates that the wave characteristics have a significant impact on the liquefaction properties (depth, width and area). (C) 2012 Elsevier B.V. All rights reserved.

AB -

In this study, an integrated model (PORO-WSSI II) for wave-seabed-structure interactions (WSSI) is developed by combining (i) the Volume-Averaged Reynolds-Averaged Navier-Stokes (VARANS) equations for wave motions in a fluid domain and the porous media flows in porous structures, and (ii) the dynamic Blot's equations for a porous elastic seabed. The effects of the porous flow in seabed and marine structures, and the fluid exchange at the interface between the fluid domain and solid domain on wave characteristics are considered. The finite difference two-step projection method and the forward time difference method are adopted to solve the VARANS equations. The volume of fluid (VOF) method is applied to track water free-surface. The finite element method and the Generalized Newmark method are respectively adopted for the space discretization and time discretization of the dynamic Biot's equations. A one-way integrating method is developed to integrate the VARANS equations with the dynamic Biot's equations. Several experimental data available in the literature are used to validate the integrated model. An overall agreement between the numerical results and the experiment data indicates that the integrated model developed for the WSSI problem is highly reliable. The integrated model is then applied to investigate the dynamic response of a large-scale composite breakwater on a seabed, and the mechanism of WSSI. Numerical results indicate that there are intensive fluid exchanges between the water body and the seabed and strong seepage forces in the seabed under the ocean wave loading. The excessive upward seepage force leads to the liquefaction of the seabed in the region under wave trough. There is a liquefaction zone in the seabed close to the bottom corner of the rubble mound, which may lead to foundation instability of the composite breakwater. The parametric study indicates that the wave characteristics have a significant impact on the liquefaction properties (depth, width and area). (C) 2012 Elsevier B.V. All rights reserved.

KW - Biot's theory KW - Porous seabed KW - Liquefaction KW - BEHAVIOR KW - SOILS KW - FLOWS KW - Integrated model KW - INDUCED PORE PRESSURES KW - POROUS-MEDIA KW - EFFECTIVE STRESSES KW - COMPOSITE BREAKWATER KW - SOLITARY WAVE KW - INDUCED DYNAMIC-RESPONSE KW - SUBMERGED BREAKWATER KW - Composite breakwater KW - Wave-seabed-structure interaction (WSSI) U2 - 10.1016/j.coastaleng.2012.08.006 DO - 10.1016/j.coastaleng.2012.08.006 M1 - Article JO - Coastal Engineering JF - Coastal Engineering SN - 0378-3839 VL - 72 SP - 1 EP - 19 ER - TY - JOUR T1 - An Investigation of the Role of Technical Analysis in Kuwait A1 - Almujamed,Hesham A1 - Fifield,Suzanne A1 - Power,David AU - Almujamed,Hesham AU - Fifield,Suzanne AU - Power,David PY - 2013 Y1 - 2013 N2 - Purpose – The purpose of this paper is to investigate the technical methods that investors in the Kuwait Stock Exchange use to evaluate ordinary shares. The research examines the extent of investors' use of technical analysis, and the technical indicators and the sources of technical information employed by investors. Further, it compares the valuation methods and the sources of information employed by Kuwaiti investors with those used by investors in other developed and emerging stock markets.

Design/methodology/approach – A semi-structured questionnaire guided the interviews with institutional investors, technical analysts and investment analysts in Kuwait.

Findings – Technical analysis is commonly used among research participants, particularly when timing their entry and exit points. The participants use a mixture of trend and pattern seeking; the Moving Average Rule was heavily used in the market but the Filter Rule Approach was not. Interviewees believed that investors did not have complete information about Kuwaiti quoted companies. Investors in Kuwait behave like their counterparts in other developed and emerging stock markets; fundamental analysis is considered the main valuation method among research participants, while technical and risk analyses were ranked second and third, respectively.

Practical implications – Interviewees in Kuwait paid more attention to technical analysis than did investors in developed countries; technical analysts looked at a company's fundamentals before they consulted graphs when deciding to purchase ordinary shares. Further, chartists followed trades of large investors to make profits. This topic needs to be investigated in emerging markets because these markets may be inefficient; trends and patterns may characterise the data from these markets and practitioners may use these techniques to exploit such patterns in returns. Further, the findings in this study may aid the regulators of these markets in their development of a framework that could improve efficiency by increasing the level of disclosure and transparency among listed firms.

Originality/value – This is one of the first studies in Kuwait to report the views of technical analysts and institutional investors about technical approaches to equity investment that are used in the market. Most studies on this topic have been conducted in developed stock markets. The current study considers the case for an emerging stock market, which is important in the Gulf and Middle East region. Further, access to technical analysts has been limited in prior research but this was not an issue in the current investigation. AB - Purpose – The purpose of this paper is to investigate the technical methods that investors in the Kuwait Stock Exchange use to evaluate ordinary shares. The research examines the extent of investors' use of technical analysis, and the technical indicators and the sources of technical information employed by investors. Further, it compares the valuation methods and the sources of information employed by Kuwaiti investors with those used by investors in other developed and emerging stock markets.

Design/methodology/approach – A semi-structured questionnaire guided the interviews with institutional investors, technical analysts and investment analysts in Kuwait.

Findings – Technical analysis is commonly used among research participants, particularly when timing their entry and exit points. The participants use a mixture of trend and pattern seeking; the Moving Average Rule was heavily used in the market but the Filter Rule Approach was not. Interviewees believed that investors did not have complete information about Kuwaiti quoted companies. Investors in Kuwait behave like their counterparts in other developed and emerging stock markets; fundamental analysis is considered the main valuation method among research participants, while technical and risk analyses were ranked second and third, respectively.

Practical implications – Interviewees in Kuwait paid more attention to technical analysis than did investors in developed countries; technical analysts looked at a company's fundamentals before they consulted graphs when deciding to purchase ordinary shares. Further, chartists followed trades of large investors to make profits. This topic needs to be investigated in emerging markets because these markets may be inefficient; trends and patterns may characterise the data from these markets and practitioners may use these techniques to exploit such patterns in returns. Further, the findings in this study may aid the regulators of these markets in their development of a framework that could improve efficiency by increasing the level of disclosure and transparency among listed firms.

Originality/value – This is one of the first studies in Kuwait to report the views of technical analysts and institutional investors about technical approaches to equity investment that are used in the market. Most studies on this topic have been conducted in developed stock markets. The current study considers the case for an emerging stock market, which is important in the Gulf and Middle East region. Further, access to technical analysts has been limited in prior research but this was not an issue in the current investigation. U2 - 10.1108/17554171311308959 DO - 10.1108/17554171311308959 M1 - Article JO - Qualitative Research in Financial Markets JF - Qualitative Research in Financial Markets IS - 1 VL - 5 SP - 43 EP - 64 ER - TY - JOUR T1 - Analysis of a continuous finite element method for H(curl,div)-elliptic interface problem A1 - Duan,Huoyuan A1 - Lin,Ping A1 - Tan,Roger C. E. AU - Duan,Huoyuan AU - Lin,Ping AU - Tan,Roger C. E. PY - 2013 Y1 - 2013 N2 - In this paper, we develop a continuous finite element method for the curlcurl-grad div vector second-order elliptic problem in a three-dimensional polyhedral domain occupied by discontinuous nonhomogeneous anisotropic materials. In spite of the fact that the curlcurl-grad div interface problem is closely related to the elliptic interface problem of vector Laplace operator type, the continuous finite element discretization of the standard variational problem of the former generally fails to give a correct solution even in the case of homogeneous media whenever the physical domain has reentrant corners and edges. To discretize the curlcurl-grad div interface problem by the continuous finite element method, we apply an element-local L2 projector to the curl operator and a pseudo-local L2 projector to the div operator, where the continuous Lagrange linear element enriched by suitable element and face bubbles may be employed. It is shown that the finite element problem retains the same coercivity property as the continuous problem. An error estimate O(hr) in an energy norm is obtained between the analytical solution and the continuous finite element solution, where the analytical solution is in ?Ll=1(Hr(Ol))3 for some r?(1/2,1] due to the domain boundary reentrant corners and edges (e.g., nonconvex polyhedron) and due to the interfaces between the different material domains in O=?Ll=1Ol . AB - In this paper, we develop a continuous finite element method for the curlcurl-grad div vector second-order elliptic problem in a three-dimensional polyhedral domain occupied by discontinuous nonhomogeneous anisotropic materials. In spite of the fact that the curlcurl-grad div interface problem is closely related to the elliptic interface problem of vector Laplace operator type, the continuous finite element discretization of the standard variational problem of the former generally fails to give a correct solution even in the case of homogeneous media whenever the physical domain has reentrant corners and edges. To discretize the curlcurl-grad div interface problem by the continuous finite element method, we apply an element-local L2 projector to the curl operator and a pseudo-local L2 projector to the div operator, where the continuous Lagrange linear element enriched by suitable element and face bubbles may be employed. It is shown that the finite element problem retains the same coercivity property as the continuous problem. An error estimate O(hr) in an energy norm is obtained between the analytical solution and the continuous finite element solution, where the analytical solution is in ?Ll=1(Hr(Ol))3 for some r?(1/2,1] due to the domain boundary reentrant corners and edges (e.g., nonconvex polyhedron) and due to the interfaces between the different material domains in O=?Ll=1Ol . U2 - 10.1007/s00211-012-0500-x DO - 10.1007/s00211-012-0500-x M1 - Article JO - Numerische Mathematik JF - Numerische Mathematik SN - 0029-599X SP - 1 EP - 37 ER - TY - CONF T1 - Beta-secretase 1 (BACE1) inhibition improves obese and diabetic phenotypes in a leptin dependent manner A1 - Meakin,P. J. A1 - Jalicy,S. M. A1 - Irvine,S. W. A1 - Ashford,M. L. J. AU - Meakin,P. J. AU - Jalicy,S. M. AU - Irvine,S. W. AU - Ashford,M. L. J. PY - 2013 Y1 - 2013 UR - http://www.diabetes.org.uk/Diabetes-UK-Professional-Conference/ M1 - Poster ER - TY - JOUR T1 - Biomarkers for illicit heroin T2 - a previously unrecognized origin of papaverine A1 - Seetohul,L. Nitin A1 - Maskell,Peter D. A1 - De Paoli,Giorgia A1 - Pounder,Derrick J. AU - Seetohul,L. Nitin AU - Maskell,Peter D. AU - De Paoli,Giorgia AU - Pounder,Derrick J. PY - 2013 Y1 - 2013 U2 - 10.1093/jat/bks099 DO - 10.1093/jat/bks099 M1 - Letter JO - Journal of Analytical Toxicology JF - Journal of Analytical Toxicology SN - 0146-4760 ER - TY - JOUR T1 - Birt-hogg-dube syndrome is a novel ciliopathy A1 - Luijten,M. A1 - Claessens,T. A1 - Basten,S. A1 - Vernooij,M. A1 - Menko,F. A1 - Nookala,R. A1 - Scott,C A1 - van Geel,M. A1 - Janssen,R. A1 - Easton,J. A1 - Vreeburg,M. A1 - Kamps,M. A1 - Land,S. A1 - Tee,A. A1 - Giles,R. A1 - Coull,B. A1 - van Steensel,M. AU - Luijten,M. AU - Claessens,T. AU - Basten,S. AU - Vernooij,M. AU - Menko,F. AU - Nookala,R. AU - Scott,C AU - van Geel,M. AU - Janssen,R. AU - Easton,J. AU - Vreeburg,M. AU - Kamps,M. AU - Land,S. AU - Tee,A. AU - Giles,R. AU - Coull,B. AU - van Steensel,M. PY - 2013 Y1 - 2013 U2 - 10.1038/jid.2013.100 DO - 10.1038/jid.2013.100 M1 - Meeting abstract JO - Journal of Investigative Dermatology JF - Journal of Investigative Dermatology SN - 0022-202X IS - S1 VL - 133 SP - S136 ER - TY - CHAP T1 - Bruxelles sans Rome T2 - Droit Européen du Divorce A1 - Fiorini,Aude AU - Fiorini,Aude PB - LexisNexis Litec CY - Paris PY - 2013 Y1 - 2013 SN - 9782711017935 VL - 39 BT - Droit Européen du Divorce SP - 701 EP - 728 ER - TY - JOUR T1 - Ca2+ signalling through CatSper and Ca2+ stores regulate different behaviours in human sperm A1 - Alasmari,Wardah A1 - Costello,Sarah A1 - Correia,Joao A1 - Oxenham,Senga K. A1 - Morris,Jennifer A1 - Fernandes,Leonor A1 - Ramalho Santos,Joao A1 - Kirkman-Brown,Jackson A1 - Michelangeli,Francesco A1 - Publicover,Stephen A1 - Barratt,Christopher L. R. AU - Alasmari,Wardah AU - Costello,Sarah AU - Correia,Joao AU - Oxenham,Senga K. AU - Morris,Jennifer AU - Fernandes,Leonor AU - Ramalho Santos,Joao AU - Kirkman-Brown,Jackson AU - Michelangeli,Francesco AU - Publicover,Stephen AU - Barratt,Christopher L. R. PY - 2013 Y1 - 2013 N2 - [Ca2+]i signaling regulates sperm motility, enabling switching between functionally different behaviours that the sperm must employ as it ascends the female tract and fertilizes the oocyte. We report that different behaviours in human sperm are recruited according to the Ca2+ signalling pathway employed. Activation of CatSper (by raising pHi or stimulating with progesterone) caused sustained [Ca2+]i elevation but did not induce hyperactivation, the whiplash-like behaviour required for progression along oviduct and penetration of the zona pellucida. In contrast, penetration into methylcellulose (mimicking penetration into cervical mucus or cumulus matrix) was enhanced by activation of CatSper. NNC55-0396, which potently blocks CatSper currents in human sperm, inhibited this effect. Treatment with 5 uM thimerosal to mobilize stored Ca2+ caused sustained [Ca2+]i elevation and induced strong, sustained hyperactivation that was completely insensitive to NNC55-0396. Thimerosal had no effect on penetration into methylcellulose. 4-aminopyridine (4-AP), a powerful modulator of sperm motility, both raised pHi and mobilized Ca2+ stored in sperm (and from microsomal membrane preparations). 4-AP potently induced hyperactivation, even in cells suspended in Ca2+-depleted medium, and also potentiated penetration into methylcellulose. The latter was sensitive to NNC55-039 but induction of hyperactivaton was not. We conclude that these two components of the sperm [Ca2+]i signaling apparatus have strikingly different effects on sperm motility. Furthermore, since release of stored Ca2+ at the sperm neck occurs by Ca2+-induced-Ca2+-release, CatSper activation will elicit functionally different behaviors according to the sensitivity of the Ca2+ store, which is regulated by capacitation and sensitive to NO from the cumulus. AB - [Ca2+]i signaling regulates sperm motility, enabling switching between functionally different behaviours that the sperm must employ as it ascends the female tract and fertilizes the oocyte. We report that different behaviours in human sperm are recruited according to the Ca2+ signalling pathway employed. Activation of CatSper (by raising pHi or stimulating with progesterone) caused sustained [Ca2+]i elevation but did not induce hyperactivation, the whiplash-like behaviour required for progression along oviduct and penetration of the zona pellucida. In contrast, penetration into methylcellulose (mimicking penetration into cervical mucus or cumulus matrix) was enhanced by activation of CatSper. NNC55-0396, which potently blocks CatSper currents in human sperm, inhibited this effect. Treatment with 5 uM thimerosal to mobilize stored Ca2+ caused sustained [Ca2+]i elevation and induced strong, sustained hyperactivation that was completely insensitive to NNC55-0396. Thimerosal had no effect on penetration into methylcellulose. 4-aminopyridine (4-AP), a powerful modulator of sperm motility, both raised pHi and mobilized Ca2+ stored in sperm (and from microsomal membrane preparations). 4-AP potently induced hyperactivation, even in cells suspended in Ca2+-depleted medium, and also potentiated penetration into methylcellulose. The latter was sensitive to NNC55-039 but induction of hyperactivaton was not. We conclude that these two components of the sperm [Ca2+]i signaling apparatus have strikingly different effects on sperm motility. Furthermore, since release of stored Ca2+ at the sperm neck occurs by Ca2+-induced-Ca2+-release, CatSper activation will elicit functionally different behaviors according to the sensitivity of the Ca2+ store, which is regulated by capacitation and sensitive to NO from the cumulus. U2 - 10.1074/jbc.M112.439356 DO - 10.1074/jbc.M112.439356 M1 - Article JO - Journal of Biological Chemistry JF - Journal of Biological Chemistry SN - 0021-9258 ER - TY - JOUR T1 - Cardiopulmonary exercise testing T2 - arm crank vs cycle ergometry A1 - Orr,J.L. A1 - Williamson,P. A1 - Anderson,W. A1 - Ross,R. A1 - McCafferty,S. A1 - Fettes,P. AU - Orr,J.L. AU - Williamson,P. AU - Anderson,W. AU - Ross,R. AU - McCafferty,S. AU - Fettes,P. PY - 2013 Y1 - 2013 N2 - This pilot study compared oxygen consumption during arm crank and cycle ergometer tests in 15 women. The mean (SD) peak oxygen consumption was less with arm cranking (25 (5) ml.kg.min) than with cycling (40 (7) ml.kg.min), p <0.0001. The mean (SD) anaerobic threshold was less with arm cranking (13 (2) ml.kg. min) than with cycling (20 (4) ml.kg.min ), p <0.0001. There was moderate correlation, r = 0.60, between the anaerobic thresholds determined by arm and leg exercise, p = 0.0007. This study suggests that arm crank cardiopulmonary exercise testing could be used for pre-operative assessment in those unable to cycle. © Anaesthesia © 2013 The Association of Anaesthetists of Great Britain and Ireland. AB - This pilot study compared oxygen consumption during arm crank and cycle ergometer tests in 15 women. The mean (SD) peak oxygen consumption was less with arm cranking (25 (5) ml.kg.min) than with cycling (40 (7) ml.kg.min), p <0.0001. The mean (SD) anaerobic threshold was less with arm cranking (13 (2) ml.kg. min) than with cycling (20 (4) ml.kg.min ), p <0.0001. There was moderate correlation, r = 0.60, between the anaerobic thresholds determined by arm and leg exercise, p = 0.0007. This study suggests that arm crank cardiopulmonary exercise testing could be used for pre-operative assessment in those unable to cycle. © Anaesthesia © 2013 The Association of Anaesthetists of Great Britain and Ireland. U2 - 10.1111/anae.12195 DO - 10.1111/anae.12195 M1 - Article JO - Anaesthesia JF - Anaesthesia SN - 0003-2409 IS - 5 VL - 68 SP - 497 EP - 501 ER - TY - JOUR T1 - Cardiovascular events after clarithromycin use in lower respiratory tract infections T2 - analysis of two prospective cohort studies A1 - Schembri,Stuart A1 - Williamson,Peter A. A1 - Short,Philip M. A1 - Singanayagam,Aran A1 - Akram,Ahsan A1 - Taylor,Joanne A1 - Singanayagam,Anika A1 - Hill,Adam T. A1 - Chalmers,James D. AU - Schembri,Stuart AU - Williamson,Peter A. AU - Short,Philip M. AU - Singanayagam,Aran AU - Akram,Ahsan AU - Taylor,Joanne AU - Singanayagam,Anika AU - Hill,Adam T. AU - Chalmers,James D. PY - 2013 Y1 - 2013 N2 - Objective To study the association of clarithromycin with cardiovascular events in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia.

Design Analysis of two prospectively collected datasets.

Setting Chronic obstructive pulmonary disease dataset including patients admitted to one of 12 hospitals around the United Kingdom between 2009 and 2011; Edinburgh pneumonia study cohort including patients admitted to NHS Lothian Hospitals between 2005 and 2009.

Population 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease and 1631 patients admitted with community acquired pneumonia.

Main outcome measures Hazard ratios for cardiovascular events at one year (defined as hospital admissions with acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina). Secondary outcomes were all cause and cardiovascular mortality at one year.

Results 268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and 171 in the community acquired pneumonia cohort over one year. After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease was associated with an increased risk of cardiovascular events and acute coronary syndrome—hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68). After multivariable adjustment, clarithromycin use in community acquired pneumonia was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38) but not acute coronary syndrome (1.65, 0.97 to 2.80). The association between clarithromycin use and cardiovascular events persisted after matching for the propensity to receive clarithromycin. A significant association was found between clarithromycin use and cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26) but not all cause mortality (1.16, 0.90 to 1.51) in acute exacerbations of chronic obstructive pulmonary disease. No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality. Longer durations of clarithromycin use were associated with more cardiovascular events. Use of ß lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin.

Conclusions The use of clarithromycin in the setting of acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia may be associated with increased cardiovascular events. These findings require confirmation in other datasets. AB - Objective To study the association of clarithromycin with cardiovascular events in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia.

Design Analysis of two prospectively collected datasets.

Setting Chronic obstructive pulmonary disease dataset including patients admitted to one of 12 hospitals around the United Kingdom between 2009 and 2011; Edinburgh pneumonia study cohort including patients admitted to NHS Lothian Hospitals between 2005 and 2009.

Population 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease and 1631 patients admitted with community acquired pneumonia.

Main outcome measures Hazard ratios for cardiovascular events at one year (defined as hospital admissions with acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina). Secondary outcomes were all cause and cardiovascular mortality at one year.

Results 268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and 171 in the community acquired pneumonia cohort over one year. After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease was associated with an increased risk of cardiovascular events and acute coronary syndrome—hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68). After multivariable adjustment, clarithromycin use in community acquired pneumonia was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38) but not acute coronary syndrome (1.65, 0.97 to 2.80). The association between clarithromycin use and cardiovascular events persisted after matching for the propensity to receive clarithromycin. A significant association was found between clarithromycin use and cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26) but not all cause mortality (1.16, 0.90 to 1.51) in acute exacerbations of chronic obstructive pulmonary disease. No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality. Longer durations of clarithromycin use were associated with more cardiovascular events. Use of ß lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin.

Conclusions The use of clarithromycin in the setting of acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia may be associated with increased cardiovascular events. These findings require confirmation in other datasets. U2 - 10.1136/bmj.f1235 DO - 10.1136/bmj.f1235 M1 - Article JO - BMJ (Clinical Research Ed.) JF - BMJ (Clinical Research Ed.) SN - 0267-0623 IS - 346 ER - TY - JOUR T1 - Cardiovascular safety of lumiracoxib T2 - a meta-analysis of randomised controlled trials in patients with osteoarthritis A1 - Mackenzie,Isla S. A1 - Wei,Li A1 - MacDonald,Thomas M. AU - Mackenzie,Isla S. AU - Wei,Li AU - MacDonald,Thomas M. PY - 2013 Y1 - 2013 N2 - Purpose: To re-evaluate the cardiovascular risk of lumiracoxib compared with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo in patients with osteoarthritis. Methods: We conducted a meta-analysis of randomised controlled trials of lumiracoxib versus placebo or other NSAIDs in patients with osteoarthritis reported up to January 2010. Both published and unpublished trials were included. PubMed searches using predefined search criteria (lumiracoxib AND osteoarthritis, limits: none; COX-189 AND osteoarthritis, limits: none) were used to obtain the relevant published trials. Novartis granted explicit access to their company studies and the right to use these study reports for the purposes of publication in peer reviewed journals. Endpoints were the Antiplatelet Trialists' Collaboration (APTC) endpoint and individual cardiovascular endpoints. Results: Meta-analysis of 6 trials of lumiracoxib versus placebo revealed no difference in cardiovascular outcomes. Meta-analysis of 12 trials of lumiracoxib versus other NSAIDs also revealed no difference. The pooled odds ratios were: 1.16 (95% CI 0.82, 1.63); 1.66 (95% CI 0.84, 3.29); 0.95 (95% CI 0.52, 1.76) and 1.04 (95% CI 0.60, 1.80) for the APTC endpoint, myocardial infarction, stroke and cardiovascular death respectively. Conclusions: The results suggest that there were no significant differences in cardiovascular outcomes between lumiracoxib and placebo or between lumiracoxib and other NSAIDs in patients with osteoarthritis. Wide confidence intervals mean that further research is needed in this area to confirm these findings. © 2012 The Author(s). AB - Purpose: To re-evaluate the cardiovascular risk of lumiracoxib compared with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo in patients with osteoarthritis. Methods: We conducted a meta-analysis of randomised controlled trials of lumiracoxib versus placebo or other NSAIDs in patients with osteoarthritis reported up to January 2010. Both published and unpublished trials were included. PubMed searches using predefined search criteria (lumiracoxib AND osteoarthritis, limits: none; COX-189 AND osteoarthritis, limits: none) were used to obtain the relevant published trials. Novartis granted explicit access to their company studies and the right to use these study reports for the purposes of publication in peer reviewed journals. Endpoints were the Antiplatelet Trialists' Collaboration (APTC) endpoint and individual cardiovascular endpoints. Results: Meta-analysis of 6 trials of lumiracoxib versus placebo revealed no difference in cardiovascular outcomes. Meta-analysis of 12 trials of lumiracoxib versus other NSAIDs also revealed no difference. The pooled odds ratios were: 1.16 (95% CI 0.82, 1.63); 1.66 (95% CI 0.84, 3.29); 0.95 (95% CI 0.52, 1.76) and 1.04 (95% CI 0.60, 1.80) for the APTC endpoint, myocardial infarction, stroke and cardiovascular death respectively. Conclusions: The results suggest that there were no significant differences in cardiovascular outcomes between lumiracoxib and placebo or between lumiracoxib and other NSAIDs in patients with osteoarthritis. Wide confidence intervals mean that further research is needed in this area to confirm these findings. © 2012 The Author(s). KW - IBUPROFEN KW - NSAIDs KW - Lumiracoxib KW - Osteoarthritis KW - BLOOD-PRESSURE KW - TOLERABILITY KW - DOUBLE-BLIND KW - KNEE KW - Cardiovascular KW - CELECOXIB KW - PLACEBO KW - 13-WEEK KW - HYPERTENSION KW - Cyclooxygenase KW - EFFICACY KW - Hypertension UR - http://www.springerlink.com/content/733366p302q11766/ U2 - 10.1007/s00228-012-1335-1 DO - 10.1007/s00228-012-1335-1 M1 - Article JO - European Journal of Clinical Pharmacology JF - European Journal of Clinical Pharmacology SN - 0031-6970 IS - 2 VL - 69 SP - 133 EP - 141 ER - TY - JOUR T1 - Cause-specific mortality in Scottish patients with colorectal cancer with and without type 2 diabetes (2000-2007) A1 - Walker,J. J. A1 - Brewster,D H A1 - Colhoun,H M A1 - Fischbacher,C M A1 - Lindsay,R S A1 - Wild,S H A1 - on behalf of the Scottish Diabetes Research Network (SDRN) Epidemiology Group AU - Walker,J. J. AU - Brewster,D H AU - Colhoun,H M AU - Fischbacher,C M AU - Lindsay,R S AU - Wild,S H AU - on behalf of the Scottish Diabetes Research Network (SDRN) Epidemiology Group PY - 2013 Y1 - 2013 N2 - AIMS/HYPOTHESIS: The objective of this study was to use Scottish national data to assess the influence of type 2 diabetes on (1) survival (overall and cause-specific) in multiple time intervals after diagnosis of colorectal cancer and (2) cause of death. METHODS: Data from the Scottish Cancer Registry were linked to data from a population-based national diabetes register. All people in Scotland diagnosed with non-metastatic cancer of the colon or rectum in 2000-2007 were included. The effect of pre-existing type 2 diabetes on survival over four discrete time intervals (5 years) after cancer diagnosis was assessed by Cox regression. Cumulative incidence functions were calculated representing the respective probabilities of death from the competing causes of colorectal cancer, cardiovascular disease, other cancers and any other cause. RESULTS: Data were available for 19,505 people with colon or rectal cancer (1,957 with pre-existing diabetes). Cause-specific mortality analyses identified a stronger association between diabetes and cardiovascular disease mortality than that between diabetes and cancer mortality. Beyond 5 years after colon cancer diagnosis, diabetes was associated with a detrimental effect on all-cause mortality after adjustment for age, socioeconomic status and cancer stage (HR [95% CI]: 1.57 [1.19, 2.06] in men; 1.84 [1.36, 2.50] in women). For patients with rectal cancer, diabetes was not associated with differential survival in any time interval. CONCLUSIONS/INTERPRETATION: Poorer survival observed for colon cancer associated with type 2 diabetes in Scotland may be explained by higher mortality from causes other than cancer. AB - AIMS/HYPOTHESIS: The objective of this study was to use Scottish national data to assess the influence of type 2 diabetes on (1) survival (overall and cause-specific) in multiple time intervals after diagnosis of colorectal cancer and (2) cause of death. METHODS: Data from the Scottish Cancer Registry were linked to data from a population-based national diabetes register. All people in Scotland diagnosed with non-metastatic cancer of the colon or rectum in 2000-2007 were included. The effect of pre-existing type 2 diabetes on survival over four discrete time intervals (5 years) after cancer diagnosis was assessed by Cox regression. Cumulative incidence functions were calculated representing the respective probabilities of death from the competing causes of colorectal cancer, cardiovascular disease, other cancers and any other cause. RESULTS: Data were available for 19,505 people with colon or rectal cancer (1,957 with pre-existing diabetes). Cause-specific mortality analyses identified a stronger association between diabetes and cardiovascular disease mortality than that between diabetes and cancer mortality. Beyond 5 years after colon cancer diagnosis, diabetes was associated with a detrimental effect on all-cause mortality after adjustment for age, socioeconomic status and cancer stage (HR [95% CI]: 1.57 [1.19, 2.06] in men; 1.84 [1.36, 2.50] in women). For patients with rectal cancer, diabetes was not associated with differential survival in any time interval. CONCLUSIONS/INTERPRETATION: Poorer survival observed for colon cancer associated with type 2 diabetes in Scotland may be explained by higher mortality from causes other than cancer. U2 - 10.1007/s00125-013-2917-x DO - 10.1007/s00125-013-2917-x M1 - Article JO - Diabetologia JF - Diabetologia IS - 7 VL - 56 SP - 1531 EP - 1541 ER - TY - JOUR T1 - CENP-A confers a reduction in height on octameric nucleosomes A1 - Miell,Matthew D.D. A1 - Barysz,Helena M. A1 - Rappsilber,Juri A1 - Allshire,Robin C. A1 - Fuller,Colin J. A1 - Straight,Aaron F. A1 - Guse,Annika A1 - Downes,Andrew A1 - Owen-Hughes,Tom AU - Miell,Matthew D.D. AU - Barysz,Helena M. AU - Rappsilber,Juri AU - Allshire,Robin C. AU - Fuller,Colin J. AU - Straight,Aaron F. AU - Guse,Annika AU - Downes,Andrew AU - Owen-Hughes,Tom PY - 2013 Y1 - 2013 N2 - Nucleosomes with histone H3 replaced by CENP-A direct kinetochore assembly. CENP-A nucleosomes from human and Drosophila have been reported to have reduced heights as compared to canonical octameric H3 nucleosomes, thus suggesting a unique tetrameric hemisomal composition. We demonstrate that octameric CENP-A nucleosomes assembled in vitro exhibit reduced heights, indicating that they are physically distinct from H3 nucleosomes and negating the need to invoke the presence of hemisomes. AB - Nucleosomes with histone H3 replaced by CENP-A direct kinetochore assembly. CENP-A nucleosomes from human and Drosophila have been reported to have reduced heights as compared to canonical octameric H3 nucleosomes, thus suggesting a unique tetrameric hemisomal composition. We demonstrate that octameric CENP-A nucleosomes assembled in vitro exhibit reduced heights, indicating that they are physically distinct from H3 nucleosomes and negating the need to invoke the presence of hemisomes. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84876862852&md5=32d7eb0425af1a77809cb10a4bdd193d U2 - 10.1038/nsmb.2574 DO - 10.1038/nsmb.2574 M1 - Article JO - Nature Structural & Molecular Biology JF - Nature Structural & Molecular Biology SN - 1545-9993 ER - TY - JOUR T1 - Centrifuge modeling of the non destructive testing of soil anchorages A1 - Palop ,K. A1 - Ivanovic,A. A1 - Brennan,A. J. AU - Palop ,K. AU - Ivanovic,A. AU - Brennan,A. J. PY - 2013 Y1 - 2013 N2 - Ground reinforcement anchorages are a means of ensuring the stability of a wide range of structures and retaining walls. The performance of an individual anchorage depends on the tensile load that the anchorage is carrying but this will change over the anchorage’s lifespan, so it is therefore necessary to have some way of measuring this load. A nondestructive technique, ground anchorage integrity testing (GRANIT), in which impulse responses of anchorages are determined to evaluate whether load transfer is maintained, has previously been developed for anchorages in rock. This research examines the possibility of extending this to soil anchorage systems. In this work, implementation of a model nondestructive testing system is tested using a geotechnical centrifuge. Load distributions along centrifuge model anchorages are measured and found to reduce gradually within the fixed length, as is the case with rock. Anchorage frequency responses to impulse loads are then evaluated to validate the consistency of the results obtained. Various anchorage inclinations and fixed lengths are also investigated, showing that inclined anchorages contain a greater range of frequencies in their signature response. The practical importance of these results is that nondestructive testing may be usable for anchorages in soil as well as anchorages in rock. Further investigation is necessary to refine the relationship between anchorage load and response frequencies. This may be accomplished using centrifuge modeling. AB - Ground reinforcement anchorages are a means of ensuring the stability of a wide range of structures and retaining walls. The performance of an individual anchorage depends on the tensile load that the anchorage is carrying but this will change over the anchorage’s lifespan, so it is therefore necessary to have some way of measuring this load. A nondestructive technique, ground anchorage integrity testing (GRANIT), in which impulse responses of anchorages are determined to evaluate whether load transfer is maintained, has previously been developed for anchorages in rock. This research examines the possibility of extending this to soil anchorage systems. In this work, implementation of a model nondestructive testing system is tested using a geotechnical centrifuge. Load distributions along centrifuge model anchorages are measured and found to reduce gradually within the fixed length, as is the case with rock. Anchorage frequency responses to impulse loads are then evaluated to validate the consistency of the results obtained. Various anchorage inclinations and fixed lengths are also investigated, showing that inclined anchorages contain a greater range of frequencies in their signature response. The practical importance of these results is that nondestructive testing may be usable for anchorages in soil as well as anchorages in rock. Further investigation is necessary to refine the relationship between anchorage load and response frequencies. This may be accomplished using centrifuge modeling. KW - Centrifuge models KW - Anchorage KW - Nondestructive tests KW - Soil stabilization U2 - 10.1061/(ASCE)GT.1943-5606.0000788 DO - 10.1061/(ASCE)GT.1943-5606.0000788 M1 - Article JO - Journal of Geotechnical and Geoenvironmental Engineering JF - Journal of Geotechnical and Geoenvironmental Engineering SN - 1090-0241 IS - 6 VL - 139 SP - 880 EP - 891 ER - TY - JOUR T1 - Centrobin controls mother-daughter centriole asymmetry in Drosophila neuroblasts A1 - Januschke,J A1 - Reina,J A1 - Llamazares,S A1 - Bertran,T A1 - Rossi,F A1 - Roig,J A1 - Gonzalez,C AU - Januschke,J AU - Reina,J AU - Llamazares,S AU - Bertran,T AU - Rossi,F AU - Roig,J AU - Gonzalez,C PY - 2013 Y1 - 2013 N2 - During interphase in Drosophila neuroblasts, the Centrobin (CNB)-positive daughter centriole retains pericentriolar material (PCM) and organizes an aster that is a key determinant of the orientation of cell division. Here we show that daughter centrioles depleted of CNB cannot fulfil this function whereas mother centrioles that carry ectopic CNB can. CNB co-precipitates with a set of centrosomal proteins that include ?-TUB, ANA2, CNN, SAS-4, ASL, DGRIP71, POLO and SAS-6. Following chemical inhibition of POLO or removal of three POLO phosphorylation sites present in CNB, the interphase microtubule aster is lost. These results demonstrate that centriolar CNB localization is both necessary and sufficient to enable centrioles to retain PCM and organize the interphase aster in Drosophila neuroblasts. They also reveal an interphase function for POLO in this process that seems to have co-opted part of the protein network involved in mitotic centrosome maturation. AB - During interphase in Dr