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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 EP - 915 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 - 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 - BackgroundAMPK (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 - AMPK modulates glucose-sensing in insulin-secreting cells by altered phosphotransfer to K 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 - 2013/4 Y1 - 2013/4 N2 - Glucose-sensing (GS) behaviour in pancreatic ß-cells is dependent on ATP-sensitive K channel (K) activity, which is controlled by the relative levels of the K ligands ATP and ADP, responsible for closing and opening K, respectively. However, the mechanism by which ß-cells transfer energy status from mitochondria to K 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 K 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 APA blocked this action of AMPK. Using conditions that maximised AMPK-induced K opening, there was a significant increase in AK1, AK2 and UCP2 mRNA expression. Thus we propose that K 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 K by phosphotransfer cascades. © 2013 The Author(s). AB - Glucose-sensing (GS) behaviour in pancreatic ß-cells is dependent on ATP-sensitive K channel (K) activity, which is controlled by the relative levels of the K ligands ATP and ADP, responsible for closing and opening K, respectively. However, the mechanism by which ß-cells transfer energy status from mitochondria to K 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 K 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 APA blocked this action of AMPK. Using conditions that maximised AMPK-induced K opening, there was a significant increase in AK1, AK2 and UCP2 mRNA expression. Thus we propose that K 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 K by phosphotransfer cascades. © 2013 The Author(s). UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875906437&md5=8960897f793bb07236619649f840c8af 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 SP - 1 EP - 13 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 - 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 - 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 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 - 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 - 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 - 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.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: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 - 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).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 - 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 - 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 - 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 - BackgroundSeveral 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.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.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 - 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.
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.
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.
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.
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.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 - BackgroundPurpose 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 - ‘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 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.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 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 - 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 - 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.Aicardi-Goutieres syndrome is a genetically determined infantile encephalopathy, manifesting as progressive microcephaly, psychomotor retardation, and in similar to 25% of patients, death in early childhood. Aicardi-Goutieres syndrome is caused by mutations in any of the genes encoding TREX1, RNASEH2-A, -B, -C and SAMHD1, with protein dysfunction hypothesized to result in the accumulation of nucleic acids within the cell, thus triggering an autoinflammatory response with increased interferon-alpha production. Astrocytes have been identified as a major source of interferon-alpha production in the brains of patients with Aicardi-Goutieres syndrome. Here, we study the effect of interferon-alpha treatment on astrocytes derived from immortalized human neural stem cells. Chronic interferon-alpha treatment promoted astrocyte activation and a reduction in cell proliferation. Moreover, chronic exposure resulted in an alteration of genes and proteins involved in the stability of white matter (ATF4, eIF2B alpha, cathepsin D, cystatin F), an increase of antigen-presenting genes (human leukocyte antigen class I) and downregulation of pro-angiogenic factors and other cytokines (vascular endothelial growth factor and IL-1). Interestingly, withdrawal of interferon-alpha for 7 days barely reversed these cellular alterations, demonstrating that the interferon-alpha mediated effects persist over time. We confirmed our in vitro findings using brain samples from patients with Aicardi-Goutieres syndrome. Our results support the idea of interferon-alpha as a key factor in the pathogenesis of Aicardi-Goutieres syndrome relating to the observed leukodystrophy and microangiopathy. Because of the sustained interferon-alpha effect, even after withdrawal, therapeutic targets for Aicardi-Goutieres syndrome, and other interferon-alpha-mediated encephalopathies, may include downstream interferon-alpha signalling cascade effectors rather than interferon-alpha alone.
AB -Aicardi-Goutieres syndrome is a genetically determined infantile encephalopathy, manifesting as progressive microcephaly, psychomotor retardation, and in similar to 25% of patients, death in early childhood. Aicardi-Goutieres syndrome is caused by mutations in any of the genes encoding TREX1, RNASEH2-A, -B, -C and SAMHD1, with protein dysfunction hypothesized to result in the accumulation of nucleic acids within the cell, thus triggering an autoinflammatory response with increased interferon-alpha production. Astrocytes have been identified as a major source of interferon-alpha production in the brains of patients with Aicardi-Goutieres syndrome. Here, we study the effect of interferon-alpha treatment on astrocytes derived from immortalized human neural stem cells. Chronic interferon-alpha treatment promoted astrocyte activation and a reduction in cell proliferation. Moreover, chronic exposure resulted in an alteration of genes and proteins involved in the stability of white matter (ATF4, eIF2B alpha, cathepsin D, cystatin F), an increase of antigen-presenting genes (human leukocyte antigen class I) and downregulation of pro-angiogenic factors and other cytokines (vascular endothelial growth factor and IL-1). Interestingly, withdrawal of interferon-alpha for 7 days barely reversed these cellular alterations, demonstrating that the interferon-alpha mediated effects persist over time. We confirmed our in vitro findings using brain samples from patients with Aicardi-Goutieres syndrome. Our results support the idea of interferon-alpha as a key factor in the pathogenesis of Aicardi-Goutieres syndrome relating to the observed leukodystrophy and microangiopathy. Because of the sustained interferon-alpha effect, even after withdrawal, therapeutic targets for Aicardi-Goutieres syndrome, and other interferon-alpha-mediated encephalopathies, may include downstream interferon-alpha signalling cascade effectors rather than interferon-alpha alone.
KW - leukodystrophy KW - INNATE IMMUNE-RESPONSE KW - IFN-ALPHA KW - ALZHEIMERS-DISEASE KW - angiopathy KW - RESTRICTION FACTOR SAMHD1 KW - BASAL GANGLIA KW - AUTOIMMUNE-DISEASE KW - PRODUCE INTERFERON KW - IN-VITRO KW - PROGRESSIVE FAMILIAL ENCEPHALOPATHY KW - astrocytes KW - VANISHING WHITE-MATTER KW - interferon UR - http://brain.oxfordjournals.org/content/136/1.toc U2 - 10.1093/brain/aws321 DO - 10.1093/brain/aws321 M1 - Article JO - Brain JF - Brain SN - 0006-8950 IS - 1 VL - 136 SP - 245 EP - 258 ER - TY - CONF 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 Y1 - 2013 UR - http://www.diabetes.org.uk/Diabetes-UK-Professional-Conference/ M1 - Poster ER - TY - JOUR T1 - Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: T2 - Evidence for a Digenic Influence on Hypertension A1 - Alvarez-Madrazo,Samantha A1 - MacKenzie,Scott M. A1 - Davies,Eleanor A1 - Fraser,Robert A1 - Lee,Wai-Kwong A1 - Brown,Morris A1 - Caulfield,Mark J. A1 - Dominiczak,Anna F. A1 - Farrall,Martin A1 - Lathrop,Mark A1 - Hedner,Thomas A1 - Melander,Olle A1 - Munroe,Patricia B. A1 - Samani,Nilesh A1 - Stewart,Paul M. A1 - Wahlstrand,Bjorn A1 - Webster,John A1 - Palmer,Colin N. A. A1 - Padmanabhan,Sandosh A1 - Connell,John M. AU - Alvarez-Madrazo,Samantha AU - MacKenzie,Scott M. AU - Davies,Eleanor AU - Fraser,Robert AU - Lee,Wai-Kwong AU - Brown,Morris AU - Caulfield,Mark J. AU - Dominiczak,Anna F. AU - Farrall,Martin AU - Lathrop,Mark AU - Hedner,Thomas AU - Melander,Olle AU - Munroe,Patricia B. AU - Samani,Nilesh AU - Stewart,Paul M. AU - Wahlstrand,Bjorn AU - Webster,John AU - Palmer,Colin N. A. AU - Padmanabhan,Sandosh AU - Connell,John M. PY - 2013 Y1 - 2013 N2 -The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n = 3340) and confirmation (n = 2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio = 1.16, P = 8.54x10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio = 1.11; P = 7.4x10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio = 0.88, P = 2.2x10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis. (Hypertension. 2013;61:232-239.). center dot Online Data Supplement
AB -The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n = 3340) and confirmation (n = 2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio = 1.16, P = 8.54x10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio = 1.11; P = 7.4x10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio = 0.88, P = 2.2x10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis. (Hypertension. 2013;61:232-239.). center dot Online Data Supplement
KW - EXCRETION KW - GENOME-WIDE ASSOCIATION KW - CONSEQUENCES KW - cortisol KW - 11-BETA HYDROXYLASE KW - CYP11B1 KW - CYP11B2 KW - aldosterone KW - haplotypes KW - ALDOSTERONE SYNTHASE KW - METAANALYSIS KW - DAHL RAT KW - BLOOD-PRESSURE VARIATION KW - LINKAGE KW - hypertension KW - MUTATIONS KW - population U2 - 10.1161/HYPERTENSIONAHA.112.200741 DO - 10.1161/HYPERTENSIONAHA.112.200741 M1 - Article JO - Hypertension JF - Hypertension SN - 0194-911X VL - 61 SP - 232 EP - 239 ER - TY - JOUR T1 - Common variant in the HMGA2 gene increases susceptibility to nephropathy in patients with type 2 diabetes A1 - Alkayyali,S. A1 - Lajer,M. A1 - Deshmukh,H. A1 - Ahlqvist,E. A1 - Colhoun,H. A1 - Isomaa,B. A1 - Rossing,P. A1 - Groop,L. A1 - Lyssenko,V. AU - Alkayyali,S. AU - Lajer,M. AU - Deshmukh,H. AU - Ahlqvist,E. AU - Colhoun,H. AU - Isomaa,B. AU - Rossing,P. AU - Groop,L. AU - Lyssenko,V. PY - 2013 Y1 - 2013 N2 -Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes.
We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmo Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n = 345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n = 784]) and non-diabetic (Malmo Preventive Project [n = 2,523], Botnia study [n = 2,247]) cohorts.
In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p = 0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n = 1,233 cases, n = 2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p = 0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n = 2,499, beta +/- SEM, -3.7 +/- 1.2 ml/min, p = 0.002) and also in non-diabetic individuals (n = 17,602, beta +/- SEM, -0.008 +/- 0.003 ml/min (log (e) ), p = 0.006).
These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.
AB -Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes.
We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmo Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n = 345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n = 784]) and non-diabetic (Malmo Preventive Project [n = 2,523], Botnia study [n = 2,247]) cohorts.
In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p = 0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n = 1,233 cases, n = 2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p = 0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n = 2,499, beta +/- SEM, -3.7 +/- 1.2 ml/min, p = 0.002) and also in non-diabetic individuals (n = 17,602, beta +/- SEM, -0.008 +/- 0.003 ml/min (log (e) ), p = 0.006).
These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.
KW - Diabetes complications KW - RISK KW - Type 2 diabetes KW - GLOMERULAR-FILTRATION-RATE KW - HMGA2 KW - COMPLICATIONS KW - FASTING GLUCOSE KW - MELLITUS KW - Nephropathy KW - SNP KW - MICROALBUMINURIA KW - PROTEINS KW - ASSOCIATION KW - KIDNEY-FUNCTION KW - LOCI U2 - 10.1007/s00125-012-2760-5 DO - 10.1007/s00125-012-2760-5 M1 - Article JO - Diabetologia JF - Diabetologia SN - 0012-186X IS - 2 VL - 56 SP - 323 EP - 329 ER - TY - JOUR T1 - Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis A1 - Fakiola,Michaela A1 - Strange,Amy A1 - Cordell,Heather J. A1 - Miller,E. Nancy A1 - Pirinen,Matti A1 - Su,Zhan A1 - Mishra,Anshuman A1 - Mehrotra,Sanjana A1 - Monteiro,Gloria R. A1 - Band,Gavin A1 - Bellenguez,Celine A1 - Dronov,Serge A1 - Edkins,Sarah A1 - Freeman,Colin A1 - Giannoulatou,Eleni A1 - Gray,Emma A1 - Hunt,Sarah E. A1 - Lacerda,Henio G. A1 - Langford,Cordelia A1 - Pearson,Richard A1 - Pontes,Nubia N. A1 - Rai,Madhukar A1 - Singh,Shri P. A1 - Smith,Linda A1 - Sousa,Olivia A1 - Vukcevic,Damjan A1 - Bramon,Elvira A1 - Brown,Matthew A. A1 - Casas,Juan P. A1 - Corvin,Aiden A1 - Duncanson,Audrey A1 - Jankowski,Janusz A1 - Markus,Hugh S. A1 - Mathew,Christopher G. A1 - Palmer,Colin N. A. A1 - Plomin,Robert A1 - Rautanen,Anna A1 - Sawcer,Stephen J. A1 - Trembath,Richard C. A1 - Viswanathan,Ananth C. A1 - Wood,Nicholas W. A1 - Wilson,Mary E. A1 - Deloukas,Panos A1 - Peltonen,Leena A1 - Christiansen,Frank A1 - Witt,Campbell A1 - Jeronimo,Selma M. B. A1 - Sundar,Shyam A1 - Spencer,Chris C. A. A1 - Blackwell,Jenefer M. A1 - Donnelly,Peter A1 - LeishGEN Consortium A1 - Wellcome Trust Case Control AU - Fakiola,Michaela AU - Strange,Amy AU - Cordell,Heather J. AU - Miller,E. Nancy AU - Pirinen,Matti AU - Su,Zhan AU - Mishra,Anshuman AU - Mehrotra,Sanjana AU - Monteiro,Gloria R. AU - Band,Gavin AU - Bellenguez,Celine AU - Dronov,Serge AU - Edkins,Sarah AU - Freeman,Colin AU - Giannoulatou,Eleni AU - Gray,Emma AU - Hunt,Sarah E. AU - Lacerda,Henio G. AU - Langford,Cordelia AU - Pearson,Richard AU - Pontes,Nubia N. AU - Rai,Madhukar AU - Singh,Shri P. AU - Smith,Linda AU - Sousa,Olivia AU - Vukcevic,Damjan AU - Bramon,Elvira AU - Brown,Matthew A. AU - Casas,Juan P. AU - Corvin,Aiden AU - Duncanson,Audrey AU - Jankowski,Janusz AU - Markus,Hugh S. AU - Mathew,Christopher G. AU - Palmer,Colin N. A. AU - Plomin,Robert AU - Rautanen,Anna AU - Sawcer,Stephen J. AU - Trembath,Richard C. AU - Viswanathan,Ananth C. AU - Wood,Nicholas W. AU - Wilson,Mary E. AU - Deloukas,Panos AU - Peltonen,Leena AU - Christiansen,Frank AU - Witt,Campbell AU - Jeronimo,Selma M. B. AU - Sundar,Shyam AU - Spencer,Chris C. A. AU - Blackwell,Jenefer M. AU - Donnelly,Peter AU - LeishGEN Consortium AU - Wellcome Trust Case Control PY - 2013 Y1 - 2013 N2 -To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P-combined = 2.76 x 10(-17) and odds ratio (OR) = 1.41, 95% confidence interval (Cl) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.
AB -To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P-combined = 2.76 x 10(-17) and odds ratio (OR) = 1.41, 95% confidence interval (Cl) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.
KW - GENES KW - GENOME-WIDE ASSOCIATION KW - MODEL KW - INFECTIOUS-DISEASES KW - SUDAN KW - NORTHEASTERN BRAZIL KW - POLYMORPHISM KW - CHAGASI KW - SCAN U2 - 10.1038/ng.2518 DO - 10.1038/ng.2518 M1 - Article JO - Nature Genetics JF - Nature Genetics SN - 1061-4036 IS - 2 VL - 45 SP - 208 EP - 213 ER - TY - JOUR T1 - Community acquired infections in older patients admitted to hospital from care homes versus the community: cohort study of microbiology and outcomes A1 - Marwick,Charis A1 - Hernandez Santiago,Virginia A1 - McCowan,Colin A1 - Broomhall,Janice A1 - Davey,Peter AU - Marwick,Charis AU - Hernandez Santiago,Virginia AU - McCowan,Colin AU - Broomhall,Janice AU - Davey,Peter PY - 2013 Y1 - 2013 N2 - BackgroundContemporary management of the axilla in breast cancer surgery remains in evolution. Axillary lymph node status in breast cancer is a major prognostic factor and remains integral to guiding adjuvant treatment decisions. There remains controversy regarding the management of the node-positive axilla in clinically node-negative Primary breast cancer. Trials to date have suggested re-evaluation of the historical therapeutic strategy that a positive sentinel node requires axillary node dissection. However, further evidence is required before modern clinical management of the axilla should be altered. As patient awareness and technical expertise grow, national rates of breast reconstruction after mastectomy continue to rise. Oncoplastic techniques continue to evolve and many patients are suitable for a plethora of reconstructive options. Despite the widespread practice of breast reconstruction globally, there is limited randomised evidence comparing the optimal type and/or timing of breast reconstruction on which to base practice. Breast reconstruction type is either purely autologous, implant-based or a combination of these two techniques. We explore the benefits and limitations of these techniques and some of the key findings of the National Mastectomy and Breast Reconstruction Audit. The timing of reconstruction after mastectomy is either immediate (a single procedure) or delayed (for an indefinite period after mastectomy). The ideal reconstruction is one that is best aligned to the patient's expectations, as this will achieve the highest levels of long-term patient satisfaction. Selecting the optimal type of breast reconstruction at the right time for the right patient remains the key challenge in breast reconstruction. (c) 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
AB -Contemporary management of the axilla in breast cancer surgery remains in evolution. Axillary lymph node status in breast cancer is a major prognostic factor and remains integral to guiding adjuvant treatment decisions. There remains controversy regarding the management of the node-positive axilla in clinically node-negative Primary breast cancer. Trials to date have suggested re-evaluation of the historical therapeutic strategy that a positive sentinel node requires axillary node dissection. However, further evidence is required before modern clinical management of the axilla should be altered. As patient awareness and technical expertise grow, national rates of breast reconstruction after mastectomy continue to rise. Oncoplastic techniques continue to evolve and many patients are suitable for a plethora of reconstructive options. Despite the widespread practice of breast reconstruction globally, there is limited randomised evidence comparing the optimal type and/or timing of breast reconstruction on which to base practice. Breast reconstruction type is either purely autologous, implant-based or a combination of these two techniques. We explore the benefits and limitations of these techniques and some of the key findings of the National Mastectomy and Breast Reconstruction Audit. The timing of reconstruction after mastectomy is either immediate (a single procedure) or delayed (for an indefinite period after mastectomy). The ideal reconstruction is one that is best aligned to the patient's expectations, as this will achieve the highest levels of long-term patient satisfaction. Selecting the optimal type of breast reconstruction at the right time for the right patient remains the key challenge in breast reconstruction. (c) 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
KW - LOCAL RECURRENCE KW - Autologous KW - IMPLANT RECONSTRUCTION KW - SKIN-REDUCING MASTECTOMY KW - AXILLARY DISSECTION KW - implant KW - axilla KW - ACELLULAR DERMAL MATRIX KW - radiotherapy KW - SENTINEL-NODE BIOPSY KW - sentinel node biopsy KW - IMMEDIATE KW - RANDOMIZED CLINICAL-TRIAL KW - FOLLOW-UP KW - SPARING MASTECTOMY KW - reconstruction U2 - 10.1016/j.clon.2012.10.009 DO - 10.1016/j.clon.2012.10.009 M1 - Article JO - Clinical Oncology JF - Clinical Oncology SN - 0936-6555 IS - 2 VL - 25 SP - 101 EP - 108 ER - TY - JOUR T1 - DEAD box RNA helicase functions in cancer A1 - Fuller-Pace,Frances V. AU - Fuller-Pace,Frances V. PY - 2013 Y1 - 2013 N2 - Members of the DEAD box family of RNA helicases are known to be involved in most cellular processes that require manipulation of RNA structure and, in many cases, exhibit other functions in addition to their established ATP-dependent RNA helicase activities. They thus play critical roles in cellular metabolism and in many cases have been implicated in cellular proliferation and/or neoplastic transformation. These proteins generally act as components of multi-protein complexes; therefore their precise role is likely to be influenced by their interacting partners and to be highly context-dependent. This may also provide an explanation for the sometimes conflicting reports suggesting that DEAD box proteins have both pro- and anti-proliferative roles in cancer. AB - Members of the DEAD box family of RNA helicases are known to be involved in most cellular processes that require manipulation of RNA structure and, in many cases, exhibit other functions in addition to their established ATP-dependent RNA helicase activities. They thus play critical roles in cellular metabolism and in many cases have been implicated in cellular proliferation and/or neoplastic transformation. These proteins generally act as components of multi-protein complexes; therefore their precise role is likely to be influenced by their interacting partners and to be highly context-dependent. This may also provide an explanation for the sometimes conflicting reports suggesting that DEAD box proteins have both pro- and anti-proliferative roles in cancer. U2 - 10.4161/rna.23312 DO - 10.4161/rna.23312 M1 - Article JO - RNA Biology JF - RNA Biology IS - 1 VL - 10 SP - 121 EP - 132 ER - TY - CONF T1 - Design in action T2 - building a model for knowledge exchange between industry and academia, using design as a strategy for business growth in Scotland A1 - Follett,Georgina A1 - Marra,Michael AU - Follett,Georgina AU - Marra,Michael PY - 2013 Y1 - 2013 N2 - As UK government and public policy bodies seek routes back to economic growth, the domestic higher education sector has been identified as a source for innovation. The Scottish economy’s particular weaknesses in industrial R&D mean that resultant knowledge exchange is critical. Design in Action proposes a model to meet these complex demands. AB - As UK government and public policy bodies seek routes back to economic growth, the domestic higher education sector has been identified as a source for innovation. The Scottish economy’s particular weaknesses in industrial R&D mean that resultant knowledge exchange is critical. Design in Action proposes a model to meet these complex demands. KW - V & A Dundee KW - V&A at Dundee UR - http://www.dmi.org/dmi/html/conference/academic12/academic.htm M1 - Paper SP - 1 EP - 10 ER - TY - CHAP T1 - Detecting and quantifying p53 isoforms at mRNA level in cell lines and tissues A1 - Khoury,M.P. A1 - Marcel,V. A1 - Fernandes,K. A1 - Diot,A. A1 - Lane,D.P. A1 - Bourdon,J.-C. AU - Khoury,M.P. AU - Marcel,V. AU - Fernandes,K. AU - Diot,A. AU - Lane,D.P. AU - Bourdon,J.-C. PB - Humana Press CY - Totowa, N.J. PY - 2013 Y1 - 2013 N2 - The TP53 gene expresses at least nine different mRNA variants (p53 isoform mRNAs), including the one encoding the canonical p53 tumor suppressor protein. We have developed scientific tools to specifically detect and quantify p53 isoform expression at mRNA level by nested RT-PCR (reverse transcription- polymerase chain reaction) and quantitative real-time RT-PCR (RT-qPCR using the TaqMan chemistry). Here, we describe these two methods, while highlighting essential points with regard to the analysis of p53 isoform mRNA expression. © 2013 Springer Science+Business Media New York. AB - The TP53 gene expresses at least nine different mRNA variants (p53 isoform mRNAs), including the one encoding the canonical p53 tumor suppressor protein. We have developed scientific tools to specifically detect and quantify p53 isoform expression at mRNA level by nested RT-PCR (reverse transcription- polymerase chain reaction) and quantitative real-time RT-PCR (RT-qPCR using the TaqMan chemistry). Here, we describe these two methods, while highlighting essential points with regard to the analysis of p53 isoform mRNA expression. © 2013 Springer Science+Business Media New York. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871891032&md5=692b46754344f704859235b2f5e9ed75 U2 - 10.1007/978-1-62703-236-0_1 DO - 10.1007/978-1-62703-236-0_1 M1 - Chapter (peer-reviewed) SN - 9781627032353 VL - 962 BT - p53 protocols T2 - p53 protocols A2 - Deb,Swati Palit ED - Deb,Swati Palit T3 - Methods in Molecular Biology T3 - en_GB SP - 1 EP - 14 ER - TY - CHAP T1 - Detecting p53 isoforms at protein level A1 - Marcel,V. A1 - Khoury,M.P. A1 - Fernandes,K. A1 - Diot,A. A1 - Lane,D.P. A1 - Bourdon,J.-C. AU - Marcel,V. AU - Khoury,M.P. AU - Fernandes,K. AU - Diot,A. AU - Lane,D.P. AU - Bourdon,J.-C. PB - Humana Press CY - Totowa, N.J. PY - 2013 Y1 - 2013 N2 - The human p53 protein isoforms are expressed in several cell lines and modulate p53 tumor suppressor activity, mainly through modulation of gene expression (1-4). Thus, identifying the pattern of p53 isoforms expression in cell lines is a key step for future studies of the p53 network (5). At the moment, the detection of p53 protein isoforms is based on the use of a panel of antibodies allowing their identification by comparing their molecular weights and their detection pattern by different antibodies (6). Here, classical protocols supplemented with technical know-how are described to detect p53 protein isoforms at protein level by Western blotting and immunoprecipitation. Furthermore, a simple method to study the impact of p53 protein isoforms on p53 transcriptional activity through luciferase reporter gene assays is provided. © 2013 Springer Science+Business Media New York. AB - The human p53 protein isoforms are expressed in several cell lines and modulate p53 tumor suppressor activity, mainly through modulation of gene expression (1-4). Thus, identifying the pattern of p53 isoforms expression in cell lines is a key step for future studies of the p53 network (5). At the moment, the detection of p53 protein isoforms is based on the use of a panel of antibodies allowing their identification by comparing their molecular weights and their detection pattern by different antibodies (6). Here, classical protocols supplemented with technical know-how are described to detect p53 protein isoforms at protein level by Western blotting and immunoprecipitation. Furthermore, a simple method to study the impact of p53 protein isoforms on p53 transcriptional activity through luciferase reporter gene assays is provided. © 2013 Springer Science+Business Media New York. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84871913092&md5=47fd1ae807b63be81efb879907410fdf U2 - 10.1007/978-1-62703-236-0_2 DO - 10.1007/978-1-62703-236-0_2 M1 - Chapter (peer-reviewed) SN - 9781627032353 VL - 962 BT - p53 protocols T2 - p53 protocols A2 - Deb,Swati Palit ED - Deb,Swati Palit T3 - Methods in Molecular Biology T3 - en_GB SP - 15 EP - 29 ER - TY - JOUR T1 - Development of an enzyme-linked immunosorbent assay for detection of cellular and in vivo LRRK2 S935 phosphorylation A1 - Delbroek,Lore A1 - Van Kolen,Kristof A1 - Steegmans,Liesbeth A1 - da Cunha,Raquel A1 - Mandemakers,Wim A1 - Daneels,Guy A1 - De Bock,Pieter-Jan A1 - Zhang,Jinwei A1 - Gevaert,Kris A1 - De Strooper,Bart A1 - Alessi,Dario R. A1 - Verstreken,Patrik A1 - Moechars,Diederik W. AU - Delbroek,Lore AU - Van Kolen,Kristof AU - Steegmans,Liesbeth AU - da Cunha,Raquel AU - Mandemakers,Wim AU - Daneels,Guy AU - De Bock,Pieter-Jan AU - Zhang,Jinwei AU - Gevaert,Kris AU - De Strooper,Bart AU - Alessi,Dario R. AU - Verstreken,Patrik AU - Moechars,Diederik W. PY - 2013 Y1 - 2013 N2 -After the discoveiy of kinase activating mutations in leucine-rich repeat kinase 2 (LRRK2) as associated with autosomal dominant forms of Parkinson's disease, inhibition of the kinase is being extensively explored as a disease modifying strategy. As signaling properties and substrate(s) of LRRK2 are poorly documented, autophosphorylation has been an important readout for the enzyme's activity. Western blotting using anti-phospho-S910 or S935 LRRK2 antibodies showed effectiveness in demonstrating inhibitory effects of compounds.
In this communication we describe two types of enzyme-linked immunosorbent assays (ELISA) to determine LRRK2 protein levels and kinase activity. Both assays take advantage of the sensitivity of the earlier described total and pS935 antibodies for detection (Nichols et al., Biochem. J. 2010) [10]. The first assay is based on anti-GFP-based capturing of overexpressed LRRK2 and is highly suitable to show cellular effects of kinase inhibitors in a 96-well format. In the other platform anti-LRRK2-based capturing allows detection of endogenously expressed LRRK2 in rat tissue with no significant signal in tissue from LRRK2 knockout rats. Furthermore, both assays showed a significant reduction in pS935 levels on cellular and transgenic R1441C/G LRRK2. With the anti-LRRK2 ELISA we were able to detect LRRK2 phosphorylation in human peripheral blood mononuclear cells (PBMC).
To conclude, we report two sensitive assays to monitor LRRK2 expression and kinase activity in samples coming from cellular and in vivo experimental settings. Both can show their value in drug screening and biomarker development but will also be useful in the elucidation of LRRK2-mediated signaling pathways. (c) 2012 Elsevier B.V. All rights reserved.
AB -After the discoveiy of kinase activating mutations in leucine-rich repeat kinase 2 (LRRK2) as associated with autosomal dominant forms of Parkinson's disease, inhibition of the kinase is being extensively explored as a disease modifying strategy. As signaling properties and substrate(s) of LRRK2 are poorly documented, autophosphorylation has been an important readout for the enzyme's activity. Western blotting using anti-phospho-S910 or S935 LRRK2 antibodies showed effectiveness in demonstrating inhibitory effects of compounds.
In this communication we describe two types of enzyme-linked immunosorbent assays (ELISA) to determine LRRK2 protein levels and kinase activity. Both assays take advantage of the sensitivity of the earlier described total and pS935 antibodies for detection (Nichols et al., Biochem. J. 2010) [10]. The first assay is based on anti-GFP-based capturing of overexpressed LRRK2 and is highly suitable to show cellular effects of kinase inhibitors in a 96-well format. In the other platform anti-LRRK2-based capturing allows detection of endogenously expressed LRRK2 in rat tissue with no significant signal in tissue from LRRK2 knockout rats. Furthermore, both assays showed a significant reduction in pS935 levels on cellular and transgenic R1441C/G LRRK2. With the anti-LRRK2 ELISA we were able to detect LRRK2 phosphorylation in human peripheral blood mononuclear cells (PBMC).
To conclude, we report two sensitive assays to monitor LRRK2 expression and kinase activity in samples coming from cellular and in vivo experimental settings. Both can show their value in drug screening and biomarker development but will also be useful in the elucidation of LRRK2-mediated signaling pathways. (c) 2012 Elsevier B.V. All rights reserved.
KW - KINASE-ACTIVITY KW - S935 phosphorylation KW - INHIBITOR KW - CYTOPLASMIC LOCALIZATION KW - PROTEIN KW - Parkinson's disease KW - PARKINSONS-DISEASE KW - DISEASE-ASSOCIATED MUTATIONS KW - MUTANT KW - GTPASE KW - 14-3-3 BINDING KW - ELISA KW - LRRK2 U2 - 10.1016/j.jpba.2012.12.002 DO - 10.1016/j.jpba.2012.12.002 M1 - Article JO - Journal of Pharmaceutical and Biomedical Analysis JF - Journal of Pharmaceutical and Biomedical Analysis SN - 0731-7085 VL - 76 SP - 49 EP - 58 ER - TY - CONF 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 Y1 - 2013 UR - http://www.diabetes.org.uk/Diabetes-UK-Professional-Conference/ M1 - Poster ER - TY - JOUR T1 - Diagnosis and management of tooth size discrepancies in orthodontic patients A1 - McSwiney ,Timothy P. A1 - Millett,Declan T. A1 - McIntyre,Grant T. AU - McSwiney ,Timothy P. AU - Millett,Declan T. AU - McIntyre,Grant T. PY - 2013 Y1 - 2013 N2 - A tooth size discrepancy (TSD) indicates disproportion in tooth sizes. TSDs should be considered in treatment planning for the orthodontic patient to ensure an optimal occlusal outcome. The method of calculation of a TSD is explained. The prevalence in orthodontic patients, their aetiology and management are outlined AB - A tooth size discrepancy (TSD) indicates disproportion in tooth sizes. TSDs should be considered in treatment planning for the orthodontic patient to ensure an optimal occlusal outcome. The method of calculation of a TSD is explained. The prevalence in orthodontic patients, their aetiology and management are outlined UR - http://www.orthodontic-update.co.uk/articlesview.asp?articleToView=0601017&pagereferrer=defaultlogged M1 - Article JO - Orthodontic Update JF - Orthodontic Update SN - 1756-6401 IS - 1 VL - 6 SP - 17 EP - 20 ER - TY - JOUR T1 - 'Digital diabetes' T2 - Looking to the future A1 - Wake,Deborah J. A1 - Cunningham,Scott G. AU - Wake,Deborah J. AU - Cunningham,Scott G. PY - 2013 Y1 - 2013 N2 - In the UK, 85% of adults use the internet, yet digital technology and web based applications have been slow to realise their potential within health care. Diabetes, a chronic disease requiring extensive self-management, could particularly benefit from an e-health approach. Whilst there are a number of independent on-line diabetes communities, mobile apps, websites and networking opportunities, these operate in silos rather than integrating with mainstream health care. This review will explore the political drivers and barriers to eHealth, and review current digital opportunities for patients and health care professionals within diabetes care. © The Author(s) 2013. AB - In the UK, 85% of adults use the internet, yet digital technology and web based applications have been slow to realise their potential within health care. Diabetes, a chronic disease requiring extensive self-management, could particularly benefit from an e-health approach. Whilst there are a number of independent on-line diabetes communities, mobile apps, websites and networking opportunities, these operate in silos rather than integrating with mainstream health care. This review will explore the political drivers and barriers to eHealth, and review current digital opportunities for patients and health care professionals within diabetes care. © The Author(s) 2013. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84875692476&md5=d9a4a32b928448c36528bd22084796ae U2 - 10.1177/1474651413477692 DO - 10.1177/1474651413477692 M1 - Article JO - British Journal of Diabetes and Vascular Disease JF - British Journal of Diabetes and Vascular Disease SN - 1474-6514 IS - 1 VL - 13 SP - 13 EP - 20 ER - TY - CHAP T1 - 'Digital motherhood' T2 - CHI '13 A1 - Gibson,Lorna A1 - Hanson,Vicki L. AU - Gibson,Lorna AU - Hanson,Vicki L. PB - Association for Computing Machinery CY - New York PY - 2013 Y1 - 2013 N2 - New mothers can experience social exclusion, particularly during the early weeks when infants are solely dependent on their mothers. We used ethnographic methods to investigate whether technology plays a role in supporting new mothers. Our research identified two core themes: (1) the need to improve confidence as a mother; and (2) the need to be more than \'18just' a mother. We reflect on these findings both in terms of those interested in designing applications and services for motherhood and also the wider CHI community. AB - New mothers can experience social exclusion, particularly during the early weeks when infants are solely dependent on their mothers. We used ethnographic methods to investigate whether technology plays a role in supporting new mothers. Our research identified two core themes: (1) the need to improve confidence as a mother; and (2) the need to be more than \'18just' a mother. We reflect on these findings both in terms of those interested in designing applications and services for motherhood and also the wider CHI community. UR - http://chi2013.acm.org/ U2 - 10.1145/2470654.2470700 DO - 10.1145/2470654.2470700 M1 - Chapter (peer-reviewed) SN - 9781450318990 BT - CHI '13 SP - 313 EP - 322 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 Y1 - 2013 N2 - BackgroundThe aim of this current study was to test the hypothesis that contemplating a recent mobile telephone conversation has a detrimental effect on measures of attentional processing in a driving situation. In this within-subjects design, hazard perception performance was compared between high and no cognitive load conditions (with or without a puzzle to solve). We tested 17 participants, all of whom were required to be in possession of a DVLA approved driving license and had completed the hazard perception portion of the British driving test. A novel dual-task paradigm, which did not require subjects to process or produce verbal information during the primary task, was employed to increase participants' cognitive load. Participants were assessed on three categories of performance measures: behavioural, eye movements and cortical activity between both high and no cognitive load conditions whilst watching 20 clips from a hazard perception test. This study was run in a laboratory of the Psychology Research Wing at the University of Dundee. Behavioural findings from the hazard perception test indicate significantly increased reaction times to hazardous stimuli and significantly increased false alarm rates to non-hazardous stimuli in the high cognitive load condition (when contemplating a previous conversation). Analyses of eye movements indicated significant increases in blink frequencies, higher saccade peak velocities and a significant reduction in the spread of fixations along the horizontal axis. Results from EEG recordings showed a significant increase in frontal and a significant decrease in occipital theta activity within the high load condition. Findings were interpreted within the framework of Corbetta, Patel and Schulmann's (2008) networks model of attention control. Our findings suggest that preoccupation with a recent conversation negatively influences the modulatory effect of the central executive on both the stimulus as well as goal-driven networks of the brain. (c) 2012 Elsevier Ltd. All rights reserved.
AB -The aim of this current study was to test the hypothesis that contemplating a recent mobile telephone conversation has a detrimental effect on measures of attentional processing in a driving situation. In this within-subjects design, hazard perception performance was compared between high and no cognitive load conditions (with or without a puzzle to solve). We tested 17 participants, all of whom were required to be in possession of a DVLA approved driving license and had completed the hazard perception portion of the British driving test. A novel dual-task paradigm, which did not require subjects to process or produce verbal information during the primary task, was employed to increase participants' cognitive load. Participants were assessed on three categories of performance measures: behavioural, eye movements and cortical activity between both high and no cognitive load conditions whilst watching 20 clips from a hazard perception test. This study was run in a laboratory of the Psychology Research Wing at the University of Dundee. Behavioural findings from the hazard perception test indicate significantly increased reaction times to hazardous stimuli and significantly increased false alarm rates to non-hazardous stimuli in the high cognitive load condition (when contemplating a previous conversation). Analyses of eye movements indicated significant increases in blink frequencies, higher saccade peak velocities and a significant reduction in the spread of fixations along the horizontal axis. Results from EEG recordings showed a significant increase in frontal and a significant decrease in occipital theta activity within the high load condition. Findings were interpreted within the framework of Corbetta, Patel and Schulmann's (2008) networks model of attention control. Our findings suggest that preoccupation with a recent conversation negatively influences the modulatory effect of the central executive on both the stimulus as well as goal-driven networks of the brain. (c) 2012 Elsevier Ltd. All rights reserved.
KW - REAL KW - Preoccupation KW - COGNITIVE WORKLOAD KW - Driving KW - MOBILE TELEPHONES KW - Electroencephalography KW - Eye movements KW - MENTAL WORKLOAD KW - ATTENTION KW - LOAD KW - Post-call distraction KW - Hazard perception performance KW - DRIVER BEHAVIOR KW - EXPERIENCE KW - Problem-solving KW - CELL PHONE CONVERSATIONS KW - VISUAL INFORMATION U2 - 10.1016/j.trf.2012.10.002 DO - 10.1016/j.trf.2012.10.002 M1 - Article JO - Transportation Research Part F: Traffic Psychology and Behaviour JF - Transportation Research Part F: Traffic Psychology and Behaviour SN - 1369-8478 VL - 17 SP - 52 EP - 62 ER - TY - JOUR T1 - Dual regulation of Glycogen Synthase Kinase 3 (GSK3)alpha/beta by Protein Kinase C (PKC)alpha and Akt promotes Thrombin-mediated Integrin alpha(IIb)beta(3) activation and granule secretion in platelets A1 - Moore,Samantha F. A1 - van den Bosch,Marion T. J. A1 - Hunter,Roger W. A1 - Sakamoto,Kei A1 - Poole,Alastair W. A1 - Hers,Ingeborg AU - Moore,Samantha F. AU - van den Bosch,Marion T. J. AU - Hunter,Roger W. AU - Sakamoto,Kei AU - Poole,Alastair W. AU - Hers,Ingeborg PY - 2013 Y1 - 2013 N2 -Glycogen synthase kinase-3 is a Ser/Thr kinase, tonically active in resting cells but inhibited by phosphorylation of an N-terminal Ser residue (Ser(21) in GSK3 alpha and Ser(9) in GSK3 beta) in response to varied external stimuli. Recent work suggests that GSK3 functions as a negative regulator of platelet function, but how GSK3 is regulated in platelets has not been examined in detail. Here, we show that early thrombin-mediated GSK3 phosphorylation (0-30 s) was blocked by PKC inhibitors and largely absent in platelets from PKC alpha knock-out mice. In contrast, late (2-5 min) GSK3 phosphorylation was dependent on the PI3K/Akt pathway. Similarly, early thrombin-mediated inhibition of GSK3 activity was blocked in PKC alpha knock-out platelets, whereas the Akt inhibitor MK2206 reduced late thrombin-mediated GSK3 inhibition and largely prevented GSK3 inhibition in PKC alpha knock-out platelets. More importantly, GSK3 phosphorylation contributes to platelet function as knock-in mice where GSK3 alpha Ser(21) and GSK3 beta Ser(9) were mutated to Ala showed a significant reduction in PAR4-mediated platelet aggregation, fibrinogen binding, and P-selectin expression, whereas the GSK3 inhibitor CHIR99021 enhanced these responses. Together, these results demonstrate that PKC alpha and Akt modulate platelet function by phosphorylating and inhibiting GSK3 alpha/beta, thereby relieving the negative effect of GSK3 alpha/beta on thrombin-mediated platelet activation.
AB -Glycogen synthase kinase-3 is a Ser/Thr kinase, tonically active in resting cells but inhibited by phosphorylation of an N-terminal Ser residue (Ser(21) in GSK3 alpha and Ser(9) in GSK3 beta) in response to varied external stimuli. Recent work suggests that GSK3 functions as a negative regulator of platelet function, but how GSK3 is regulated in platelets has not been examined in detail. Here, we show that early thrombin-mediated GSK3 phosphorylation (0-30 s) was blocked by PKC inhibitors and largely absent in platelets from PKC alpha knock-out mice. In contrast, late (2-5 min) GSK3 phosphorylation was dependent on the PI3K/Akt pathway. Similarly, early thrombin-mediated inhibition of GSK3 activity was blocked in PKC alpha knock-out platelets, whereas the Akt inhibitor MK2206 reduced late thrombin-mediated GSK3 inhibition and largely prevented GSK3 inhibition in PKC alpha knock-out platelets. More importantly, GSK3 phosphorylation contributes to platelet function as knock-in mice where GSK3 alpha Ser(21) and GSK3 beta Ser(9) were mutated to Ala showed a significant reduction in PAR4-mediated platelet aggregation, fibrinogen binding, and P-selectin expression, whereas the GSK3 inhibitor CHIR99021 enhanced these responses. Together, these results demonstrate that PKC alpha and Akt modulate platelet function by phosphorylating and inhibiting GSK3 alpha/beta, thereby relieving the negative effect of GSK3 alpha/beta on thrombin-mediated platelet activation.
KW - INSULIN KW - INHIBITORS KW - COLLAGEN KW - MICE KW - AGGREGATION KW - PHOSPHORYLATION KW - PHOSPHOINOSITIDE 3-KINASE KW - G(I) SIGNALING PATHWAYS U2 - 10.1074/jbc.M112.429936 DO - 10.1074/jbc.M112.429936 M1 - Article JO - Journal of Biological Chemistry JF - Journal of Biological Chemistry SN - 0021-9258 IS - 6 VL - 288 SP - 3918 EP - 3928 ER - TY - JOUR T1 - Dye lasing in optically manipulated liquid aerosols A1 - Karadag,Y. A1 - Aas,M. A1 - Anand,S. A1 - McGloin,D. A1 - Kiraz,A. AU - Karadag,Y. AU - Aas,M. AU - Anand,S. AU - McGloin,D. AU - Kiraz,A. PY - 2013 Y1 - 2013 N2 - We report lasing in airborne, rhodamine B-doped glycerol–water droplets with diameters ranging between 7.7 and 11.0 µm, which were localized using optical tweezers. While being trapped near the focal point of an infrared laser, the droplets were pumped with a Q-switched green laser. Our experiments revealed nonlinear dependence of the intensity of the droplet whispering gallery modes (WGMs) on the pump laser fluence, indicating dye lasing. The average wavelength of the lasing WGMs could be tuned between 600 and 630 nm by changing the droplet size. These results may lead to new ways of probing airborne particles, exploiting the high sensitivity of stimulated emission to small perturbations in the droplet laser cavity and the gain medium.Background: The obesity epidemic has resulted in more overweight/obese women before and during pregnancy. Their offspring tend to have higher birth weights and more body fat, and carry an increased risk of obesity later in life. These effects may partly be related to the heightened risk of gestational diabetes, occurring in at least 16% of all pregnancies irrespective of current body weight. Methods: An ILSI Europe workshop reviewed the key contributors leading to adverse outcomes in pregnancy and childhood, including gestational weight gain and nutrition. New research opportunities from prospective mother-child cohort studies were explored. Results: Simple measures of gestational weight gain provide insufficient detail of the underlying physiological and metabolic adaptations occurring in pregnancy, and should be complemented by measures of body composition, metabolic and endocrine responses. Recordings of maternal dietary intake and nutrient status are often limited and potential correlations with gestational weight gain have been poorly studied. Many pregnancies in overweight/obese women are uncomplicated and result in offspring of normal weight, leaving the main determinants of later adverse outcomes to be clarified. Conclusions: The workshop provided insights of primary measurements for the characterization of sustainable nutritional intervention strategies in the mother, infant and child for preventing obesity in later life. copyright (C) 2013 S. Karger AG, Basel
AB -Background: The obesity epidemic has resulted in more overweight/obese women before and during pregnancy. Their offspring tend to have higher birth weights and more body fat, and carry an increased risk of obesity later in life. These effects may partly be related to the heightened risk of gestational diabetes, occurring in at least 16% of all pregnancies irrespective of current body weight. Methods: An ILSI Europe workshop reviewed the key contributors leading to adverse outcomes in pregnancy and childhood, including gestational weight gain and nutrition. New research opportunities from prospective mother-child cohort studies were explored. Results: Simple measures of gestational weight gain provide insufficient detail of the underlying physiological and metabolic adaptations occurring in pregnancy, and should be complemented by measures of body composition, metabolic and endocrine responses. Recordings of maternal dietary intake and nutrient status are often limited and potential correlations with gestational weight gain have been poorly studied. Many pregnancies in overweight/obese women are uncomplicated and result in offspring of normal weight, leaving the main determinants of later adverse outcomes to be clarified. Conclusions: The workshop provided insights of primary measurements for the characterization of sustainable nutritional intervention strategies in the mother, infant and child for preventing obesity in later life. copyright (C) 2013 S. Karger AG, Basel
KW - Obesity KW - MATERNAL OBESITY KW - BODY-MASS INDEX KW - DIABETES-MELLITUS KW - GESTATIONAL WEIGHT-GAIN KW - Insulin resistance KW - Pregnancy KW - METABOLIC SYNDROME KW - RANDOMIZED CLINICAL-TRIAL KW - PREGNANCY OUTCOMES KW - DEVELOPMENTAL ORIGINS KW - BIRTH COHORTS KW - BROWN ADIPOSE-TISSUE U2 - 10.1159/000345598 DO - 10.1159/000345598 M1 - Article JO - Annals of Nutrition and Metabolism JF - Annals of Nutrition and Metabolism SN - 0250-6807 IS - 2 VL - 62 SP - 137 EP - 145 ER - TY - JOUR T1 - Efficiency and risk in commercial banking T2 - empirical evidence from East Asian countries A1 - Chan,Sok Gee A1 - Karim,Mohd Zaini Abd A1 - Burton,Bruce A1 - Aktan,Bora AU - Chan,Sok Gee AU - Karim,Mohd Zaini Abd AU - Burton,Bruce AU - Aktan,Bora PY - 2013 Y1 - 2013 N2 - This paper analyses the effects of off-balance sheet (OBS) activities and various types of risks on the cost and profit efficiencies of banks in seven East Asian countries between 2001 and 2008. Cost and profit efficiency scores are estimated using the data envelopment analysis approach. The results of this analysis are then used to identify the impact of OBS activities and risk exposures on cost and profit efficiencies using a Tobit regression. Bank insolvency risk (as measured by z-scores) is positively related to profit efficiency, while interest sensitivity, size, equity to total assets and OBS exposures all impact on cost efficiency. The analysis of the impact of input and output slacks illustrates that in around 1 in 5 cases banks' cost efficiency can be improved by adjusting the former variables, whereas in only around 1 in 100 cases a similar outcome is possible for profit efficiency. © 2013 Copyright Taylor and Francis Group, LLC. AB - This paper analyses the effects of off-balance sheet (OBS) activities and various types of risks on the cost and profit efficiencies of banks in seven East Asian countries between 2001 and 2008. Cost and profit efficiency scores are estimated using the data envelopment analysis approach. The results of this analysis are then used to identify the impact of OBS activities and risk exposures on cost and profit efficiencies using a Tobit regression. Bank insolvency risk (as measured by z-scores) is positively related to profit efficiency, while interest sensitivity, size, equity to total assets and OBS exposures all impact on cost efficiency. The analysis of the impact of input and output slacks illustrates that in around 1 in 5 cases banks' cost efficiency can be improved by adjusting the former variables, whereas in only around 1 in 100 cases a similar outcome is possible for profit efficiency. © 2013 Copyright Taylor and Francis Group, LLC. KW - bank efficiency KW - other depository institutions KW - micro finance institutions KW - mortgages KW - model construction and estimation KW - government policy and regulation UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872975092&md5=5bb2b0385e6dcd0c78176d00a5d786fa U2 - 10.1080/1351847X.2012.745008 DO - 10.1080/1351847X.2012.745008 M1 - Article JO - European Journal of Finance JF - European Journal of Finance SN - 1351-847X ER - TY - JOUR T1 - Electromechanical Behaviour of Nafion-based Soft Actuators A1 - Naji,Leila A1 - Chudek,John A. A1 - Abel,Eric W. A1 - Baker,Richard T. AU - Naji,Leila AU - Chudek,John A. AU - Abel,Eric W. AU - Baker,Richard T. PY - 2013 Y1 - 2013 N2 - Soft actuators based on Ionic Polymer–Metal Composites (IPMCs) are of considerable interest for applications in biomedical devices and robotics. In this work, thin commercial and thick laboratory-prepared Nafion membranes were made into model IPMC actuator devices by incorporation of Pt electrode layers. In extensive electromechanical tests the maximum average tip displacement andThis study evaluated the efficacy and safety of lisdexamfetamine dimesylate (LDX) compared with placebo in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in Europe. Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference arm. Patients (6-17 years old) with a baseline ADHD Rating Scale version IV (ADHD-RS-IV) total score =28 were randomized (1:1:1) to dose-optimized LDX (30, 50, or 70mg/day), OROS-MPH (18, 36, or 54mg/day) or placebo for 7 weeks. Primary and key secondary efficacy measures were the investigator-rated ADHD-RS-IV and the Clinical Global Impressions-Improvement (CGI-I) rating, respectively. Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms, and vital signs. Of 336 patients randomized, 196 completed the study. The difference between LDX and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was -18.6 (95% confidence interval [CI]: -21.5 to -15.7) (p<0.001; effect size, 1.80). The difference between OROS-MPH and placebo
in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was13.0(95% CI: 5.9 to 10.2) (p<0.001; effect size, 1.26). The proportions (95% CI) of patients showing improvement (CGI-I of 1 or 2) at endpoint were 78% (70–86), 14% (8–21), and 61% (51–70) for LDX, placebo, and OROS-MPH. The most common TEAEs for LDX were decreased
appetite, headache, and insomnia. Mean changes in vital signs were modest and consistent with the known profile of LDX. LDX was effective and generally well tolerated in children and adolescents with ADHD.
This study evaluated the efficacy and safety of lisdexamfetamine dimesylate (LDX) compared with placebo in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in Europe. Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference arm. Patients (6-17 years old) with a baseline ADHD Rating Scale version IV (ADHD-RS-IV) total score =28 were randomized (1:1:1) to dose-optimized LDX (30, 50, or 70mg/day), OROS-MPH (18, 36, or 54mg/day) or placebo for 7 weeks. Primary and key secondary efficacy measures were the investigator-rated ADHD-RS-IV and the Clinical Global Impressions-Improvement (CGI-I) rating, respectively. Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms, and vital signs. Of 336 patients randomized, 196 completed the study. The difference between LDX and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was -18.6 (95% confidence interval [CI]: -21.5 to -15.7) (p<0.001; effect size, 1.80). The difference between OROS-MPH and placebo
in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was13.0(95% CI: 5.9 to 10.2) (p<0.001; effect size, 1.26). The proportions (95% CI) of patients showing improvement (CGI-I of 1 or 2) at endpoint were 78% (70–86), 14% (8–21), and 61% (51–70) for LDX, placebo, and OROS-MPH. The most common TEAEs for LDX were decreased
appetite, headache, and insomnia. Mean changes in vital signs were modest and consistent with the known profile of LDX. LDX was effective and generally well tolerated in children and adolescents with ADHD.
The carboxy-terminal truncated p53 alternative spliced isoforms, p53 beta and p53 gamma, are expressed at disparate levels in cancer and are suggested to influence treatment response and therapy outcome. However, their functional role in cancer remains to be elucidated. We investigated their individual functionality in the p53(null) background of cell lines H1299 and SAOS-2 by stable retroviral transduction or transient transfection. Expression status of p53 beta and p53 gamma protein was found to correlate with increased response to camptothecin and doxorubicin chemotherapy. Decreased DNA synthesis and clonogenicity in p53 beta and p53 gamma congenic H1299 was accompanied by increased p21((CIP1/WAF1)), Bax and Mdm2 proteins. Chemotherapy induced p53 isoform degradation, most prominent for p53 gamma. The proteasome inhibitor bortezomib substantially increased basal p53 gamma protein level, while the level of p53 beta protein was unaffected. Treatment with dicoumarol, a putative blocker of the proteasome-related NAD(P)H quinone oxidoreductase NQO1, effectively attenuated basal p53 gamma protein level in spite of bortezomib treatment. Although in vitro proliferation and clonogenicity assays indicated a weak suppressive effect by p53 beta and p53 gamma expression, studies of in vivo subcutaneous H1299 tumor growth demonstrated a significantly increased growth by expression of either p53 isoforms. This study suggests that p53 beta and p53 gamma share functionality in chemosensitizing and tumor growth enhancement but comprise distinct regulation at the protein level.
AB -The carboxy-terminal truncated p53 alternative spliced isoforms, p53 beta and p53 gamma, are expressed at disparate levels in cancer and are suggested to influence treatment response and therapy outcome. However, their functional role in cancer remains to be elucidated. We investigated their individual functionality in the p53(null) background of cell lines H1299 and SAOS-2 by stable retroviral transduction or transient transfection. Expression status of p53 beta and p53 gamma protein was found to correlate with increased response to camptothecin and doxorubicin chemotherapy. Decreased DNA synthesis and clonogenicity in p53 beta and p53 gamma congenic H1299 was accompanied by increased p21((CIP1/WAF1)), Bax and Mdm2 proteins. Chemotherapy induced p53 isoform degradation, most prominent for p53 gamma. The proteasome inhibitor bortezomib substantially increased basal p53 gamma protein level, while the level of p53 beta protein was unaffected. Treatment with dicoumarol, a putative blocker of the proteasome-related NAD(P)H quinone oxidoreductase NQO1, effectively attenuated basal p53 gamma protein level in spite of bortezomib treatment. Although in vitro proliferation and clonogenicity assays indicated a weak suppressive effect by p53 beta and p53 gamma expression, studies of in vivo subcutaneous H1299 tumor growth demonstrated a significantly increased growth by expression of either p53 isoforms. This study suggests that p53 beta and p53 gamma share functionality in chemosensitizing and tumor growth enhancement but comprise distinct regulation at the protein level.
KW - APOPTOSIS KW - CARCINOMA KW - P53 ISOFORMS KW - DEGRADATION KW - MDM2 KW - DNA-DAMAGE KW - P73 KW - MODELS KW - CANCER KW - ACUTE MYELOID-LEUKEMIA U2 - 10.1371/journal.pone.0056276 DO - 10.1371/journal.pone.0056276 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 2 VL - 8 ER - TY - JOUR T1 - External validity of randomized controlled trials of glycaemic control and vascular disease T2 - how representative are participants? A1 - Saunders,C. A1 - Byrne,C.D. A1 - Guthrie,B. A1 - Lindsay,R.S. A1 - Mcknight,J.A. A1 - Philip,S. A1 - Sattar,N. A1 - Walker,J.J. A1 - Wild,S.H. A1 - Brady,I. A1 - Chalmers,J. A1 - Colhoun,H. A1 - Cunningham,S. A1 - Elder,R. A1 - Emslie-Smith,A. A1 - Fischbacher,C. A1 - Govan,L. A1 - Jones,N. A1 - Leese,G. A1 - Levine,D. A1 - Livingstone,S. A1 - Looker,H. A1 - McAlpine,R. A1 - Morris,A. A1 - Pearson,D. A1 - Petrie,J. AU - Saunders,C. AU - Byrne,C.D. AU - Guthrie,B. AU - Lindsay,R.S. AU - Mcknight,J.A. AU - Philip,S. AU - Sattar,N. AU - Walker,J.J. AU - Wild,S.H. AU - Brady,I. AU - Chalmers,J. AU - Colhoun,H. AU - Cunningham,S. AU - Elder,R. AU - Emslie-Smith,A. AU - Fischbacher,C. AU - Govan,L. AU - Jones,N. AU - Leese,G. AU - Levine,D. AU - Livingstone,S. AU - Looker,H. AU - McAlpine,R. AU - Morris,A. AU - Pearson,D. AU - Petrie,J. PY - 2013 Y1 - 2013 N2 - Aims: To describe the proportion of people with Type 2 diabetes living in Scotland who meet eligibility criteria for inclusion in several large randomized controlled trials of glycaemic control to inform physicians and guideline developers about the generalizibility of trial results. Methods: A literature review was performed to identify large trials assessing the impact of glycaemic control on risk of macrovascular disease. Inclusion and exclusion criteria from each trial were applied to data on the population of people with a diagnosis of Type 2 diabetes living in Scotland in 2008 (n = 180 590) in a population-based cross-sectional study and the number and proportion of people eligible for each trial was determined. Results: Seven trials were identified. The proportion of people with Type 2 diabetes who met the eligibility criteria for the trials ranged from 3.5 to 50.7%. Trial participants were younger at age of diagnosis of diabetes and at time of trial recruitment than in the Scottish study population. The application of upper age criteria excluded the largest proportion of patients, with up to 39% of people with Type 2 diabetes ineligible for a trial with the most stringent criteria based on age alone. Conclusions: We found that many of the large trials of glycaemic control among people with Type 2 diabetes have limited external validity when applied to a population-based cohort of people with Type 2 diabetes. In particular, the age distribution of trial participants often does not reflect that of people with Type 2 diabetes in a contemporary British population. © 2012 Diabetes UK. AB - Aims: To describe the proportion of people with Type 2 diabetes living in Scotland who meet eligibility criteria for inclusion in several large randomized controlled trials of glycaemic control to inform physicians and guideline developers about the generalizibility of trial results. Methods: A literature review was performed to identify large trials assessing the impact of glycaemic control on risk of macrovascular disease. Inclusion and exclusion criteria from each trial were applied to data on the population of people with a diagnosis of Type 2 diabetes living in Scotland in 2008 (n = 180 590) in a population-based cross-sectional study and the number and proportion of people eligible for each trial was determined. Results: Seven trials were identified. The proportion of people with Type 2 diabetes who met the eligibility criteria for the trials ranged from 3.5 to 50.7%. Trial participants were younger at age of diagnosis of diabetes and at time of trial recruitment than in the Scottish study population. The application of upper age criteria excluded the largest proportion of patients, with up to 39% of people with Type 2 diabetes ineligible for a trial with the most stringent criteria based on age alone. Conclusions: We found that many of the large trials of glycaemic control among people with Type 2 diabetes have limited external validity when applied to a population-based cohort of people with Type 2 diabetes. In particular, the age distribution of trial participants often does not reflect that of people with Type 2 diabetes in a contemporary British population. © 2012 Diabetes UK. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84874174557&md5=945c91b2ad63b8612241b245f1fd9894 U2 - 10.1111/dme.12047 DO - 10.1111/dme.12047 M1 - Article JO - Diabetic Medicine JF - Diabetic Medicine IS - 3 VL - 30 SP - 300 EP - 308 ER - TY - JOUR T1 - Eye movements in reading T2 - Some theoretical context A1 - Radach,R. A1 - Kennedy,Alan AU - Radach,R. AU - Kennedy,Alan PY - 2013 Y1 - 2013 N2 - The study of eye movements has proven to be one of the most successful approaches in research on reading. In this overview, it is argued that a major reason for this success is that eye movement measurement is not just a methodology-the control of eye movements is actually part and parcel of the dynamics of information processing within the task of reading itself. Some major developments over the last decade are discussed with a focus on the issue of spatially distributed word processing and its relation to the development of reading models. The survey ends with a description of two newly emerging trends in the field: the study of continuous reading in non-Roman writing systems and the broadening of the scope of research to encompass individual differences and developmental issues. © 2013 Copyright The Experimental Psychology Society. AB - The study of eye movements has proven to be one of the most successful approaches in research on reading. In this overview, it is argued that a major reason for this success is that eye movement measurement is not just a methodology-the control of eye movements is actually part and parcel of the dynamics of information processing within the task of reading itself. Some major developments over the last decade are discussed with a focus on the issue of spatially distributed word processing and its relation to the development of reading models. The survey ends with a description of two newly emerging trends in the field: the study of continuous reading in non-Roman writing systems and the broadening of the scope of research to encompass individual differences and developmental issues. © 2013 Copyright The Experimental Psychology Society. KW - Eye movements KW - Models of reading KW - Parafoveal processing KW - Serial processing KW - parallel processing UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84872266150&md5=e2dba0d4938503a39cae69f8a36fdd16 U2 - 10.1080/17470218.2012.750676 DO - 10.1080/17470218.2012.750676 M1 - Article JO - Quarterly Journal of Experimental Psychology JF - Quarterly Journal of Experimental Psychology SN - 1747-0218 ER - TY - JOUR T1 - Free Trade and Empire in the Anglo-Irish Commercial Propositions of 1785 A1 - Livesey,James AU - Livesey,James PY - 2013 Y1 - 2013 N2 - William Pitt's 1785 proposal for a free trade area between Britain and Ireland attempted to use free trade as a mechanism of imperial integration. It was a response to the agitation for political reform in Ireland and followed the attainment of legislative independence in 1782. The proposal aimed at coordinating economic and fiscal policy between the kingdoms without imposing explicit political controls. This article establishes that the measure failed because of the lack of consensus around the idea of free trade. Three contrasting ideas of free trade became apparent in the debates around the propositions of 1785: imperial or neomercantilist free trade, Smithean free trade, and national or neo-Machiavellian free trade. Imperial free trade was critical of monopolies but sought to organize trade to the benefit of the imperial metropole; Smithean free trade saw open markets as a discipline that assured efficiency but required imperial institutional frameworks, legally secured, to function. Neo-Machiavellian free trade asserted the right of every political community to organize its trade according to its interests. The article establishes the genealogy of these three positions in pamphlet debates and political correspondence in Britain and Ireland from 1689 to 1785. It argues that majority political opinion in Ireland, with exceptions, understood free trade in a neo-Machiavellian sense, while Pitt was committed to a Smithean ideal. The propositions collapsed because these internal tensions became more evident under the pressure of criticism. Liberal political economy did not of itself offer a route to a British exceptionality that finessed the tensions inherent in empire. AB - William Pitt's 1785 proposal for a free trade area between Britain and Ireland attempted to use free trade as a mechanism of imperial integration. It was a response to the agitation for political reform in Ireland and followed the attainment of legislative independence in 1782. The proposal aimed at coordinating economic and fiscal policy between the kingdoms without imposing explicit political controls. This article establishes that the measure failed because of the lack of consensus around the idea of free trade. Three contrasting ideas of free trade became apparent in the debates around the propositions of 1785: imperial or neomercantilist free trade, Smithean free trade, and national or neo-Machiavellian free trade. Imperial free trade was critical of monopolies but sought to organize trade to the benefit of the imperial metropole; Smithean free trade saw open markets as a discipline that assured efficiency but required imperial institutional frameworks, legally secured, to function. Neo-Machiavellian free trade asserted the right of every political community to organize its trade according to its interests. The article establishes the genealogy of these three positions in pamphlet debates and political correspondence in Britain and Ireland from 1689 to 1785. It argues that majority political opinion in Ireland, with exceptions, understood free trade in a neo-Machiavellian sense, while Pitt was committed to a Smithean ideal. The propositions collapsed because these internal tensions became more evident under the pressure of criticism. Liberal political economy did not of itself offer a route to a British exceptionality that finessed the tensions inherent in empire. KW - Britain KW - Drennan, William KW - Empire KW - Free Trade KW - Ireland KW - Liberty KW - Oitt, William KW - Political Economy KW - Smith, Adam KW - Tucker, Josiah U2 - 10.1017/jbr.2012.62 DO - 10.1017/jbr.2012.62 M1 - Article JO - Journal of British Studies JF - Journal of British Studies SN - 0021-9371 IS - 1 VL - 52 SP - 103 EP - 127 ER - TY - JOUR T1 - FR-H3 T2 - a new QTL to assist in the development of fall-sown barley with superior low temperature tolerance A1 - Fisk,Scott P. A1 - Cuesta-Marcos,Alfonso A1 - Cistue,Luis A1 - Russell,Joanne A1 - Smith,Kevin P. A1 - Baenziger,Stephen A1 - Bedo,Zoltan A1 - Corey,Ann A1 - Filichkin,Tanya A1 - Karsai,Ildiko A1 - Waugh,Robbie A1 - Hayes,Patrick M. AU - Fisk,Scott P. AU - Cuesta-Marcos,Alfonso AU - Cistue,Luis AU - Russell,Joanne AU - Smith,Kevin P. AU - Baenziger,Stephen AU - Bedo,Zoltan AU - Corey,Ann AU - Filichkin,Tanya AU - Karsai,Ildiko AU - Waugh,Robbie AU - Hayes,Patrick M. PY - 2013 Y1 - 2013 N2 -Fall-sown barley will be increasingly important in the era of climate change due to higher yield potential and efficient use of water resources. Resistance/tolerance to abiotic stresses will be critical, and foremost among the abiotic stresses is low temperature. Simultaneous gene discovery and breeding will accelerate the development of agronomically relevant fall-sown barley germplasm with resistance to low temperature. We developed two doubled haploid mapping populations using two lines from the University of Nebraska (NE) and one line from Oregon State University (OR): NB3437f/OR71 (facultative x facultative) and NB713/OR71 (winter x facultative). Both were genotyped with a custom 384 oligonucleotide pool assay (OPA). QTL analyses were performed for low temperature tolerance (LTT) and vernalization sensitivity (VS). The role of VRN-H2 in VS was confirmed and a novel alternative winter allele at VRN-H3 was discovered in the Nebraska germplasm. FR-H2 was identified as a probable determinant of LTT and a new QTL, FR-H3, was discovered on chromosome 1H that accounted for up to 48 % of the phenotypic variation in field survival at St. Paul, MN, USA. The discovery of FR-H3 is a significant advancement in barley LTT genetics and will assist in developing the next generation of fall-sown varieties.
AB -Fall-sown barley will be increasingly important in the era of climate change due to higher yield potential and efficient use of water resources. Resistance/tolerance to abiotic stresses will be critical, and foremost among the abiotic stresses is low temperature. Simultaneous gene discovery and breeding will accelerate the development of agronomically relevant fall-sown barley germplasm with resistance to low temperature. We developed two doubled haploid mapping populations using two lines from the University of Nebraska (NE) and one line from Oregon State University (OR): NB3437f/OR71 (facultative x facultative) and NB713/OR71 (winter x facultative). Both were genotyped with a custom 384 oligonucleotide pool assay (OPA). QTL analyses were performed for low temperature tolerance (LTT) and vernalization sensitivity (VS). The role of VRN-H2 in VS was confirmed and a novel alternative winter allele at VRN-H3 was discovered in the Nebraska germplasm. FR-H2 was identified as a probable determinant of LTT and a new QTL, FR-H3, was discovered on chromosome 1H that accounted for up to 48 % of the phenotypic variation in field survival at St. Paul, MN, USA. The discovery of FR-H3 is a significant advancement in barley LTT genetics and will assist in developing the next generation of fall-sown varieties.
KW - HORDEUM-VULGARE L KW - CEREALS KW - WINTERHARDINESS KW - VERNALIZATION KW - FLOWERING-LOCUS-T KW - GROWTH HABIT KW - EXPRESSION KW - ARABIDOPSIS KW - GENE FAMILY KW - WHEAT U2 - 10.1007/s00122-012-1982-8 DO - 10.1007/s00122-012-1982-8 M1 - Article JO - Theoretical and Applied Genetics JF - Theoretical and Applied Genetics SN - 0040-5752 IS - 2 VL - 126 SP - 335 EP - 347 ER - TY - JOUR T1 - From formalin to thiel embalming T2 - What changes? One anatomy department's experiences A1 - Eisma,R. A1 - Lamb,C. A1 - Soames,R.W. AU - Eisma,R. AU - Lamb,C. AU - Soames,R.W. PY - 2013 Y1 - 2013 N2 - In 2009, the Centre for Anatomy and Human Identification started Thiel embalming on a small scale to assess (i) the suitability for our current teaching in which long-lasting dissection courses are key, (ii) the potential for new collaborations and activities, and (iii) the practical implications of changing our embalming method from formalin to Thiel. Twenty six Thiel-embalmed cadavers have been used for dissection by staff and students on a taught MSc course, as a model for clinical and surgical training, and increasingly as a model for evaluation of new medical devices and procedures. Our experiences with dissection were mostly positive especially for teaching the musculoskeletal system. Internal organs handle differently from formalin-fixed organs and dissection manuals need to be adjusted to reflect this. Durability of the cadavers was not an issue, though changes are seen over time due to gradual fluid loss. We have started new collaborations related to postgraduate anatomy teaching and advanced training in surgical and clinical skills. In general, feedback is very positive and demand for cadavers outstrips our current limited supply. Thiel-embalmed cadavers were found to provide a unique opportunity for evaluation of medical products especially in areas where no suitable alternative model is available, and without the complications associated with clinical testing. This has resulted in new collaborations and research projects. As a result Thiel-embalmed cadavers are used for longer and for more activities than formalin cadavers: this requires changes in our procedures and staff roles. Clin. Anat., 2013. © 2013 Wiley Periodicals, Inc. AB - In 2009, the Centre for Anatomy and Human Identification started Thiel embalming on a small scale to assess (i) the suitability for our current teaching in which long-lasting dissection courses are key, (ii) the potential for new collaborations and activities, and (iii) the practical implications of changing our embalming method from formalin to Thiel. Twenty six Thiel-embalmed cadavers have been used for dissection by staff and students on a taught MSc course, as a model for clinical and surgical training, and increasingly as a model for evaluation of new medical devices and procedures. Our experiences with dissection were mostly positive especially for teaching the musculoskeletal system. Internal organs handle differently from formalin-fixed organs and dissection manuals need to be adjusted to reflect this. Durability of the cadavers was not an issue, though changes are seen over time due to gradual fluid loss. We have started new collaborations related to postgraduate anatomy teaching and advanced training in surgical and clinical skills. In general, feedback is very positive and demand for cadavers outstrips our current limited supply. Thiel-embalmed cadavers were found to provide a unique opportunity for evaluation of medical products especially in areas where no suitable alternative model is available, and without the complications associated with clinical testing. This has resulted in new collaborations and research projects. As a result Thiel-embalmed cadavers are used for longer and for more activities than formalin cadavers: this requires changes in our procedures and staff roles. Clin. Anat., 2013. © 2013 Wiley Periodicals, Inc. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84873590951&md5=b9bd6eb134739c214a14bc231d831803 U2 - 10.1002/ca.22222 DO - 10.1002/ca.22222 M1 - Article JO - Clinical Anatomy JF - Clinical Anatomy SN - 0897-3806 ER - TY - JOUR T1 - From the Street to the Laboratory T2 - Analytical Profiles of Methoxetamine, 3-Methoxyeticyclidine and 3-Methoxyphencyclidine and their Determination in Three Biological Matrices A1 - De Paoli,Giorgia A1 - Brandt,Simon D A1 - Wallach,Jason A1 - Archer,Roland P A1 - Pounder,Derrick J AU - De Paoli,Giorgia AU - Brandt,Simon D AU - Wallach,Jason AU - Archer,Roland P AU - Pounder,Derrick J PY - 2013 Y1 - 2013 N2 - Three psychoactive arylcyclohexylamines, advertised as "research chemicals," were obtained from an online retailer and characterized by gas chromatography ion trap electron and chemical ionization mass spectrometry, nuclear magnetic resonance spectroscopy and diode array detection. The three phencyclidines were identified as 2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone (methoxetamine), N-ethyl-1-(3-methoxyphenyl)cyclohexanamine and 1-[1-(3-methoxyphenyl)cyclohexyl]piperidine. A qualitative/quantitative method of analysis was developed and validated using liquid chromatography (HPLC) electrospray tandem mass spectrometry and ultraviolet (UV) detection for the determination of these compounds in blood, urine and vitreous humor. HPLC-UV proved to be a robust, accurate and precise method for the qualitative and quantitative analysis of these substances in biological fluids (0.16-5.0 mg/L), whereas the mass spectrometer was useful as a confirmatory tool. AB - Three psychoactive arylcyclohexylamines, advertised as "research chemicals," were obtained from an online retailer and characterized by gas chromatography ion trap electron and chemical ionization mass spectrometry, nuclear magnetic resonance spectroscopy and diode array detection. The three phencyclidines were identified as 2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone (methoxetamine), N-ethyl-1-(3-methoxyphenyl)cyclohexanamine and 1-[1-(3-methoxyphenyl)cyclohexyl]piperidine. A qualitative/quantitative method of analysis was developed and validated using liquid chromatography (HPLC) electrospray tandem mass spectrometry and ultraviolet (UV) detection for the determination of these compounds in blood, urine and vitreous humor. HPLC-UV proved to be a robust, accurate and precise method for the qualitative and quantitative analysis of these substances in biological fluids (0.16-5.0 mg/L), whereas the mass spectrometer was useful as a confirmatory tool. U2 - 10.1093/jat/bkt023 DO - 10.1093/jat/bkt023 M1 - Article JO - Journal of Analytical Toxicology JF - Journal of Analytical Toxicology SN - 0146-4760 ER - TY - JOUR T1 - Fungal biotransformation of zinc silicate and sulfide mineral ores. A1 - Wei,Zhan A1 - Liang,Xinjin A1 - Pendlowski,Helen A1 - Hillier,Stephen A1 - Suntornvongsagul,Kallaya A1 - Sihanonth,Prakitsin A1 - Gadd,Geoffrey Michael AU - Wei,Zhan AU - Liang,Xinjin AU - Pendlowski,Helen AU - Hillier,Stephen AU - Suntornvongsagul,Kallaya AU - Sihanonth,Prakitsin AU - Gadd,Geoffrey Michael PY - 2013 Y1 - 2013 N2 -In this work, several fungi with geoactive properties, including Aspergillus niger, Beauveria caledonica and Serpula himantioides, were used to investigate their potential bioweathering effects on zinc silicate and zinc sulfide ores used in zinc extraction and smelting, to gain understanding of the roles that fungi may play in transformations of such minerals in the soil, and effects on metal mobility. Despite the recalcitrance of these minerals, new biominerals resulted from fungal interactions with both the silicate and the sulfide, largely resulting from organic acid excretion. Zinc oxalate dihydrate was formed through oxalate excretion by the test fungi and the mineral surfaces showed varying patterns of bioweathering and biomineral formation. In addition, calcium oxalate was formed from the calcium present in the mineral ore fractions, as well as calcite. Such metal immobilization may indicate that the significance of fungi in effecting metal mobilization from mineral ores such as zinc silicate and zinc sulfide is rather limited, especially if compared with bacterial sulfide leaching. Nevertheless, important bioweathering activities of fungi are confirmed which could be of local significance in soils polluted by such materials, as well as in the mycorrhizosphere.
AB -In this work, several fungi with geoactive properties, including Aspergillus niger, Beauveria caledonica and Serpula himantioides, were used to investigate their potential bioweathering effects on zinc silicate and zinc sulfide ores used in zinc extraction and smelting, to gain understanding of the roles that fungi may play in transformations of such minerals in the soil, and effects on metal mobility. Despite the recalcitrance of these minerals, new biominerals resulted from fungal interactions with both the silicate and the sulfide, largely resulting from organic acid excretion. Zinc oxalate dihydrate was formed through oxalate excretion by the test fungi and the mineral surfaces showed varying patterns of bioweathering and biomineral formation. In addition, calcium oxalate was formed from the calcium present in the mineral ore fractions, as well as calcite. Such metal immobilization may indicate that the significance of fungi in effecting metal mobilization from mineral ores such as zinc silicate and zinc sulfide is rather limited, especially if compared with bacterial sulfide leaching. Nevertheless, important bioweathering activities of fungi are confirmed which could be of local significance in soils polluted by such materials, as well as in the mycorrhizosphere.
KW - Fungi KW - Biominerals KW - Zinc silicate KW - Zinc sulfide KW - oxalate KW - Bioweathering U2 - 10.1111/1462-2920.12089 DO - 10.1111/1462-2920.12089 M1 - Article JO - Environmental Microbiology JF - Environmental Microbiology SN - 1462-2912 ER - TY - JOUR T1 - Genetic variants predicting left ventricular hypertrophy in a diabetic population A1 - Parry,Helen A1 - Donnelly,Louise A1 - Van Zuydam,Natalie A1 - Doney,Alex A1 - Elder,Douglas A1 - Morris,Andrew A1 - Struthers,Allan D. A1 - Palmer,Colin A1 - Lang,Chim AU - Parry,Helen AU - Donnelly,Louise AU - Van Zuydam,Natalie AU - Doney,Alex AU - Elder,Douglas AU - Morris,Andrew AU - Struthers,Allan D. AU - Palmer,Colin AU - Lang,Chim PY - 2013 Y1 - 2013 U2 - 10.1016/S0735-1097(13)60598-7 DO - 10.1016/S0735-1097(13)60598-7 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 - E598 ER - TY - CHAP T1 - Germ cell apoptosis and DNA damage responses A1 - Bailly,Aymeric A1 - Gartner,Anton AU - Bailly,Aymeric AU - Gartner,Anton PB - Springer CY - New York PY - 2013 Y1 - 2013 N2 - In the past 12 years, since the first description of C. elegans germ cell apoptosis, this area of research rapidly expanded. It became evident that multiple genetic pathways lead to the apoptotic demise of germ cells. We are only beginning to understand how these pathways that all require the CED-9/Bcl-2, Apaf-1/CED-4 and CED-3 caspase core apoptosis components are regulated. Physiological apoptosis, which likely accounts for the elimination of more than 50% of all germ cells, even in unperturbed conditions, is likely to be required to maintain tissue homeostasis. The best-studied pathways lead to DNA damage-induced germ cell apoptosis in response to a variety of genotoxic stimuli. This apoptosis appears to be regulated similar to DNA damage-induced apoptosis in the mouse germ line and converges on p53 family transcription factors. DNA damage response pathways not only lead to apoptosis induction, but also directly affect DNA repair, and a transient cell cycle arrest of mitotic germ cells. Finally, distinct pathways activate germ cell apoptosis in response to defects in meiotic recombination and meiotic chromosome pairing. © 2013 Springer Science+Business Media New York. AB - In the past 12 years, since the first description of C. elegans germ cell apoptosis, this area of research rapidly expanded. It became evident that multiple genetic pathways lead to the apoptotic demise of germ cells. We are only beginning to understand how these pathways that all require the CED-9/Bcl-2, Apaf-1/CED-4 and CED-3 caspase core apoptosis components are regulated. Physiological apoptosis, which likely accounts for the elimination of more than 50% of all germ cells, even in unperturbed conditions, is likely to be required to maintain tissue homeostasis. The best-studied pathways lead to DNA damage-induced germ cell apoptosis in response to a variety of genotoxic stimuli. This apoptosis appears to be regulated similar to DNA damage-induced apoptosis in the mouse germ line and converges on p53 family transcription factors. DNA damage response pathways not only lead to apoptosis induction, but also directly affect DNA repair, and a transient cell cycle arrest of mitotic germ cells. Finally, distinct pathways activate germ cell apoptosis in response to defects in meiotic recombination and meiotic chromosome pairing. © 2013 Springer Science+Business Media New York. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84867539316&md5=8bae59a1d8cfed2a1bcee4c0386522d9 U2 - 10.1007/978-1-4614-4015-4 DO - 10.1007/978-1-4614-4015-4 M1 - Other chapter contribution SN - 9781461440147 VL - 757 BT - Germ Cell Development in C. elegans T2 - Germ Cell Development in C. elegans A2 - Schedl,Tim ED - Schedl,Tim T3 - Advances in Experimental Medicine and Biology T3 - en_GB SP - 249 EP - 276 ER - TY - CONF 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 Y1 - 2013 UR - http://www.diabetes.org.uk/Diabetes-UK-Professional-Conference/ M1 - Poster ER - TY - BOOK T1 - Gilles Deleuze’s Difference and Repetition T2 - a Critical Introduction and Guide A1 - Williams,James AU - Williams,James PB - Edinburgh University Press CY - Edinburgh PY - 2013 Y1 - 2013 UR - http://www.euppublishing.com/ M1 - Book BT - Gilles Deleuze’s Difference and Repetition SN - 9780748668809 SN - 9780748668816 ER - TY - JOUR T1 - Glycaemic control and the development of heart failure A1 - Parry,Helen A1 - Donnelly,Louise A1 - Van Zuydam,Natalie A1 - Morris,Andrew A1 - Elder,Douglas H. A1 - Doney,Alex S. F. A1 - Palmer,Colin N. A. A1 - Lang,Chim C. AU - Parry,Helen AU - Donnelly,Louise AU - Van Zuydam,Natalie AU - Morris,Andrew AU - Elder,Douglas H. AU - Doney,Alex S. F. AU - Palmer,Colin N. A. AU - Lang,Chim C. PY - 2013 Y1 - 2013 U2 - 10.1016/S0735-1097(13)60566-5 DO - 10.1016/S0735-1097(13)60566-5 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 - E566 ER - TY - JOUR T1 - Guest editorial A1 - Rieu-Clarke,Alistair A1 - Kinna,Remy A1 - Loures,Flavia AU - Rieu-Clarke,Alistair AU - Kinna,Remy AU - Loures,Flavia PY - 2013 Y1 - 2013 U2 - 10.1080/02508060.2013.780230 DO - 10.1080/02508060.2013.780230 M1 - Article JO - Water International JF - Water International SN - 0250-8060 IS - 2 VL - 38 SP - 109 EP - 111 ER - TY - JOUR T1 - Guidelines for people not for diseases T2 - the challenges of applying UK clinical guidelines to people with multimorbidity A1 - Hughes,Lloyd D. A1 - McMurdo,Marion E. T. A1 - Guthrie,Bruce AU - Hughes,Lloyd D. AU - McMurdo,Marion E. T. AU - Guthrie,Bruce PY - 2013 Y1 - 2013 N2 - BACKGROUND: currently one of the major challenges facing clinical guidelines is multimorbidity. Current guidelines are not designed to consider the cumulative impact of treatment recommendations on people with several conditions, nor to allow comparison of relative benefits or risks. This is despite the fact that multimorbidity is a common phenomenon. OBJECTIVE: to examine the extent to which National Institute of Health and Clinical Excellence (NICE) guidelines address patient comorbidity, patient centred care and patient compliance to treatment recommendations. METHODS: five NICE clinical guidelines were selected for review (type-2 diabetes mellitus, secondary prevention for people with myocardial infarction, osteoarthritis, chronic obstructive pulmonary disease and depression) as these conditions are common causes of comorbidity and the guidelines had all been produced since 2007. Two authors extracted information from each full guideline and noted the extent to which the guidelines accounted for patient comorbidity, patient centred care and patient compliance. The cumulative recommended treatment, follow-up and self-care regime for two hypothetical patients were then created to illustrate the potential cumulative impact of applying single disease recommendations to people with multimorbidity. RESULTS: comorbidity and patient adherence were inconsistently accounted for in the guidelines, ranging from extensive discussion to none at all. Patient centred care was discussed in generic terms across the guidelines with limited disease-specific recommendations for clinicians. Explicitly following guideline recommendations for our two hypothetical patients would lead to a considerable treatment burden, even when recommendations were followed for mild to moderate conditions. In addition, the follow-up and self-care regime was complex potentially presenting problems for patient compliance. CONCLUSION: clinical guidelines have played an important role in improving healthcare for people with long-term conditions. However, in people with multimorbidity current guideline recommendations rapidly cumulate to drive polypharmacy, without providing guidance on how best to prioritise recommendations for individuals in whom treatment burden will sometimes be overwhelming. AB - BACKGROUND: currently one of the major challenges facing clinical guidelines is multimorbidity. Current guidelines are not designed to consider the cumulative impact of treatment recommendations on people with several conditions, nor to allow comparison of relative benefits or risks. This is despite the fact that multimorbidity is a common phenomenon. OBJECTIVE: to examine the extent to which National Institute of Health and Clinical Excellence (NICE) guidelines address patient comorbidity, patient centred care and patient compliance to treatment recommendations. METHODS: five NICE clinical guidelines were selected for review (type-2 diabetes mellitus, secondary prevention for people with myocardial infarction, osteoarthritis, chronic obstructive pulmonary disease and depression) as these conditions are common causes of comorbidity and the guidelines had all been produced since 2007. Two authors extracted information from each full guideline and noted the extent to which the guidelines accounted for patient comorbidity, patient centred care and patient compliance. The cumulative recommended treatment, follow-up and self-care regime for two hypothetical patients were then created to illustrate the potential cumulative impact of applying single disease recommendations to people with multimorbidity. RESULTS: comorbidity and patient adherence were inconsistently accounted for in the guidelines, ranging from extensive discussion to none at all. Patient centred care was discussed in generic terms across the guidelines with limited disease-specific recommendations for clinicians. Explicitly following guideline recommendations for our two hypothetical patients would lead to a considerable treatment burden, even when recommendations were followed for mild to moderate conditions. In addition, the follow-up and self-care regime was complex potentially presenting problems for patient compliance. CONCLUSION: clinical guidelines have played an important role in improving healthcare for people with long-term conditions. However, in people with multimorbidity current guideline recommendations rapidly cumulate to drive polypharmacy, without providing guidance on how best to prioritise recommendations for individuals in whom treatment burden will sometimes be overwhelming. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84869111288&md5=98919faeb2da11d1357965daf79934e7 U2 - 10.1093/ageing/afs100 DO - 10.1093/ageing/afs100 M1 - Article JO - Age and Ageing JF - Age and Ageing IS - 1 VL - 42 SP - 62 EP - 69 ER - TY - JOUR T1 - Handle with care T2 - self-esteem influences on students undertaking personal care tasks A1 - Fenton,Jane A1 - Miller,David AU - Fenton,Jane AU - Miller,David PY - 2013 Y1 - 2013 N2 - Social care tasks are not always seen as an important part of social work education by students. However, they can bring many benefits in terms of personal satisfaction as well as professional development. This paper offers a reinterpretation of data reported in a recent paper by Fenton and Walker (2012), in which the authors reported findings from interviews with a group of students who had undertaken personal care tasks whilst on practice learning opportunities (PLOs). In that original interpretation, the interviews were deconstructed with reference to the concept of value/behaviour congruence i.e. the satisfaction that arises when workers can base their practice on their values, particularly in regard to helping (Fenton, 2011).The current paper offers an alternative conceptual framework through which to analyse the findings: a two-dimensional model of self esteem (Mruk ,2006). It is suggested that the transformative process the students experienced, from reluctance and upset at the thought of undertaking personal care tasks to real positivity and enthusiasm, can be understood in terms of processes of self esteem protection and enhancement. The analysis offers further insight into the benefits as well as the risks associated with encouraging students to undertake these tasks. Some implications for social work education are considered. AB - Social care tasks are not always seen as an important part of social work education by students. However, they can bring many benefits in terms of personal satisfaction as well as professional development. This paper offers a reinterpretation of data reported in a recent paper by Fenton and Walker (2012), in which the authors reported findings from interviews with a group of students who had undertaken personal care tasks whilst on practice learning opportunities (PLOs). In that original interpretation, the interviews were deconstructed with reference to the concept of value/behaviour congruence i.e. the satisfaction that arises when workers can base their practice on their values, particularly in regard to helping (Fenton, 2011).The current paper offers an alternative conceptual framework through which to analyse the findings: a two-dimensional model of self esteem (Mruk ,2006). It is suggested that the transformative process the students experienced, from reluctance and upset at the thought of undertaking personal care tasks to real positivity and enthusiasm, can be understood in terms of processes of self esteem protection and enhancement. The analysis offers further insight into the benefits as well as the risks associated with encouraging students to undertake these tasks. Some implications for social work education are considered. KW - social work KW - self-worth KW - self-competence KW - self-esteem KW - personal care KW - practice learning U2 - 10.1080/02615479.2013.770831 DO - 10.1080/02615479.2013.770831 M1 - Article JO - Social Work Education JF - Social Work Education SN - 0261-5479 ER - TY - JOUR T1 - Harmonious chromatic number of directed graphs A1 - Edwards,Keith J. AU - Edwards,Keith J. PY - 2013 Y1 - 2013 N2 - We consider the extension to directed graphs of the concepts of harmonious colouring and complete colouring. We give an upper bound for the harmonious chromatic number of a general directed graph, and show that determining the exact value of the harmonious chromatic number is NP-hard for directed graphs of bounded degree (in fact graphs with maximum indegree and outdegree 2); the complexity of the corresponding undirected case is not known. We also consider complete colourings, and show that in the directed case the existence of a complete colouring is NP-complete. We also show that the interpolation property for complete colourings fails in the directed case. AB - We consider the extension to directed graphs of the concepts of harmonious colouring and complete colouring. We give an upper bound for the harmonious chromatic number of a general directed graph, and show that determining the exact value of the harmonious chromatic number is NP-hard for directed graphs of bounded degree (in fact graphs with maximum indegree and outdegree 2); the complexity of the corresponding undirected case is not known. We also consider complete colourings, and show that in the directed case the existence of a complete colouring is NP-complete. We also show that the interpolation property for complete colourings fails in the directed case. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84870398504&md5=0f726b7c34a8a6953b7ca3f1dbd3cf81 U2 - 10.1016/j.dam.2012.09.003 DO - 10.1016/j.dam.2012.09.003 M1 - Article JO - Discrete Applied Mathematics JF - Discrete Applied Mathematics SN - 0166-218X IS - 3 VL - 161 SP - 369 EP - 376 ER - TY - JOUR T1 - Herpes simplex encephalitis following microvascular decompression for trigeminal neuralgia Case report A1 - Tang,Hon A1 - Falcone,Francisco A1 - Eljamel,Sam AU - Tang,Hon AU - Falcone,Francisco AU - Eljamel,Sam PY - 2013 Y1 - 2013 N2 -The authors present the first reported case of herpes simplex encephalitis (HSE) precipitated by trigeminal nerve microvascular decompression (MVD). The presentation of this specific case together with the pathogenesis and management of HSE are discussed, with a relevant literature review.
This 29-year-old woman with treatment-resistant trigeminal neuralgia underwent a successful elective MVD of the right trigeminal nerve. She was discharged but was readmitted 1 week postoperatively with clinical signs and symptoms of meningitis. A CSF sample was obtained through lumbar puncture before she was treated initially with ceftriaxone. The polymerase chain reaction test of CSF was later positive for herpes simplex virus Type 1, at which point the patient was switched to a 2-week course of intravenous acyclovir before being discharged.
Although this disease is rare, to avoid a delay in antiviral treatment the authors suggest that HSE should be considered in any patient presenting with a meningoencephalitic picture following MVD. (http://thejns.org/doi/abs/10.3171/2012.11.JNS121386)
AB -The authors present the first reported case of herpes simplex encephalitis (HSE) precipitated by trigeminal nerve microvascular decompression (MVD). The presentation of this specific case together with the pathogenesis and management of HSE are discussed, with a relevant literature review.
This 29-year-old woman with treatment-resistant trigeminal neuralgia underwent a successful elective MVD of the right trigeminal nerve. She was discharged but was readmitted 1 week postoperatively with clinical signs and symptoms of meningitis. A CSF sample was obtained through lumbar puncture before she was treated initially with ceftriaxone. The polymerase chain reaction test of CSF was later positive for herpes simplex virus Type 1, at which point the patient was switched to a 2-week course of intravenous acyclovir before being discharged.
Although this disease is rare, to avoid a delay in antiviral treatment the authors suggest that HSE should be considered in any patient presenting with a meningoencephalitic picture following MVD. (http://thejns.org/doi/abs/10.3171/2012.11.JNS121386)
KW - MANAGEMENT KW - CEREBROSPINAL-FLUID KW - microvascular decompression KW - INFECTIONS KW - POLYMERASE-CHAIN-REACTION KW - REACTIVATION KW - herpes simplex encephalitis KW - pain KW - DIAGNOSIS KW - VIRUS KW - NERVE KW - GUIDELINES U2 - 10.3171/2012.11.JNS121386 DO - 10.3171/2012.11.JNS121386 M1 - Article JO - Journal of Neurology, Neurosurgery and Psychiatry JF - Journal of Neurology, Neurosurgery and Psychiatry SN - 0022-3085 IS - 3 VL - 118 SP - 530 EP - 533 ER - TY - CONF 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 Y1 - 2013 UR - http://www.diabetes.org.uk/Diabetes-UK-Professional-Conference/ M1 - Poster ER - TY - JOUR T1 - Humeral head arthroplasty and its ability to restore original humeral head geometry A1 - Harrold,Fraser A1 - Wigderowitz,Carlos AU - Harrold,Fraser AU - Wigderowitz,Carlos PY - 2013 Y1 - 2013 N2 -Background: Modern prosthetic components are designed to enable restoration of proximal humeral morphology, provided that a precise osteotomy of the humeral head at the level of the anatomic neck is performed. To determine whether a simulated osteotomy and replacement arthroplasty with an idealized implant were able to restore original head geometry.
Materials and methods: A handheld digitizer and surface laser scanner were used to digitize 24 humeri. Computer models were used to simulate an osteotomy, performed at the anterior cartilage-metaphyseal interface, and reconstruct the head with a spherical prosthetic head. The head diameter, radius of curvature, and inclination and retroversion angles were calculated for each specimen and compared with the original humeral head.
Results: The simulated osteotomy resulted in a 4.8 degrees decrease in inclination (P <.01) and 11.3 degrees increase in retroversion (P <.001). The radius of curvature in the coronal plane was not significantly different (P = .284). However, in the axial plane, the prosthesis was significantly larger than the original head for both head diameter (P <.001) and radius of curvature (P <.05). Discussion: The study suggests that the humeral head is not a perfect segment of a sphere and an osteotomy along the anterior cartilage-metaphyseal interface does not remove only the proximal humeral articular surface. Even with a fully adaptable prosthetic implant, replacement arthroplasty is not able to restore original head geometry.
Conclusions: Alterations to head geometry with the osteotomy described may alter the line of force through the prosthetic joint, producing eccentric loading at the glenoid, and contribute to early failure.
AB -Background: Modern prosthetic components are designed to enable restoration of proximal humeral morphology, provided that a precise osteotomy of the humeral head at the level of the anatomic neck is performed. To determine whether a simulated osteotomy and replacement arthroplasty with an idealized implant were able to restore original head geometry.
Materials and methods: A handheld digitizer and surface laser scanner were used to digitize 24 humeri. Computer models were used to simulate an osteotomy, performed at the anterior cartilage-metaphyseal interface, and reconstruct the head with a spherical prosthetic head. The head diameter, radius of curvature, and inclination and retroversion angles were calculated for each specimen and compared with the original humeral head.
Results: The simulated osteotomy resulted in a 4.8 degrees decrease in inclination (P <.01) and 11.3 degrees increase in retroversion (P <.001). The radius of curvature in the coronal plane was not significantly different (P = .284). However, in the axial plane, the prosthesis was significantly larger than the original head for both head diameter (P <.001) and radius of curvature (P <.05). Discussion: The study suggests that the humeral head is not a perfect segment of a sphere and an osteotomy along the anterior cartilage-metaphyseal interface does not remove only the proximal humeral articular surface. Even with a fully adaptable prosthetic implant, replacement arthroplasty is not able to restore original head geometry.
Conclusions: Alterations to head geometry with the osteotomy described may alter the line of force through the prosthetic joint, producing eccentric loading at the glenoid, and contribute to early failure.
KW - osteotomy KW - humerus KW - RETROVERSION KW - PROSTHETIC DESIGN KW - PROXIMAL HUMERUS KW - TOTAL SHOULDER ARTHROPLASTY KW - REPLACEMENT KW - OSTEOARTHRITIS KW - COMPLICATIONS KW - CONTACT KW - geometry KW - GLENOHUMERAL JOINT KW - ARTICULAR GEOMETRY KW - anatomy KW - Shoulder KW - arthroplasty U2 - 10.1016/j.jse.2012.01.027 DO - 10.1016/j.jse.2012.01.027 M1 - Article JO - Journal of shoulder and elbow surgery JF - Journal of shoulder and elbow surgery SN - 1058-2746 IS - 1 VL - 22 SP - 115 EP - 121 ER - TY - CHAP T1 - Hybrid Courts in Retrospect T2 - The Ashgate Research Companion to International Criminal Law A1 - McAuliffe,Padraig AU - McAuliffe,Padraig PB - Ashgate CY - London PY - 2013 Y1 - 2013 M1 - Chapter SN - 9781409419181 BT - The Ashgate Research Companion to International Criminal Law A2 - Hayes,Niamh ED - Hayes,Niamh SP - 453 EP - 473 ER - TY - JOUR T1 - Hydrophilic Strong Anion Exchange (hSAX) Chromatography for Highly Orthogonal Peptide Separation of Complex Proteomes A1 - Ritorto,Maria Stella A1 - Cook,Ken A1 - Tyagi,Kshitiz A1 - Pedrioli,Patrick G. A. A1 - Trost,Matthias AU - Ritorto,Maria Stella AU - Cook,Ken AU - Tyagi,Kshitiz AU - Pedrioli,Patrick G. A. AU - Trost,Matthias PY - 2013 Y1 - 2013 N2 - Due to its compatibility and orthogonality to reversed phase (RP) liquid chromatography (LC) separation, ion exchange chromatography, and mainly strong cation exchange (SCX), has often been the first choice in multidimensional LC experiments in proteomics. Here, we have tested the ability of three strong anion exchanger (SAX) columns differing in their hydrophobicity to fractionate RAW264.7 macrophage cell lysate. IonPac AS24, a strong anion exchange material with ultralow hydrophobicity, demonstrated to be superior to other materials by fractionation and separation of tryptic peptides from both a mixture of 6 proteins as well as mouse cell lysate. The chromatography displayed very high orthogonality and high robustness depending on the hydrophilicity of column chemistry, which we termed hydrophilic strong anion exchange (hSAX). Mass spectrometry analysis of 34 SAX fractions from RAW264.7 macrophage cell lysate digest resulted in an identification of 9469 unique proteins and 126318 distinct peptides in one week of instrument time. Moreover, when compared to an optimized high pH/low pH RP separation approach, the method presented here raised the identification of proteins and peptides by 10 and 28%, respectively. This novel hSAX approach provides robust, reproducible, and highly orthogonal separation of complex protein digest samples for deep coverage proteome analysis. AB - Due to its compatibility and orthogonality to reversed phase (RP) liquid chromatography (LC) separation, ion exchange chromatography, and mainly strong cation exchange (SCX), has often been the first choice in multidimensional LC experiments in proteomics. Here, we have tested the ability of three strong anion exchanger (SAX) columns differing in their hydrophobicity to fractionate RAW264.7 macrophage cell lysate. IonPac AS24, a strong anion exchange material with ultralow hydrophobicity, demonstrated to be superior to other materials by fractionation and separation of tryptic peptides from both a mixture of 6 proteins as well as mouse cell lysate. The chromatography displayed very high orthogonality and high robustness depending on the hydrophilicity of column chemistry, which we termed hydrophilic strong anion exchange (hSAX). Mass spectrometry analysis of 34 SAX fractions from RAW264.7 macrophage cell lysate digest resulted in an identification of 9469 unique proteins and 126318 distinct peptides in one week of instrument time. Moreover, when compared to an optimized high pH/low pH RP separation approach, the method presented here raised the identification of proteins and peptides by 10 and 28%, respectively. This novel hSAX approach provides robust, reproducible, and highly orthogonal separation of complex protein digest samples for deep coverage proteome analysis. U2 - 10.1021/pr301011r DO - 10.1021/pr301011r M1 - Article JO - Journal of Proteome Research JF - Journal of Proteome Research ER - TY - JOUR T1 - Identification and Characterization of miRNA Transcriptome in Potato by High-Throughput Sequencing A1 - Zhang,Runxuan A1 - Marshall,David A1 - Bryan,Glenn J. A1 - Hornyik,Csaba AU - Zhang,Runxuan AU - Marshall,David AU - Bryan,Glenn J. AU - Hornyik,Csaba PY - 2013 Y1 - 2013 N2 -Micro RNAs (miRNAs) represent a class of short, non-coding, endogenous RNAs which play important roles in post-transcriptional regulation of gene expression. While the diverse functions of miRNAs in model plants have been well studied, the impact of miRNAs in crop plant biology is poorly understood. Here we used high-throughput sequencing and bioinformatics analysis to analyze miRNAs in the tuber bearing crop potato (Solanum tuberosum). Small RNAs were analysed from leaf and stolon tissues. 28 conserved miRNA families were found and potato-specific miRNAs were identified and validated by RNA gel blot hybridization. The size, origin and predicted targets of conserved and potato specific miRNAs are described. The large number of miRNAs and complex population of small RNAs in potato suggest important roles for these non-coding RNAs in diverse physiological and metabolic pathways.
AB -Micro RNAs (miRNAs) represent a class of short, non-coding, endogenous RNAs which play important roles in post-transcriptional regulation of gene expression. While the diverse functions of miRNAs in model plants have been well studied, the impact of miRNAs in crop plant biology is poorly understood. Here we used high-throughput sequencing and bioinformatics analysis to analyze miRNAs in the tuber bearing crop potato (Solanum tuberosum). Small RNAs were analysed from leaf and stolon tissues. 28 conserved miRNA families were found and potato-specific miRNAs were identified and validated by RNA gel blot hybridization. The size, origin and predicted targets of conserved and potato specific miRNAs are described. The large number of miRNAs and complex population of small RNAs in potato suggest important roles for these non-coding RNAs in diverse physiological and metabolic pathways.
KW - GENES KW - ROLES KW - SIRNA BIOGENESIS KW - GENOME SEQUENCE KW - MICRORNAS KW - EXPRESSION KW - ARABIDOPSIS KW - STRESS RESPONSES KW - EVOLUTION KW - PLANT SMALL RNAS U2 - 10.1371/journal.pone.0057233 DO - 10.1371/journal.pone.0057233 M1 - Article JO - PLoS ONE JF - PLoS ONE SN - 1932-6203 IS - 2 VL - 8 ER - TY - JOUR T1 - Image processing for near earth object optical guidance systems A1 - Rowell,N. A1 - Parkes,S. A1 - Dunstan,M. AU - Rowell,N. AU - Parkes,S. AU - Dunstan,M. PY - 2013 Y1 - 2013 N2 - A feature tracking algorithm is described, which is designed to support optical navigation of autonomous spacecraft. The algorithm is based on an existing system designed for use in planetary entry, descent, and landing (EDL) scenarios and includes several extra processing steps aimed at improving the performance. The algorithm is tested against the original by processing synthetic image streams of an asteroid and a lunar-type surface, taking care to use realistic surface reflectance models. The tracked features are processed to extract estimates of the camera motion between frames, and the results are compared with the ground truth to assess the robustness and accuracy of the feature tracking. © 1965-2011 IEEE. AB - A feature tracking algorithm is described, which is designed to support optical navigation of autonomous spacecraft. The algorithm is based on an existing system designed for use in planetary entry, descent, and landing (EDL) scenarios and includes several extra processing steps aimed at improving the performance. The algorithm is tested against the original by processing synthetic image streams of an asteroid and a lunar-type surface, taking care to use realistic surface reflectance models. The tracked features are processed to extract estimates of the camera motion between frames, and the results are compared with the ground truth to assess the robustness and accuracy of the feature tracking. © 1965-2011 IEEE. UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-84876129340&md5=e36369a786bfc394a1e47f047dc69bde U2 - 10.1109/TAES.2013.6494399 DO - 10.1109/TAES.2013.6494399 M1 - Article JO - IEEE Transactions on Aerospace and Electronic Systems JF - IEEE Transactions on Aerospace and Electronic Systems SN - 0018-9251 IS - 2 VL - 49 SP - 1057 EP - 1072 ER - TY - JOUR T1 - Imitation of tongue protrusion in human neonates T2 - specificity of the response in a large sample A1 - Nagy,Emese A1 - Pilling,Karen A1 - Orvos,Hajnalka A1 - Molnar,Peter AU - Nagy,Emese AU - Pilling,Karen AU - Orvos,Hajnalka AU - Molnar,Peter PY - 2013 Y1 - 2013 U2 - 10.1037/a0031127 DO - 10.1037/a0031127 M1 - Article JO - Developmental Psychology JF - Developmental Psychology SN - 0012-1649 ER - TY - JOUR T1 - Impact of atopic dermatitis and loss-of-function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis A1 - Visser,M. J. A1 - Landeck,L. A1 - Campbell,L. E. A1 - McLean,W. H. I. A1 - Weidinger,S. A1 - Calkoen,F. A1 - John,S. M. A1 - Kezic,S. AU - Visser,M. J. AU - Landeck,L. AU - Campbell,L. E. AU - McLean,W. H. I. AU - Weidinger,S. AU - Calkoen,F. AU - John,S. M. AU - Kezic,S. PY - 2013 Y1 - 2013 N2 -Background Atopic dermatitis (AD) and loss-of-function mutations in the filaggrin gene (FLG) are both associated with chronic irritant contact dermatitis (ICD). As FLG mutations also are a major risk factor for AD, it is not clear whether FLG mutations are an independent risk factor for ICD or whether the risk is mediated by AD.
Objectives To investigate the relative contribution and interaction of FLG mutations and AD in German patients with occupational ICD and controls (vocational school apprentices).
Methods A total of 634 patients and 393 controls were genotyped for R501X, 2282del4, R2447X and S3247X. Current or past flexural eczema was used as an indicator of AD.
Results FLG mutations were found in 15.9% of the patients with ICD and 8.3% of the controls, with a crude odds ratio (OR) of 2.09 [95% confidence interval (CI) 1.33-3.28] for the combined genotype. The adjusted OR for FLG mutations, corrected for AD, was 1.62 (95% CI 1.01-2.58). Subjects with AD were at approximately three times higher risk of developing ICD than controls (OR 2.89; 95% CI 2.09-3.99). There was no evidence of an interaction between these two risk factors.
Conclusions Our results indicate that both FLG mutations and AD increase the risk of ICD. Individuals with concurrent FLG mutations and AD are at the highest risk of developing ICD.
AB -Background Atopic dermatitis (AD) and loss-of-function mutations in the filaggrin gene (FLG) are both associated with chronic irritant contact dermatitis (ICD). As FLG mutations also are a major risk factor for AD, it is not clear whether FLG mutations are an independent risk factor for ICD or whether the risk is mediated by AD.
Objectives To investigate the relative contribution and interaction of FLG mutations and AD in German patients with occupational ICD and controls (vocational school apprentices).
Methods A total of 634 patients and 393 controls were genotyped for R501X, 2282del4, R2447X and S3247X. Current or past flexural eczema was used as an indicator of AD.
Results FLG mutations were found in 15.9% of the patients with ICD and 8.3% of the controls, with a crude odds ratio (OR) of 2.09 [95% confidence interval (CI) 1.33-3.28] for the combined genotype. The adjusted OR for FLG mutations, corrected for AD, was 1.62 (95% CI 1.01-2.58). Subjects with AD were at approximately three times higher risk of developing ICD than controls (OR 2.89; 95% CI 2.09-3.99). There was no evidence of an interaction between these two risk factors.
Conclusions Our results indicate that both FLG mutations and AD increase the risk of ICD. Individuals with concurrent FLG mutations and AD are at the highest risk of developing ICD.
KW - HAND ECZEMA KW - CONFER SUSCEPTIBILITY KW - STRATUM-CORNEUM KW - EARLY-ONSET KW - POPULATION KW - TRANSEPIDERMAL WATER-LOSS KW - SKIN KW - PROSPECTIVELY-FOLLOWED COHORT KW - ICHTHYOSIS VULGARIS KW - NULL MUTATIONS U2 - 10.1111/bjd.12083 DO - 10.1111/bjd.12083 M1 - Article JO - British Journal of Dermatology JF - British Journal of Dermatology SN - 0007-0963 IS - 2 VL - 168 SP - 326 EP - 332 ER - TY - JOUR T1 - Impact of health-care accessibility and social deprivation on diabetes related foot disease A1 - Leese,G. P. A1 - Feng,Z. A1 - Leese,R. M. A1 - Dibben,C. A1 - Emslie-Smith,A. AU - Leese,G. P. AU - Feng,Z. AU - Leese,R. M. AU - Dibben,C. AU - Emslie-Smith,A. PY - 2013 Y1 - 2013 N2 -Aims To determine whether geography and/or social deprivation influences the occurrence of foot ulcers or amputations in patients with diabetes. Methods A population-based cohort of people with diabetes (n=15983) were identified between 2004 and 2006. Community and hospital data on diabetes care, podiatry care and onset of ulceration and amputation was linked using a unique patient identifier, which is used for all patient contacts with health-care professionals. Postcode was used to calculate social deprivation and distances to general practice and hospital care. Results Over 3years' follow-up 670 patients with diabetes developed new foot ulcers (42 per 1000) and 99 proceeded to amputation (6 per 1000). The most deprived quintile had a 1.7-fold (95% CI 1.22.3) increased risk of developing a foot ulcer. Distance from general practitioner or hospital clinic and lack of attendance at community retinal screening did not predict foot ulceration or amputation. Previous ulcer (OR 15.1, 95% CI 11.619.6), insulin use (OR 2.7, 95% CI 2.13.5), absent foot pulses (5.9: 4.77.5) and impaired monofilament sensation (OR 6.5, 95% CI 5.08.4) all predicted foot ulceration. Previous foot ulcer, absent pulses and impaired monofilaments also predicted amputation. Conclusion Social deprivation is an important factor, especially for the development of foot ulcers. Geographical aspects such as accessibility to the general practitioner or hospital clinic are not associated with foot ulceration or amputation in this large UK cohort study.
AB -Aims To determine whether geography and/or social deprivation influences the occurrence of foot ulcers or amputations in patients with diabetes. Methods A population-based cohort of people with diabetes (n=15983) were identified between 2004 and 2006. Community and hospital data on diabetes care, podiatry care and onset of ulceration and amputation was linked using a unique patient identifier, which is used for all patient contacts with health-care professionals. Postcode was used to calculate social deprivation and distances to general practice and hospital care. Results Over 3years' follow-up 670 patients with diabetes developed new foot ulcers (42 per 1000) and 99 proceeded to amputation (6 per 1000). The most deprived quintile had a 1.7-fold (95% CI 1.22.3) increased risk of developing a foot ulcer. Distance from general practitioner or hospital clinic and lack of attendance at community retinal screening did not predict foot ulceration or amputation. Previous ulcer (OR 15.1, 95% CI 11.619.6), insulin use (OR 2.7, 95% CI 2.13.5), absent foot pulses (5.9: 4.77.5) and impaired monofilament sensation (OR 6.5, 95% CI 5.08.4) all predicted foot ulceration. Previous foot ulcer, absent pulses and impaired monofilaments also predicted amputation. Conclusion Social deprivation is an important factor, especially for the development of foot ulcers. Geographical aspects such as accessibility to the general practitioner or hospital clinic are not associated with foot ulceration or amputation in this large UK cohort study.
KW - RISK KW - LOWER-EXTREMITY AMPUTATION KW - RATES KW - ASSOCIATION KW - UK POPULATION U2 - 10.1111/dme.12108 DO - 10.1111/dme.12108 M1 - Article JO - Diabetic Medicine JF - Diabetic Medicine SN - 0742-3071 IS - 4 VL - 30 SP - 484 EP - 490 ER - TY - JOUR T1 - Improving student selection using multiple mini-interviews with multifaceted rasch modeling A1 - Till,Hettie A1 - Myford,Carol A1 - Dowell,Jonathan AU - Till,Hettie AU - Myford,Carol AU - Dowell,Jonathan PY - 2013 Y1 - 2013 N2 - PURPOSE: The authors report multiple mini-interview (MMI) selection process data at the University of Dundee Medical School; staff, students, and simulated patients were examiners and investigated how effective this process was in separating candidates for entry into medical school according to the attributes measured, whether the different groups of examiners exhibited systematic differences in their rating patterns, and what effect such differences might have on candidates' scores. METHOD: The 452 candidates assessed in 2009 rotated through the same 10-station MMI that measured six noncognitive attributes. Each candidate was rated by one examiner in each station. Scores were analyzed using Facets software, with candidates, examiners, and stations as facets. The computer program calculated fair average scores that adjusted for examiner severity/leniency and station difficulty. RESULTS: The MMI reliably (0.89) separated the candidates into four statistically distinct levels of noncognitive ability. The Rasch measures accounted for 31.69% of the total variance in the ratings (candidates 16.01%, examiners 11.32%, and stations 4.36%). Students rated more severely than staff and also had more unexpected ratings. Adjusting scores for examiner severity/leniency and station difficulty would have changed the selection outcomes for 9.6% of the candidates. CONCLUSIONS: The analyses highlighted the fact that quality control monitoring is essential to ensure fairness when ranking candidates according to scores obtained in the MMI. The results can be used to identify examiners needing further training, or who should not be included again, as well as stations needing review. "Fair average" scores should be used for ranking the candidates. AB - PURPOSE: The authors report multiple mini-interview (MMI) selection process data at the University of Dundee Medical School; staff, students, and simulated patients were examiners and investigated how effective this process was in separating candidates for entry into medical school according to the attributes measured, whether the different groups of examiners exhibited systematic differences in their rating patterns, and what effect such differences might have on candidates' scores. METHOD: The 452 candidates assessed in 2009 rotated through the same 10-station MMI that measured six noncognitive attributes. Each candidate was rated by one examiner in each station. Scores were analyzed using Facets software, with candidates, examiners, and stations as facets. The computer program calculated fair average scores that adjusted for examiner severity/leniency and station difficulty. RESULTS: The MMI reliably (0.89) separated the candidates into four statistically distinct levels of noncognitive ability. The Rasch measures accounted for 31.69% of the total variance in the ratings (candidates 16.01%, examiners 11.32%, and stations 4.36%). Students rated more severely than staff and also had more unexpected ratings. Adjusting scores for examiner severity/leniency and station difficulty would have changed the selection outcomes for 9.6% of the candidates. CONCLUSIONS: The analyses highlighted the fact that quality control monitoring is essential to ensure fairness when ranking candidates according to scores obtained in the MMI. The results can be used to identify examiners needing further training, or who should not be included again, as well as stations needing review. "Fair average" scores should be used for ranking the candidates. U2 - 10.