High-resolution imaging of human atherosclerotic carotid plaques with micro18F-FDG PET scanning exploring plaque vulnerability

FDG-PET can be used to identify vulnerable plaques in atherosclerotic disease. Clinical FDG-PET camera systems are restricted in terms of resolution for the visualization of detailed inflammation patterns in smaller vascular structures. The aim of the study is to evaluate the possible added value of a high-resolution microPET system in excised carotid plaques using FDG. In this study, 17 patients with planned carotid endarterectomy were included. Excised plaques were incubated in FDG and subsequently imaged with microPET. Macrophage presence in plaques was evaluated semi-quantitatively by immunohistochemistry. Plaque calcification was assessed additionally with CT and correlated to FDG uptake. Finally, FDG uptake and macrophage infiltration were compared with patient symptomatology. Heterogeneous distributions and variable intensities of FDG uptake were found within the plaques. A positive correlation between the distribution of macrophages and the FDG uptake (r = 0.68, P <.01) was found. A negative correlation was found between areas of calcifications and FDG uptake (r = -0.84, P <.001). Ratio FDG(max) values as well as degree of CD68 accumulation were significantly higher in CVA patients compared with TIA or amaurosis fugax patients (P <.05) and CVA patients compared with asymptomatic patients (P <.05). This ex vivo study demonstrates that excised carotid plaques can be visualized in detail using FDG microPET. Enhancement of clinical PET/CT resolution for similar imaging results in patients is needed

Exposure-in-vivo containing interventions to improve work functioning of workers with anxiety disorder: a systematic review

<p>Abstract</p> <p>Background</p> <p>Anxiety disorders are associated with functional disability, sickness absence, and decreased productivity. Effective treatments of anxiety disorders can result in remission of symptoms. However the effects on work related outcomes are largely unknown. Exposure in vivo is potentially well fit to improve work-related outcomes. This study systematically reviews the effectiveness of exposure-in-vivo containing interventions in reducing work-related adverse outcomes in workers with anxiety disorders.</p> <p>Methods</p> <p>A systematic study search was conducted in Medline, Cinahl, Embase and Psycinfo. Two reviewers independently extracted data and from each study assessed the quality of evidence by using the GRADE approach. We performed a meta-analysis if data showed sufficient clinical homogeneity.</p> <p>Results</p> <p>Seven studies containing 11 exposure-in-vivo interventions were included. Four studies were focused on Obsessive Compulsive Disorder (OCD), two on Post Traumatic Stress Disorder (PTSD), and one on a mixed group of OCD and severe phobias. The studies were grouped according to type of anxiety disorder and subsequently according to type of comparisons. For OCD, exposure-in-vivo containing interventions can yield better work-related outcomes compared to medication (SSRIs) and relaxation but not better compared to response prevention. The results on anxiety outcomes were similar. The net contribution of exposure in vivo in two OCD intervention programs is also presented as a meta-analysis and shows significant positive results on work role limitations. The calculated pooled effect size with 95% confidence interval was 0.72 (0.28, 1.15). For PTSD, exposure-in-vivo containing interventions can yield better work-related and anxiety-related outcomes compared to a waiting-list but not better compared to imaginal exposure.</p> <p>Conclusions</p> <p>Exposure in vivo as part of an anxiety treatment can reduce work-related adverse outcomes in workers with OCD and PTSD better than various other anxiety treatments or a waiting-list. We recommend that it should be studied how the results of these studies can be transferred to the practice of occupational health professionals and how clinicians can make better use of them to improve work-related outcomes. In future research, priority should be given to high-quality randomised controlled trials (RCTs) in which exposure-in-vivo containing interventions are applied to a variety of anxiety disorders and compared with other clinical anxiety treatments such as SSRIs. Work-related outcomes, in particular work functioning and sickness absence, need to be assessed with reliable and valid measures.</p

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Severe Airway Epithelial Injury, Aberrant Repair and Bronchiolitis Obliterans Develops after Diacetyl Instillation in Rats

Bronchiolitis obliterans (BO) is a fibrotic lung disease that occurs in a variety of clinical settings, including toxin exposures, autoimmunity and lung or bone marrow transplant. Despite its increasing clinical importance, little is known regarding the underlying disease mechanisms due to a lack of adequate small animal BO models. Recent epidemiological studies have implicated exposure to diacetyl (DA), a volatile component of artificial butter flavoring, as a cause of BO in otherwise healthy factory workers. Our overall hypothesis is that DA induces severe epithelial injury and aberrant repair that leads to the development of BO. Therefore, the objectives of this study were 1) to determine if DA, delivered by intratracheal instillation (ITI), would lead to the development of BO in rats and 2) to characterize epithelial regeneration and matrix repair after ITI of DA.Male Sprague-Dawley rats were treated with a single dose of DA (125 mg/kg) or sterile water (vehicle control) by ITI. Instilled DA resulted in airway specific injury, followed by rapid epithelial regeneration, and extensive intraluminal airway fibrosis characteristic of BO. Increased airway resistance and lung fluid neutrophilia occurred with the development of BO, similar to human disease. Despite rapid epithelial regeneration after DA treatment, expression of the normal phenotypic markers, Clara cell secretory protein and acetylated tubulin, were diminished. In contrast, expression of the matrix component Tenascin C was significantly increased, particularly evident within the BO lesions.We have established that ITI of DA results in BO, creating a novel chemical-induced animal model that replicates histological, biological and physiological features of the human disease. Furthermore, we demonstrate that dysregulated epithelial repair and excessive matrix Tenacin C deposition occur in BO, providing new insights into potential disease mechanisms and therapeutic targets

Diagnostic algorithm, prognostic factors and surgical treatment of metastatic cancer diseases of the long bones and spine

Oncological management of skeletal metastases has changed dramatically in the last few decades. A significant number of patients survive for many years with their metastases.Surgeons are more active and the technical repertoire is broader, from plates to intramedullary devices to (tumour) endoprostheses.The philosophy of treatment should be different in the case of a trauma-related fracture and a pathological fracture. A proper algorithm for establishing a diagnosis and evaluation of prognostic factors helps in planning the surgical intervention.The aim of palliative surgery is usually to eliminate pain and to allow the patient to regain his/her mobility as well as to improve the quality of life through minimally invasive techniques using life-long durable devices.In a selected group of patients with an oncologically controlled primary tumour site and a solitary bone metastasis with positive prognostic factors, which meet the criteria for radical excision (approximately 10% to 15% of the cases), a promising three to five years of survival may be achieved, especially in cases of metastases from breast and kidney cancer.Spinal metastases require meticulous evaluation because decisions on treatment mostly depend on the tumour type, segmental stability, the patient's symptoms and general state of health.Advanced radiotherapy combined with minimally invasive surgical techniques (minimally invasive stabilisation and separation surgery) provides durable local control with a low complication rate in a number of patients. Cite this article: EFORT Open Rev 2017;2:372-381

Who leads research productivity growth? Guidelines for R&D policy-makers

[EN] This paper evaluates to what extent policy-makers have been able to promote the creation and consolidation of comprehensive research groups that contribute to the implementation of a successful innovation system. Malmquist productivity indices are applied in the case of the Spanish Food Technology Program, finding that a large size and a comprehensive multi-dimensional research output are the key features of the leading groups exhibiting high efficiency and productivity levels. While identifying these groups as benchmarks, we conclude that the financial grants allocated by the program, typically aimed at small-sized and partially oriented research groups, have not succeeded in reorienting them in time so as to overcome their limitations. We suggest that this methodology offers relevant conclusions to policy evaluation methods, helping policy-makers to readapt and reorient policies and their associated means, most notably resource allocation (financial schemes), to better respond to the actual needs of research groups in their search for excellence (micro-level perspective), and to adapt future policy design to the achievement of medium-long term policy objectives (meso and macro-level).Jiménez Saez, F.; Zabala Iturriagagoitia, JM.; Zofio, JL. (2013). Who leads research productivity growth? Guidelines for R&D policy-makers. Scientometrics. 94(1):273-303. doi:10.1007/s11192-012-0763-0S273303941Abbring, J. H., & Heckman, J. J. (2008). Dynamic policy analysis. In L. Mátyás & P. Sevestre (Eds.), The econometrics of panel data (3rd ed., pp. 795–863). Heidelberg: Springer.Acosta Ballesteros, J., & Modrego Rico, A. (2001). Public financing of cooperative R&D projects in Spain: the concerted projects under the national R&D plan. Research Policy, 30, 625–641.Arbel, A. (1981). Policy evaluation in the dynamic input–output model. International Journal of Systems Science, 12, 255–260.Arnold, E. (2004). Evaluation research and innovation policy: A systems world needs systems evaluations. Research Evaluation, 13, 3–17.Arrow, J. K. (1962). Economic welfare and the allocation of resources for inventions. In R. Nelson (Ed.), The rate and direction of inventive activity: Economic and social factor (pp. 609–625). Princeton: Princeton University Press and NBER.Autio, E. (1997). New, technology-based firms in innovation networks symplectic and generative impacts. Research Policy, 26, 263–281.Balk, B. (2001). Scale efficiency and productivity change. Journal of Productivity Analysis, 15, 153–183.Balzat, M., & Hanusch, H. (2004). Recent trends in the research on national innovation systems. Journal of Evolutionary Economics, 14, 197–210.Berg, S. A., Førsund, F. R., & Jansen, E. S. (1992). Malmquist indices of productivity growth during the deregulation of Norwegian banking. Scandinavian Journal of Economics, 94, S211–S228.Bergek, A., Carlsson, B., Lindmark, S., Rickne, A., & Jacobsson, S. (2008). Analyzing the functional dynamics of technological innovation systems: A scheme of analysis. Research Policy, 37, 407–429.Bonaccorsi, A., & Daraio, C. (2005). Exploring size and agglomeration effects on public research productivity. Scientometrics, 63(1), 87–120.Buisseret, T. J., Cameron, H., & Georghiou, L. (1995). What difference does it make? Additionality in the public support of R&D in large firms. International Journal of Technology Management, 10, 587–600.Bustelo, M. (2006). The potential role of standards and guidelines in the development of an evaluation culture in Spain. Evaluation, 12, 437–453.Chavas, J. P., & Cox, T. M. (1999). A generalized distance function and the analysis of production efficiency. Southern Economic Journal, 66, 295–318.CICYT. (1987). Programa Nacional de Tecnología de los Alimentos. Madrid: Ministerio de Educación y Ciencia.CICYT (1988). Plan Nacional de Investigación Científica y Desarrollo Tecnológico 1988–1991. Ministerio de Educación y Ciencia, Secretaría de Estado de Universidades e Investigación, Madrid.Cooper, W. W., Seiford, L. M., & Tone, K. (2000). Data envelopment analysis: A comprehensive text with models, applications, references and DEA-software. Boston: Kluwer Academic Publishers.David, P., Mowery, D., & Steinmueller, W. E. (1994). Analyzing the economic payoffs from basic research. In D. Mowery (Ed.), Science and technology policy in interdependent economies (pp. 57–78). Boston: Kluwer Academic Publishers.Dopfer, K., Foster, J., & Potts, J. (2004). Micro-meso-macro. Journal of Evolutionary Economics, 14, 263–279.Edquist, C., & Hommen, L. (2008). Comparing national systems of innovation in Asia and Europe: Theory and comparative framework. In C. Edquist & L. Hommen (Eds.), Small country innovation systems: Globalisation, change and policy in Asia and Europe (pp. 1–28). Cheltenham: Edward Elgar.Färe, R., Grosskopf, S., Norris, M., & Zhang, Z. (1994). Productivity growth, technical progress, and efficiency change in industrialized countries. American Economic Review, 84, 66–83.Farrell, M. (1957). The measurement of productive efficiency. Journal of the Royal Statistical Society, Series A, General, 120(3), 253–281.Førsund, F. R. (1993). Productivity growth in Norwegian ferries. In H. O. Fried, C. A. K. Lovell, & S. S. Schmidt (Eds.), The measurement of productive efficiency: Techniques and applications (pp. 352–373). New York: Oxford University Press.Førsund, F. R. (1997). The Malmquist productivity index, TFP and scale. University of Oslo, Oslo: Working Paper, Department of Economics and Business Administration.Freeman, C. (1987). Technology policy and economic performance: Lessons from Japan. London: Printer Publishers.García-Martínez, M., & Briz, J. (2000). Innovation in the Spanish food & drink industry. International Food and Agribusiness Management Review, 3, 155–176.Gibbons, M., Limoges, C., Nowotny, H., Schwartzman, S., Scott, P., & Trow, M. (1994). The new production of knowledge: The dynamics of science and research in contemporary societies. London: Sage Publications.Grammatikopoulos, V., Kousteiios, A., Tsigilis, N., & Theodorakis, Y. (2004). Applying dynamic evaluation approach in education. Studies in Educational Evaluation, 30, 255–263.Grifell-Tatjé, E., & Lovell, C. A. K. (1999). A generalized Malmquist productivity index. Top, 7(1), 81–101.Grimpe, C., & Sofka, W. (2007). Search patterns and absorptive capacity: A comparison of low- and high-technology firms from thirteen European countries. Discussion paper no. 07-062. Centre for European Economic Research (ZEW), Mannheim, Germany.Guan, J., & Wang, J. (2004). Evaluation and interpretation of knowledge production efficiency. Scientometrics, 59(1), 131–155.Hekkert, M. P., Suurs, R. A. A., Negro, S. O., Kuhlmann, S., & Smits, R. E. H. M. (2007). Functions of innovation systems: A new approach for analysing technological change. Technological Forecasting and Social Change, 74, 413–432.Jiménez-Sáez, F. (2005). Una Evaluación del Programa Nacional de Tecnología de Alimentos: análisis de la articulación fomentada sobre el Sistema Alimentario de Innovación en España. PhD dissertation, Servicio de Publicaciones de la Universidad Politécnica de Valencia, Valencia.Jiménez-Sáez, F., Zabala-Iturriagagoitia, J. M., Zofío, J. L., & Castro-Martínez, E. (2011). Evaluating research efficiency within National R&D Programmes. Research Policy, 40, 230–241.Kao, C. (2008). Efficiency analysis of university departments: An empirical study. OMEGA, 36, 653–664.Kuhlmann, S. (2003). Evaluation of research and innovation policies: A discussion of trends with examples from Germany. International Journal of Technology Management, 26, 131–149.Laitinen, E. K. (2002). A dynamic performance measurement system: Evidence from small Finnish technology companies. Scandinavian Journal of Management, 18, 65–99.Laranja, M., Uyarra, E., & Flanagan, K. (2008). Policies for science, technology and innovation: Translating rationales into regional policies in a multi-level setting. Research Policy, 37(5), 823–835.Lee, T.-L., & von Tunzelman, N. (2005). A dynamic analytic approach to national innovation systems: The IC industry in Taiwan. Research Policy, 34, 425–440.Lipsey, R., & Carlaw, K. (1998). A structuralist assessment of technology policies: Taking Schumpeter seriously on policy. Ottawa: Industry Canada Research Publications Program.Lipsey, R., Carlaw, K., & Bekar, C. (2005). Economic transformations: General purpose technologies and long term economic growth. Oxford: Oxford University Press.Lundvall, B. Å. (1992). National systems of innovation: Toward a theory of innovation and interactive learning. London: Printer Publishers.Lundvall, B. Å., Johnson, B., Andersen, E. S., & Dalum, B. (2002). National systems of production, innovation and competence building. Research Policy, 31, 213–231.Markard, J., & Truffer, B. (2008). Actor-oriented analysis of innovation systems: Exploring micro-meso level linkages in the case of stationary fuel cells. Technology Analysis & Strategic Management, 20, 443–464.Metcalfe, J. S. (2002). Equilibrium and evolutionary foundations of competition and technology policy: New perspectives on the division of labour and the innovation process. CRIC Working Papers series, University of Manchester.Miettinen, R. (1999). The riddle of things. Activity theory and actor network theory as approaches of studying innovations. Mind, Culture and Activity, 6, 170–195.Molas-Gallart, J., & Davies, A. (2006). Toward theory-led evaluation: The experience of European science, technology, and innovation policies. American Journal of Evaluation, 27, 64–82.Mytelka, L. K., & Smith, K. (2002). Policy learning and innovation theory: An interactive and co-evolving process. Research Policy, 31, 1467–1479.Olazarán, M., Lavía, C., & Otero, B. (2004). ¿Hacia una segunda transición en la ciencia? Política científica y grupos de investigación. Revista Española de Sociología, 4, 143–172.Potts, J. (2007). The innovation system & economic evolution. Productivity commission submission, public support for science & innovation, productivity commission, Camberra.Ray, S., & Desli, E. (1997). Productivity growth, technical progress, and efficiency change in industrialized countries: Comment. American Economic Review, 87(5), 1033–1039.Rip, A., & Nederhof, A. J. (1986). Between dirigism and laissez-faire: Effects of implementing the science policy priority for biotechnology in the Netherlands. Research Policy, 15, 253–268.Schmidt, E. K., Graversen, E. K., & Langberg, K. (2003). Innovation and dynamics in public research environments in Denmark: A research-policy perspective. Science and Public Policy, 30, 107–116.Schmoch, U., & Schubert, T. (2009). Sustainability of incentives for excellent research—The German case. Scientometrics, 81(1), 195–218.Shephard, R. (1970). Theory of cost and production functions. New Jersey: Princeton University Press.Simar, L., & Wilson, P. W. (1998). Productivity growth in industrialized countries. Discussion paper 9810, Universite Catholique de Louvain, Belgium.Van Raan, A. F. J. (2000). R&D evaluation at the beginning of the new century. Research Evaluation, 8, 81–86.Zofio, J. L. (2007). Malmquist productivity index decompositions: A unifying framework. Applied Economics, 39, 2371–2387.Zofio, J. L., & Lovell, C. A. K. (1998). Yet another Malmquist productivity index decomposition. Working paper, Department of Economics, University of Georgia, Athens, GA 30602, USA.Zofio, J. L., & Lovell, C. A. K. (2001). Graph efficiency and productivity measures: An application to US agriculture. Applied Economics, 33(10), 1433–1442.Zofio, J. L., & Prieto, A. M. (2006). Return to dollar, generalized distance function and the Fisher productivity index. Spanish Economic Review, 8, 113–138

Triacylglycerol Fatty Acid Composition in Diet-Induced Weight Loss in Subjects with Abnormal Glucose Metabolism – the GENOBIN Study

BACKGROUND: The effect of weight loss on different plasma lipid subclasses at the molecular level is unknown. The aim of this study was to examine whether a diet-induced weight reduction result in changes in the extended plasma lipid profiles (lipidome) in subjects with features of metabolic syndrome in a 33-week intervention. METHODOLOGY/PRINCIPAL FINDINGS: Plasma samples of 9 subjects in the weight reduction group and 10 subjects in the control group were analyzed using mass spectrometry based lipidomic and fatty acid analyses. Body weight decreased in the weight reduction group by 7.8+/-2.9% (p<0.01). Most of the serum triacylglycerols and phosphatidylcholines were reduced. The decrease in triacylglycerols affected predominantly the saturated short chain fatty acids. This decrease of saturated short chain fatty acid containing triacylglycerols correlated with the increase of insulin sensitivity. However, levels of several longer chain fatty acids, including arachidonic and docosahexanoic acid, were not affected by weight loss. Levels of other lipids known to be associated with obesity such as sphingolipids and lysophosphatidylcholines were not altered by weight reduction. CONCLUSIONS/SIGNIFICANCE: Diet-induced weight loss caused significant changes in global lipid profiles in subjects with abnormal glucose metabolism. The observed changes may affect insulin sensitivity and glucose metabolism in these subjects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00621205

Extra-cellular matrix proteins induce matrix metalloproteinase-1 (MMP-1) activity and increase airway smooth muscle contraction in asthma

Airway remodelling describes the histopathological changes leading to fixed airway obstruction in patients with asthma and includes extra-cellular matrix (ECM) deposition. Matrix metalloproteinase-1 (MMP-1) is present in remodelled airways but its relationship with ECM proteins and the resulting functional consequences are unknown. We used airway smooth muscle cells (ASM) and bronchial biopsies from control donors and patients with asthma to examine the regulation of MMP-1 by ECM in ASM cells and the effect of MMP-1 on ASM contraction. Collagen-I and tenascin-C induced MMP-1 protein expression, which for tenascin-C, was greater in asthma derived ASM cells. Tenascin-C induced MMP-1 expression was dependent on ERK1/2, JNK and p38 MAPK activation and attenuated by function blocking antibodies against the β1 and β3 integrin subunits. Tenascin-C and MMP-1 were not expressed in normal airways but co-localised in the ASM bundles and reticular basement membrane of patients with asthma. Further, ECM from asthma derived ASM cells stimulated MMP-1 expression to a greater degree than ECM from normal ASM. Bradykinin induced contraction of ASM cells seeded in 3D collagen gels was reduced by the MMP inhibitor ilomastat and by siRNA knockdown of MMP-1. In summary, the induction of MMP-1 in ASM cells by tenascin-C occurs in part via integrin mediated MAPK signalling. MMP-1 and tenascin-C are co-localised in the smooth muscle bundles of patients with asthma where this interaction may contribute to enhanced airway contraction. Our findings suggest that ECM changes in airway remodelling via MMP-1 could contribute to an environment promoting greater airway narrowing in response to broncho-constrictor stimuli and worsening asthma symptoms

Global Analysis of the Impact of Environmental Perturbation on cis-Regulation of Gene Expression

Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent by which controlled, environmental perturbation influences cis-eQTLs is unclear. We carried out large-scale induction experiments using primary human bone cells derived from unrelated donors of Swedish origin treated with 18 different stimuli (7 treatments and 2 controls, each assessed at 2 time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t = 2h), dexamethasone (DEX) (t = 24h), and PGE2 (t = 24h). Using these treatments and control, we performed expression profiling for 18,144 RefSeq transcripts on biological replicates of the complete study cohort of 113 individuals (ntotal = 782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs (defined as SNPs located within the gene ±250 kb). We found that 93% of cis-eQTLs at 1% FDR were observed in at least one additional treatment, and in fact, on average, only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment. Treatment-specific cis-regulatory effects were, however, 2- to 6-fold more abundant among differently expressed genes upon treatment. We further followed-up and validated the DEX–specific cis-regulation of the MYO6 and TNC loci and found top cis-regulatory variants located 180 kb and 250 kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interactions between cellular environment and cis-variants are relatively rare (∼1.5%), but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here