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Sample records for nonsymbolic pde indicating

  1. Biomolecular surface construction by PDE transform.

    Science.gov (United States)

    Zheng, Qiong; Yang, Siyang; Wei, Guo-Wei

    2012-03-01

    This work proposes a new framework for the surface generation based on the partial differential equation (PDE) transform. The PDE transform has recently been introduced as a general approach for the mode decomposition of images, signals, and data. It relies on the use of arbitrarily high-order PDEs to achieve the time-frequency localization, control the spectral distribution, and regulate the spatial resolution. The present work provides a new variational derivation of high-order PDE transforms. The fast Fourier transform is utilized to accomplish the PDE transform so as to avoid stringent stability constraints in solving high-order PDEs. As a consequence, the time integration of high-order PDEs can be done efficiently with the fast Fourier transform. The present approach is validated with a variety of test examples in two-dimensional and three-dimensional settings. We explore the impact of the PDE transform parameters, such as the PDE order and propagation time, on the quality of resulting surfaces. Additionally, we utilize a set of 10 proteins to compare the computational efficiency of the present surface generation method and a standard approach in Cartesian meshes. Moreover, we analyze the present method by examining some benchmark indicators of biomolecular surface, that is, surface area, surface-enclosed volume, solvation free energy, and surface electrostatic potential. A test set of 13 protein molecules is used in the present investigation. The electrostatic analysis is carried out via the Poisson-Boltzmann equation model. To further demonstrate the utility of the present PDE transform-based surface method, we solve the Poisson-Nernst-Planck equations with a PDE transform surface of a protein. Second-order convergence is observed for the electrostatic potential and concentrations. Finally, to test the capability and efficiency of the present PDE transform-based surface generation method, we apply it to the construction of an excessively large biomolecule, a

  2. PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

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    Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen

    2016-01-01

    Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092

  3. Symbolic behavior in regular classrooms. A specification of symbolic and non-symbolic behavior

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    Stefan eBillinger

    2011-06-01

    Full Text Available Students’ capabilities to use symbolic information in classroom setting could be expected to influence their possibilities to be active and participating. The development of strategies for teachers to compensate for reduced capability need specific operational definition of symbolic behavior. Fifty-three students, aged 11 to 13 years old, 29 boys and 24 girls, from three classes in the same Swedish compulsory regular school participated in the current study. After a short training sequence 25 students (47% were defined as showing symbolic behavior (symbolic, and 28 students (53% were not (non-symbolic, based on their follow-up test performances. Symbolic and non-symbolic differed significantly on post test performances (p. < .05. Surprisingly, non-symbolic behavior deteriorated their performance, while symbolic enhanced their performance (p. < .05. The results indicate that the operational definition used in the present study may be useful in further studies relating the capability to show symbolic behavior and students’ activity and participation in classroom settings.

  4. PDE9A, PDE10A, and PDE11A expression in rat trigeminovascular pain signalling system

    DEFF Research Database (Denmark)

    Kruse, Lars S; Møller, Morten; Tibaek, Maiken

    2009-01-01

    as neocortex and cerebellar cortex. Real-time PCR and Western blotting showed that PDE9A, PDE10A and PDE11A are expressed in components of the rat trigeminovascular pain signalling system including middle cerebral artery, basilar artery, meninges, trigeminal ganglion and spinal trigeminal nucleus. Aorta...... and mesenteric artery as well as cerebral neocortex and cerebellar cortex also showed expression of PDE9A, PDE10A and PDE11A. Immunohistochemistry revealed that PDE9A, PDE10A and PDE11A are localised in the cytosol of nerve cell bodies of the trigeminal ganglion. We here present, for the first time...

  5. The emperor's new clothes: PDE5 and the heart.

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    Chantal V Degen

    Full Text Available Phosphodiesterase-5 (PDE5 is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP activates protein kinase G (PKG, which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction, dog (control and HFpEF as well as human (healthy and failing heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design.

  6. Towards Optimal PDE Simulations

    International Nuclear Information System (INIS)

    Keyes, David

    2009-01-01

    The Terascale Optimal PDE Solvers (TOPS) Integrated Software Infrastructure Center (ISIC) was created to develop and implement algorithms and support scientific investigations performed by DOE-sponsored researchers. These simulations often involve the solution of partial differential equations (PDEs) on terascale computers. The TOPS Center researched, developed and deployed an integrated toolkit of open-source, optimal complexity solvers for the nonlinear partial differential equations that arise in many DOE application areas, including fusion, accelerator design, global climate change and reactive chemistry. The algorithms created as part of this project were also designed to reduce current computational bottlenecks by orders of magnitude on terascale computers, enabling scientific simulation on a scale heretofore impossible.

  7. Terascale Optimal PDE Simulations

    Energy Technology Data Exchange (ETDEWEB)

    David Keyes

    2009-07-28

    The Terascale Optimal PDE Solvers (TOPS) Integrated Software Infrastructure Center (ISIC) was created to develop and implement algorithms and support scientific investigations performed by DOE-sponsored researchers. These simulations often involve the solution of partial differential equations (PDEs) on terascale computers. The TOPS Center researched, developed and deployed an integrated toolkit of open-source, optimal complexity solvers for the nonlinear partial differential equations that arise in many DOE application areas, including fusion, accelerator design, global climate change and reactive chemistry. The algorithms created as part of this project were also designed to reduce current computational bottlenecks by orders of magnitude on terascale computers, enabling scientific simulation on a scale heretofore impossible.

  8. Fractions We Cannot Ignore: The Nonsymbolic Ratio Congruity Effect

    Science.gov (United States)

    Matthews, Percival G.; Lewis, Mark R.

    2017-01-01

    Although many researchers theorize that primitive numerosity processing abilities may lay the foundation for whole number concepts, other classes of numbers, like fractions, are sometimes assumed to be inaccessible to primitive architectures. This research presents evidence that the automatic processing of nonsymbolic magnitudes affects processing…

  9. Altered Parietal Activation during Non-symbolic Number Comparison in Children with Prenatal Alcohol Exposure

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    Keri J. Woods

    2018-01-01

    -syndromal heavily exposed children activation was impaired in the right PSPL, but spared in the right IPS. These results extend previous findings of poor right IPS recruitment during symbolic number processing in FAS/PFAS, indicating that mental representation of relative quantity is affected by prenatal alcohol exposure for both symbolic and non-symbolic representations of quantity.

  10. Nonsymbolic and symbolic magnitude comparison skills as longitudinal predictors of mathematical achievement

    NARCIS (Netherlands)

    Xenidou-Dervou, I.; Molenaar, D.; Ansari, D.; van der Schoot, M.; van Lieshout, E.C.D.M.

    What developmental roles do nonsymbolic (e.g., dot arrays) and symbolic (i.e., Arabic numerals) magnitude comparison skills play in children's mathematics? We assessed a large sample in kindergarten, grade 1 and 2 on two well-known nonsymbolic and symbolic magnitude comparison measures. We also

  11. Two systems of non-symbolic numerical cognition

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    Daniel C. Hyde

    2011-11-01

    Full Text Available Studies of human adults, infants, and non-human animals demonstrate that non-symbolic numerical cognition is supported by at least two distinct cognitive systems: a ‘parallel individuation system’ that encodes the numerical identity of individual items and an ‘approximate number system’ that encodes the approximate numerical magnitude, or numerosity, of a set. The exact nature of these systems, however, have been debated for over a hundred years. Some argue that the non-symbolic representation of small numbers (< 4 is carried out solely by the parallel individuation system and the non-symbolic representation of large numbers (> 4 is carried out solely by the approximate number system. Others argue that all numbers are represented by the approximate number system. This debate has been fueled largely by some studies showing dissociations in processing and other studies showing similar processing of small and large numbers. Recent work has addressed this debate by showing that the two systems are present and distinct from early infancy, persist despite the acquisition of a symbolic number system, activate distinct cortical networks, and engage differentially based attentional constraints. Based on the recent discoveries, I provide a hypothesis that may explain the puzzling findings and makes testable predictions as to when each system will be engaged. In particular, when items are presented under conditions that allow selection of individuals, they will be represented as distinct mental items through parallel individuation and not as a numerical magnitude. In contrast, when items are presented outside attentional limits (e.g. too many, too close together, under high attentional load, they will be represented as a single mental numerical magnitude and not as distinct mental items. These predictions provide a basis on which researchers can further investigate the role of each system in the development of uniquely human numerical thought.

  12. The effect of visual parameters on neural activation during nonsymbolic number comparison and its relation to math competency.

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    Wilkey, Eric D; Barone, Jordan C; Mazzocco, Michèle M M; Vogel, Stephan E; Price, Gavin R

    2017-10-01

    Nonsymbolic numerical comparison task performance (whereby a participant judges which of two groups of objects is numerically larger) is thought to index the efficiency of neural systems supporting numerical magnitude perception, and performance on such tasks has been related to individual differences in math competency. However, a growing body of research suggests task performance is heavily influenced by visual parameters of the stimuli (e.g. surface area and dot size of object sets) such that the correlation with math is driven by performance on trials in which number is incongruent with visual cues. Almost nothing is currently known about whether the neural correlates of nonsymbolic magnitude comparison are also affected by visual congruency. To investigate this issue, we used functional magnetic resonance imaging (fMRI) to analyze neural activity during a nonsymbolic comparison task as a function of visual congruency in a sample of typically developing high school students (n = 36). Further, we investigated the relation to math competency as measured by the preliminary scholastic aptitude test (PSAT) in 10th grade. Our results indicate that neural activity was modulated by the ratio of the dot sets being compared in brain regions previously shown to exhibit an effect of ratio (i.e. left anterior cingulate, left precentral gyrus, left intraparietal sulcus, and right superior parietal lobe) when calculated from the average of congruent and incongruent trials, as it is in most studies, and that the effect of ratio within those regions did not differ as a function of congruency condition. However, there were significant differences in other regions in overall task-related activation, as opposed to the neural ratio effect, when congruent and incongruent conditions were contrasted at the whole-brain level. Math competency negatively correlated with ratio-dependent neural response in the left insula across congruency conditions and showed distinct correlations when

  13. Distribution of PDE8A in the nervous system of the Sprague-Dawley rat

    DEFF Research Database (Denmark)

    Kruse, Lars Schack; Møller, Morten; Kruuse, Christina

    2011-01-01

    in the brain of adult male Sprague-Dawley rats and in the trigeminal ganglion. PDE8A was confined to neuronal perikaryal cytoplasm and to processes extending from those perikarya. The neurons exhibiting PDE8A-immunoreactivity were widely distributed in the forebrain, brain stem, and cerebellum. Strongly...... immunoreactive neurons were located in the olfactory bulb, the septal area, zona incerta, and reticular nucleus of the thalamus. Less immunoreactivity was seen in the hippocampus and cerebral cortex. Intense staining was detected in both the substantia nigra and the sensory trigeminal nucleus. In cerebellum PDE8....... The localization of the cAMP degrading PDE8A may indicate a role for PDE8A in cAMP signaling related to pain transmission, motor function, cognition and olfaction....

  14. The Developmental Onset of Symbolic Approximation: Beyond Nonsymbolic Representations, The Language of Numbers Matters

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    Iro eXenidou-Dervou

    2015-04-01

    Full Text Available Symbolic (i.e., with Arabic numerals approximate arithmetic with large numerosities is an important predictor of mathematics. It was previously evidenced to onset before formal schooling at the kindergarten age (Gilmore et al., 2007 and was assumed to map onto pre-existing nonsymbolic (i.e., abstract magnitudes representations. With a longitudinal study (Experiment 1, we show, for the first time, that nonsymbolic and symbolic arithmetic demonstrate different developmental trajectories. In contrast to Gilmore et al.’s (2007 findings, Experiment 1 showed that symbolic arithmetic onsets in grade 1, with the start of formal schooling, not earlier. Gilmore et al. (2007 had examined English-speaking children, whereas we assessed a large Dutch-speaking sample. The Dutch language for numbers can be cognitively more demanding, for example, due to the inversion property in numbers above twenty. Thus, for instance, the number 48 is named in Dutch achtenveertig (eight and forty instead of forty eight. To examine the effect of the language of numbers, we conducted a cross-cultural study with English- and Dutch-speaking children that had similar SES and math achievement skills (Experiment 2. Results demonstrated that Dutch-speaking kindergarteners lagged behind English-speaking children in symbolic arithmetic, not nonsymbolic and demonstrated a WM overload in symbolic arithmetic, not nonsymbolic. Also, we show for the first time that the ability to name two-digit numbers highly correlates with symbolic approximate arithmetic not nonsymbolic. Our experiments empirically demonstrate that the symbolic number system is modulated more by development and education than the nonsymbolic system. Also, in contrast to the nonsymbolic system, the symbolic system is modulated by language.

  15. Trends in PDE constrained optimization

    CERN Document Server

    Benner, Peter; Engell, Sebastian; Griewank, Andreas; Harbrecht, Helmut; Hinze, Michael; Rannacher, Rolf; Ulbrich, Stefan

    2014-01-01

    Optimization problems subject to constraints governed by partial differential equations (PDEs) are among the most challenging problems in the context of industrial, economical and medical applications. Almost the entire range of problems in this field of research was studied and further explored as part of the Deutsche Forschungsgemeinschaft (DFG) priority program 1253 on “Optimization with Partial Differential Equations” from 2006 to 2013. The investigations were motivated by the fascinating potential applications and challenging mathematical problems that arise in the field of PDE constrained optimization. New analytic and algorithmic paradigms have been developed, implemented and validated in the context of real-world applications. In this special volume, contributions from more than fifteen German universities combine the results of this interdisciplinary program with a focus on applied mathematics.   The book is divided into five sections on “Constrained Optimization, Identification and Control”...

  16. Identification of cancer cytotoxic modulators of PDE3A by predictive chemogenomics

    Science.gov (United States)

    de Waal, Luc; Lewis, Timothy A.; Rees, Matthew G.; Tsherniak, Aviad; Wu, Xiaoyun; Choi, Peter S.; Gechijian, Lara; Hartigan, Christina; Faloon, Patrick W.; Hickey, Mark J.; Tolliday, Nicola; Carr, Steven A.; Clemons, Paul A.; Munoz, Benito; Wagner, Bridget K.; Shamji, Alykhan F.; Koehler, Angela N.; Schenone, Monica; Burgin, Alex B.; Schreiber, Stuart L.; Greulich, Heidi; Meyerson, Matthew

    2015-01-01

    High cancer death rates indicate the need for new anti-cancer therapeutic agents. Approaches to discover new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds by phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the phosphodiesterase 3A gene, PDE3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells while others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggesting a neomorphic activity. Co-expression of SLFN12 with PDE3A correlates with DNMDP sensitivity, while depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery. PMID:26656089

  17. The impact of symbolic and non-symbolic quantity on spatial learning.

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    Koleen McCrink

    Full Text Available An implicit mapping of number to space via a "mental number line" occurs automatically in adulthood. Here, we systematically explore the influence of differing representations of quantity (no quantity, non-symbolic magnitudes, and symbolic numbers and directional flow of stimuli (random flow, left-to-right, or right-to-left on learning and attention via a match-to-sample working memory task. When recalling a cognitively demanding string of spatial locations, subjects performed best when information was presented right-to-left. When non-symbolic or symbolic numerical arrays were embedded in these spatial locations, and mental number line congruency prompted, this effect was attenuated and in some cases reversed. In particular, low-performing female participants who viewed increasing non-symbolic number arrays paired with the spatial locations exhibited better recall for left-to-right directional flow information relative to right-to-left, and better processing for the left side of space relative to the right side of space. The presence of symbolic number during spatial learning enhanced recall to a greater degree than non-symbolic number--especially for female participants, and especially when cognitive load is high--and this difference was independent of directional flow of information. We conclude that quantity representations have the potential to scaffold spatial memory, but this potential is subtle, and mediated by the nature of the quantity and the gender and performance level of the learner.

  18. (Non-)symbolic magnitude processing in children with mathematical difficulties: A meta-analysis.

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    Schwenk, Christin; Sasanguie, Delphine; Kuhn, Jörg-Tobias; Kempe, Sophia; Doebler, Philipp; Holling, Heinz

    2017-05-01

    Symbolic and non-symbolic magnitude representations, measured by digit or dot comparison tasks, are assumed to underlie the development of arithmetic skills. The comparison distance effect (CDE) has been suggested as a hallmark of the preciseness of mental magnitude representations. It implies that two magnitudes are harder to discriminate when the numerical distance between them is small, and may therefore differ in children with mathematical difficulties (MD), i.e. low mathematical achievement or dyscalculia. However, empirical findings on the CDE in children with MD are heterogeneous, and only few studies assess both symbolic and non-symbolic skills. This meta-analysis therefore integrates 44 symbolic and 48 non-symbolic response time (RT) outcomes reported in nineteen studies (N=1630 subjects, aged 6-14 years). Independent of age, children with MD show significantly longer mean RTs than typically achieving controls, particularly on symbolic (Hedges' g=0.75; 95% CI [0.51; 0.99]), but to a significantly lower extent also on non-symbolic (g=0.24; 95% CI [0.13; 0.36]) tasks. However, no group differences were found for the CDE. Extending recent work, these meta-analytical findings on children with MD corroborate the diagnostic importance of magnitude comparison speed in symbolic tasks. By contrast, the validity of CDE measures in assessing MD is questioned. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. [A study of PDE6B gene mutation and phenotype in Chinese cases with retinitis pigmentosa].

    Science.gov (United States)

    Cui, Yun; Zhao, Kan-xing; Wang, Li; Wang, Qing; Zhang, Wei; Chen, Wei-ying; Wang, Li-ming

    2003-01-01

    To identify the mutation spectrum of phosphodiesterase beta subunit (PDE6B) gene, the incidence in Chinese patients with retinitis pigmentosa (RP) and their clinical phenotypic characteristics. Screening of mutations within PDE6B gene was performed using polymerase chain reaction-heteroduplex-single strand conformation polymorphism (PCR-SSCP) and DNA sequence in 35 autosomal recessive (AR) RP and 55 sporadic RP cases. The phenotypes of the patients with the gene mutation were examined and analyzed. Novel complex heterozygous variants of PDE6B gene in a sporadic case, a T to C transversion in codon 323 resulting in the substitution of Gly by Ser and 2 base pairs (bp: G and T) insert between the 27th-28th bp upstream of the 5'-end of exon 10 were both present in a same isolate RP. But they are not found in 100 unrelated healthy individuals. Ocular findings showed diffuse pigmentary retinal degeneration in the midperipheral and peripheral fundi, optic atrophy and vessel attenuation. Multi-focal ERG indicated that the rod function was more severely deteriorated. A mutation was found in a case with RP in a ARRP family, a G to A transversion at 19th base upstream 5'-end of exon 11 (within intron 10) of PDE6B gene. A sporadic RP carried a sequence variant of PDE6B gene, a G to C transition, at the 15th base adjacent to the 3'-end of exon l8. In another isolate case with RP was found 2 bp (GT) insert between 31st and 32nd base upstream 5'-end of exon 4 (in intron 3) of PDE6B gene. There are novel complex heterozygous mutations of PDE6B gene responsible for a sporadic RP patient in China. This gene mutation associated with rod deterioration and RP. Several DNA variants were found in introns of PDE6B gene in national population.

  20. Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish.

    Science.gov (United States)

    Viringipurampeer, I A; Shan, X; Gregory-Evans, K; Zhang, J P; Mohammadi, Z; Gregory-Evans, C Y

    2014-05-01

    Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c(w59) mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c(w59) embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed. Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c(w59) mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

  1. Children’s Non-symbolic, Symbolic Addition and Their Mapping Capacity at 4–7 Years Old

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    Yanjun Li

    2017-07-01

    Full Text Available The study aimed to examine the developmental trajectories of non-symbolic and symbolic addition capacities in children and the mapping ability between these two. We assessed 106 4- to 7-year-old children and found that 4-year-olds were able to do non-symbolic addition but not symbolic addition. Five-year-olds and older were able to do symbolic addition and their performance in symbolic addition exceeded non-symbolic addition in grade 1 (approximate age 7. These results suggested non-symbolic addition ability emerges earlier and is less affected by formal mathematical education than symbolic addition. Meanwhile, we tested children’s bi-directional mapping ability using a novel task and found that children were able to map between symbolic and non-symbolic representations of number at age 5. Their ability in mapping non-symbolic to symbolic number became more proficient in grade 1 (approximate age 7. This suggests children at age 7 have developed a relatively mature symbolic representation system.

  2. Discovery of a novel orally active PDE-4 inhibitor effective in an ovalbumin-induced asthma murine model.

    Science.gov (United States)

    Kwak, Hyun Jeong; Nam, Ji Yeon; Song, Jin Sook; No, Zaesung; Yang, Sung Don; Cheon, Hyae Gyeong

    2012-06-15

    Phosphodiesterase-4 (PDE-4) is responsible for metabolizing adenosine 3',5'-cyclic monophosphate that reduces the activation of a wide range of inflammatory cells including eosinophils. PDE-4 inhibitors are under development for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Herein, we report a novel PDE-4 inhibitor, PDE-423 (3-[1-(3-cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl]-benzoic acid), which shows good in vitro and in vivo oral activities. PDE-423 exhibited in vitro IC(50)s of 140 nM and 550 nM in enzyme assay and cell-based assay, respectively. In vivo study using ovalbumin-induced asthmatic mice revealed that PDE-423 reduced methacholine-stimulated airway hyperreactivity in a dose-dependent manner by once daily oral administration (ED(50)=18.3 mg/kg), in parallel with decreased eosinophil peroxidase activity and improved lung histology. In addition, PDE-423 was effective in diminishing lipopolysaccharide-induced neutrophilia in vivo as well as in vitro. Oral administration of PDE-423 (100 mg/kg) had no effect on the duration of xylazine/ketamine-induced anesthesia and did not induce vomiting incidence in ferrets up to the dose of 1000 mg/kg. The present study indicates that a novel PDE-4 inhibitor, PDE-423, has good pharmacological profiles implicating this as a potential candidate for the development of a new anti-asthmatic drug. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Cyclic AMP-specific phosphodiesterase, PDE8A1, is activated by protein kinase A-mediated phosphorylation

    OpenAIRE

    Brown, Kim M.; Lee, Louisa C.Y; Findlay, Jane E.; Day, Jonathan P.; Baillie, George S.

    2012-01-01

    The cyclic AMP-specific phosphodiesterase PDE8 has been shown to play a pivotal role in important processes such as steroidogenesis, T cell adhesion, regulation of heart beat and chemotaxis. However, no information exists on how the activity of this enzyme is regulated. We show that under elevated cAMP conditions, PKA acts to phosphorylate PDE8A on serine 359 and this action serves to enhance the activity of the enzyme. This is the first indication that PDE8 activity can be modulated by a kin...

  4. Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory.

    Science.gov (United States)

    Havekes, Robbert; Park, Alan J; Tolentino, Rosa E; Bruinenberg, Vibeke M; Tudor, Jennifer C; Lee, Yool; Hansen, Rolf T; Guercio, Leonardo A; Linton, Edward; Neves-Zaph, Susana R; Meerlo, Peter; Baillie, George S; Houslay, Miles D; Abel, Ted

    2016-08-24

    Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular compartments. The

  5. Aging and the number sense: preserved basic non-symbolic numerical processing and enhanced basic symbolic processing

    Directory of Open Access Journals (Sweden)

    Jade Eloise eNorris

    2015-07-01

    Full Text Available Aging often leads to general cognitive decline in domains such as memory and attention. The effect of aging on numerical cognition, particularly on foundational numerical skills known as the Number Sense, is not well known. Early research focused on the effect of aging on arithmetic. Recent studies have begun to investigate the impact of healthy aging on basic numerical skills, but focused on non-symbolic quantity discrimination alone. Moreover, contradictory findings have emerged. The current study aimed to further investigate the impact of aging on basic non-symbolic and symbolic numerical skills. A group of 25 younger (18-25 and 25 older adults (60-77 participated in non-symbolic and symbolic numerical comparison tasks. Mathematical and spelling abilities were also measured. Results showed that aging had no effect on foundational non-symbolic numerical skills, as both groups performed similarly (RTs, accuracy and Weber fractions (w. All participants showed decreased non-symbolic acuity (accuracy and w in trials requiring inhibition. However, aging appears to be associated with a greater decline in discrimination speed in such trials. Furthermore, aging seems to have a positive impact on mathematical ability and basic symbolic numerical processing, as older participants attained significantly higher mathematical achievement scores, and performed significantly better on the symbolic comparison task than younger participants. The findings suggest that aging and its lifetime exposure to numbers may lead to better mathematical achievement and stronger basic symbolic numerical skills. Our results further support the observation that basic non-symbolic numerical skills are resilient to aging, but that aging may exacerbate poorer performance on trials requiring inhibitory processes. These findings lend further support to the notion that preserved basic numerical skills in aging may reflect the preservation of an innate, primitive and embedded Number

  6. Developmental dyscalculia: compensatory mechanisms in left intraparietal regions in response to nonsymbolic magnitudes

    Directory of Open Access Journals (Sweden)

    Starke Marc

    2009-08-01

    Full Text Available Abstract Background Functional magnetic resonance imaging (fMRI studies investigating the neural mechanisms underlying developmental dyscalculia are scarce and results are thus far inconclusive. Main aim of the present study is to investigate the neural correlates of nonsymbolic number magnitude processing in children with and without dyscalculia. Methods 18 children (9 with dyscalculia were asked to solve a non-symbolic number magnitude comparison task (finger patterns during brain scanning. For the spatial control task identical stimuli were employed, instructions varying only (judgment of palm rotation. This design enabled us to present identical stimuli with identical visual processing requirements in the experimental and the control task. Moreover, because numerical and spatial processing relies on parietal brain regions, task-specific contrasts are expected to reveal true number-specific activations. Results Behavioral results during scanning reveal that despite comparable (almost at ceiling performance levels, task-specific activations were stronger in dyscalculic children in inferior parietal cortices bilaterally (intraparietal sulcus, supramarginal gyrus, extending to left angular gyrus. Interestingly, fMRI signal strengths reflected a group × task interaction: relative to baseline, controls produced significant deactivations in (intraparietal regions bilaterally in response to number but not spatial processing, while the opposite pattern emerged in dyscalculics. Moreover, beta weights in response to number processing differed significantly between groups in left – but not right – (intraparietal regions (becoming even positive in dyscalculic children. Conclusion Overall, findings are suggestive of (a less consistent neural activity in right (intraparietal regions upon processing nonsymbolic number magnitudes; and (b compensatory neural activity in left (intraparietal regions in developmental dyscalculia.

  7. Developmental dyscalculia: compensatory mechanisms in left intraparietal regions in response to nonsymbolic magnitudes.

    Science.gov (United States)

    Kaufmann, Liane; Vogel, Stephan E; Starke, Marc; Kremser, Christian; Schocke, Michael; Wood, Guilherme

    2009-08-05

    Functional magnetic resonance imaging (fMRI) studies investigating the neural mechanisms underlying developmental dyscalculia are scarce and results are thus far inconclusive. Main aim of the present study is to investigate the neural correlates of nonsymbolic number magnitude processing in children with and without dyscalculia. 18 children (9 with dyscalculia) were asked to solve a non-symbolic number magnitude comparison task (finger patterns) during brain scanning. For the spatial control task identical stimuli were employed, instructions varying only (judgment of palm rotation). This design enabled us to present identical stimuli with identical visual processing requirements in the experimental and the control task. Moreover, because numerical and spatial processing relies on parietal brain regions, task-specific contrasts are expected to reveal true number-specific activations. Behavioral results during scanning reveal that despite comparable (almost at ceiling) performance levels, task-specific activations were stronger in dyscalculic children in inferior parietal cortices bilaterally (intraparietal sulcus, supramarginal gyrus, extending to left angular gyrus). Interestingly, fMRI signal strengths reflected a group x task interaction: relative to baseline, controls produced significant deactivations in (intra)parietal regions bilaterally in response to number but not spatial processing, while the opposite pattern emerged in dyscalculics. Moreover, beta weights in response to number processing differed significantly between groups in left - but not right - (intra)parietal regions (becoming even positive in dyscalculic children). Overall, findings are suggestive of (a) less consistent neural activity in right (intra)parietal regions upon processing nonsymbolic number magnitudes; and (b) compensatory neural activity in left (intra)parietal regions in developmental dyscalculia.

  8. PDE7B is involved in nandrolone decanoate hydrolysis in liver cytosol and its transcription is up-regulated by androgens in HepG2

    Directory of Open Access Journals (Sweden)

    Emmanuel eStrahm

    2014-05-01

    Full Text Available Most androgenic drugs are available as esters for a prolonged depot action. However the enzymes involved in the hydrolysis of the esters have not been identified. There is one study indicating that PDE7B may be involved in the activation of testosterone enanthate. The aims are to identify the cellular compartments where the hydrolysis of testosterone enanthate and nandrolone decanoate occurs, and to investigate the involvement of PDE7B in the activation. We also determined if testosterone and nandrolone affect the expression of the PDE7B gene. The hydrolysis studies were performed in isolated human liver cytosolic and microsomal preparations with and without specific PDE7B inhibitor. The gene expression was studied in human hepatoma cells (HepG2 exposed to testosterone and nandrolone. We show that PDE7B serves as a catalyst of the hydrolysis of testosterone enanthate and nandrolone decanoate in liver cytosol. The gene expression of PDE7B was significantly induced 3- and 5- fold after 2 hours exposure to 1 µM testosterone enanthate and nandrolone decanoate, respectively. These results show that PDE7B is involved in the activation of esterified nandrolone and testosterone and that the gene expression of PDE7B is induced by supra-physiological concentrations of androgenic drugs.

  9. Novel Rock Detection Intelligence for Space Exploration Based on Non-Symbolic Algorithms and Concepts

    Science.gov (United States)

    Yildirim, Sule; Beachell, Ronald L.; Veflingstad, Henning

    2007-01-01

    Future space exploration can utilize artificial intelligence as an integral part of next generation space rover technology to make the rovers more autonomous in performing mission objectives. The main advantage of the increased autonomy through a higher degree of intelligence is that it allows for greater utilization of rover resources by reducing the frequency of time consuming communications between rover and earth. In this paper, we propose a space exploration application of our research on a non-symbolic algorithm and concepts model. This model is based on one of the most recent approaches of cognitive science and artificial intelligence research, a parallel distributed processing approach. We use the Mars rovers. Sprit and Opportunity, as a starting point for proposing what rovers in the future could do if the presented model of non-symbolic algorithms and concepts is embedded in a future space rover. The chosen space exploration application for this paper, novel rock detection, is only one of many potential space exploration applications which can be optimized (through reduction of the frequency of rover-earth communications. collection and transmission of only data that is distinctive/novel) through the use of artificial intelligence technology compared to existing approaches.

  10. Foundations of children's numerical and mathematical skills: the roles of symbolic and nonsymbolic representations of numerical magnitude.

    Science.gov (United States)

    Lyons, Ian M; Ansari, Daniel

    2015-01-01

    Numerical and mathematical skills are critical predictors of academic success. The last three decades have seen a substantial growth in our understanding of how the human mind and brain represent and process numbers. In particular, research has shown that we share with animals the ability to represent numerical magnitude (the total number of items in a set) and that preverbal infants can process numerical magnitude. Further research has shown that similar processing signatures characterize numerical magnitude processing across species and developmental time. These findings suggest that an approximate system for nonsymbolic (e.g., dot arrays) numerical magnitude representation serves as the basis for the acquisition of cultural, symbolic (e.g., Arabic numerals) representations of numerical magnitude. This chapter explores this hypothesis by reviewing studies that have examined the relation between individual differences in nonsymbolic numerical magnitude processing and symbolic math abilities (e.g., arithmetic). Furthermore, we examine the extent to which the available literature provides strong evidence for a link between symbolic and nonsymbolic representations of numerical magnitude at the behavioral and neural levels of analysis. We conclude that claims that symbolic number abilities are grounded in the approximate system for the nonsymbolic representation of numerical magnitude are not strongly supported by the available evidence. Alternative models and future research directions are discussed. © 2015 Elsevier Inc. All rights reserved.

  11. Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis.

    Directory of Open Access Journals (Sweden)

    Peter Sandner

    Full Text Available Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO / cyclic guanosine monophosphate (cGMP/phosphodiesterase type 5 (PDE5 system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a the sex-specific PDE5 distribution in the rat ureter; b the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors and BAY41-2272 (sGC stimulator on induced ureteral contractility in rats and c the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats' ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of "ureteral crises" and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain.

  12. Quantity processing in deaf and hard of hearing children: evidence from symbolic and nonsymbolic comparison tasks.

    Science.gov (United States)

    Rodríguez-Santos, José Miguel; Calleja, Marina; García-Orza, Javier; Iza, Mauricio; Damas, Jesús

    2014-01-01

    Deaf children usually achieve lower scores on numerical tasks than normally hearing peers. Explanations for mathematical disabilities in hearing children are based on quantity representation deficits (Geary, 1994) or on deficits in accessing these representations (Rousselle & Noël, 2008). The present study aimed to verify, by means of symbolic (Arabic digits) and nonsymbolic (dot constellations and hands) magnitude comparison tasks, whether deaf children show deficits in representations or in accessing numerical representations. The study participants were 10 prelocutive deaf children and 10 normally hearing children. Numerical distance and magnitude were manipulated. Response time (RT) analysis showed similar magnitude and distance effects in both groups on the 3 tasks. However, slower RTs were observed among the deaf participants on the symbolic task alone. These results suggest that although both groups' quantity representations were similar, the deaf group experienced a delay in accessing representations from symbolic codes.

  13. Symbolic and non-symbolic number magnitude processing in children with developmental dyscalculia.

    Science.gov (United States)

    Castro Cañizares, Danilka; Reigosa Crespo, Vivian; González Alemañy, Eduardo

    2012-11-01

    The aim of this study was to evaluate if children with Developmental Dyscalculia (DD) exhibit a general deficit in magnitude representations or a specific deficit in the connection of symbolic representations with the corresponding analogous magnitudes. DD was diagnosed using a timed arithmetic task. The experimental magnitude comparison tasks were presented in non-symbolic and symbolic formats. DD and typically developing (TD) children showed similar numerical distance and size congruity effects. However, DD children performed significantly slower in the symbolic task. These results are consistent with the access deficit hypothesis, according to which DD children's deficits are caused by difficulties accessing magnitude information from numerical symbols rather than in processing numerosities per se.

  14. Development of brain systems for nonsymbolic numerosity and the relationship to formal math academic achievement.

    Science.gov (United States)

    Haist, Frank; Wazny, Jarnet H; Toomarian, Elizabeth; Adamo, Maha

    2015-02-01

    A central question in cognitive and educational neuroscience is whether brain operations supporting nonlinguistic intuitive number sense (numerosity) predict individual acquisition and academic achievement for symbolic or "formal" math knowledge. Here, we conducted a developmental functional magnetic resonance imaging (MRI) study of nonsymbolic numerosity task performance in 44 participants including 14 school age children (6-12 years old), 14 adolescents (13-17 years old), and 16 adults and compared a brain activity measure of numerosity precision to scores from the Woodcock-Johnson III Broad Math index of math academic achievement. Accuracy and reaction time from the numerosity task did not reliably predict formal math achievement. We found a significant positive developmental trend for improved numerosity precision in the parietal cortex and intraparietal sulcus specifically. Controlling for age and overall cognitive ability, we found a reliable positive relationship between individual math achievement scores and parietal lobe activity only in children. In addition, children showed robust positive relationships between math achievement and numerosity precision within ventral stream processing areas bilaterally. The pattern of results suggests a dynamic developmental trajectory for visual discrimination strategies that predict the acquisition of formal math knowledge. In adults, the efficiency of visual discrimination marked by numerosity acuity in ventral occipital-temporal cortex and hippocampus differentiated individuals with better or worse formal math achievement, respectively. Overall, these results suggest that two different brain systems for nonsymbolic numerosity acuity may contribute to individual differences in math achievement and that the contribution of these systems differs across development. © 2014 Wiley Periodicals, Inc.

  15. The influence of math anxiety on symbolic and non-symbolic magnitude processing.

    Science.gov (United States)

    Dietrich, Julia F; Huber, Stefan; Moeller, Korbinian; Klein, Elise

    2015-01-01

    Deficits in basic numerical abilities have been investigated repeatedly as potential risk factors of math anxiety. Previous research suggested that also a deficient approximate number system (ANS), which is discussed as being the foundation for later math abilities, underlies math anxiety. However, these studies examined this hypothesis by investigating ANS acuity using a symbolic number comparison task. Recent evidence questions the view that ANS acuity can be assessed using a symbolic number comparison task. To investigate whether there is an association between math anxiety and ANS acuity, we employed both a symbolic number comparison task and a non-symbolic dot comparison task, which is currently the standard task to assess ANS acuity. We replicated previous findings regarding the association between math anxiety and the symbolic distance effect for response times. High math anxious individuals showed a larger distance effect than less math anxious individuals. However, our results revealed no association between math anxiety and ANS acuity assessed using a non-symbolic dot comparison task. Thus, our results did not provide evidence for the hypothesis that a deficient ANS underlies math anxiety. Therefore, we propose that a deficient ANS does not constitute a risk factor for the development of math anxiety. Moreover, our results suggest that previous interpretations regarding the interaction of math anxiety and the symbolic distance effect have to be updated. We suggest that impaired number comparison processes in high math anxious individuals might account for the results rather than deficient ANS representations. Finally, impaired number comparison processes might constitute a risk factor for the development of math anxiety. Implications for current models regarding the origins of math anxiety are discussed.

  16. The influence of math anxiety on symbolic and non-symbolic magnitude processing

    Directory of Open Access Journals (Sweden)

    Julia Felicitas Dietrich

    2015-10-01

    Full Text Available Deficits in basic numerical abilities have been investigated repeatedly as potential risk factors of math anxiety. Previous research suggested that also a deficient approximate number system (ANS, which is discussed as being the foundation for later math abilities, underlies math anxiety. However, these studies examined this hypothesis by investigating ANS acuity using a symbolic number comparison task. Recent evidence questions the view that ANS acuity can be assessed using a symbolic number comparison task. To investigate whether there is an association between math anxiety and ANS acuity, we employed both a symbolic number comparison task and a non-symbolic dot comparison task, which is currently the standard task to assess ANS acuity. We replicated previous findings regarding the association between math anxiety and the symbolic distance effect for response times. High math anxious individuals showed a larger distance effect than less math anxious individuals. However, our results revealed no association between math anxiety and ANS acuity assessed using a non-symbolic dot comparison task. Thus, our results did not provide evidence for the hypothesis that a deficient ANS underlies math anxiety. Therefore, we propose that a deficient ANS does not constitute a risk factor for the development of math anxiety. Moreover, our results suggest that previous interpretations regarding the interaction of math anxiety and the symbolic distance effect have to be updated. We suggest that impaired number comparison processes in high math anxious individuals might account for the results rather than deficient ANS representations. Finally, impaired number comparison processes might constitute a risk factor for the development of math anxiety. Implications for current models regarding the origins of math anxiety are discussed.

  17. Selective Extraction of Entangled Textures via Adaptive PDE Transform

    Directory of Open Access Journals (Sweden)

    Yang Wang

    2012-01-01

    Full Text Available Texture and feature extraction is an important research area with a wide range of applications in science and technology. Selective extraction of entangled textures is a challenging task due to spatial entanglement, orientation mixing, and high-frequency overlapping. The partial differential equation (PDE transform is an efficient method for functional mode decomposition. The present work introduces adaptive PDE transform algorithm to appropriately threshold the statistical variance of the local variation of functional modes. The proposed adaptive PDE transform is applied to the selective extraction of entangled textures. Successful separations of human face, clothes, background, natural landscape, text, forest, camouflaged sniper and neuron skeletons have validated the proposed method.

  18. Direct interaction of the inhibitory gamma-subunit of Rod cGMP phosphodiesterase (PDE6) with the PDE6 GAFa domains.

    Science.gov (United States)

    Muradov, Khakim G; Granovsky, Alexey E; Schey, Kevin L; Artemyev, Nikolai O

    2002-03-26

    Retinal rod and cone cGMP phosphodiesterases (PDE6 family) function as the effector enzyme in the vertebrate visual transduction cascade. The activity of PDE6 catalytic subunits is controlled by the Pgamma-subunits. In addition to the inhibition of cGMP hydrolysis at the catalytic sites, Pgamma is known to stimulate a noncatalytic binding of cGMP to the regulatory GAFa-GAFb domains of PDE6. The latter role of Pgamma has been attributed to its polycationic region. To elucidate the structural basis for the regulation of cGMP binding to the GAF domains of PDE6, a photoexcitable peptide probe corresponding to the polycationic region of Pgamma, Pgamma-21-45, was specifically cross-linked to rod PDE6alphabeta. The site of Pgamma-21-45 cross-linking was localized to Met138Gly139 within the PDE6alpha GAFa domain using mass spectrometric analysis. Chimeras between PDE5 and cone PDE6alpha', containing GAFa and/or GAFb domains of PDE6alpha' have been generated to probe a potential role of the GAFb domains in binding to Pgamma. Analysis of the inhibition of the PDE5/PDE6alpha' chimeras by Pgamma supported the role of PDE6 GAFa but not GAFb domains in the interaction with Pgamma. Our results suggest that a direct binding of the polycationic region of Pgamma to the GAFa domains of PDE6 may lead to a stabilization of the noncatalytic cGMP-binding sites.

  19. Stopping test of iterative methods for solving PDE

    International Nuclear Information System (INIS)

    Wang Bangrong

    1991-01-01

    In order to assure the accuracy of the numerical solution of the iterative method for solving PDE (partial differential equation), the stopping test is very important. If the coefficient matrix of the system of linear algebraic equations is strictly diagonal dominant or irreducible weakly diagonal dominant, the stopping test formulas of the iterative method for solving PDE is proposed. Several numerical examples are given to illustrate the applications of the stopping test formulas

  20. Eye-movement patterns during nonsymbolic and symbolic numerical magnitude comparison and their relation to math calculation skills.

    Science.gov (United States)

    Price, Gavin R; Wilkey, Eric D; Yeo, Darren J

    2017-05-01

    A growing body of research suggests that the processing of nonsymbolic (e.g. sets of dots) and symbolic (e.g. Arabic digits) numerical magnitudes serves as a foundation for the development of math competence. Performance on magnitude comparison tasks is thought to reflect the precision of a shared cognitive representation, as evidence by the presence of a numerical ratio effect for both formats. However, little is known regarding how visuo-perceptual processes are related to the numerical ratio effect, whether they are shared across numerical formats, and whether they relate to math competence independently of performance outcomes. The present study investigates these questions in a sample of typically developing adults. Our results reveal a pattern of associations between eye-movement measures, but not their ratio effects, across formats. This suggests that ratio-specific visuo-perceptual processing during magnitude processing is different across nonsymbolic and symbolic formats. Furthermore, eye movements are related to math performance only during symbolic comparison, supporting a growing body of literature suggesting symbolic number processing is more strongly related to math outcomes than nonsymbolic magnitude processing. Finally, eye-movement patterns, specifically fixation dwell time, continue to be negatively related to math performance after controlling for task performance (i.e. error rate and reaction time) and domain general cognitive abilities (IQ), suggesting that fluent visual processing of Arabic digits plays a unique and important role in linking symbolic number processing to formal math abilities. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. An electrophysiological investigation of non-symbolic magnitude processing: numerical distance effects in children with and without mathematical learning disabilities.

    Science.gov (United States)

    Heine, Angela; Wissmann, Jacqueline; Tamm, Sascha; De Smedt, Bert; Schneider, Michael; Stern, Elsbeth; Verschaffel, Lieven; Jacobs, Arthur M

    2013-09-01

    The aim of the present study was to probe electrophysiological effects of non-symbolic numerical processing in 20 children with mathematical learning disabilities (mean age = 99.2 months) compared to a group of 20 typically developing matched controls (mean age = 98.4 months). EEG data were obtained while children were tested with a standard non-symbolic numerical comparison paradigm that allowed us to investigate the effects of numerical distance manipulations for different set sizes, i.e., the classical subitizing, counting and estimation ranges. Effects of numerical distance manipulations on event-related potential (ERP) amplitudes as well as activation patterns of underlying current sources were analyzed. In typically developing children, the amplitudes of a late parietal positive-going ERP component showed systematic numerical distance effects that did not depend on set size. For the group of children with mathematical learning disabilities, ERP distance effects were found only for stimuli within the subitizing range. Current source density analysis of distance-related group effects suggested that areas in right inferior parietal regions are involved in the generation of the parietal ERP amplitude differences. Our results suggest that right inferior parietal regions are recruited differentially by controls compared to children with mathematical learning disabilities in response to non-symbolic numerical magnitude processing tasks, but only for stimuli with set sizes that exceed the subitizing range. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. The inotropic effect of the active metabolite of levosimendan, OR-1896, is mediated through inhibition of PDE3 in rat ventricular myocardium.

    Directory of Open Access Journals (Sweden)

    Øivind Ørstavik

    Full Text Available We recently published that the positive inotropic response (PIR to levosimendan can be fully accounted for by phosphodiesterase (PDE inhibition in both failing human heart and normal rat heart. To determine if the PIR of the active metabolite OR-1896, an important mediator of the long-term clinical effects of levosimendan, also results from PDE3 inhibition, we compared the effects of OR-1896, a representative Ca2+ sensitizer EMD57033 (EMD, levosimendan and other PDE inhibitors.Contractile force was measured in rat ventricular strips. PDE assay was conducted on rat ventricular homogenate. cAMP was measured using RII_epac FRET-based sensors.OR-1896 evoked a maximum PIR of 33 ± 10% above basal at 1 μM. This response was amplified in the presence of the PDE4 inhibitor rolipram (89 ± 14% and absent in the presence of the PDE3 inhibitors cilostamide (0.5 ± 5.3% or milrinone (3.2 ± 4.4%. The PIR was accompanied by a lusitropic response, and both were reversed by muscarinic receptor stimulation with carbachol and absent in the presence of β-AR blockade with timolol. OR-1896 inhibited PDE activity and increased cAMP levels at concentrations giving PIRs. OR-1896 did not sensitize the concentration-response relationship to extracellular Ca2+. Levosimendan, OR-1896 and EMD all increased the sensitivity to β-AR stimulation. The combination of either EMD and levosimendan or EMD and OR-1896 further sensitized the response, indicating at least two different mechanisms responsible for the sensitization. Only EMD sensitized the α1-AR response.The observed PIR to OR-1896 in rat ventricular strips is mediated through PDE3 inhibition, enhancing cAMP-mediated effects. These results further reinforce our previous finding that Ca2+ sensitization does not play a significant role in the inotropic (and lusitropic effect of levosimendan, nor of its main metabolite OR-1896.

  3. New Therapeutic Applications of Phosphodiesterase 5 Inhibitors (PDE5-Is).

    Science.gov (United States)

    Ribaudo, Giovanni; Pagano, Mario Angelo; Bova, Sergio; Zagotto, Giuseppe

    2016-01-01

    Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED). In addition to this, sildenafil and tadalafil, have also been approved for the treatment of pulmonary arterial hypertension. Due to its expression and localization in many tissues, PDE5 and its regulation has been reported to be involved in several other diseases. We aim to provide an updated overview of the emerging therapeutic applications of PDE5-Is besides ED, taking into account the latest ongoing research reports. We searched online databases (Pubmed, Reaxys, Scopus) to lay the bases for an accurate, quality criteria-based literature update. We focused our attention on most recent research reports, in particular when supported by pre-clinical and clinical data. The regulation of PDE5 may influence pathological conditions such as, among the others, heart failure, cystic fibrosis, cancer, CNS-related diseases, diabetes and dysfunctions affecting male urinary/reproductive system. Sildenafil, vardenafil, tadalafil and the other chemical entities considered PDE5-Is showed overall positive results and significant improvements in the studied disease, thus some discordant results, in particular when comparing pre-clinical and clinical data, have to be pointed out, suggesting that further insights are needed especially to assess the exact molecular pathway underlying.

  4. PDE1A inhibition elicits cGMP-dependent relaxation of rat mesenteric arteries

    DEFF Research Database (Denmark)

    Khammy, Makhala Michell; Dalsgaard, Thomas; Larsen, Peter Hjorringgaard

    2017-01-01

    (EC50 = 32 nM). Inhibition of NOS with L-NAME, soluble GC with ODQ, or PKG with Rp-8-Br-PET-cGMP all attenuated PDE1 inhibition-induced relaxation, whereas PKA inhibition with H89 had no effect. CONCLUSION AND IMPLICATIONS: Pde1a was the dominant PDE1 isoform present in VSMC and relaxation mediated...... by PDE1A-inhibition was predominantly driven by enhanced cGMP signalling. These results imply that isoform-selective PDE1 inhibitors are powerful investigative tools allowing examination of physiological and pathological roles of PDE1 isoforms....

  5. Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction.

    Science.gov (United States)

    Chen, Si; Knight, Walter E; Yan, Chen

    2018-04-23

    Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.

  6. Multiscale Reaction-Diffusion Algorithms: PDE-Assisted Brownian Dynamics

    KAUST Repository

    Franz, Benjamin

    2013-06-19

    Two algorithms that combine Brownian dynami cs (BD) simulations with mean-field partial differential equations (PDEs) are presented. This PDE-assisted Brownian dynamics (PBD) methodology provides exact particle tracking data in parts of the domain, whilst making use of a mean-field reaction-diffusion PDE description elsewhere. The first PBD algorithm couples BD simulations with PDEs by randomly creating new particles close to the interface, which partitions the domain, and by reincorporating particles into the continuum PDE-description when they cross the interface. The second PBD algorithm introduces an overlap region, where both descriptions exist in parallel. It is shown that the overlap region is required to accurately compute variances using PBD simulations. Advantages of both PBD approaches are discussed and illustrative numerical examples are presented. © 2013 Society for Industrial and Applied Mathematics.

  7. Optimization with PDE constraints ESF networking program 'OPTPDE'

    CERN Document Server

    2014-01-01

    This book on PDE Constrained Optimization contains contributions on the mathematical analysis and numerical solution of constrained optimal control and optimization problems where a partial differential equation (PDE) or a system of PDEs appears as an essential part of the constraints. The appropriate treatment of such problems requires a fundamental understanding of the subtle interplay between optimization in function spaces and numerical discretization techniques and relies on advanced methodologies from the theory of PDEs and numerical analysis as well as scientific computing. The contributions reflect the work of the European Science Foundation Networking Programme ’Optimization with PDEs’ (OPTPDE).

  8. Symbolic Number Comparison Is Not Processed by the Analog Number System: Different Symbolic and Non-symbolic Numerical Distance and Size Effects

    Directory of Open Access Journals (Sweden)

    Attila Krajcsi

    2018-02-01

    Full Text Available HIGHLIGHTSWe test whether symbolic number comparison is handled by an analog noisy system.Analog system model has systematic biases in describing symbolic number comparison.This suggests that symbolic and non-symbolic numbers are processed by different systems.Dominant numerical cognition models suppose that both symbolic and non-symbolic numbers are processed by the Analog Number System (ANS working according to Weber's law. It was proposed that in a number comparison task the numerical distance and size effects reflect a ratio-based performance which is the sign of the ANS activation. However, increasing number of findings and alternative models propose that symbolic and non-symbolic numbers might be processed by different representations. Importantly, alternative explanations may offer similar predictions to the ANS prediction, therefore, former evidence usually utilizing only the goodness of fit of the ANS prediction is not sufficient to support the ANS account. To test the ANS model more rigorously, a more extensive test is offered here. Several properties of the ANS predictions for the error rates, reaction times, and diffusion model drift rates were systematically analyzed in both non-symbolic dot comparison and symbolic Indo-Arabic comparison tasks. It was consistently found that while the ANS model's prediction is relatively good for the non-symbolic dot comparison, its prediction is poorer and systematically biased for the symbolic Indo-Arabic comparison. We conclude that only non-symbolic comparison is supported by the ANS, and symbolic number comparisons are processed by other representation.

  9. Associations of non-symbolic and symbolic numerical magnitude processing with mathematical competence: a meta-analysis.

    Science.gov (United States)

    Schneider, Michael; Beeres, Kassandra; Coban, Leyla; Merz, Simon; Susan Schmidt, S; Stricker, Johannes; De Smedt, Bert

    2017-05-01

    Many studies have investigated the association between numerical magnitude processing skills, as assessed by the numerical magnitude comparison task, and broader mathematical competence, e.g. counting, arithmetic, or algebra. Most correlations were positive but varied considerably in their strengths. It remains unclear whether and to what extent the strength of these associations differs systematically between non-symbolic and symbolic magnitude comparison tasks and whether age, magnitude comparison measures or mathematical competence measures are additional moderators. We investigated these questions by means of a meta-analysis. The literature search yielded 45 articles reporting 284 effect sizes found with 17,201 participants. Effect sizes were combined by means of a two-level random-effects regression model. The effect size was significantly higher for the symbolic (r = .302, 95% CI [.243, .361]) than for the non-symbolic (r = .241, 95% CI [.198, .284]) magnitude comparison task and decreased very slightly with age. The correlation was higher for solution rates and Weber fractions than for alternative measures of comparison proficiency. It was higher for mathematical competencies that rely more heavily on the processing of magnitudes (i.e. mental arithmetic and early mathematical abilities) than for others. The results support the view that magnitude processing is reliably associated with mathematical competence over the lifespan in a wide range of tasks, measures and mathematical subdomains. The association is stronger for symbolic than for non-symbolic numerical magnitude processing. So symbolic magnitude processing might be a more eligible candidate to be targeted by diagnostic screening instruments and interventions for school-aged children and for adults. © 2016 John Wiley & Sons Ltd.

  10. The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices

    NARCIS (Netherlands)

    Kistemaker, Loes E M; Oenema, Tjitske A; Baarsma, Hoeke A; Bos, I. Sophie T.; Schmidt, Martina; Facchinetti, Fabrizio; Civelli, Maurizio; Villetti, Gino; Gosens, Reinoud

    2017-01-01

    Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced

  11. Non-symbolic numerical distance effect in children with and without developmental dyscalculia: a parametric fMRI study.

    Science.gov (United States)

    Kucian, Karin; Loenneker, Thomas; Martin, Ernst; von Aster, Michael

    2011-01-01

    This study investigated areas of brain activation related to non-symbolic distance effects in children with and without developmental dyscalculia (DD). We examined 15 children with DD (11.3 years) and 15 controls (10.6 years) by means of functional magnetic resonance imaging (fMRI). Both groups displayed similar behavioral performance, but differences in brain activation were observed, particularly in the supplementary motor area and the right fusiform gyrus, where children with DD demonstrated stronger activation. These results suggest that dyscalculic children engage areas attributed to higher difficulty in response selection more than control children, possibly due to a deficient development of a spatial number representation in DD.

  12. PDE4 and mAKAPβ are nodal organizers of β2-ARs nuclear PKA signaling in cardiac myocytes.

    Science.gov (United States)

    Bedioune, Ibrahim; Lefebvre, Florence; Lechêne, Patrick; Varin, Audrey; Domergue, Valérie; Kapiloff, Michael S; Fischmeister, Rodolphe; Vandecasteele, Grégoire

    2018-05-03

    β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear PKA activity in cardiomyocytes. We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation. Both β1- and β2-AR stimulation increased cAMP and activated PKA in the cytoplasm. While the two receptors also increased cAMP in the nucleus, only β1-ARs increased nuclear PKA activity and up-regulated the PKA target gene and pro-apoptotic factor, inducible cAMP element repressor (ICER). Inhibition of PDE4, but not Gi, PDE3, GRK2 nor caveolae disruption disclosed nuclear PKA activation and ICER induction by β2-ARs. Both nuclear and cytoplasmic PKI prevented nuclear PKA activation and ICER induction by β1-ARs, indicating that PKA activation outside the nucleus is required for subsequent nuclear PKA activation and ICER mRNA expression. Cytoplasmic PKI also blocked ICER induction by β2-AR stimulation (with concomitant PDE4 inhibition). However, in this case nuclear PKI decreased ICER up-regulation by only 30%, indicating that other mechanisms are involved. Down-regulation of mAKAPβ partially inhibited nuclear PKA activation upon β1-AR stimulation, and drastically decreased nuclear PKA activation upon β2-AR stimulation in the presence of PDE4 inhibition. β1- and β2-ARs differentially regulate nuclear PKA activity and ICER expression in cardiomyocytes. PDE4 insulates a mAKAPβ-targeted PKA pool at the nuclear envelope that prevents nuclear PKA activation upon β2-AR stimulation.

  13. Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a.

    Science.gov (United States)

    Hufgard, Jillian R; Williams, Michael T; Skelton, Matthew R; Grubisha, Olivera; Ferreira, Filipa M; Sanger, Helen; Wright, Mary E; Reed-Kessler, Tracy M; Rasmussen, Kurt; Duman, Ronald S; Vorhees, Charles V

    2017-06-01

    Major depressive disorder is a leading cause of suicide and disability. Despite this, current antidepressants provide insufficient efficacy in more than 60% of patients. Most current antidepressants are presynaptic reuptake inhibitors; postsynaptic signal regulation has not received as much attention as potential treatment targets. We examined the effects of disruption of the postsynaptic cyclic nucleotide hydrolyzing enzyme, phosphodiesterase (PDE) 1b, on depressive-like behavior and the effects on PDE1B protein in wild-type (WT) mice following stress. Littermate knockout (KO) and WT mice were tested in locomotor activity, tail suspension (TST), and forced swim tests (FST). FST was also used to compare the effects of two antidepressants, fluoxetine and bupropion, in KO versus WT mice. Messenger RNA (mRNA) expression changes were also determined. WT mice underwent acute or chronic stress and markers of stress and PDE1B expression were examined. Pde1b KO mice exhibited decreased TST and FST immobility. When treated with antidepressants, both WT and KO mice showed decreased FST immobility and the effect was additive in KO mice. Mice lacking Pde1b had increased striatal Pde10a mRNA expression. In WT mice, acute and chronic stress upregulated PDE1B expression while PDE10A expression was downregulated after chronic but not acute stress. PDE1B is a potential therapeutic target for depression treatment because of the antidepressant-like phenotype seen in Pde1b KO mice.

  14. Novel selective PDE type 1 inhibitors cause vasodilatation and lower blood pressure in rats

    DEFF Research Database (Denmark)

    Laursen, Morten; Beck, Lilliana; Kehler, Jan

    2017-01-01

    BACKGROUND AND PURPOSE: The PDE enzymes (PDE1-11) hydrolyse and thus inactivate cyclic nucleotides and are important in the regulation of the cardiovascular system. Here,we have investigated the effects on the cardiovascular system, of two novel selective PDE1 inhibitors, Lu AF41228 and Lu AF58027...... and Lu AF58027 inhibited PDE1A, PDE1B and PDE1C enzyme activity, while micromolar concentrations were required to observe inhibitory effects at other PDEs. RT-PCR revealed expression of PDE1A, PDE1B and PDE1C in rat brain, heart and aorta, but only PDE1A and PDE1B in mesenteric arteries. In rat isolated...... and Lu AF58027 dose-dependently lowered mean BP and increased heart rate. In conscious rats with telemetric pressure transducers, repeated dosing with Lu AF41228 lowered mean arterial BP 10-15 mmHg and increased heart rate. CONCLUSIONS AND IMPLICATIONS: These novel PDE1 inhibitors induce vasodilation...

  15. Is PDE4 too difficult a drug target?

    Science.gov (United States)

    Higgs, Gerry

    2010-05-01

    The search for selective inhibitors of PDE4 as novel anti-inflammatory drugs has continued for more than 30 years. Although several compounds have demonstrated therapeutic effects in diseases such as asthma, COPD, atopic dermatitis and psoriasis, none have reached the market. A persistent challenge in the development of PDE4 inhibitors has been drug-induced gastrointestinal adverse effects, such as nausea. However, extensive clinical trials with well-tolerated doses of roflumilast (Daxas; Nycomed/Mitsubishi Tanabe Pharma Corp/Forest Laboratories Inc) in COPD, a disease that is generally unresponsive to existing therapies, have demonstrated significant therapeutic improvements. In addition, GlaxoSmithKline plc is developing 256066, an inhaled formulation of a PDE4 inhibitor that has demonstrated efficacy in trials in asthma, and apremilast from Celgene Corp has been reported to be effective for the treatment of psoriasis. Despite the challenges and complications that have been encountered during the development of PDE4 inhibitors, these drugs may provide a genuinely novel class of anti-inflammatory agents, and there are several compounds in development that could fulfill that promise.

  16. Commutator identities on associative algebras and integrability of nonlinear pde's

    OpenAIRE

    Pogrebkov, A. K.

    2007-01-01

    It is shown that commutator identities on associative algebras generate solutions of linearized integrable equations. Next, a special kind of the dressing procedure is suggested that in a special class of integral operators enables to associate to such commutator identity both nonlinear equation and its Lax pair. Thus problem of construction of new integrable pde's reduces to construction of commutator identities on associative algebras.

  17. Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum.

    Science.gov (United States)

    Toque, Haroldo A; Teixeira, Cleber E; Lorenzetti, Raquel; Okuyama, Cristina E; Antunes, Edson; De Nucci, Gilberto

    2008-09-04

    Nitrergic nerves and endothelial cells release nitric oxide (NO) in the corpus cavernosum, a key mediator that stimulates soluble guanylyl cyclase to increase cGMP levels causing penile erection. Phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, prolong the NO effects by inhibiting cGMP breakdown. Here, we report a novel PDE5 inhibitor, lodenafil carbonate, (Bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate) that is a dimer of lodenafil. We therefore aimed to compare the effects of sildenafil, lodenafil and lodenafil carbonate on in vitro human and rabbit cavernosal relaxations, activity of crude PDE extracts from human platelets, as well as stability and metabolic studies in rat, dog and human plasma. Pharmacokinetic evaluations after intravenous and oral administration were performed in male beagles. Functional experiments were conducted using organ bath techniques. Pharmacokinetics was studied in beagles by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), following oral or intravascular administration. All PDE5 inhibitors tested concentration-dependently relaxed (0.001-100 microM) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 microM) or electrical field stimulation (EFS, 1-20 Hz) were markedly potentiated by sildenafil, lodenafil and lodenafil carbonate. Lodenafil carbonate was more potent to inhibit the cGMP hydrolysis in PDE extracts compared with lodenafil and sildenafil. Following intravascular and single oral administration of lodenafil carbonate, only lodenafil and norlodenafil were detected in vivo. These results indicate that lodenafil carbonate works as a prodrug, being lodenafil the active moiety of lodenafil carbonate.

  18. The multinational Men's Attitudes to Life Events and Sexuality (MALES) Study Phase II: understanding PDE5 inhibitor treatment seeking patterns, among men with erectile dysfunction.

    Science.gov (United States)

    Fisher, William A; Rosen, Raymond C; Eardley, Ian; Niederberger, Craig; Nadel, Andrea; Kaufman, Joel; Sand, Michael

    2004-09-01

    The aim of Phase II of the Men's Attitudes to Life Events and Sexuality (MALES) Study is to explore PDE5 inhibitor treatment seeking among men with erectile dysfunction (ED). Phase II of the MALES study involved 2,912 men, aged 20-75 years, from 8 countries (U.S., U.K., Germany, France, Italy, Spain, Mexico, and Brazil), who reported ED. Participants were recruited from the MALES Phase I sample [1] and via booster methods (e.g., physician referral, street interception), and completed self-report questionnaires concerning the characteristics of their ED, their efforts to seek PDE5 inhibitor treatment for their sexual dysfunction, and attitudinal and referent influences that potentially affect treatment-seeking. Statistical analyses focus on identification of correlates of PDE5 inhibitor treatment seeking. PDE5 inhibitor utilization is strongly associated with ED sufferers' assessment of the severity of their sexual dysfunction, with their belief that medication for ED is dangerous, and with their perceptions of whether physicians, other professionals, and spouses or family members are supportive of their seeking treatment. ED sufferers who evaluate their sexual dysfunction as severe, who believe that medication for ED is not dangerous, and who perceive support for treatment seeking from referent others, are more likely to utilize PDE5 inhibitor treatment. Findings indicate that perceived ED severity, beliefs about ED medication, and referent influences are strongly correlated with utilization of PDE5 inhibitor therapy. These findings aid our understanding of factors that may incline men with ED to seek-or to avoid-PDE5 inhibitor therapy for their sexual dysfunction, and provide a basis for clinical and educational interventions to assist men with ED to seek appropriate treatment.

  19. Estimating the magnitude of near-membrane PDE4 activity in living cells.

    Science.gov (United States)

    Xin, Wenkuan; Feinstein, Wei P; Britain, Andrea L; Ochoa, Cristhiaan D; Zhu, Bing; Richter, Wito; Leavesley, Silas J; Rich, Thomas C

    2015-09-15

    Recent studies have demonstrated that functionally discrete pools of phosphodiesterase (PDE) activity regulate distinct cellular functions. While the importance of localized pools of enzyme activity has become apparent, few studies have estimated enzyme activity within discrete subcellular compartments. Here we present an approach to estimate near-membrane PDE activity. First, total PDE activity is measured using traditional PDE activity assays. Second, known cAMP concentrations are dialyzed into single cells and the spatial spread of cAMP is monitored using cyclic nucleotide-gated channels. Third, mathematical models are used to estimate the spatial distribution of PDE activity within cells. Using this three-tiered approach, we observed two pharmacologically distinct pools of PDE activity, a rolipram-sensitive pool and an 8-methoxymethyl IBMX (8MM-IBMX)-sensitive pool. We observed that the rolipram-sensitive PDE (PDE4) was primarily responsible for cAMP hydrolysis near the plasma membrane. Finally, we observed that PDE4 was capable of blunting cAMP levels near the plasma membrane even when 100 μM cAMP were introduced into the cell via a patch pipette. Two compartment models predict that PDE activity near the plasma membrane, near cyclic nucleotide-gated channels, was significantly lower than total cellular PDE activity and that a slow spatial spread of cAMP allowed PDE activity to effectively hydrolyze near-membrane cAMP. These results imply that cAMP levels near the plasma membrane are distinct from those in other subcellular compartments; PDE activity is not uniform within cells; and localized pools of AC and PDE activities are responsible for controlling cAMP levels within distinct subcellular compartments. Copyright © 2015 the American Physiological Society.

  20. A General Symbolic PDE Solver Generator: Beyond Explicit Schemes

    Directory of Open Access Journals (Sweden)

    K. Sheshadri

    2003-01-01

    Full Text Available This paper presents an extension of our Mathematica- and MathCode-based symbolic-numeric framework for solving a variety of partial differential equation (PDE problems. The main features of our earlier work, which implemented explicit finite-difference schemes, include the ability to handle (1 arbitrary number of dependent variables, (2 arbitrary dimensionality, and (3 arbitrary geometry, as well as (4 developing finite-difference schemes to any desired order of approximation. In the present paper, extensions of this framework to implicit schemes and the method of lines are discussed. While C++ code is generated, using the MathCode system for the implicit method, Modelica code is generated for the method of lines. The latter provides a preliminary PDE support for the Modelica language. Examples illustrating the various aspects of the solver generator are presented.

  1. In vitro differentiation of human monocytes to macrophages: change of PDE profile and its relationship to suppression of tumour necrosis factor-α release by PDE inhibitors

    Science.gov (United States)

    Gantner, Florian; Kupferschmidt, Rochus; Schudt, Christian; Wendel, Albrecht; Hatzelmann, Armin

    1997-01-01

    During in vitro culture in 10% human AB serum, human peripheral blood monocytes acquire a macrophage-like phenotype. The underlying differentiation was characterized by increased activities of the macrophage marker enzymes unspecific esterase (NaF-insensitive form) and acid phosphatase, as well as by a down-regulation in surface CD14 expression. In parallel, a dramatic change in the phosphodiesterase (PDE) profile became evident within a few days that strongly resembled that previously described for human alveolar macrophages. Whereas PDE1 and PDE3 activities were augmented, PDE4 activity, which represented the major cyclic AMP-hydrolysing activity of peripheral blood monocytes, rapidly declined. Monocytes and monocyte-derived macrophages responded to lipopolysaccharide (LPS) with the release of tumour necrosis factor-α (TNF). In line with the change in CD14 expression, the EC50 value of LPS for induction of TNF release increased from approximately 0.1 ng ml−1 in peripheral blood monocytes to about 2 ng ml−1 in macrophages. Both populations of cells were equally susceptible towards inhibition of TNF release by cyclic AMP elevating agents such as dibutyryl cyclic AMP, prostaglandin E2 (PGE2) or forskolin, which all led to a complete abrogation of TNF production in a concentration-dependent manner and which were more efficient than the glucocorticoid dexamethasone. In monocytes, PDE4 selective inhibitors (rolipram, RP73401) suppressed TNF formation by 80%, whereas motapizone, a PDE3 selective compound, exerted a comparatively weak effect (10–15% inhibition). Combined use of PDE3 plus PDE4 inhibitors resulted in an additive effect and fully abrogated LPS-induced TNF release as did the mixed PDE3/4 inhibitor tolafentrine. In monocyte-derived macrophages, neither PDE3- nor PDE4-selective drugs markedly affected TNF generation when used alone (<15% inhibition), whereas in combination, they led to a maximal inhibition of TNF formation by about 40–50

  2. Identification of the gamma subunit-interacting residues on photoreceptor cGMP phosphodiesterase, PDE6alpha '.

    Science.gov (United States)

    Granovsky, A E; Artemyev, N O

    2000-12-29

    Photoreceptor cGMP phosphodiesterase (PDE6) is the effector enzyme in the G protein-mediated visual transduction cascade. In the dark, the activity of PDE6 is shut off by the inhibitory gamma subunit (Pgamma). Chimeric proteins between cone PDE6alpha' and cGMP-binding and cGMP-specific PDE (PDE5) have been constructed and expressed in Sf9 cells to study the mechanism of inhibition of PDE6 catalytic activity by Pgamma. Substitution of the segment PDE5-(773-820) by the corresponding PDE6alpha'-(737-784) sequence in the wild-type PDE5 or in a PDE5/PDE6alpha' chimera containing the catalytic domain of PDE5 results in chimeric enzymes capable of inhibitory interaction with Pgamma. The catalytic properties of the chimeric PDEs remained similar to those of PDE5. Ala-scanning mutational analysis of the Pgamma-binding region, PDE6alpha'-(750-760), revealed PDE6alpha' residues essential for the interaction. The M758A mutation markedly impaired and the Q752A mutation moderately impaired the inhibition of chimeric PDE by Pgamma. The analysis of the catalytic properties of mutant PDEs and a model of the PDE6 catalytic domain suggest that residues Met(758) and Gln(752) directly bind Pgamma. A model of the PDE6 catalytic site shows that PDE6alpha'-(750-760) forms a loop at the entrance to the cGMP-binding pocket. Binding of Pgamma to Met(758) would effectively block access of cGMP to the catalytic cavity, providing a structural basis for the mechanism of PDE6 inhibition.

  3. A General Symbolic PDE Solver Generator: Explicit Schemes

    Directory of Open Access Journals (Sweden)

    K. Sheshadri

    2003-01-01

    Full Text Available A symbolic solver generator to deal with a system of partial differential equations (PDEs in functions of an arbitrary number of variables is presented; it can also handle arbitrary domains (geometries of the independent variables. Given a system of PDEs, the solver generates a set of explicit finite-difference methods to any specified order, and a Fourier stability criterion for each method. For a method that is stable, an iteration function is generated symbolically using the PDE and its initial and boundary conditions. This iteration function is dynamically generated for every PDE problem, and its evaluation provides a solution to the PDE problem. A C++/Fortran 90 code for the iteration function is generated using the MathCode system, which results in a performance gain of the order of a thousand over Mathematica, the language that has been used to code the solver generator. Examples of stability criteria are presented that agree with known criteria; examples that demonstrate the generality of the solver and the speed enhancement of the generated C++ and Fortran 90 codes are also presented.

  4. PDE5 inhibitors blunt inflammation in human BPH: a potential mechanism of action for PDE5 inhibitors in LUTS.

    Science.gov (United States)

    Vignozzi, Linda; Gacci, Mauro; Cellai, Ilaria; Morelli, Annamaria; Maneschi, Elena; Comeglio, Paolo; Santi, Raffaella; Filippi, Sandra; Sebastianelli, Arcangelo; Nesi, Gabriella; Serni, Sergio; Carini, Marco; Maggi, Mario

    2013-09-01

    Metabolic syndrome (MetS) and benign prostate hyperplasia (BPH)/low urinary tract symptoms (LUTS) are often comorbid. Chronic inflammation is one of the putative links between these diseases. Phosphodiesterase type 5 inhibitors (PDE5i) are recognized as an effective treatment of BPH-related LUTS. One proposed mechanism of action of PDE5 is the inhibition of intraprostatic inflammation. In this study we investigate whether PDE5i could blunt inflammation in the human prostate. Evaluation of the effect of tadalafil and vardenafil on secretion of interleukin 8 (IL-8, a surrogate marker of prostate inflammation) by human myofibroblast prostatic cells (hBPH) exposed to different inflammatory stimuli. We preliminary evaluate histological features of prostatic inflammatory infiltrates in BPH patients enrolled in a randomized, double bind, placebo controlled study aimed at investigating the efficacy of vardenafil (10 mg/day, for 12 weeks) on BPH/LUTS. In vitro treatment with tadalafil or vardenafil on hBPH reduced IL-8 secretion induced by either TNFα or metabolic factors, including oxidized low-density lipoprotein, oxLDL, to the same extent as a PDE5-insensitive PKG agonist Sp-8-Br-PET-cGMP. These effects were reverted by the PKG inhibitor KT5823, suggesting a cGMP/PKG-dependency. Treatment with tadalafil or vardenafil significantly suppressed oxLDL receptor (LOX-1) expression. Histological evaluation of anti-CD45 staining (CD45 score) in prostatectomy specimens of BPH patients showed a positive association with MetS severity. Reduced HDL-cholesterol and elevated triglycerides were the only MetS factors significantly associated with CD45 score. In the MetS cohort there was a significant lower CD45 score in the vardenafil-arm versus the placebo-one. © 2013 Wiley Periodicals, Inc.

  5. New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment.

    Science.gov (United States)

    Brullo, Chiara; Ricciarelli, Roberta; Prickaerts, Jos; Arancio, Ottavio; Massa, Matteo; Rotolo, Chiara; Romussi, Alessia; Rebosio, Claudia; Marengo, Barbara; Pronzato, Maria Adelaide; van Hagen, Britt T J; van Goethem, Nick P; D'Ursi, Pasqualina; Orro, Alessandro; Milanesi, Luciano; Guariento, Sara; Cichero, Elena; Fossa, Paola; Fedele, Ernesto; Bruno, Olga

    2016-11-29

    Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles. Molecular modeling studies highlighted the pivotal role of a polar alkyl chain in conferring selective enzyme interaction. Compound 8a showed PDE4D3 selective inhibition and was able to increase intracellular cAMP levels in neuronal cells, as well as in the hippocampus of freely moving rats. Furthermore, 8a was able to readily cross the blood-brain barrier and enhanced memory performance in mice without causing any emetic-like behavior. These data support the view that PDE4D is an adequate molecular target to restore memory deficits in different neuropathologies, including AD, and also indicate compound 8a as a promising candidate for further preclinical development. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  6. The Development of Symbolic and Non-Symbolic Number Line Estimations: Three Developmental Accounts Contrasted Within Cross-Sectional and Longitudinal Data

    Directory of Open Access Journals (Sweden)

    Delphine Sasanguie

    2016-12-01

    Full Text Available Three theoretical accounts have been put forward for the development of children’s response patterns on number line estimation tasks: the log-to-linear representational shift, the two-linear-to-linear transformation and the proportion judgment account. These three accounts have not been contrasted, however, within one study, using one single criterion to determine which model provides the best fit. The present study contrasted these three accounts by examining first, second and sixth graders with a symbolic and non-symbolic number line estimation task (Experiment 1. In addition, first and second graders were tested again one year later (Experiment 2. In case of symbolic estimations, the proportion judgment account described the data best. Most young children’s non-symbolic estimation patterns were best described by a logarithmic model (within the log-to-lin account, whereas those of most older children were best described by the simple power model (within the proportion judgment account.

  7. Functions of PDE3 Isoforms in Cardiac Muscle

    Science.gov (United States)

    Movsesian, Matthew; Ahmad, Faiyaz

    2018-01-01

    Isoforms in the PDE3 family of cyclic nucleotide phosphodiesterases have important roles in cyclic nucleotide-mediated signalling in cardiac myocytes. These enzymes are targeted by inhibitors used to increase contractility in patients with heart failure, with a combination of beneficial and adverse effects on clinical outcomes. This review covers relevant aspects of the molecular biology of the isoforms that have been identified in cardiac myocytes; the roles of these enzymes in modulating cAMP-mediated signalling and the processes mediated thereby; and the potential for targeting these enzymes to improve the profile of clinical responses. PMID:29415428

  8. Simulation of Stochastic Processes by Coupled ODE-PDE

    Science.gov (United States)

    Zak, Michail

    2008-01-01

    A document discusses the emergence of randomness in solutions of coupled, fully deterministic ODE-PDE (ordinary differential equations-partial differential equations) due to failure of the Lipschitz condition as a new phenomenon. It is possible to exploit the special properties of ordinary differential equations (represented by an arbitrarily chosen, dynamical system) coupled with the corresponding Liouville equations (used to describe the evolution of initial uncertainties in terms of joint probability distribution) in order to simulate stochastic processes with the proscribed probability distributions. The important advantage of the proposed approach is that the simulation does not require a random-number generator.

  9. Children’s Mapping between Non-Symbolic and Symbolic Numerical Magnitudes and Its Association with Timed and Untimed Tests of Mathematics Achievement

    Science.gov (United States)

    Brankaer, Carmen; Ghesquière, Pol; De Smedt, Bert

    2014-01-01

    The ability to map between non-symbolic numerical magnitudes and Arabic numerals has been put forward as a key factor in children’s mathematical development. This mapping ability has been mainly examined indirectly by looking at children’s performance on a symbolic magnitude comparison task. The present study investigated mapping in a more direct way by using a task in which children had to choose which of two choice quantities (Arabic digits or dot arrays) matched the target quantity (dot array or Arabic digit), thereby focusing on small quantities ranging from 1 to 9. We aimed to determine the development of mapping over time and its relation to mathematics achievement. Participants were 36 first graders (M = 6 years 8 months) and 46 third graders (M = 8 years 8 months) who all completed mapping tasks, symbolic and non-symbolic magnitude comparison tasks and standardized timed and untimed tests of mathematics achievement. Findings revealed that children are able to map between non-symbolic and symbolic representations and that this mapping ability develops over time. Moreover, we found that children’s mapping ability is related to timed and untimed measures of mathematics achievement, over and above the variance accounted for by their numerical magnitude comparison skills. PMID:24699664

  10. Parallel PDE-Based Simulations Using the Common Component Architecture

    International Nuclear Information System (INIS)

    McInnes, Lois C.; Allan, Benjamin A.; Armstrong, Robert; Benson, Steven J.; Bernholdt, David E.; Dahlgren, Tamara L.; Diachin, Lori; Krishnan, Manoj Kumar; Kohl, James A.; Larson, J. Walter; Lefantzi, Sophia; Nieplocha, Jarek; Norris, Boyana; Parker, Steven G.; Ray, Jaideep; Zhou, Shujia

    2006-01-01

    The complexity of parallel PDE-based simulations continues to increase as multimodel, multiphysics, and multi-institutional projects become widespread. A goal of component based software engineering in such large-scale simulations is to help manage this complexity by enabling better interoperability among various codes that have been independently developed by different groups. The Common Component Architecture (CCA) Forum is defining a component architecture specification to address the challenges of high-performance scientific computing. In addition, several execution frameworks, supporting infrastructure, and general purpose components are being developed. Furthermore, this group is collaborating with others in the high-performance computing community to design suites of domain-specific component interface specifications and underlying implementations. This chapter discusses recent work on leveraging these CCA efforts in parallel PDE-based simulations involving accelerator design, climate modeling, combustion, and accidental fires and explosions. We explain how component technology helps to address the different challenges posed by each of these applications, and we highlight how component interfaces built on existing parallel toolkits facilitate the reuse of software for parallel mesh manipulation, discretization, linear algebra, integration, optimization, and parallel data redistribution. We also present performance data to demonstrate the suitability of this approach, and we discuss strategies for applying component technologies to both new and existing applications

  11. [Efficacy and tolerance of PDE-5 in the treatment of erectile dysfunction in schizophrenic patients: A literature review].

    Science.gov (United States)

    Bacconi, L; Gressier, F

    2017-02-01

    Sexual dysfunction is an important public health problem in men and is associated with reduced quality of life. It is more common in patients with schizophrenia. It is well-established that antipsychotic drugs cause sexual dysfunction with consequences on the quality of life of patients, adherence to treatment, and public health costs. Phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are indicated for the management of erectile dysfunction. However, there is little information on such treatment in schizophrenic patients. This literature review aimed to summarize the current data on the efficacy and tolerability of PDE-5 inhibitors in the erectile dysfunction in schizophrenic patients. PubMed, PsycInfo and Cochrane databases were searched for studies published until August 2014. Only 6 studies met the inclusion criteria. Three were randomized, double-blind, cross-over, placebo-controlled trials and three were open studies. Various scales were used to measure erectile and orgasmic function, desire, satisfaction during intercourse, overall satisfaction, quality of life and intensity of schizophrenic symptoms. In the 3 randomized studies (one with sildenafil 25-50 mg, one with lodenafil carbonate 80 mg/j and the last one with tadalafil 10 mg), the rate of participants who completed the trial was high (around 95 %). All three included patients with schizophrenia or schizophrenia spectrum disorders. Patients reported significant improvement on sexual dysfunction. However, no statistical difference was reported between lodenafil and placebo, on different scales, suggesting a very important placebo effect in patients with schizophrenia. All three found a good tolerance of PDE-5 inhibitors. Side effects were rare and were mainly nasal congestion, headaches, nausea and dizziness. There were no major side effects or drug interactions. Considering the 3 open studies, 2 involved sildenafil and one tadalafil. All concluded in improved erectile and orgasmic

  12. Co-possession of phosphodiesterase type-5 inhibitors (PDE5-I) with nitrates.

    Science.gov (United States)

    Chang, Li-Ling; Ma, Mark; Allmen, Heather von; Henderson, Scott C; Harper, Kristine; Hornbuckle, Kenneth

    2010-06-01

    Estimate the proportion of phosphodiesterase type-5 inhibitor (PDE5-I) patients who co-possess nitrates and compare the proportion of tadalafil patients dispensed nitrates to a matched control group. Secondarily, examine the percentage of co-possession of PDE5-Is and nitrates where the products were dispensed on the same day or written by the same prescriber. Male patients aged 18+ years filling PDE5-I prescriptions between December 2003 and March 2006 were identified using a U.S. longitudinal prescription database (IMS Health LRx). Similar patients not dispensed a PDE5-I during this period were matched to the tadalafil-dispensed cohort using a propensity score approach. Co-possession, as a proxy for concurrent use, was defined as an overlap in time on therapy for a PDE5-I and nitrate and was compared for the three PDE5-Is and for tadalafil to the matched control group. Among 601,063 tadalafil patients, 3.31% were dispensed a nitrate during the study period, compared to 6.18% in control patients (n = 601,063). When co-possessed prescriptions were defined by overlapping exposure periods, the proportion of PDE5-I patients with co-possessed nitrates ranged from 1.44% (tadalafil) to 1.72% (vardenafil) and 2.13% (sildenafil). Co-possession percentages of PDE5-I prescriptions were 0.83% for tadalafil and 1.07% for sildenafil and vardenafil. The majority (54.29%) of co-possessed PDE5-I and nitrate prescriptions had the nitrate dispensed prior to the PDE5-I prescription identified in the study cohort. Keeping in mind the limitations of observational studies, these results suggest that co-dispensing of nitrates and PDE5-Is is low. Compared to control patients, the proportion of nitrate co-possession was lowest for patients filling tadalafil. Tadalafil patients also had the lowest co-possessed proportion among the three PDE5-I cohorts. While the majority of co-possessed drug pairs were prescribed by different providers, the highest percentage of co-prescribing from the same

  13. Block-triangular preconditioners for PDE-constrained optimization

    KAUST Repository

    Rees, Tyrone; Stoll, Martin

    2010-01-01

    In this paper we investigate the possibility of using a block-triangular preconditioner for saddle point problems arising in PDE-constrained optimization. In particular, we focus on a conjugate gradient-type method introduced by Bramble and Pasciak that uses self-adjointness of the preconditioned system in a non-standard inner product. We show when the Chebyshev semi-iteration is used as a preconditioner for the relevant matrix blocks involving the finite element mass matrix that the main drawback of the Bramble-Pasciak method-the appropriate scaling of the preconditioners-is easily overcome. We present an eigenvalue analysis for the block-triangular preconditioners that gives convergence bounds in the non-standard inner product and illustrates their competitiveness on a number of computed examples. Copyright © 2010 John Wiley & Sons, Ltd.

  14. Block-triangular preconditioners for PDE-constrained optimization

    KAUST Repository

    Rees, Tyrone

    2010-11-26

    In this paper we investigate the possibility of using a block-triangular preconditioner for saddle point problems arising in PDE-constrained optimization. In particular, we focus on a conjugate gradient-type method introduced by Bramble and Pasciak that uses self-adjointness of the preconditioned system in a non-standard inner product. We show when the Chebyshev semi-iteration is used as a preconditioner for the relevant matrix blocks involving the finite element mass matrix that the main drawback of the Bramble-Pasciak method-the appropriate scaling of the preconditioners-is easily overcome. We present an eigenvalue analysis for the block-triangular preconditioners that gives convergence bounds in the non-standard inner product and illustrates their competitiveness on a number of computed examples. Copyright © 2010 John Wiley & Sons, Ltd.

  15. Administration of PDE4 Inhibitors Suppressed the Pannus-Like Inflammation by Inhibition of Cytokine Production by Macrophages and Synovial Fibroblast Proliferation

    Directory of Open Access Journals (Sweden)

    Katsuya Kobayashi

    2007-01-01

    Full Text Available A marked proliferation of synovial fibroblasts in joints leads to pannus formation in rheumatoid arthritis (RA. Various kinds of cytokines are produced in the pannus. The purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4 inhibitors in a new animal model for the evaluation of pannus formation and cytokine production in the pannus. Mice sensitized with methylated bovine serum albumin (mBSA were challenged by subcutaneous implantation of a membrane filter soaked in mBSA solution in the back of the mice. Drugs were orally administered for 10 days. The granuloma formed around the filter was collected on day 11. It was chopped into pieces and cultured in vitro for 24 hr. The cytokines were measured in the supernatants. The type of cytokines produced in the granuloma was quite similar to those produced in pannus in RA. Both PDE4 inhibitors, KF66490 and SB207499, suppressed the production of IL-1β, TNF-α, and IL-12, and the increase in myeloperoxidase activity, a marker enzyme for neutrophils and hydroxyproline content. Compared to leflunomide, PDE4 inhibitors more strongly suppressed IL-12 production and the increase in myeloperoxidase activity. PDE4 inhibitors also inhibited lipopolysaccharide-induced TNF-α and IL-12 production from thioglycolate-induced murine peritoneal macrophages and the proliferation of rat synovial fibroblasts. These results indicate this model makes it easy to evaluate the effect of drugs on various cytokine productions in a granuloma without any purification step and may be a relevant model for evaluating novel antirheumatic drugs on pannus formation in RA. PDE4 inhibitors could have therapeutic effects on pannus formation in RA by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.

  16. Administration of PDE4 inhibitors suppressed the pannus-like inflammation by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.

    Science.gov (United States)

    Kobayashi, Katsuya; Suda, Toshio; Manabe, Haruhiko; Miki, Ichiro

    2007-01-01

    A marked proliferation of synovial fibroblasts in joints leads to pannus formation in rheumatoid arthritis (RA). Various kinds of cytokines are produced in the pannus. The purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4) inhibitors in a new animal model for the evaluation of pannus formation and cytokine production in the pannus. Mice sensitized with methylated bovine serum albumin (mBSA) were challenged by subcutaneous implantation of a membrane filter soaked in mBSA solution in the back of the mice. Drugs were orally administered for 10 days. The granuloma formed around the filter was collected on day 11. It was chopped into pieces and cultured in vitro for 24 hr. The cytokines were measured in the supernatants. The type of cytokines produced in the granuloma was quite similar to those produced in pannus in RA. Both PDE4 inhibitors, KF66490 and SB207499, suppressed the production of IL-1beta, TNF-alpha, and IL-12, and the increase in myeloperoxidase activity, a marker enzyme for neutrophils and hydroxyproline content. Compared to leflunomide, PDE4 inhibitors more strongly suppressed IL-12 production and the increase in myeloperoxidase activity. PDE4 inhibitors also inhibited lipopolysaccharide-induced TNF-alpha and IL-12 production from thioglycolate-induced murine peritoneal macrophages and the proliferation of rat synovial fibroblasts. These results indicate this model makes it easy to evaluate the effect of drugs on various cytokine productions in a granuloma without any purification step and may be a relevant model for evaluating novel antirheumatic drugs on pannus formation in RA. PDE4 inhibitors could have therapeutic effects on pannus formation in RA by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.

  17. DISC1, PDE4B, and NDE1 at the centrosome and synapse

    International Nuclear Information System (INIS)

    Bradshaw, Nicholas J.; Ogawa, Fumiaki; Antolin-Fontes, Beatriz; Chubb, Jennifer E.; Carlyle, Becky C.; Christie, Sheila; Claessens, Antoine; Porteous, David J.; Millar, J. Kirsty

    2008-01-01

    Disrupted-In-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependant Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.

  18. Convergence acceleration for time-independent first-order PDE using optimal PNB-approximations

    Energy Technology Data Exchange (ETDEWEB)

    Holmgren, S.; Branden, H. [Uppsala Univ. (Sweden)

    1996-12-31

    We consider solving time-independent (steady-state) flow problems in 2D or 3D governed by hyperbolic or {open_quotes}almost hyperbolic{close_quotes} systems of partial differential equations (PDE). Examples of such PDE are the Euler and the Navier-Stokes equations. The PDE is discretized using a finite difference or finite volume scheme with arbitrary order of accuracy. If the matrix B describes the discretized differential operator and u denotes the approximate solution, the discrete problem is given by a large system of equations.

  19. A conformational switch in the inhibitory gamma-subunit of PDE6 upon enzyme activation by transducin.

    Science.gov (United States)

    Granovsky, A E; Artemyev, N O

    2001-11-06

    In response to light, a photoreceptor G protein, transducin, activates cGMP-phosphodiesterase (PDE6) by displacing the inhibitory gamma-subunits (Pgamma) from the enzyme's catalytic sites. Evidence suggests that the activation of PDE6 involves a conformational change of the key inhibitory C-terminal domain of Pgamma. In this study, the C-terminal region of Pgamma, Pgamma-73-85, has been targeted for Ala-scanning mutagenesis to identify the point-to-point interactions between Pgamma and the PDE6 catalytic subunits and to probe the nature of the conformational change. Pgamma mutants were tested for their ability to inhibit PDE6 and a chimeric PDE5-conePDE6 enzyme containing the Pgamma C-terminus-binding site of cone PDE. This analysis has revealed that in addition to previously characterized Ile86 and Ile87, important inhibitory contact residues of Pgamma include Asn74, His75, and Leu78. The patterns of mutant PDE5-conePDE6 enzyme inhibition suggest the interaction between the PgammaAsn74/His75 sequence and Met758 of the cone PDE6alpha' catalytic subunit. This interaction, and the interaction between the PgammaIle86/Ile87 and PDE6alpha'Phe777/Phe781 residues, is most consistent with an alpha-helical structure of the Pgamma C-terminus. The analysis of activation of PDE6 enzymes containing Pgamma mutants with Ala-substituted transducin-contact residues demonstrated the critical role of PgammaLeu76. Accordingly, we hypothesize that the initial step in PDE6 activation involves an interaction of transducin-alpha with PgammaLeu76. This interaction introduces a bend into the alpha-helical structure of the Pgamma C-terminus, allowing transducin-alpha to further twist the C-terminus thereby uncovering the catalytic pocket of PDE6.

  20. Association between individual differences in non-symbolic number acuity and math performance: a meta-analysis.

    Science.gov (United States)

    Chen, Qixuan; Li, Jingguang

    2014-05-01

    Many recent studies have examined the association between number acuity, which is the ability to rapidly and non-symbolically estimate the quantity of items appearing in a scene, and symbolic math performance. However, various contradictory results have been reported. To comprehensively evaluate the association between number acuity and symbolic math performance, we conduct a meta-analysis to synthesize the results observed in previous studies. First, a meta-analysis of cross-sectional studies (36 samples, N = 4705) revealed a significant positive correlation between these skills (r = 0.20, 95% CI = [0.14, 0.26]); the association remained after considering other potential moderators (e.g., whether general cognitive abilities were controlled). Moreover, a meta-analysis of longitudinal studies revealed 1) that number acuity may prospectively predict later math performance (r = 0.24, 95% CI = [0.11, 0.37]; 6 samples) and 2) that number acuity is retrospectively correlated to early math performance as well (r = 0.17, 95% CI = [0.07, 0.26]; 5 samples). In summary, these pieces of evidence demonstrate a moderate but statistically significant association between number acuity and math performance. Based on the estimated effect sizes, power analyses were conducted, which suggested that many previous studies were underpowered due to small sample sizes. This may account for the disparity between findings in the literature, at least in part. Finally, the theoretical and practical implications of our meta-analytic findings are presented, and future research questions are discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Fast Multipole-Based Elliptic PDE Solver and Preconditioner

    KAUST Repository

    Ibeid, Huda

    2016-12-07

    Exascale systems are predicted to have approximately one billion cores, assuming Gigahertz cores. Limitations on affordable network topologies for distributed memory systems of such massive scale bring new challenges to the currently dominant parallel programing model. Currently, there are many efforts to evaluate the hardware and software bottlenecks of exascale designs. It is therefore of interest to model application performance and to understand what changes need to be made to ensure extrapolated scalability. Fast multipole methods (FMM) were originally developed for accelerating N-body problems for particle-based methods in astrophysics and molecular dynamics. FMM is more than an N-body solver, however. Recent efforts to view the FMM as an elliptic PDE solver have opened the possibility to use it as a preconditioner for even a broader range of applications. In this thesis, we (i) discuss the challenges for FMM on current parallel computers and future exascale architectures, with a focus on inter-node communication, and develop a performance model that considers the communication patterns of the FMM for spatially quasi-uniform distributions, (ii) employ this performance model to guide performance and scaling improvement of FMM for all-atom molecular dynamics simulations of uniformly distributed particles, and (iii) demonstrate that, beyond its traditional use as a solver in problems for which explicit free-space kernel representations are available, the FMM has applicability as a preconditioner in finite domain elliptic boundary value problems, by equipping it with boundary integral capability for satisfying conditions at finite boundaries and by wrapping it in a Krylov method for extensibility to more general operators. Compared with multilevel methods, FMM is capable of comparable algebraic convergence rates down to the truncation error of the discretized PDE, and it has superior multicore and distributed memory scalability properties on commodity

  2. Collocation methods for uncertainty quanti cation in PDE models with random data

    KAUST Repository

    Nobile, Fabio

    2014-01-01

    address interpolatory approximations where the PDE is solved on a sparse grid of Gauss points in the probability space and the solutions thus obtained interpolated by multivariate polynomials. We present recent results on optimized sparse grids in which

  3. Computer-Aided Transformation of PDE Models: Languages, Representations, and a Calculus of Operations

    Science.gov (United States)

    2016-01-05

    Computer-aided transformation of PDE models: languages, representations, and a calculus of operations A domain-specific embedded language called...languages, representations, and a calculus of operations Report Title A domain-specific embedded language called ibvp was developed to model initial...Computer-aided transformation of PDE models: languages, representations, and a calculus of operations 1 Vision and background Physical and engineered systems

  4. PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

    Science.gov (United States)

    Molenaar, Peter; Christ, Torsten; Hussain, Rizwan I; Engel, Andreas; Berk, Emanuel; Gillette, Katherine T; Chen, Lu; Galindo-Tovar, Alejandro; Krobert, Kurt A; Ravens, Ursula; Levy, Finn Olav; Kaumann, Alberto J

    2013-01-01

    Background and Purpose PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3–1 μM) or PDE4 inhibitor rolipram (1–10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental Approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1 adrenoceptors (β2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2 adrenoceptors (β1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s. Key Results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and Implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1 and β2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of

  5. Mutation in rod PDE6 linked to congenital stationary night blindness impairs the enzyme inhibition by its gamma-subunit.

    Science.gov (United States)

    Muradov, Khakim G; Granovsky, Alexey E; Artemyev, Nikolai O

    2003-03-25

    Photoreceptor cGMP phosphodiesterase (PDE6) is the effector enzyme in the vertebrate visual transduction cascade. The activity of rod PDE6 catalytic alpha- and beta-subunits is blocked in the dark by two inhibitory Pgamma-subunits. The inhibition is released upon light-stimulation of photoreceptor cells. Mutation H258N in PDE6beta has been linked to congenital stationary night blindness (CSNB) in a large Danish family (Rambusch pedigree) (Gal, A., Orth, U., Baehr, W., Schwinger, E., and Rosenberg, T. (1994) Nat. Genet. 7, 64-67.) We have analyzed the consequences of this mutation for PDE6 function using a Pgamma-sensitive PDE6alpha'/PDE5 chimera, Chi16. Biochemical analysis of the H257N mutant, an equivalent of PDE6betaH258N, demonstrates that this substitution does not alter the ability of chimeric PDE to dimerize or the enzyme's catalytic properties. The sensitivity of H257N to a competitive inhibitor zaprinast was also unaffected. However, the mutant displayed a significant impairment in the inhibitory interaction with Pgamma, which was apparent from a approximately 20-fold increase in the K(i) value (46 nM) and incomplete maximal inhibition. The inhibitory defect of H257N is not due to perturbation of noncatalytic cGMP binding to the PDE6alpha' GAF domains. The noncatalytic cGMP-binding characteristics of the H257N mutant were similar to those of the parent PDE6alpha'/PDE5 chimera. Since rod PDE6 in the Rambusch CSNB is a catalytic heterodimer of the wild-type PDE6alpha and mutant PDE6beta, Chi16 and H257N were coexpressed, and a heterodimeric PDE, Chi16/H257N, was isolated. It displayed two Pgamma inhibitory sites with the K(i) values of 5 and 57 nM. Our results support the hypothesis that mutation H258N in PDE6beta causes CSNB through incomplete inhibition of PDE6 activity by Pgamma, which leads to desensitization of rod photoreceptors.

  6. PDE 7 inhibitors: new potential drugs for the therapy of spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Irene Paterniti

    Full Text Available BACKGROUND: Primary traumatic mechanical injury to the spinal cord (SCI causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs, which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g to the dura via a four-level T5-T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score, and TNF-α, IL-6, COX-2 and iNOS expression. CONCLUSIONS/SIGNIFICANCE: All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI.

  7. Gene Therapy in a Large Animal Model of PDE6A-Retinitis Pigmentosa

    Directory of Open Access Journals (Sweden)

    Freya M. Mowat

    2017-06-01

    Full Text Available Despite mutations in the rod phosphodiesterase 6-alpha (PDE6A gene being well-recognized as a cause of human retinitis pigmentosa, no definitive treatments have been developed to treat this blinding disease. We performed a trial of retinal gene augmentation in the Pde6a mutant dog using Pde6a delivery by capsid-mutant adeno-associated virus serotype 8, previously shown to have a rapid onset of transgene expression in the canine retina. Subretinal injections were performed in 10 dogs at 29–44 days of age, and electroretinography and vision testing were performed to assess functional outcome. Retinal structure was assessed using color fundus photography, spectral domain optical coherence tomography, and histology. Immunohistochemistry was performed to examine transgene expression and expression of other retinal genes. Treatment resulted in improvement in dim light vision and evidence of rod function on electroretinographic examination. Photoreceptor layer thickness in the treated area was preserved compared with the contralateral control vector treated or uninjected eye. Improved rod and cone photoreceptor survival, rhodopsin localization, cyclic GMP levels and bipolar cell dendrite distribution was observed in treated areas. Some adverse effects including foci of retinal separation, foci of retinal degeneration and rosette formation were identified in both AAV-Pde6a and control vector injected regions. This is the first description of successful gene augmentation for Pde6a retinitis pigmentosa in a large animal model. Further studies will be necessary to optimize visual outcomes and minimize complications before translation to human studies.

  8. PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

    Science.gov (United States)

    Nelson, Michael D; Rader, Florian; Tang, Xiu; Tavyev, Jane; Nelson, Stanley F; Miceli, M Carrie; Elashoff, Robert M; Sweeney, H Lee; Victor, Ronald G

    2014-06-10

    To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis. © 2014 American Academy of Neurology.

  9. A penalty method for PDE-constrained optimization in inverse problems

    International Nuclear Information System (INIS)

    Leeuwen, T van; Herrmann, F J

    2016-01-01

    Many inverse and parameter estimation problems can be written as PDE-constrained optimization problems. The goal is to infer the parameters, typically coefficients of the PDE, from partial measurements of the solutions of the PDE for several right-hand sides. Such PDE-constrained problems can be solved by finding a stationary point of the Lagrangian, which entails simultaneously updating the parameters and the (adjoint) state variables. For large-scale problems, such an all-at-once approach is not feasible as it requires storing all the state variables. In this case one usually resorts to a reduced approach where the constraints are explicitly eliminated (at each iteration) by solving the PDEs. These two approaches, and variations thereof, are the main workhorses for solving PDE-constrained optimization problems arising from inverse problems. In this paper, we present an alternative method that aims to combine the advantages of both approaches. Our method is based on a quadratic penalty formulation of the constrained optimization problem. By eliminating the state variable, we develop an efficient algorithm that has roughly the same computational complexity as the conventional reduced approach while exploiting a larger search space. Numerical results show that this method indeed reduces some of the nonlinearity of the problem and is less sensitive to the initial iterate. (paper)

  10. Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors.

    Science.gov (United States)

    Chino, Ayaka; Seo, Ryushi; Amano, Yasushi; Namatame, Ichiji; Hamaguchi, Wataru; Honbou, Kazuya; Mihara, Takuma; Yamazaki, Mayako; Tomishima, Masaki; Masuda, Naoyuki

    2018-01-01

    In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure-activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

  11. A PDE Pricing Framework for Cross-Currency Interest Rate Derivatives with Target Redemption Features

    Science.gov (United States)

    Christara, Christina C.; Minh Dang, Duy; Jackson, Kenneth R.; Lakhany, Asif

    2010-09-01

    We propose a general framework for efficient pricing via a partial differential equation (PDE) approach for exotic cross-currency interest rate (IR) derivatives, with strong emphasis on long-dated foreign exchange (FX) IR hybrids, namely Power Reverse Dual Currency (PRDC) swaps with a FX Target Redemption (FX-TARN) provision. The FX-TARN provision provides a cap on the FX-linked PRDC coupon amounts, and once the accumulated coupon amount reaches this cap, the underlying PRDC swap terminates. Our PDE pricing framework is based on an auxiliary state variable to keep track of the total accumulated PRDC coupon amount. Finite differences on uniform grids and the Alternating Direction Implicit (ADI) method are used for the spatial and time discretizations, respectively, of the model-dependent PDE corresponding to each discretized value of the auxiliary variable. Numerical examples illustrating the convergence properties of the numerical methods are provided.

  12. PDE5 Inhibitors As Potential Tools In The Treatment Of Cystic Fibrosis

    Directory of Open Access Journals (Sweden)

    Sabrina eNoel

    2012-09-01

    Full Text Available Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF, there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5 inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.

  13. A boundary PDE feedback control approach for the stabilization of mortgage price dynamics

    Science.gov (United States)

    Rigatos, G.; Siano, P.; Sarno, D.

    2017-11-01

    Several transactions taking place in financial markets are dependent on the pricing of mortgages (loans for the purchase of residences, land or farms). In this article, a method for stabilization of mortgage price dynamics is developed. It is considered that mortgage prices follow a PDE model which is equivalent to a multi-asset Black-Scholes PDE. Actually it is a diffusion process evolving in a 2D assets space, where the first asset is the house price and the second asset is the interest rate. By applying semi-discretization and a finite differences scheme this multi-asset PDE is transformed into a state-space model consisting of ordinary nonlinear differential equations. For the local subsystems, into which the mortgage PDE is decomposed, it becomes possible to apply boundary-based feedback control. The controller design proceeds by showing that the state-space model of the mortgage price PDE stands for a differentially flat system. Next, for each subsystem which is related to a nonlinear ODE, a virtual control input is computed, that can invert the subsystem's dynamics and can eliminate the subsystem's tracking error. From the last row of the state-space description, the control input (boundary condition) that is actually applied to the multi-factor mortgage price PDE system is found. This control input contains recursively all virtual control inputs which were computed for the individual ODE subsystems associated with the previous rows of the state-space equation. Thus, by tracing the rows of the state-space model backwards, at each iteration of the control algorithm, one can finally obtain the control input that should be applied to the mortgage price PDE system so as to assure that all its state variables will converge to the desirable setpoints. By showing the feasibility of such a control method it is also proven that through selected modification of the PDE boundary conditions the price of the mortgage can be made to converge and stabilize at specific

  14. Adaptive wavelet collocation methods for initial value boundary problems of nonlinear PDE's

    Science.gov (United States)

    Cai, Wei; Wang, Jian-Zhong

    1993-01-01

    We have designed a cubic spline wavelet decomposition for the Sobolev space H(sup 2)(sub 0)(I) where I is a bounded interval. Based on a special 'point-wise orthogonality' of the wavelet basis functions, a fast Discrete Wavelet Transform (DWT) is constructed. This DWT transform will map discrete samples of a function to its wavelet expansion coefficients in O(N log N) operations. Using this transform, we propose a collocation method for the initial value boundary problem of nonlinear PDE's. Then, we test the efficiency of the DWT transform and apply the collocation method to solve linear and nonlinear PDE's.

  15. N Termini of apPDE4 Isoforms Are Responsible for Targeting the Isoforms to Different Cellular Membranes

    Science.gov (United States)

    Jang, Deok-Jin; Park, Soo-Won; Lee, Jin-A; Lee, Changhoon; Chae, Yeon-Su; Park, Hyungju; Kim, Min-Jeong; Choi, Sun-Lim; Lee, Nuribalhae; Kim, Hyoung; Kaang, Bong-Kiun

    2010-01-01

    Phosphodiesterases (PDEs) are known to play a key role in the compartmentalization of cAMP signaling; however, the molecular mechanisms underlying intracellular localization of different PDE isoforms are not understood. In this study, we have found that each of the supershort, short, and long forms of apPDE4 showed distinct localization in the…

  16. Role of Ser102 and Ser104 as Regulators of cGMP Hydrolysis by PDE5A

    DEFF Research Database (Denmark)

    Carøe Nordgaard, Julie; Kruse, Lars Schack; Gammeltoft, Steen

    2014-01-01

    -N-AS neuroblastoma cells as C-terminal fusions with green fluorescent protein. Transfected cells were treated with sildenafil, cilostazol, glyceryl trinitrate, calcitonin gene-related peptide (CGRP) or sumatriptan. PDE5A-GFP fusion proteins were localized in fixed cells by immunofluorescence and PDE activity...

  17. A comparison of the inhibitory activity of selective PDE4 inhibitors on eosinophil recruitment in guinea pig skin

    Directory of Open Access Journals (Sweden)

    Mauro M Teixeira

    1997-12-01

    Full Text Available The elevation of intracellular cyclic AMP by phosphodiesterase (PDE4 inhibitors in eosinophils is associated with inhibition of the activation and recruitment of these cells. We have previously shown that systemic treatment with the PDE4 inhibitor rolipram effectively inhibt eosinophil migration in guinea pig skin. In the present study we compare the oral potency and efficacy of the PDE4 inhibitors rolipram, RP 73401 and CDP 840 on allergic and PAF-induced eosinophil recruitment. Rolipram and RP 73401 were equally effective and potent when given by the oral route and much more active than the PDE4 inhibitor CDP 840. We suggest that this guinea pig model of allergic and mediator-induced eosinophil recruitment is both a sensitive and simple tool to test the efficacy and potency of PDE4 inhibitors in vivo.

  18. Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia

    DEFF Research Database (Denmark)

    Grau, Tanja; Artemyev, Nikolai O; Rosenberg, Thomas

    2011-01-01

    study on PDE6C mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins. Twelve affected patients from seven independent families segregating PDE6C mutations were......Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive...... identified in our total patient cohort of 492 independent families. Eleven different PDE6C mutations were found including two nonsense mutations, three mutations affecting transcript splicing as shown by minigene assays, one 1 bp-insertion and five missense mutations. We also performed a detailed functional...

  19. Comparison of preconditioned Krylov subspace iteration methods for PDE-constrained optimization problems

    Czech Academy of Sciences Publication Activity Database

    Axelsson, Owe; Farouq, S.; Neytcheva, M.

    2017-01-01

    Roč. 74, č. 1 (2017), s. 19-37 ISSN 1017-1398 Institutional support: RVO:68145535 Keywords : PDE-constrained optimization problems * finite elements * iterative solution method s * preconditioning Subject RIV: BA - General Mathematics OBOR OECD: Applied mathematics Impact factor: 1.241, year: 2016 https://link.springer.com/article/10.1007%2Fs11075-016-0136-5

  20. #DDOD Use Case: Access to Medicare Part D Drug Event File (PDE) for cost transparency

    Data.gov (United States)

    U.S. Department of Health & Human Services — SUMMARY DDOD use case to request access to Medicare Part D Drug Event File (PDE) for cost transparency to pharmacies and patients. WHAT IS A USE CASE? A “Use Case”...

  1. Research on odor interaction between aldehyde compounds via a partial differential equation (PDE) model.

    Science.gov (United States)

    Yan, Luchun; Liu, Jiemin; Qu, Chen; Gu, Xingye; Zhao, Xia

    2015-01-28

    In order to explore the odor interaction of binary odor mixtures, a series of odor intensity evaluation tests were performed using both individual components and binary mixtures of aldehydes. Based on the linear relation between the logarithm of odor activity value and odor intensity of individual substances, the relationship between concentrations of individual constituents and their joint odor intensity was investigated by employing a partial differential equation (PDE) model. The obtained results showed that the binary odor interaction was mainly influenced by the mixing ratio of two constituents, but not the concentration level of an odor sample. Besides, an extended PDE model was also proposed on the basis of the above experiments. Through a series of odor intensity matching tests for several different binary odor mixtures, the extended PDE model was proved effective at odor intensity prediction. Furthermore, odorants of the same chemical group and similar odor type exhibited similar characteristics in the binary odor interaction. The overall results suggested that the PDE model is a more interpretable way of demonstrating the odor interactions of binary odor mixtures.

  2. Molecular Bases of PDE4D Inhibition by Memory-Enhancing GEBR Library Compounds.

    Science.gov (United States)

    Prosdocimi, Tommaso; Mollica, Luca; Donini, Stefano; Semrau, Marta S; Lucarelli, Anna Paola; Aiolfi, Egidio; Cavalli, Andrea; Storici, Paola; Alfei, Silvana; Brullo, Chiara; Bruno, Olga; Parisini, Emilio

    2018-05-01

    Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure-activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone. Furthermore, we assessed the stability of the observed ligand conformations in the context of the intact enzyme using molecular dynamics simulations. The longer and more flexible ligands appear to be capable of forming contacts with the regulatory portion of the enzyme, thus possibly allowing some degree of selectivity between the different PDE4 isoforms.

  3. Comparison of preconditioned Krylov subspace iteration methods for PDE-constrained optimization problems

    Czech Academy of Sciences Publication Activity Database

    Axelsson, Owe; Farouq, S.; Neytcheva, M.

    2017-01-01

    Roč. 74, č. 1 (2017), s. 19-37 ISSN 1017-1398 Institutional support: RVO:68145535 Keywords : PDE-constrained optimization problems * finite elements * iterative solution methods * preconditioning Subject RIV: BA - General Mathematics OBOR OECD: Applied mathematics Impact factor: 1.241, year: 2016 https://link.springer.com/article/10.1007%2Fs11075-016-0136-5

  4. Using system theory and energy methods to prove existence of non-linear PDE's

    NARCIS (Netherlands)

    Zwart, H.J.

    2015-01-01

    In this discussion paper we present an idea of combining techniques known from systems theory with energy estimates to show existence for a class of non-linear partial differential equations (PDE's). At the end of the paper a list of research questions with possible approaches is given.

  5. Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype.

    Science.gov (United States)

    Libé, Rossella; Horvath, Anelia; Vezzosi, Delphine; Fratticci, Amato; Coste, Joel; Perlemoine, Karine; Ragazzon, Bruno; Guillaud-Bataille, Marine; Groussin, Lionel; Clauser, Eric; Raffin-Sanson, Marie-Laure; Siegel, Jennifer; Moran, Jason; Drori-Herishanu, Limor; Faucz, Fabio Rueda; Lodish, Maya; Nesterova, Maria; Bertagna, Xavier; Bertherat, Jerome; Stratakis, Constantine A

    2011-01-01

    Carney complex (CNC) is an autosomal dominant multiple neoplasia, caused mostly by inactivating mutations of the regulatory subunit 1A of the protein kinase A (PRKAR1A). Primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine manifestation of CNC with a great inter-individual variability. Germline, protein-truncating mutations of phosphodiesterase type 11A (PDE11A) have been described to predispose to a variety of endocrine tumors, including adrenal and testicular tumors. Our objective was to investigate the role of PDE11A as a possible gene modifier of the phenotype in a series of 150 patients with CNC. A higher frequency of PDE11A variants in patients with CNC compared with healthy controls was found (25.3 vs. 6.8%, P CNC patients, those with PPNAD were significantly more frequently carriers of PDE11A variants compared with patients without PPNAD (30.8 vs. 13%, P = 0.025). Furthermore, men with PPNAD were significantly more frequently carriers of PDE11A sequence variants (40.7%) than women with PPNAD (27.3%) (P CNC patients, a high frequency of PDE11A variants, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation.

  6. The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices.

    Science.gov (United States)

    Kistemaker, Loes E M; Oenema, Tjitske A; Baarsma, Hoeke A; Bos, I Sophie T; Schmidt, Martina; Facchinetti, Fabrizio; Civelli, Maurizio; Villetti, Gino; Gosens, Reinoud

    2017-09-01

    Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 μM) or TGF-β 1 (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-β release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3-100 nM), whereas roflumilast (1 µM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1-30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-β 1 -induced remodeling, but rather, it inhibited methacholine-induced TGF-β release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-β release and bronchoconstriction. Copyright © 2017 the American Physiological Society.

  7. Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats.

    Directory of Open Access Journals (Sweden)

    Abdallah Ahnaou

    Full Text Available Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A and activation of metabotropic glutamate receptor (mGluR2 signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1 model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA antagonist phencyclidine (PCP; 2 confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3 evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not.

  8. Phosphodiesterase profile of human B lymphocytes from normal and atopic donors and the effects of PDE inhibition on B cell proliferation

    Science.gov (United States)

    Gantner, Florian; Götz, Christine; Gekeler, Volker; Schudt, Christian; Wendel, Albrecht; Hatzelmann, Armin

    1998-01-01

    CD19+ B lymphocytes were purified from the peripheral blood of normal and atopic subjects to analyse and compare the phosphodiesterase (PDE) activity profile, PDE mRNA expression and the importance of PDE activity for the regulation of B cell function.The majority of cyclic AMP hydrolyzing activity of human B cells was cytosolic PDE4, followed by cytosolic PDE7-like activity; marginal PDE3 activity was found only in the particulate B cell fraction. PDE1, PDE2 and PDE5 activities were not detected.By cDNA-PCR analysis mRNA of the PDE4 subtypes A, B (splice variant PDE4B2) and D were detected. In addition, a weak signal for PDE3A was found.No differences in PDE activities or mRNA expression of PDE subtypes were found in B cells from either normal or atopic subjects.Stimulation of B lymphocytes with the polyclonal stimulus lipopolysaccharide (LPS) induced a proliferative response in a time- and concentration-dependent manner, which was increased in the presence of interleukin-4 (IL-4). PDE4 inhibitors (rolipram, piclamilast) led to an increase in the cellular cyclic AMP concentration and to an augmentation of proliferation, whereas a PDE3 inhibitor (motapizone) was ineffective, which is in accordance with the PDE profile found. The proliferation enhancing effect of the PDE4 inhibitors was partly mimicked by the cyclic AMP analogues dibutyryl (db) cyclic AMP and 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole-3′,5′-cyclic monophosphorothioate, Sp-isomer (dcl-cBIMPS), respectively. However, at concentrations exceeding 100 μM db-cyclic AMP suppressed B lymphocyte proliferation, probably as a result of cytotoxicity. Prostaglandin E2 (PGE2, 1 μM) and forskolin (10 μM) did not affect B cell proliferation, even when given in combination with rolipram.Inhibition of protein kinase A (PKA) by differentially acting selective inhibitors (KT 5720, Rp-8-Br-cyclic AMPS) decreased the proliferative response of control cells and reversed the proliferation enhancing effects

  9. Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Tu Zhude [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States)], E-mail: tuz@mir.wustl.edu; Xu Jinbin; Jones, Lynne A.; Li Shihong; Mach, Robert H. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States)

    2010-05-15

    Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, a specific inhibitor of phosphodiesterase (PDE) 10A with IC{sub 50} values of 36 nM for PDE10A, 1,300 nM for PDE3A and 320 nM for PDE4D, has served as a useful pharmaceutical tool to study the physiological role of PDE10A. Here, we report the radiosynthesis of [{sup 11}C]papaverine and the in vitro and in vivo evaluation of [{sup 11}C]papaverine as a potential positron emission tomography (PET) radiotracer for imaging PDE10A in the central nervous system (CNS). The radiosynthesis of papaverine with {sup 11}C was achieved by O-methylation of the corresponding des-methyl precursor with [{sup 11}C]methyl iodide. [{sup 11}C]papaverine was obtained with {approx}70% radiochemical yield and a specific activity >10 Ci/{mu}mol. In vitro autoradiography studies of rat and monkey brain sections revealed selective binding of [{sup 11}C]papaverine to PDE10A enriched regions: the striatum of rat brain and the caudate and putamen of rhesus monkey brain. The biodistribution of [{sup 11}C]papaverine in rats at 5 min demonstrated an initially higher accumulation in striatum than in other brain regions, however the washout was rapid. MicroPET imaging studies in rhesus macaques similarly displayed initial specific uptake in the striatum with very rapid clearance of [{sup 11}C]papaverine from brain. Our initial evaluation suggests that despite papaverine's utility for in vitro studies and as a pharmaceutical tool, [{sup 11}C]papaverine is not an ideal radioligand for clinical imaging of PDE10A in the CNS. Analogs of papaverine having a higher potency for inhibiting PDE10A and improved pharmacokinetic properties will be necessary for imaging this enzyme with PET.

  10. Adaptive observer for the joint estimation of parameters and input for a coupled wave PDE and infinite dimensional ODE system

    KAUST Repository

    Belkhatir, Zehor; Mechhoud, Sarra; Laleg-Kirati, Taous-Meriem

    2016-01-01

    This paper deals with joint parameters and input estimation for coupled PDE-ODE system. The system consists of a damped wave equation and an infinite dimensional ODE. This model describes the spatiotemporal hemodynamic response in the brain

  11. Hyperprolactinemia contributes to reproductive deficit in male rats chronically administered PDE5 inhibitors (sildenafil and tadalafil and opioid (tramadol

    Directory of Open Access Journals (Sweden)

    V.U. Nna

    2016-09-01

    Conclusion: Serum prolactin concentration correlated negatively with male reproductive hormones and may play a major role in reproductive deficits associated with chronic use of PDE5 inhibitors and opioids.

  12. Effect of PVA and PDE on selected structural characteristics of extrusion-cooked starch foams

    Directory of Open Access Journals (Sweden)

    Maciej Combrzyński

    2018-03-01

    Full Text Available Abstract The aim of this work was to determine selected physical properties of biodegradable thermoplastic starch (TPS filling foams manufactured by extrusion-cooking technique from different combinations of potato starch and two additives: poly(vinyl alcohol PVA and Plastronfoam PDE. Foams were processed with seven starch/additives combinations at two different extruder-cooker’s screw rotational speeds. The densities of starch foams depended significantly on the additive type and content. The linear relationship between the Young modulus and the ultimate compression force and apparent density was found. The foams processed with the addition of PVA had low density, porosity and lower values of the Young modulus than the foams prepared with PDE.

  13. Plano de Desenvolvimento da Escola (PDE-Escola): ferramenta de autonomia escolar?

    OpenAIRE

    Schimonek, Elisangela Maria Pereira; Muranaka, Maria Aparecida Segatto

    2013-01-01

    Resumo O presente artigo objetiva promover uma análise da implantação do PDE-Escola em duas unidades educacionais do município de Limeira-SP, que apresentaram o IDEB/2007 abaixo da média nacional e que foram direcionadas a implantar o Programa a partir de 2009. O PDE-Escola trata-se de um programa do Governo Federal que se proclama capaz de viabilizar a autonomia, a obtenção de melhores resultados educacionais e a modernização da estrutura, organização e gestão escolar a partir da adoção d...

  14. PERSEPSI PENGOLAH DATA TERHADAP EFEKTIVITAS PDE HOTEL BERBINTANG DI KOTA DENPASAR

    Directory of Open Access Journals (Sweden)

    I KETUT SUWARTHA

    2010-07-01

    Full Text Available The development of information technology provides more expectations for the businessman, spesifically in the hotel sector. Nevertheless, in it’s implementation raise expectation gap between the user of the information and data processing in the Electronic Data Processing (PDE. The objective of this research is to find out the effectivity and dimension that should be improved on the side of data processing perception in the Electronic Data Processing (PDE of  star hotels  in Denpasar. The data collected by using questionnaire and interview and the data analysis technique used in this research is quantitative analysis technique. The conclusions from the analysis are (1 data processing perception included in the category of very effective by 81.64%, (2 there are three dimensions which needs more attention and improved, namely time dimension, report variation dimension or out put, information quality dimension.

  15. Mesh dependence in PDE-constrained optimisation an application in tidal turbine array layouts

    CERN Document Server

    Schwedes, Tobias; Funke, Simon W; Piggott, Matthew D

    2017-01-01

    This book provides an introduction to PDE-constrained optimisation using finite elements and the adjoint approach. The practical impact of the mathematical insights presented here are demonstrated using the realistic scenario of the optimal placement of marine power turbines, thereby illustrating the real-world relevance of best-practice Hilbert space aware approaches to PDE-constrained optimisation problems. Many optimisation problems that arise in a real-world context are constrained by partial differential equations (PDEs). That is, the system whose configuration is to be optimised follows physical laws given by PDEs. This book describes general Hilbert space formulations of optimisation algorithms, thereby facilitating optimisations whose controls are functions of space. It demonstrates the importance of methods that respect the Hilbert space structure of the problem by analysing the mathematical drawbacks of failing to do so. The approaches considered are illustrated using the optimisation problem arisin...

  16. FAST COMMUNICATION: A PDE Based Two Level Model of the Masking Property of the Human Ear

    OpenAIRE

    Xin, Jack; Qi, Yingyong

    2003-01-01

    Human ear has the masking property that certain audible sound becomes inaudible in the presence of another sound. Masking is quantified by the raised threshold from the absolute hearing threshold in quiet. It is of scientific and practical importance to compute masking thresholds. Empirical models on masking have applications in low bit rate digital music compression. A first principle based two level model is developed with partial differential equation (PDE) at the periphe...

  17. Improving Fiber Alignment in HARDI by Combining Contextual PDE Flow with Constrained Spherical Deconvolution.

    Directory of Open Access Journals (Sweden)

    J M Portegies

    Full Text Available We propose two strategies to improve the quality of tractography results computed from diffusion weighted magnetic resonance imaging (DW-MRI data. Both methods are based on the same PDE framework, defined in the coupled space of positions and orientations, associated with a stochastic process describing the enhancement of elongated structures while preserving crossing structures. In the first method we use the enhancement PDE for contextual regularization of a fiber orientation distribution (FOD that is obtained on individual voxels from high angular resolution diffusion imaging (HARDI data via constrained spherical deconvolution (CSD. Thereby we improve the FOD as input for subsequent tractography. Secondly, we introduce the fiber to bundle coherence (FBC, a measure for quantification of fiber alignment. The FBC is computed from a tractography result using the same PDE framework and provides a criterion for removing the spurious fibers. We validate the proposed combination of CSD and enhancement on phantom data and on human data, acquired with different scanning protocols. On the phantom data we find that PDE enhancements improve both local metrics and global metrics of tractography results, compared to CSD without enhancements. On the human data we show that the enhancements allow for a better reconstruction of crossing fiber bundles and they reduce the variability of the tractography output with respect to the acquisition parameters. Finally, we show that both the enhancement of the FODs and the use of the FBC measure on the tractography improve the stability with respect to different stochastic realizations of probabilistic tractography. This is shown in a clinical application: the reconstruction of the optic radiation for epilepsy surgery planning.

  18. Optimality conditions for the numerical solution of optimization problems with PDE constraints :

    Energy Technology Data Exchange (ETDEWEB)

    Aguilo Valentin, Miguel Alejandro; Ridzal, Denis

    2014-03-01

    A theoretical framework for the numerical solution of partial di erential equation (PDE) constrained optimization problems is presented in this report. This theoretical framework embodies the fundamental infrastructure required to e ciently implement and solve this class of problems. Detail derivations of the optimality conditions required to accurately solve several parameter identi cation and optimal control problems are also provided in this report. This will allow the reader to further understand how the theoretical abstraction presented in this report translates to the application.

  19. Boundary Control of Linear Uncertain 1-D Parabolic PDE Using Approximate Dynamic Programming.

    Science.gov (United States)

    Talaei, Behzad; Jagannathan, Sarangapani; Singler, John

    2018-04-01

    This paper develops a near optimal boundary control method for distributed parameter systems governed by uncertain linear 1-D parabolic partial differential equations (PDE) by using approximate dynamic programming. A quadratic surface integral is proposed to express the optimal cost functional for the infinite-dimensional state space. Accordingly, the Hamilton-Jacobi-Bellman (HJB) equation is formulated in the infinite-dimensional domain without using any model reduction. Subsequently, a neural network identifier is developed to estimate the unknown spatially varying coefficient in PDE dynamics. Novel tuning law is proposed to guarantee the boundedness of identifier approximation error in the PDE domain. A radial basis network (RBN) is subsequently proposed to generate an approximate solution for the optimal surface kernel function online. The tuning law for near optimal RBN weights is created, such that the HJB equation error is minimized while the dynamics are identified and closed-loop system remains stable. Ultimate boundedness (UB) of the closed-loop system is verified by using the Lyapunov theory. The performance of the proposed controller is successfully confirmed by simulation on an unstable diffusion-reaction process.

  20. [Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption].

    Science.gov (United States)

    Silva, Adauto Carvalho; Toffoletto, Odaly; Lucio, Luiz Antonio Galvão; Santos, Paula Ferreira Dos; Afiune, Jorge Barros; Massud Filho, João; Tufik, Sergio

    2010-02-01

    Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74% when drug intake was associated with alcohol. These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

  1. Repercussão cardiovascular, com e sem álcool, do carbonato de lodenafila, um novo inibidor da PDE5 Repercusión cardiovascular, con y sin alcohol, del carbonato de lodenafila, un nuevo inhibidor de la PDE5 Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption

    OpenAIRE

    Adauto Carvalho Silva; Odaly Toffoletto; Luiz Antonio Galvão Lucio; Paula Ferreira dos Santos; Jorge Barros Afiune; João Massud Filho; Sergio Tufik

    2010-01-01

    FUNDAMENTO: A disfunção erétil afeta um grande número de homens no mundo e os inibidores de PDE 5 (iPDE5) estão entre os principais métodos de tratamento desses pacientes. O consumo social de álcool e o ato sexual apresentam uma relação considerável. Portanto, a associação entre álcool e iPDE5 pode ocorrer. O carbonato de lodenafila é um novo iPDE5 desenvolvido por uma empresa brasileira. OBJETIVO: Avaliar a repercussão cardiovascular do carbonato de lodenafila, associado ou não ao álcool, as...

  2. Influence of the PDE5 inhibitor tadalafil on redox status and antioxidant defense system in C2C12 skeletal muscle cells.

    Science.gov (United States)

    Duranti, Guglielmo; Ceci, Roberta; Sgrò, Paolo; Sabatini, Stefania; Di Luigi, Luigi

    2017-05-01

    Phosphodiesterase type 5 inhibitors (PDE5Is), widely known for their beneficial effects onto male erectile dysfunction, seem to exert favorable effects onto metabolism as well. Tadalafil exposure increases oxidative metabolism of C2C12 skeletal muscle cells. A rise in fatty acid (FA) metabolism, requiring more oxygen, could induce a larger reactive oxygen species (ROS) release as a byproduct thus leading to a redox imbalance. The aim of this study was to determine how PDE5I tadalafil influences redox status in skeletal muscle cells to match the increasing oxidative metabolism. To this purpose, differentiated C2C12 skeletal muscle cells were treated with tadalafil and analyzed for total antioxidant capacity (TAC) and glutathione levels as marker of redox status; enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) engaged in antioxidant defense; and lipid peroxidation (TBARS) and protein carbonyls (PrCar) as markers of oxidative damage. Tadalafil increased total intracellular glutathione (tGSH), CAT, SOD, and GPx enzymatic activities while no changes were found in TAC. A perturbation of redox status, as showed by the decrease in the ratio between reduced/oxidized glutathione (GSH/GSSG), was observed. Nevertheless, it did not cause any change in TBARS and PrCar levels probably due to the enhancement in the antioxidant enzymatic network. Taken together, these data indicate that tadalafil, besides improving oxidative metabolism, may be beneficial to skeletal muscle cells by enhancing the enzymatic antioxidant system capacity.

  3. Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance.

    Science.gov (United States)

    Xia, Wenmin; Pessentheiner, Ariane R; Hofer, Dina C; Amor, Melina; Schreiber, Renate; Schoiswohl, Gabriele; Eichmann, Thomas O; Walenta, Evelyn; Itariu, Bianca; Prager, Gerhard; Hackl, Hubert; Stulnig, Thomas; Kratky, Dagmar; Rülicke, Thomas; Bogner-Strauss, Juliane G

    2018-05-15

    Elevated circulating fatty acids (FAs) contribute to obesity-associated metabolic complications, but the mechanisms by which insulin suppresses lipolysis are poorly understood. We show that α/β-hydrolase domain-containing 15 (ABHD15) is required for the anti-lipolytic action of insulin in white adipose tissue (WAT). Neither insulin nor glucose treatments can suppress FA mobilization in global and conditional Abhd15-knockout (KO) mice. Accordingly, insulin signaling is impaired in Abhd15-KO adipocytes, as indicated by reduced AKT phosphorylation, glucose uptake, and de novo lipogenesis. In vitro data reveal that ABHD15 associates with and stabilizes phosphodiesterase 3B (PDE3B). Accordingly, PDE3B expression is decreased in the WAT of Abhd15-KO mice, mechanistically explaining increased protein kinase A (PKA) activity, hormone-sensitive lipase (HSL) phosphorylation, and undiminished FA release upon insulin signaling. Ultimately, Abhd15-KO mice develop insulin resistance. Notably, ABHD15 expression is decreased in humans with obesity and diabetes compared to humans with obesity and normal glucose tolerance, identifying ABHD15 as a potential therapeutic target to mitigate insulin resistance. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Phosphodiesterase (PDE5) inhibition assay for rapid detection of erectile dysfunction drugs and analogs in sexual enhancement products.

    Science.gov (United States)

    Santillo, Michael F; Mapa, Mapa S T

    2018-02-28

    Products marketed as dietary supplements for sexual enhancement are frequently adulterated with phosphodiesterase-5 (PDE5) inhibitors, which are erectile dysfunction drugs or their analogs that can cause adverse health effects. Due to widespread adulteration, a rapid screening assay was developed to detect PDE5 inhibitors in adulterated products. The assay employs fluorescence detection and is based on measuring inhibition of PDE5 activity, the pharmacological mechanism shared among the adulterants. Initially, the assay reaction scheme was established and characterized, followed by analysis of 9 representative PDE5 inhibitors (IC 50 , 0.4-4.0 ng mL -1 ), demonstrating sensitive detection in matrix-free solutions. Next, dietary supplements serving as matrix blanks (n = 25) were analyzed to determine matrix interference and establish a threshold value; there were no false positives. Finally, matrix blanks were spiked with 9 individual PDE5 inhibitors, along with several mixtures. All 9 adulterants were successfully detected (≤ 5 % false negative rate; n = 20) at a concentration of 1.00 mg g -1 , which is over 5 times lower than concentrations commonly encountered in adulterated products. A major distinction of the PDE5 inhibition assay is the ability to detect adulterants without prior knowledge of their chemical structures, demonstrating a broad-based detection capability that can address a continuously evolving threat of new adulterants. The PDE5 inhibition assay can analyze over 40 samples simultaneously within 15 minutes and involves a single incubation step and simple data analysis, all of which are advantageous for combating the widespread adulteration of sex-enhancement products. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

  5. Linderane Suppresses Hepatic Gluconeogenesis by Inhibiting the cAMP/PKA/CREB Pathway Through Indirect Activation of PDE 3 via ERK/STAT3

    Directory of Open Access Journals (Sweden)

    Wei Xie

    2018-05-01

    Full Text Available The role of phosphodiesterase 3 (PDE3, a cyclic AMP (cAMP-degrading enzyme, in modulating gluconeogenesis remains unknown. Here, linderane, a natural compound, was found to inhibit gluconeogenesis by activating hepatic PDE3 in rat primary hepatocytes. The underlying molecular mechanism and its effects on whole-body glucose and lipid metabolism were investigated. The effect of linderane on gluconeogenesis, cAMP content, phosphorylation of cAMP-response element-binding protein (CREB and PDE activity were examined in cultured primary hepatocytes and C57BL/6J mice. The precise mechanism by which linderane activates PDE3 and inhibits the cAMP pathway was explored using pharmacological inhibitors. The amelioration of metabolic disorders was observed in ob/ob mice. Linderane inhibited gluconeogenesis, reduced phosphoenolpyruvate carboxykinase (Pck1 and glucose-6-phosphatase (G6pc gene expression, and decreased intracellular cAMP concentration and CREB phosphorylation in rat primary hepatocytes under both basal and forskolin-stimulated conditions. In rat primary hepatocytes, it also increased total PDE and PDE3 activity but not PDE4 activity. The suppressive effect of linderane on the cAMP pathway and gluconeogenesis was abolished by the non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX and the specific PDE3 inhibitor cilostazol. Linderane indirectly activated PDE3 through extracellular regulated protein kinase 1/2 (ERK1/2 and signal transducer and activator of transcription 3 (STAT3 activation. Linderane improved glucose and lipid metabolism after chronic oral administration in ob/ob mice. Our findings revealed linderane as an indirect PDE3 activator that suppresses gluconeogenesis through cAMP pathway inhibition and has beneficial effects on metabolic syndromes in ob/ob mice. This investigation highlighted the potential for PDE3 activation in the treatment of type 2 diabetes.

  6. Notes on a PDE system for biological network formation

    KAUST Repository

    Haskovec, Jan

    2016-01-22

    We present new analytical and numerical results for the elliptic–parabolic system of partial differential equations proposed by Hu and Cai, which models the formation of biological transport networks. The model describes the pressure field using a Darcy’s type equation and the dynamics of the conductance network under pressure force effects. Randomness in the material structure is represented by a linear diffusion term and conductance relaxation by an algebraic decay term. The analytical part extends the results of Haskovec et al. (2015) regarding the existence of weak and mild solutions to the whole range of meaningful relaxation exponents. Moreover, we prove finite time extinction or break-down of solutions in the spatially one-dimensional setting for certain ranges of the relaxation exponent. We also construct stationary solutions for the case of vanishing diffusion and critical value of the relaxation exponent, using a variational formulation and a penalty method. The analytical part is complemented by extensive numerical simulations. We propose a discretization based on mixed finite elements and study the qualitative properties of network structures for various parameter values. Furthermore, we indicate numerically that some analytical results proved for the spatially one-dimensional setting are likely to be valid also in several space dimensions.

  7. A numerical investigation into the ability of the Poisson PDE to extract the mass-density from land-based gravity data: A case study of salt diapirs in the north coast of the Persian Gulf

    Science.gov (United States)

    AllahTavakoli, Yahya; Safari, Abdolreza

    2017-08-01

    This paper is counted as a numerical investigation into the capability of Poisson's Partial Differential Equation (PDE) at Earth's surface to extract the near-surface mass-density from land-based gravity data. For this purpose, first it focuses on approximating the gradient tensor of Earth's gravitational potential by means of land-based gravity data. Then, based on the concepts of both the gradient tensor and Poisson's PDE at the Earth's surface, certain formulae are proposed for the mass-density determination. Furthermore, this paper shows how the generalized Tikhonov regularization strategy can be used for enhancing the efficiency of the proposed approach. Finally, in a real case study, the formulae are applied to 6350 gravity stations located within a part of the north coast of the Persian Gulf. The case study numerically indicates that the proposed formulae, provided by Poisson's PDE, has the ability to convert land-based gravity data into the terrain mass-density which has been used for depicting areas of salt diapirs in the region of the case study.

  8. Exploring pyrazolo[3,4-d]pyrimidine phosphodiesterase 1 (PDE1) inhibitors: a predictive approach combining comparative validated multiple molecular modelling techniques.

    Science.gov (United States)

    Amin, Sk Abdul; Bhargava, Sonam; Adhikari, Nilanjan; Gayen, Shovanlal; Jha, Tarun

    2018-02-01

    Phosphodiesterase 1 (PDE1) is a potential target for a number of neurodegenerative disorders such as Schizophrenia, Parkinson's and Alzheimer's diseases. A number of pyrazolo[3,4-d]pyrimidine PDE1 inhibitors were subjected to different molecular modelling techniques [such as regression-based quantitative structure-activity relationship (QSAR): multiple linear regression, support vector machine and artificial neural network; classification-based QSAR: Bayesian modelling and Recursive partitioning; Monte Carlo based QSAR; Open3DQSAR; pharmacophore mapping and molecular docking analyses] to get a detailed knowledge about the physicochemical and structural requirements for higher inhibitory activity. The planarity of the pyrimidinone ring plays an important role for PDE1 inhibition. The N-methylated function at the 5th position of the pyrazolo[3,4-d]pyrimidine core is required for interacting with the PDE1 enzyme. The cyclopentyl ring fused with the parent scaffold is necessary for PDE1 binding potency. The phenylamino substitution at 3rd position is crucial for PDE1 inhibition. The N2-substitution at the pyrazole moiety is important for PDE1 inhibition compared to the N1-substituted analogues. Moreover, the p-substituted benzyl side chain at N2-position helps to enhance the PDE1 inhibitory profile. Depending on these observations, some new molecules are predicted that may possess better PDE1 inhibition.

  9. TO BE OR NOT TO BE: AN INFORMATIVE NON-SYMBOLIC NUMERICAL MAGNITUDE PROCESSING STUDY ABOUT SMALL VERSUS LARGE NUMBERS IN INFANTS

    Directory of Open Access Journals (Sweden)

    Annelies CEULEMANS

    2014-03-01

    Full Text Available Many studies tested the association between numerical magnitude processing and mathematical achievement with conflicting findings reported for individuals with mathematical learning disorders. Some of the inconsistencies might be explained by the number of non-symbolic stimuli or dot collections used in studies. It has been hypothesized that there is an object-file system for ‘small’ and an analogue magnitude system for ‘large’ numbers. This two-system account has been supported by the set size limit of the object-file system (three items. A boundary was defined, accordingly, categorizing numbers below four as ‘small’ and from four and above as ‘large’. However, data on ‘small’ number processing and on the ‘boundary’ between small and large numbers are missing. In this contribution we provide data from infants discriminating between the number sets 4 vs. 8 and 1 vs. 4, both containing the number four combined with a small and a large number respectively. Participants were 25 and 26 full term 9-month-olds for 4 vs. 8 and 1 vs. 4 respectively. The stimuli (dots were controlled for continuous variables. Eye-tracking was combined with the habituation paradigm. The results showed that the infants were successful in discriminating 1 from 4, but failed to discriminate 4 from 8 dots. This finding supports the assumption of the number four as a ‘small’ number and enlarges the object-file system’s limit. This study might help to explain inconsistencies in studies. Moreover, the information may be useful in answering parent’s questions about challenges that vulnerable children with number processing problems, such as children with mathematical learning disorders, might encounter. In addition, the study might give some information on the stimuli that can be used to effectively foster children’s magnitude processing skills.

  10. Collocation methods for uncertainty quanti cation in PDE models with random data

    KAUST Repository

    Nobile, Fabio

    2014-01-06

    In this talk we consider Partial Differential Equations (PDEs) whose input data are modeled as random fields to account for their intrinsic variability or our lack of knowledge. After parametrizing the input random fields by finitely many independent random variables, we exploit the high regularity of the solution of the PDE as a function of the input random variables and consider sparse polynomial approximations in probability (Polynomial Chaos expansion) by collocation methods. We first address interpolatory approximations where the PDE is solved on a sparse grid of Gauss points in the probability space and the solutions thus obtained interpolated by multivariate polynomials. We present recent results on optimized sparse grids in which the selection of points is based on a knapsack approach and relies on sharp estimates of the decay of the coefficients of the polynomial chaos expansion of the solution. Secondly, we consider regression approaches where the PDE is evaluated on randomly chosen points in the probability space and a polynomial approximation constructed by the least square method. We present recent theoretical results on the stability and optimality of the approximation under suitable conditions between the number of sampling points and the dimension of the polynomial space. In particular, we show that for uniform random variables, the number of sampling point has to scale quadratically with the dimension of the polynomial space to maintain the stability and optimality of the approximation. Numerical results show that such condition is sharp in the monovariate case but seems to be over-constraining in higher dimensions. The regression technique seems therefore to be attractive in higher dimensions.

  11. A homotopy analysis method for the option pricing PDE in illiquid markets

    Science.gov (United States)

    E-Khatib, Youssef

    2012-09-01

    One of the shortcomings of the Black and Scholes model on option pricing is the assumption that trading the underlying asset does not affect the underlying asset price. This can happen in perfectly liquid markets and it is evidently not viable in markets with imperfect liquidity (illiquid markets). It is well-known that markets with imperfect liquidity are more realistic. Thus, the presence of price impact while studying options is very important. This paper investigates a solution for the option pricing PDE in illiquid markets using the homotopy analysis method.

  12. Alternating Direction Implicit (ADI) schemes for a PDE-based image osmosis model

    Science.gov (United States)

    Calatroni, L.; Estatico, C.; Garibaldi, N.; Parisotto, S.

    2017-10-01

    We consider Alternating Direction Implicit (ADI) splitting schemes to compute efficiently the numerical solution of the PDE osmosis model considered by Weickert et al. in [10] for several imaging applications. The discretised scheme is shown to preserve analogous properties to the continuous model. The dimensional splitting strategy traduces numerically into the solution of simple tridiagonal systems for which standard matrix factorisation techniques can be used to improve upon the performance of classical implicit methods, even for large time steps. Applications to the shadow removal problem are presented.

  13. Key role of phosphodiesterase 4A (PDE4A) in autophagy triggered by yessotoxin

    International Nuclear Information System (INIS)

    Fernández-Araujo, A.; Alfonso, A.; Vieytes, M.R.; Botana, L.M.

    2015-01-01

    Highlights: • YTX activates autophagic cell death after 48 h of treatment. • After 24 h of YTX incubation, the autophagic LC3B expression is increased. • High LC3B levels after 24 h can be related with extrinsic apoptosis activated by YTX. • PDEA4 plays a key role in the autophagy activation. - Abstract: Understanding the mechanism of action of the yessotoxin (YTX) is crucial since this drug has potential pharmacological effects in allergic processes, tumor proliferation and neurodegenerative diseases. It has been described that YTX activates apoptosis after 24 h of treatment, while after 48 h of incubation with the toxin a decrease in cell viability corresponding to cellular differentiation or non-apoptotic cell death was observed. In this paper, these processes were extensively studied by using the erythroleukemia K-562 cell line. On one hand, events of K-562 cell differentiation into erythrocytes after YTX treatment were studied using hemin as positive control of cell differentiation. Cell differentiation was studied through the cyclic nucleotide response element binding (phospho-CREB) and the transferrin receptor (TfR) expression. On the other hand, using rapamycin as positive control, autophagic hallmarks, as non-apoptotic cell death, were studied after toxin exposure. In this case, the mechanistic target of rapamycin (mTOR) and light chain 3B (LC3B) levels were measured to check autophagy activation. The results showed that cell differentiation was not occurring after 48 h of toxin incubation while at this time the autophagy was triggered. Furthermore after 24 h of toxin treatment none of these processes were activated. In addition, the role of the type 4A phosphodiesterase (PDE4A), the intracellular target of YTX, was checked. PDE4A-silencing experiments showed different regulation steps of PDE4A in the autophagic processes triggered either by traditional compounds or YTX. In summary, after 48 h YTX treatment PDE4A-dependent autophagy, as non

  14. Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.

    Science.gov (United States)

    Chino, Ayaka; Masuda, Naoyuki; Amano, Yasushi; Honbou, Kazuya; Mihara, Takuma; Yamazaki, Mayako; Tomishima, Masaki

    2014-07-01

    In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition. Copyright © 2014. Published by Elsevier Ltd.

  15. Law of large numbers and central limit theorem for randomly forced PDE's

    CERN Document Server

    Shirikyan, A

    2004-01-01

    We consider a class of dissipative PDE's perturbed by an external random force. Under the condition that the distribution of perturbation is sufficiently non-degenerate, a strong law of large numbers (SLLN) and a central limit theorem (CLT) for solutions are established and the corresponding rates of convergence are estimated. It is also shown that the estimates obtained are close to being optimal. The proofs are based on the property of exponential mixing for the problem in question and some abstract SLLN and CLT for mixing-type Markov processes.

  16. Association study of PDE4B gene variants in Scandinavian schizophrenia and bipolar disorder multicenter case-control samples

    DEFF Research Database (Denmark)

    Kähler, Anna K; Otnæss, Mona K; Wirgenes, Katrine V

    2010-01-01

    The phosphodiesterase 4B (PDE4B), which is involved in cognitive function in animal models, is a candidate susceptibility gene for schizophrenia (SZ) and bipolar disorder (BP). Variations in PDE4B have previously been associated with SZ, with a suggested gender-specific effect. We have genotyped......SNPs were nominally associated (0.0005 gender-specific subgroups. None of these findings remained significant after correction for multiple testing. However, a number of tagSNPs found to be nominally associated with SZ and BP...... were located in a high LD region spanning the splice site of PDE4B3, an isoform with altered brain expression in BP patients. Four tagSNPs were associated with SZ in women, but none in men, in agreement with the previously reported gender-specific effect. Proxies of two nominally associated SNPs...

  17. Modulation of oxazolone-induced hypersensitivity in mice by selective PDE inhibitors

    Directory of Open Access Journals (Sweden)

    I. Moodley

    1995-01-01

    Full Text Available The effects of PDE inhibitors on oxazolone-induced contact hypersensitivity (CS were studied in mice. Rolipram, Ro 20-1724 and theophylline dose dependently inhibited CS but none caused >53% inhibition. ED30 values at 24 h before challenge for rolipram, Ro 20-1724 and theophylline were 2.1, 5.4 and 30.4 mg/kg, p.o., respectively. Milrinone and SKF 94836 at 30 mg/kg caused a small, but significant inhibition of 13% and 18%, respectively, although the inhibition (8% caused by zaprinast was not significant. Betamethasone (10 mg/kg, p.o. caused a marked inhibition (80% as did indomethacin (65% at 5 mg/kg, p.o.. Rolipram and Ro 20-1724 inhibited proliferation of mouse lymphoblasts with IC50 values of 0.08 μM and 0.83 μM, respectively. In contrast, zaprinast caused only a weak inhibition (IC50 = 119 μM of lymphocyte proliferation, whereas SKF 94836 and theophylline failed to cause any significant inhibition at 100 μM (26% and 2%, respectively. These findings suggest that PDE IV isozymes play a principal role in mediating CS by inhibiting lymphocyte activation.

  18. Numerical Methods for Pricing American Options with Time-Fractional PDE Models

    Directory of Open Access Journals (Sweden)

    Zhiqiang Zhou

    2016-01-01

    Full Text Available In this paper we develop a Laplace transform method and a finite difference method for solving American option pricing problem when the change of the option price with time is considered as a fractal transmission system. In this scenario, the option price is governed by a time-fractional partial differential equation (PDE with free boundary. The Laplace transform method is applied to the time-fractional PDE. It then leads to a nonlinear equation for the free boundary (i.e., optimal early exercise boundary function in Laplace space. After numerically finding the solution of the nonlinear equation, the Laplace inversion is used to transform the approximate early exercise boundary into the time space. Finally the approximate price of the American option is obtained. A boundary-searching finite difference method is also proposed to solve the free-boundary time-fractional PDEs for pricing the American options. Numerical examples are carried out to compare the Laplace approach with the finite difference method and it is confirmed that the former approach is much faster than the latter one.

  19. Output Feedback-Based Boundary Control of Uncertain Coupled Semilinear Parabolic PDE Using Neurodynamic Programming.

    Science.gov (United States)

    Talaei, Behzad; Jagannathan, Sarangapani; Singler, John

    2018-04-01

    In this paper, neurodynamic programming-based output feedback boundary control of distributed parameter systems governed by uncertain coupled semilinear parabolic partial differential equations (PDEs) under Neumann or Dirichlet boundary control conditions is introduced. First, Hamilton-Jacobi-Bellman (HJB) equation is formulated in the original PDE domain and the optimal control policy is derived using the value functional as the solution of the HJB equation. Subsequently, a novel observer is developed to estimate the system states given the uncertain nonlinearity in PDE dynamics and measured outputs. Consequently, the suboptimal boundary control policy is obtained by forward-in-time estimation of the value functional using a neural network (NN)-based online approximator and estimated state vector obtained from the NN observer. Novel adaptive tuning laws in continuous time are proposed for learning the value functional online to satisfy the HJB equation along system trajectories while ensuring the closed-loop stability. Local uniformly ultimate boundedness of the closed-loop system is verified by using Lyapunov theory. The performance of the proposed controller is verified via simulation on an unstable coupled diffusion reaction process.

  20. Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

    Science.gov (United States)

    Susuki-Miyata, Seiko; Miyata, Masanori; Lee, Byung-Cheol; Xu, Haidong; Kai, Hirofumi; Yan, Chen; Li, Jian-Dong

    2015-01-01

    Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of PDE4B up-regulation, which could be counterproductive for suppressing inflammation. Thus, understanding how PDE4B is up-regulated in the context of the complex pathogenesis and medications of COPD may help improve the efficacy and possibly ameliorate the tolerance of roflumilast. Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae (NTHi), a major bacterial cause of COPD exacerbation, to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo. Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners. We also found that protein kinase A catalytic subunit β (PKA-Cβ) and nuclear factor-κB (NF-κB) p65 subunit were required for the synergistic induction of PDE4B2. PKA-Cβ phosphorylates p65 in a cAMP-dependent manner. Moreover, Ser276 of p65 is critical for mediating the PKA-Cβ–induced p65 phosphorylation and the synergistic induction of PDE4B2. Collectively, our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of PDE4 inhibitor. PMID:25831493

  1. Solving large-scale PDE-constrained Bayesian inverse problems with Riemann manifold Hamiltonian Monte Carlo

    Science.gov (United States)

    Bui-Thanh, T.; Girolami, M.

    2014-11-01

    We consider the Riemann manifold Hamiltonian Monte Carlo (RMHMC) method for solving statistical inverse problems governed by partial differential equations (PDEs). The Bayesian framework is employed to cast the inverse problem into the task of statistical inference whose solution is the posterior distribution in infinite dimensional parameter space conditional upon observation data and Gaussian prior measure. We discretize both the likelihood and the prior using the H1-conforming finite element method together with a matrix transfer technique. The power of the RMHMC method is that it exploits the geometric structure induced by the PDE constraints of the underlying inverse problem. Consequently, each RMHMC posterior sample is almost uncorrelated/independent from the others providing statistically efficient Markov chain simulation. However this statistical efficiency comes at a computational cost. This motivates us to consider computationally more efficient strategies for RMHMC. At the heart of our construction is the fact that for Gaussian error structures the Fisher information matrix coincides with the Gauss-Newton Hessian. We exploit this fact in considering a computationally simplified RMHMC method combining state-of-the-art adjoint techniques and the superiority of the RMHMC method. Specifically, we first form the Gauss-Newton Hessian at the maximum a posteriori point and then use it as a fixed constant metric tensor throughout RMHMC simulation. This eliminates the need for the computationally costly differential geometric Christoffel symbols, which in turn greatly reduces computational effort at a corresponding loss of sampling efficiency. We further reduce the cost of forming the Fisher information matrix by using a low rank approximation via a randomized singular value decomposition technique. This is efficient since a small number of Hessian-vector products are required. The Hessian-vector product in turn requires only two extra PDE solves using the adjoint

  2. PDE7B is a novel, prognostically significant mediator of glioblastoma growth whose expression is regulated by endothelial cells.

    Directory of Open Access Journals (Sweden)

    Michael D Brooks

    Full Text Available Cell-cell interactions between tumor cells and constituents of their microenvironment are critical determinants of tumor tissue biology and therapeutic responses. Interactions between glioblastoma (GBM cells and endothelial cells (ECs establish a purported cancer stem cell niche. We hypothesized that genes regulated by these interactions would be important, particularly as therapeutic targets. Using a computational approach, we deconvoluted expression data from a mixed physical co-culture of GBM cells and ECs and identified a previously undescribed upregulation of the cAMP specific phosphodiesterase PDE7B in GBM cells in response to direct contact with ECs. We further found that elevated PDE7B expression occurs in most GBM cases and has a negative effect on survival. PDE7B overexpression resulted in the expansion of a stem-like cell subpopulation in vitro and increased tumor growth and aggressiveness in an in vivo intracranial GBM model. Collectively these studies illustrate a novel approach for studying cell-cell interactions and identifying new therapeutic targets like PDE7B in GBM.

  3. Immunohistochemical distribution of cAMP- and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate

    NARCIS (Netherlands)

    Uckert, Stefan; Oelke, Matthias; Stief, Christian G.; Andersson, K.-E.; Jonas, Udo; Hedlund, Petter

    2006-01-01

    With the introduction of sildenafil citrate (Viagra), the concept of phosphodiesterase (PDE) inhibition has gained tremendous interest in the field of urology. Cyclic nucleotide second messengers cGMP and cAMP have been assumed to be involved in the control of the normal function of the prostate.

  4. New PDE-based methods for image enhancement using SOM and Bayesian inference in various discretization schemes

    International Nuclear Information System (INIS)

    Karras, D A; Mertzios, G B

    2009-01-01

    A novel approach is presented in this paper for improving anisotropic diffusion PDE models, based on the Perona–Malik equation. A solution is proposed from an engineering perspective to adaptively estimate the parameters of the regularizing function in this equation. The goal of such a new adaptive diffusion scheme is to better preserve edges when the anisotropic diffusion PDE models are applied to image enhancement tasks. The proposed adaptive parameter estimation in the anisotropic diffusion PDE model involves self-organizing maps and Bayesian inference to define edge probabilities accurately. The proposed modifications attempt to capture not only simple edges but also difficult textural edges and incorporate their probability in the anisotropic diffusion model. In the context of the application of PDE models to image processing such adaptive schemes are closely related to the discrete image representation problem and the investigation of more suitable discretization algorithms using constraints derived from image processing theory. The proposed adaptive anisotropic diffusion model illustrates these concepts when it is numerically approximated by various discretization schemes in a database of magnetic resonance images (MRI), where it is shown to be efficient in image filtering and restoration applications

  5. Structure-Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Novel PDE10 Inhibitors with Antioxidant Activities

    Science.gov (United States)

    Li, Jinxuan; Chen, Jing-Yi; Deng, Ya-Lin; Zhou, Qian; Wu, Yinuo; Wu, Deyan; Luo, Hai-Bin

    2018-05-01

    Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of thirteen designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

  6. Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

    Science.gov (United States)

    Goto, Taiji; Shiina, Akiko; Yoshino, Toshiharu; Mizukami, Kiyoshi; Hirahara, Kazuki; Suzuki, Osamu; Sogawa, Yoshitaka; Takahashi, Tomoko; Mikkaichi, Tsuyoshi; Nakao, Naoki; Takahashi, Mizuki; Hasegawa, Masashi; Sasaki, Shigeki

    2013-11-15

    5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.). Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. A Phase I clinical trial of lodenafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, in healthy male volunteers.

    Science.gov (United States)

    Mendes, Gustavo D; dos Santos Filho, Hilton Oliveira; dos Santos Pereira, Alberto; Mendes, Fabiana D; Ilha, Jaime O; Alkharfy, Khalid M; De Nucci, Gilberto

    2012-12-01

    Lodenafil carbonate is a new phosphodiesterase Type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 - 100 mg) single oral doses to healthy male volunteers (n = 33). The study was an open label, dose-escalation, Phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg - 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16, 20 and 24 h post-dosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements, clinical and laboratory exams and ECG revealed no significant changes even at higher doses. Lodenafil carbonate was not detected in any samples, indicating that it acts as a prodrug. The mean lodenafil pharmacokinetic parameters for tmax and t1/2 were 1.6 ( ± 0.4) h and 3.3 ( ± 1.1) h, respectively. This study demonstrated that lodenafil carbonate was well tolerated and showed a good safety profile in healthy male volunteers.

  8. Involvement of NO-cGMP pathway in anti-hyperalgesic effect of PDE5 inhibitor tadalafil in experimental hyperalgesia.

    Science.gov (United States)

    Otari, K V; Upasani, C D

    2015-08-01

    The association of elevated level of cyclic guanosine monophosphate (cGMP) with inhibition of hyperalgesia and involvement of nitric oxide (NO)-cGMP pathway in the modulation of pain perception was previously reported. Phosphodiesterases 5 (PDE5) inhibitors, sildenafil and tadalafil (TAD) used in erectile dysfunction, are known to act via the NO-cGMP pathway. TAD exerts its action by increasing the levels of intracellular cGMP. Hence, the present study investigated the effect of TAD 5, 10, or 20 mg/kg, per os (p.o.) or L-NAME 20 mg/kg, intraperitoneally (i.p.) and TAD (20 mg/kg, p.o.) in carrageenan- and diabetes-induced hyperalgesia in rats using hot plate test at 55 ± 2 °C. In carrageenan- and diabetes-induced hyperalgesia, TAD (10 and 20 mg/kg, p.o.) significantly increased paw withdrawal latencies (PWLs) as compared to the control group. L-NAME significantly decreased PWLs as compared to the normal group and aggravated the hyperalgesia. Moreover, significant difference in PWLs of L-NAME and TAD 20 was evident. Co-administration of L-NAME (20 mg/kg) with TAD (20 mg/kg) showed significant difference in PWLs as compared to the TAD (20 mg/kg), indicating L-NAME reversed and antagonized TAD-induced anti-hyperalgesia. This suggested an important role of NO-cGMP pathway in TAD-induced anti-hyperalgesic effect.

  9. PdeH, a high-affinity cAMP phosphodiesterase, is a key regulator of asexual and pathogenic differentiation in Magnaporthe oryzae.

    Directory of Open Access Journals (Sweden)

    Ravikrishna Ramanujam

    2010-05-01

    Full Text Available Cyclic AMP-dependent pathways mediate the communication between external stimuli and the intracellular signaling machinery, thereby influencing important aspects of cellular growth, morphogenesis and differentiation. Crucial to proper function and robustness of these signaling cascades is the strict regulation and maintenance of intracellular levels of cAMP through a fine balance between biosynthesis (by adenylate cyclases and hydrolysis (by cAMP phosphodiesterases. We functionally characterized gene-deletion mutants of a high-affinity (PdeH and a low-affinity (PdeL cAMP phosphodiesterase in order to gain insights into the spatial and temporal regulation of cAMP signaling in the rice-blast fungus Magnaporthe oryzae. In contrast to the expendable PdeL function, the PdeH activity was found to be a key regulator of asexual and pathogenic development in M. oryzae. Loss of PdeH led to increased accumulation of intracellular cAMP during vegetative and infectious growth. Furthermore, the pdeHDelta showed enhanced conidiation (2-3 fold, precocious appressorial development, loss of surface dependency during pathogenesis, and highly reduced in planta growth and host colonization. A pdeHDelta pdeLDelta mutant showed reduced conidiation, exhibited dramatically increased (approximately 10 fold cAMP levels relative to the wild type, and was completely defective in virulence. Exogenous addition of 8-Br-cAMP to the wild type simulated the pdeHDelta defects in conidiation as well as in planta growth and development. While a fully functional GFP-PdeH was cytosolic but associated dynamically with the plasma membrane and vesicular compartments, the GFP-PdeL localized predominantly to the nucleus. Based on data from cAMP measurements and Real-Time RTPCR, we uncover a PdeH-dependent biphasic regulation of cAMP levels during early and late stages of appressorial development in M. oryzae. We propose that PdeH-mediated sustenance and dynamic regulation of cAMP signaling

  10. Image denoising: Learning the noise model via nonsmooth PDE-constrained optimization

    KAUST Repository

    Reyes, Juan Carlos De los; Schö nlieb, Carola-Bibiane

    2013-01-01

    We propose a nonsmooth PDE-constrained optimization approach for the determination of the correct noise model in total variation (TV) image denoising. An optimization problem for the determination of the weights corresponding to different types of noise distributions is stated and existence of an optimal solution is proved. A tailored regularization approach for the approximation of the optimal parameter values is proposed thereafter and its consistency studied. Additionally, the differentiability of the solution operator is proved and an optimality system characterizing the optimal solutions of each regularized problem is derived. The optimal parameter values are numerically computed by using a quasi-Newton method, together with semismooth Newton type algorithms for the solution of the TV-subproblems. © 2013 American Institute of Mathematical Sciences.

  11. A Generic High-performance GPU-based Library for PDE solvers

    DEFF Research Database (Denmark)

    Glimberg, Stefan Lemvig; Engsig-Karup, Allan Peter

    , the privilege of high-performance parallel computing is now in principle accessible for many scientific users, no matter their economic resources. Though being highly effective units, GPUs and parallel architectures in general, pose challenges for software developers to utilize their efficiency. Sequential...... legacy codes are not always easily parallelized and the time spent on conversion might not pay o in the end. We present a highly generic C++ library for fast assembling of partial differential equation (PDE) solvers, aiming at utilizing the computational resources of GPUs. The library requires a minimum...... of GPU computing knowledge, while still oering the possibility to customize user-specic solvers at kernel level if desired. Spatial dierential operators are based on matrix free exible order nite dierence approximations. These matrix free operators minimize both memory consumption and main memory access...

  12. Parallels between control PDE's (Partial Differential Equations) and systems of ODE's (Ordinary Differential Equations)

    Science.gov (United States)

    Hunt, L. R.; Villarreal, Ramiro

    1987-01-01

    System theorists understand that the same mathematical objects which determine controllability for nonlinear control systems of ordinary differential equations (ODEs) also determine hypoellipticity for linear partial differentail equations (PDEs). Moreover, almost any study of ODE systems begins with linear systems. It is remarkable that Hormander's paper on hypoellipticity of second order linear p.d.e.'s starts with equations due to Kolmogorov, which are shown to be analogous to the linear PDEs. Eigenvalue placement by state feedback for a controllable linear system can be paralleled for a Kolmogorov equation if an appropriate type of feedback is introduced. Results concerning transformations of nonlinear systems to linear systems are similar to results for transforming a linear PDE to a Kolmogorov equation.

  13. Simulation of ODE/PDE models with MATLAB, OCTAVE and SCILAB scientific and engineering applications

    CERN Document Server

    Vande Wouwer, Alain; Vilas, Carlos

    2014-01-01

    Simulation of ODE/PDE Models with MATLAB®, OCTAVE and SCILAB shows the reader how to exploit a fuller array of numerical methods for the analysis of complex scientific and engineering systems than is conventionally employed. The book is dedicated to numerical simulation of distributed parameter systems described by mixed systems of algebraic equations, ordinary differential equations (ODEs) and partial differential equations (PDEs). Special attention is paid to the numerical method of lines (MOL), a popular approach to the solution of time-dependent PDEs, which proceeds in two basic steps: spatial discretization and time integration. Besides conventional finite-difference and -element techniques, more advanced spatial-approximation methods are examined in some detail, including nonoscillatory schemes and adaptive-grid approaches. A MOL toolbox has been developed within MATLAB®/OCTAVE/SCILAB. In addition to a set of spatial approximations and time integrators, this toolbox includes a collection of applicatio...

  14. Image denoising: Learning the noise model via nonsmooth PDE-constrained optimization

    KAUST Repository

    Reyes, Juan Carlos De los

    2013-11-01

    We propose a nonsmooth PDE-constrained optimization approach for the determination of the correct noise model in total variation (TV) image denoising. An optimization problem for the determination of the weights corresponding to different types of noise distributions is stated and existence of an optimal solution is proved. A tailored regularization approach for the approximation of the optimal parameter values is proposed thereafter and its consistency studied. Additionally, the differentiability of the solution operator is proved and an optimality system characterizing the optimal solutions of each regularized problem is derived. The optimal parameter values are numerically computed by using a quasi-Newton method, together with semismooth Newton type algorithms for the solution of the TV-subproblems. © 2013 American Institute of Mathematical Sciences.

  15. Modeling and Simulation of High Dimensional Stochastic Multiscale PDE Systems at the Exascale

    Energy Technology Data Exchange (ETDEWEB)

    Kevrekidis, Ioannis [Princeton Univ., NJ (United States)

    2017-03-22

    The thrust of the proposal was to exploit modern data-mining tools in a way that will create a systematic, computer-assisted approach to the representation of random media -- and also to the representation of the solutions of an array of important physicochemical processes that take place in/on such media. A parsimonious representation/parametrization of the random media links directly (via uncertainty quantification tools) to good sampling of the distribution of random media realizations. It also links directly to modern multiscale computational algorithms (like the equation-free approach that has been developed in our group) and plays a crucial role in accelerating the scientific computation of solutions of nonlinear PDE models (deterministic or stochastic) in such media – both solutions in particular realizations of the random media, and estimation of the statistics of the solutions over multiple realizations (e.g. expectations).

  16. Partial regularity of weak solutions to a PDE system with cubic nonlinearity

    Science.gov (United States)

    Liu, Jian-Guo; Xu, Xiangsheng

    2018-04-01

    In this paper we investigate regularity properties of weak solutions to a PDE system that arises in the study of biological transport networks. The system consists of a possibly singular elliptic equation for the scalar pressure of the underlying biological network coupled to a diffusion equation for the conductance vector of the network. There are several different types of nonlinearities in the system. Of particular mathematical interest is a term that is a polynomial function of solutions and their partial derivatives and this polynomial function has degree three. That is, the system contains a cubic nonlinearity. Only weak solutions to the system have been shown to exist. The regularity theory for the system remains fundamentally incomplete. In particular, it is not known whether or not weak solutions develop singularities. In this paper we obtain a partial regularity theorem, which gives an estimate for the parabolic Hausdorff dimension of the set of possible singular points.

  17. Muscle MRS detects elevated PDE/ATP ratios prior to fatty infiltration in Becker muscular dystrophy.

    Science.gov (United States)

    Wokke, B H; Hooijmans, M T; van den Bergen, J C; Webb, A G; Verschuuren, J J; Kan, H E

    2014-11-01

    Becker muscular dystrophy (BMD) is characterized by progressive muscle weakness. Muscles show structural changes (fatty infiltration, fibrosis) and metabolic changes, both of which can be assessed using MRI and MRS. It is unknown at what stage of the disease process metabolic changes arise and how this might vary for different metabolites. In this study we assessed metabolic changes in skeletal muscles of Becker patients, both with and without fatty infiltration, quantified via Dixon MRI and (31) P MRS. MRI and (31) P MRS scans were obtained from 25 Becker patients and 14 healthy controls using a 7 T MR scanner. Five lower-leg muscles were individually assessed for fat and muscle metabolite levels. In the peroneus, soleus and anterior tibialis muscles with non-increased fat levels, PDE/ATP ratios were higher (P < 0.02) compared with controls, whereas in all muscles with increased fat levels PDE/ATP ratios were higher compared with healthy controls (P ≤ 0.05). The Pi /ATP ratio in the peroneus muscles was higher in muscles with increased fat fractions (P = 0.005), and the PCr/ATP ratio was lower in the anterior tibialis muscles with increased fat fractions (P = 0.005). There were no other significant changes in metabolites, but an increase in tissue pH was found in all muscles of the total group of BMD patients in comparison with healthy controls (P < 0.05). These findings suggest that (31) P MRS can be used to detect early changes in individual muscles of BMD patients, which are present before the onset of fatty infiltration. Copyright © 2014 John Wiley & Sons, Ltd.

  18. Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A).

    Science.gov (United States)

    Hu, Essa; Kunz, Roxanne K; Chen, Ning; Rumfelt, Shannon; Siegmund, Aaron; Andrews, Kristin; Chmait, Samer; Zhao, Sharon; Davis, Carl; Chen, Hang; Lester-Zeiner, Dianna; Ma, Ji; Biorn, Christopher; Shi, Jianxia; Porter, Amy; Treanor, James; Allen, Jennifer R

    2013-11-14

    Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.

  19. Use of the KlADH3 promoter for the quantitative production of the murine PDE5A isoforms in the yeast Kluyveromyces lactis.

    Science.gov (United States)

    Cardarelli, Silvia; Giorgi, Mauro; Naro, Fabio; Malatesta, Francesco; Biagioni, Stefano; Saliola, Michele

    2017-09-22

    Phosphodiesterases (PDE) are a superfamily of enzymes that hydrolyse cyclic nucleotides (cAMP/cGMP), signal molecules in transduction pathways regulating crucial aspects of cell life. PDEs regulate the intensity and duration of the cyclic nucleotides signal modulating the downstream biological effect. Due to this critical role associated with the extensive distribution and multiplicity of isozymes, the 11 mammalian families (PDE1 to PDE11) constitute key therapeutic targets. PDE5, one of these cGMP-specific hydrolysing families, is the molecular target of several well known drugs used to treat erectile dysfunction and pulmonary hypertension. Kluyveromyces lactis, one of the few yeasts capable of utilizing lactose, is an attractive host alternative to Saccharomyces cerevisiae for heterologous protein production. Here we established K. lactis as a powerful host for the quantitative production of the murine PDE5 isoforms. Using the promoter of the highly expressed KlADH3 gene, multicopy plasmids were engineered to produce the native and recombinant Mus musculus PDE5 in K. lactis. Yeast cells produced large amounts of the purified A1, A2 and A3 isoforms displaying K m , V max and Sildenafil inhibition values similar to those of the native murine enzymes. PDE5 whose yield was nearly 1 mg/g wet weight biomass for all three isozymes (30 mg/L culture), is well tolerated by K. lactis cells without major growth deficiencies and interferences with the endogenous cAMP/cGMP signal transduction pathways. To our knowledge, this is the first time that the entire PDE5 isozymes family containing both regulatory and catalytic domains has been produced at high levels in a heterologous eukaryotic organism. K. lactis has been shown to be a very promising host platform for large scale production of mammalian PDEs for biochemical and structural studies and for the development of new specific PDE inhibitors for therapeutic applications in many pathologies.

  20. Repercussão cardiovascular, com e sem álcool, do carbonato de lodenafila, um novo inibidor da PDE5

    OpenAIRE

    Silva, Adauto Carvalho; Toffoletto, Odaly; Lucio, Luiz Antonio Galvão; Santos, Paula Ferreira dos; Afiune, Jorge Barros; Massud Filho, João; Tufik, Sergio

    2010-01-01

    FUNDAMENTO: A disfunção erétil afeta um grande número de homens no mundo e os inibidores de PDE 5 (iPDE5) estão entre os principais métodos de tratamento desses pacientes. O consumo social de álcool e o ato sexual apresentam uma relação considerável. Portanto, a associação entre álcool e iPDE5 pode ocorrer. O carbonato de lodenafila é um novo iPDE5 desenvolvido por uma empresa brasileira. OBJETIVO: Avaliar a repercussão cardiovascular do carbonato de lodenafila, associado ou não ao álcool, as...

  1. Increase of Intracellular Cyclic AMP by PDE4 Inhibitors Affects HepG2 Cell Cycle Progression and Survival.

    Science.gov (United States)

    Massimi, Mara; Cardarelli, Silvia; Galli, Francesca; Giardi, Maria Federica; Ragusa, Federica; Panera, Nadia; Cinque, Benedetta; Cifone, Maria Grazia; Biagioni, Stefano; Giorgi, Mauro

    2017-06-01

    Type 4 cyclic nucleotide phosphodiesterases (PDE4) are major members of a superfamily of enzymes (PDE) involved in modulation of intracellular signaling mediated by cAMP. Broadly expressed in most human tissues and present in large amounts in the liver, PDEs have in the last decade been key therapeutic targets for several inflammatory diseases. Recently, a significant body of work has underscored their involvement in different kinds of cancer, but with no attention paid to liver cancer. The present study investigated the effects of two PDE4 inhibitors, rolipram and DC-TA-46, on the growth of human hepatoma HepG2 cells. Treatment with these inhibitors caused a marked increase of intracellular cAMP level and a dose- and time-dependent effect on cell growth. The concentrations of inhibitors that halved cell proliferation to about 50% were used for cell cycle experiments. Rolipram (10 μM) and DC-TA-46 (0.5 μM) produced a decrease of cyclin expression, in particular of cyclin A, as well as an increase in p21, p27 and p53, as evaluated by Western blot analysis. Changes in the intracellular localization of cyclin D1 were also observed after treatments. In addition, both inhibitors caused apoptosis, as demonstrated by an Annexin-V cytofluorimetric assay and analysis of caspase-3/7 activity. Results demonstrated that treatment with PDE4 inhibitors affected HepG2 cell cycle and survival, suggesting that they might be useful as potential adjuvant, chemotherapeutic or chemopreventive agents in hepatocellular carcinoma. J. Cell. Biochem. 118: 1401-1411, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. Pricing index-based catastrophe bonds: Part 1: Formulation and discretization issues using a numerical PDE approach

    Science.gov (United States)

    Unger, André J. A.

    2010-02-01

    This work is the first installment in a two-part series, and focuses on the development of a numerical PDE approach to price components of a Bermudan-style callable catastrophe (CAT) bond. The bond is based on two underlying stochastic variables; the PCS index which posts quarterly estimates of industry-wide hurricane losses as well as a single-factor CIR interest rate model for the three-month LIBOR. The aggregate PCS index is analogous to losses claimed under traditional reinsurance in that it is used to specify a reinsurance layer. The proposed CAT bond model contains a Bermudan-style call feature designed to allow the reinsurer to minimize their interest rate risk exposure on making substantial fixed coupon payments using capital from the reinsurance premium. Numerical PDE methods are the fundamental strategy for pricing early-exercise constraints, such as the Bermudan-style call feature, into contingent claim models. Therefore, the objective and unique contribution of this first installment in the two-part series is to develop a formulation and discretization strategy for the proposed CAT bond model utilizing a numerical PDE approach. Object-oriented code design is fundamental to the numerical methods used to aggregate the PCS index, and implement the call feature. Therefore, object-oriented design issues that relate specifically to the development of a numerical PDE approach for the component of the proposed CAT bond model that depends on the PCS index and LIBOR are described here. Formulation, numerical methods and code design issues that relate to aggregating the PCS index and introducing the call option are the subject of the companion paper.

  3. Closed-Form Formulas vs. PDE Based Numerical Solution for the FRAP Data Processing: Theoretical and Practical Comparison

    Czech Academy of Sciences Publication Activity Database

    Papáček, Š.; Macdonald, B.; Matonoha, Ctirad

    2017-01-01

    Roč. 73, č. 8 (2017), s. 1673-1683 ISSN 0898-1221 Grant - others:GA MŠk(CZ) ED2.1.00/01.0024; GA MŠk(CZ) LO1205 Institutional support: RVO:67985807 Keywords : fluorescence recovery after photobleaching (FRAP) * parameter estimation * sensitivity analysis * partial differential equation (PDE) Subject RIV: BA - General Mathematics OBOR OECD: Applied mathematics Impact factor: 1.531, year: 2016

  4. Comparison of preconditioned Krylov subspace iteration methods for PDE-constrained optimization problems - Poisson and convection-diffusion control

    Czech Academy of Sciences Publication Activity Database

    Axelsson, Owe; Farouq, S.; Neytcheva, M.

    2016-01-01

    Roč. 73, č. 3 (2016), s. 631-633 ISSN 1017-1398 R&D Projects: GA MŠk ED1.1.00/02.0070 Institutional support: RVO:68145535 Keywords : PDE-constrained optimization problems * finite elements * iterative solution methods Subject RIV: BA - General Mathematics Impact factor: 1.241, year: 2016 http://link.springer.com/article/10.1007%2Fs11075-016-0111-1

  5. Chronic Inhibition of PDE5 Limits Pro-Inflammatory Monocyte-Macrophage Polarization in Streptozotocin-Induced Diabetic Mice.

    Science.gov (United States)

    Venneri, Mary Anna; Giannetta, Elisa; Panio, Giuseppe; De Gaetano, Rita; Gianfrilli, Daniele; Pofi, Riccardo; Masciarelli, Silvia; Fazi, Francesco; Pellegrini, Manuela; Lenzi, Andrea; Naro, Fabio; Isidori, Andrea M

    2015-01-01

    Diabetes mellitus is characterized by changes in endothelial cells that alter monocyte recruitment, increase classic (M1-type) tissue macrophage infiltration and lead to self-sustained inflammation. Our and other groups recently showed that chronic inhibition of phosphodiesterase-5 (PDE5i) affects circulating cytokine levels in patients with diabetes; whether PDE5i also affects circulating monocytes and tissue inflammatory cell infiltration remains to be established. Using murine streptozotocin (STZ)-induced diabetes and in human vitro cell-cell adhesion models we show that chronic hyperglycemia induces changes in myeloid and endothelial cells that alter monocyte recruitment and lead to self-sustained inflammation. Continuous PDE5i with sildenafil (SILD) expanded tissue anti-inflammatory TIE2-expressing monocytes (TEMs), which are known to limit inflammation and promote tissue repair. Specifically, SILD: 1) normalizes the frequency of circulating pro-inflammatory monocytes triggered by hyperglycemia (53.7 ± 7.9% of CD11b+Gr-1+ cells in STZ vs. 30.4 ± 8.3% in STZ+SILD and 27.1 ± 1.6% in CTRL, PTEMs (30.9 ± 3.6% in STZ+SILD vs. 6.9 ± 2.7% in STZ, P TEMs are defective in chronic hyperglycemia and that SILD normalizes their levels by facilitating the shift from classic (M1-like) to alternative (M2-like)/TEM macrophage polarization. Restoration of tissue TEMs with PDE5i could represent an additional pharmacological tool to prevent end-organ diabetic complications.

  6. PDE4 inhibition reduces neointima formation and inhibits VCAM-1 expression and histone methylation in an Epac-dependent manner.

    Science.gov (United States)

    Lehrke, Michael; Kahles, Florian; Makowska, Anna; Tilstam, Pathricia V; Diebold, Sebastian; Marx, Judith; Stöhr, Robert; Hess, Katharina; Endorf, Elizabeth B; Bruemmer, Dennis; Marx, Nikolaus; Findeisen, Hannes M

    2015-04-01

    Phosphodiesterase 4 (PDE4) activity mediates cAMP-dependent smooth muscle cell (SMC) activation following vascular injury. In this study we have investigated the effects of specific PDE4 inhibition with roflumilast on SMC proliferation and inflammatory activation in vitro and neointima formation following guide wire-induced injury of the femoral artery in mice in vivo. In vitro, roflumilast did not affect SMC proliferation, but diminished TNF-α induced expression of the vascular cell adhesion molecule 1 (VCAM-1). Specific activation of the cAMP effector Epac, but not PKA activation mimicked the effects of roflumilast on VCAM-1 expression. Consistently, the reduction of VCAM-1 expression was rescued following inhibition of Epac. TNF-α induced NFκB p65 translocation and VCAM-1 promoter activity were not altered by roflumilast in SMCs. However, roflumilast treatment and Epac activation repressed the induction of the activating epigenetic histone mark H3K4me2 at the VCAM-1 promoter, while PKA activation showed no effect. Furthermore, HDAC inhibition blocked the inhibitory effect of roflumilast on VCAM-1 expression. Both, roflumilast and Epac activation reduced monocyte adhesion to SMCs in vitro. Finally, roflumilast treatment attenuated femoral artery intima-media ratio by more than 50% after 4weeks. In summary, PDE4 inhibition regulates VCAM-1 through a novel Epac-dependent mechanism, which involves regulatory epigenetic components and reduces neointima formation following vascular injury. PDE4 inhibition and Epac activation might represent novel approaches for the treatment of vascular diseases, including atherosclerosis and in-stent restenosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling.

    Science.gov (United States)

    Monterisi, Stefania; Lobo, Miguel J; Livie, Craig; Castle, John C; Weinberger, Michael; Baillie, George; Surdo, Nicoletta C; Musheshe, Nshunge; Stangherlin, Alessandra; Gottlieb, Eyal; Maizels, Rory; Bortolozzi, Mario; Micaroni, Massimo; Zaccolo, Manuela

    2017-05-02

    cAMP/PKA signalling is compartmentalised with tight spatial and temporal control of signal propagation underpinning specificity of response. The cAMP-degrading enzymes, phosphodiesterases (PDEs), localise to specific subcellular domains within which they control local cAMP levels and are key regulators of signal compartmentalisation. Several components of the cAMP/PKA cascade are located to different mitochondrial sub-compartments, suggesting the presence of multiple cAMP/PKA signalling domains within the organelle. The function and regulation of these domains remain largely unknown. Here, we describe a novel cAMP/PKA signalling domain localised at mitochondrial membranes and regulated by PDE2A2. Using pharmacological and genetic approaches combined with real-time FRET imaging and high resolution microscopy, we demonstrate that in rat cardiac myocytes and other cell types mitochondrial PDE2A2 regulates local cAMP levels and PKA-dependent phosphorylation of Drp1. We further demonstrate that inhibition of PDE2A, by enhancing the hormone-dependent cAMP response locally, affects mitochondria dynamics and protects from apoptotic cell death.

  8. PDE-Foam - a probability-density estimation method using self-adapting phase-space binning

    CERN Document Server

    Dannheim, Dominik; Voigt, Alexander; Grahn, Karl-Johan; Speckmayer, Peter

    2009-01-01

    Probability-Density Estimation (PDE) is a multivariate discrimination technique based on sampling signal and background densities defined by event samples from data or Monte-Carlo (MC) simulations in a multi-dimensional phase space. To efficiently use large event samples to estimate the probability density, a binary search tree (range searching) is used in the PDE-RS implementation. It is a generalisation of standard likelihood methods and a powerful classification tool for problems with highly non-linearly correlated observables. In this paper, we present an innovative improvement of the PDE method that uses a self-adapting binning method to divide the multi-dimensional phase space in a finite number of hyper-rectangles (cells). The binning algorithm adjusts the size and position of a predefined number of cells inside the multidimensional phase space, minimizing the variance of the signal and background densities inside the cells. The binned density information is stored in binary trees, allowing for a very ...

  9. Current drug therapy of patients with BPH-LUTS with the special emphasis on PDE5 inhibitors.

    Science.gov (United States)

    Kolontarev, Konstantin; Govorov, Alexander; Kasyan, George; Priymak, Diana; Pushkar, Dmitry

    2016-01-01

    Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptom (LUTS) development in men [1]. The intensity of the symptoms may vary from mild to severe, significantly affecting the quality of life. Erectile dysfunction (ED) is one of the most challenging issues in modern urology that significantly influences the quality of life in men worldwide. The objective of this literature review was to analyze the current drug therapies of patients with BPH-LUTS, with the special emphasis on PDE5 inhibitors. The authors searched the literature for the period from 2000 until 2015 in MEDLINE and PubMed. Twenty-three articles were selected based on their reliability. A detailed analysis of the selected papers was performed. Primary attention was given to articles describing the use of PDE5. Works describing the use of different groups of drugs in patients with BPH-LUTS were also selected. The current literature analysis suggests that the introduction of PDE5 inhibitors in clinical practice for the treatment of patients with BPH-LUTS will allow for significant expansion of the therapeutic options for the treatment of this disease.

  10. The pde2 gene of Saccharomyces cerevisiae is allelic to rca1 and encodes a phosphodiesterase which protects the cell from extracellular cAMP.

    Science.gov (United States)

    Wilson, R B; Renault, G; Jacquet, M; Tatchell, K

    1993-07-05

    The high affinity cAMP phosphodiesterase, encoded by PDE2, is an important component of the cAMP-dependent protein kinase signaling system in Saccharomyces cerevisiae. An unexpected phenotype of pde2 mutants is sensitivity to external cAMP. This trait has been found independently for rca1 mutants and has been used to monitor the effects of cAMP on several biological processes. We demonstrate here that RCA1 is identical to PDE2. Further analysis of the phenotype of pde2 deletions reveal that exogenously added cAMP results in an increase in the internal level of cAMP. This increase slows down the rate of cell division by increasing the length of the G1 phase of the cell cycle and leads to increased cell volume. Also, cells with a disrupted PDE2 gene previously arrested by nutrient starvation rapidly lose thermotolerance when incubated with exogenous cAMP. From these observations we propose that a role of the PDE2-encoded phosphodiesterase may be to help insulate the internal cAMP pools from the external environment. This protective role might also be important in other eukaryotic organisms where cAMP is a key second messenger.

  11. Development of a Scintillation Proximity Assay (SPA) Based, High Throughput Screening Feasible Method for the Identification of PDE12 Activity Modulators.

    Science.gov (United States)

    Mang, Samuel; Bucher, Hannes; Nickolaus, Peter

    2016-01-01

    The scintillation proximity assay (SPA) technology has been widely used to establish high throughput screens (HTS) for a range of targets in the pharmaceutical industry. PDE12 (aka. 2'- phosphodiesterase) has been published to participate in the degradation of oligoadenylates that are involved in the establishment of an antiviral state via the activation of ribonuclease L (RNAse-L). Degradation of oligoadenylates by PDE12 terminates these antiviral activities, leading to decreased resistance of cells for a variety of viral pathogens. Therefore inhibitors of PDE12 are discussed as antiviral therapy. Here we describe the use of the yttrium silicate SPA bead technology to assess inhibitory activity of compounds against PDE12 in a homogeneous, robust HTS feasible assay using tritiated adenosine-P-adenylate ([3H]ApA) as substrate. We found that the used [3H]ApA educt, was not able to bind to SPA beads, whereas the product [3H]AMP, as known before, was able to bind to SPA beads. This enables the measurement of PDE12 activity on [3H]ApA as a substrate using a wallac microbeta counter. This method describes a robust and high throughput capable format in terms of specificity, commonly used compound solvents, ease of detection and assay matrices. The method could facilitate the search for PDE12 inhibitors as antiviral compounds.

  12. Accelerated Optimization in the PDE Framework: Formulations for the Active Contour Case

    KAUST Repository

    Yezzi, Anthony; Sundaramoorthi, Ganesh

    2017-01-01

    Following the seminal work of Nesterov, accelerated optimization methods have been used to powerfully boost the performance of first-order, gradient-based parameter estimation in scenarios where second-order optimization strategies are either inapplicable or impractical. Not only does accelerated gradient descent converge considerably faster than traditional gradient descent, but it also performs a more robust local search of the parameter space by initially overshooting and then oscillating back as it settles into a final configuration, thereby selecting only local minimizers with a basis of attraction large enough to contain the initial overshoot. This behavior has made accelerated and stochastic gradient search methods particularly popular within the machine learning community. In their recent PNAS 2016 paper, Wibisono, Wilson, and Jordan demonstrate how a broad class of accelerated schemes can be cast in a variational framework formulated around the Bregman divergence, leading to continuum limit ODE's. We show how their formulation may be further extended to infinite dimension manifolds (starting here with the geometric space of curves and surfaces) by substituting the Bregman divergence with inner products on the tangent space and explicitly introducing a distributed mass model which evolves in conjunction with the object of interest during the optimization process. The co-evolving mass model, which is introduced purely for the sake of endowing the optimization with helpful dynamics, also links the resulting class of accelerated PDE based optimization schemes to fluid dynamical formulations of optimal mass transport.

  13. Accelerated Optimization in the PDE Framework: Formulations for the Active Contour Case

    KAUST Repository

    Yezzi, Anthony

    2017-11-27

    Following the seminal work of Nesterov, accelerated optimization methods have been used to powerfully boost the performance of first-order, gradient-based parameter estimation in scenarios where second-order optimization strategies are either inapplicable or impractical. Not only does accelerated gradient descent converge considerably faster than traditional gradient descent, but it also performs a more robust local search of the parameter space by initially overshooting and then oscillating back as it settles into a final configuration, thereby selecting only local minimizers with a basis of attraction large enough to contain the initial overshoot. This behavior has made accelerated and stochastic gradient search methods particularly popular within the machine learning community. In their recent PNAS 2016 paper, Wibisono, Wilson, and Jordan demonstrate how a broad class of accelerated schemes can be cast in a variational framework formulated around the Bregman divergence, leading to continuum limit ODE\\'s. We show how their formulation may be further extended to infinite dimension manifolds (starting here with the geometric space of curves and surfaces) by substituting the Bregman divergence with inner products on the tangent space and explicitly introducing a distributed mass model which evolves in conjunction with the object of interest during the optimization process. The co-evolving mass model, which is introduced purely for the sake of endowing the optimization with helpful dynamics, also links the resulting class of accelerated PDE based optimization schemes to fluid dynamical formulations of optimal mass transport.

  14. Lipolytic effect of a polyphenolic citrus dry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes. Mechanism of action by inhibition of cAMP-phosphodiesterase (PDE).

    Science.gov (United States)

    Dallas, Constantin; Gerbi, Alain; Tenca, Guillaume; Juchaux, Franck; Bernard, François-Xavier

    2008-10-01

    The present study investigated the lipolytic (break of fat stored) effect of a citrus-based polyphenolic dietary supplement (SINETROL) at human adipocytes (ex vivo), body fat (clinical) and biochemical levels (inhibition of phosphodiesterase). Free fatty acids (FFA) release was used as indicator of human adipocyte lipolysis and SINETROL activity has been compared with known lipolytic products (isoproterenol, theopylline and caffeine). SINETROL stimulated significantly the lipolytic activity in a range of 6 fold greater than the control. Moreover, SINETROL has 2.1 greater activity than guarana 12% caffeine while its content in caffeine is 3 times lower. Clinically, two groups of 10 volunteers with BMI relevant of overweight were compared during 4 and 12 weeks with 1.4 g/day SINETROL and placebo supplementation. In the SINETROL Group the body fat (%) decreased with a significant difference of 5.53% and 15.6% after 4 and 12 weeks, respectively, while the body weight (kg) decreased with a significant difference of 2.2 and 5.2 kg after 4 and 12 weeks, respectively. These observed effects are linked to SINETROL polyphenolic composition and its resulting synergistic activity. SINETROL is a potent inhibitor of cAMP-phosphodiesterase (PDE) (97%) compared to other purified compounds (cyanidin-3 glycoside, narangin, caffeine). These results suggest that SINETROL has a strong lipolytic effect mediated by cAMP-PDE inhibition. SINETROL may serve to prevent obesity by decreasing BMI.

  15. Phosphodiesterase-9 (PDE9) inhibition with BAY 73-6691 increases corpus cavernosum relaxations mediated by nitric oxide-cyclic GMP pathway in mice.

    Science.gov (United States)

    da Silva, F H; Pereira, M N; Franco-Penteado, C F; De Nucci, G; Antunes, E; Claudino, M A

    2013-01-01

    Phosphodiesterase-9 (PDE9) specifically hydrolyzes cyclic GMP, and was detected in human corpus cavernosum. However, no previous studies explored the selective PDE9 inhibition with BAY 73-6691 in corpus cavernosum relaxations. Therefore, this study aimed to characterize the PDE9 mRNA expression in mice corpus cavernosum, and investigate the effects of BAY 73-6691 in endothelium-dependent and -independent relaxations, along with the nitrergic corpus cavernosum relaxations. Male mice received daily gavage of BAY 73-6691 (or dimethylsulfoxide) at 3 mg kg(-1) per day for 21 days. Relaxant responses to acetylcholine (ACh), nitric oxide (NO) (as acidified sodium nitrite; NaNO2 solution), sildenafil and electrical-field stimulation (EFS) were obtained in corpus cavernosum in control and BAY 73-6691-treated mice. BAY 73-6691 was also added in vitro 30 min before construction of concentration-responses and frequency curves. PDE9A and PDE5 mRNA expression was detected in the mice corpus cavernosum in a similar manner. In vitro addition of BAY 73-6691 neither itself relaxed mice corpus cavernosum nor changed the NaNO2, sildenafil and EFS-induced relaxations. However, in mice treated chronically with BAY 73-6691, the potency (pEC50) values for ACh, NaNO2 and sildenafil were significantly greater compared with control group. The maximal responses (Emax) to NaNO2 and sildenafil were also significantly greater in BAY 73-6691-treated mice. BAY 73-6691 treatment also significantly increased the magnitude and duration of the nitrergic corpus cavernosum relaxations (8-32 Hz). In conclusion, murine corpus cavernosum expresses PDE9 mRNA. Prolonged PDE9 inhibition with BAY 73-6691 amplifies the NO-cGMP-mediated cavernosal responses, and may be of therapeutic value for erectile dysfunction.

  16. Dropout in the treatment of erectile dysfunction with PDE5: a study on predictors and a qualitative analysis of reasons for discontinuation.

    Science.gov (United States)

    Carvalheira, Ana A; Pereira, Nuno Monteiro; Maroco, João; Forjaz, Vera

    2012-09-01

    Phosphodiesterase type 5 inhibitors (PDE5) are currently the first line treatment for erectile dysfunction (ED). However, previous research shows that PDE5 treatments have high discontinuation rates. Understanding the reasons for discontinuing PDE5 will be necessary to optimize the response to treatment. The main goals were: (i) to analyze discontinuation rate of PDE5; (ii) to identify the discontinuation predictors; and (iii) to study the reasons for discontinuation using a qualitative methodology. The PDE5 discontinuation rates, predictors, and reasons for discontinuation treatment. A total of 327 men with clinical diagnosis for ED who had been treated with PDE5 were successfully interviewed by telephone, after giving their informed consent by snail mail. Telephone interviews, concerning their ongoing treatment, were carried out using a standardized questionnaire form with quantitative and qualitative items. Participation rate was 71.8%. Of the total sample, 160 men (48.9%) had discontinued PDE5 treatment. The discontinuation rate was higher among men with diabetes (73%) and in iatrogenic group (65%), and lower in venogenic etiology (38.7%). We differentiated three groups of men who discontinued treatment (i) during the first 3 months (55.1%); (ii) between 4 and 12 months (26.9%); and (iii) after a period of 12 months (18%). Qualitative analyses revealed diverse reasons for discontinuation: non-effectiveness of PDE5 (36.8%), psychological factors (e.g., anxiety, negative emotions, fears, concerns, dysfunctional beliefs) (17.5%), erection recovery (14.4%), and concerns about the cardiovascular safety of PDE5 (8.7%) were the most common. Older men and men whose partners were involved in the treatment, were less likely to discontinue treatment. Half the subjects discontinued medication. Mostly, there was a combination of factors that led to discontinuation: non-effectiveness and psychosocial factors appear to be the main reasons. Addressing those factors will allow

  17. The Person-Event Data Environment (PDE: Leveraging Big Data for Studies of Psychological Strengths in Soldiers

    Directory of Open Access Journals (Sweden)

    Loryana L. Vie

    2013-12-01

    Full Text Available The Department of Defense (DoD strives to efficiently manage the large volumes of administrative data collected and repurpose this information for research and analyses with policy implications. This need is especially present in the United States Army, which maintains numerous electronic databases with information on more than one million Active-Duty, Reserve, and National Guard soldiers, their family members, and Army civilian employees. The accumulation of vast amounts of digitized health, military service, and demographic data thus approaches, and may even exceed, traditional benchmarks for Big Data. Given the challenges of disseminating sensitive personal and health information, the Person-Event Data Environment (PDE was created to unify disparate Army and DoD databases in a secure cloud-based enclave. This electronic repository serves the ultimate goal of achieving cost efficiencies in psychological and healthcare studies and provides a platform for collaboration among diverse scientists. This paper provides an overview of the uses of the PDE to perform command surveillance and policy analysis for Army leadership. The paper highlights the confluence of both economic and behavioral science perspectives elucidating empirically-based studies examining relations between psychological assets, health, and healthcare utilization. Specific examples explore the role of psychological assets in major cost drivers such as medical expenditures both during deployment and stateside, drug use, attrition from basic training, and low reenlistment rates. Through creation of the PDE, the Army and scientific community can now capitalize on the vast amounts of personnel, financial, medical, training and education, deployment and security systems that influence Army-wide policies and procedures.

  18. A "Reverse-Schur" Approach to Optimization With Linear PDE Constraints: Application to Biomolecule Analysis and Design.

    Science.gov (United States)

    Bardhan, Jaydeep P; Altman, Michael D; Tidor, B; White, Jacob K

    2009-01-01

    We present a partial-differential-equation (PDE)-constrained approach for optimizing a molecule's electrostatic interactions with a target molecule. The approach, which we call reverse-Schur co-optimization, can be more than two orders of magnitude faster than the traditional approach to electrostatic optimization. The efficiency of the co-optimization approach may enhance the value of electrostatic optimization for ligand-design efforts-in such projects, it is often desirable to screen many candidate ligands for their viability, and the optimization of electrostatic interactions can improve ligand binding affinity and specificity. The theoretical basis for electrostatic optimization derives from linear-response theory, most commonly continuum models, and simple assumptions about molecular binding processes. Although the theory has been used successfully to study a wide variety of molecular binding events, its implications have not yet been fully explored, in part due to the computational expense associated with the optimization. The co-optimization algorithm achieves improved performance by solving the optimization and electrostatic simulation problems simultaneously, and is applicable to both unconstrained and constrained optimization problems. Reverse-Schur co-optimization resembles other well-known techniques for solving optimization problems with PDE constraints. Model problems as well as realistic examples validate the reverse-Schur method, and demonstrate that our technique and alternative PDE-constrained methods scale very favorably compared to the standard approach. Regularization, which ordinarily requires an explicit representation of the objective function, can be included using an approximate Hessian calculated using the new BIBEE/P (boundary-integral-based electrostatics estimation by preconditioning) method.

  19. A “Reverse-Schur” Approach to Optimization With Linear PDE Constraints: Application to Biomolecule Analysis and Design

    Science.gov (United States)

    Bardhan, Jaydeep P.; Altman, Michael D.

    2009-01-01

    We present a partial-differential-equation (PDE)-constrained approach for optimizing a molecule’s electrostatic interactions with a target molecule. The approach, which we call reverse-Schur co-optimization, can be more than two orders of magnitude faster than the traditional approach to electrostatic optimization. The efficiency of the co-optimization approach may enhance the value of electrostatic optimization for ligand-design efforts–in such projects, it is often desirable to screen many candidate ligands for their viability, and the optimization of electrostatic interactions can improve ligand binding affinity and specificity. The theoretical basis for electrostatic optimization derives from linear-response theory, most commonly continuum models, and simple assumptions about molecular binding processes. Although the theory has been used successfully to study a wide variety of molecular binding events, its implications have not yet been fully explored, in part due to the computational expense associated with the optimization. The co-optimization algorithm achieves improved performance by solving the optimization and electrostatic simulation problems simultaneously, and is applicable to both unconstrained and constrained optimization problems. Reverse-Schur co-optimization resembles other well-known techniques for solving optimization problems with PDE constraints. Model problems as well as realistic examples validate the reverse-Schur method, and demonstrate that our technique and alternative PDE-constrained methods scale very favorably compared to the standard approach. Regularization, which ordinarily requires an explicit representation of the objective function, can be included using an approximate Hessian calculated using the new BIBEE/P (boundary-integral-based electrostatics estimation by preconditioning) method. PMID:23055839

  20. Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family.

    Science.gov (United States)

    Hmani-Aifa, Mounira; Benzina, Zeineb; Zulfiqar, Fareeha; Dhouib, Houria; Shahzadi, Amber; Ghorbel, Abdelmonem; Rebaï, Ahmed; Söderkvist, Peter; Riazuddin, Sheikh; Kimberling, William J; Ayadi, Hammadi

    2009-04-01

    Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disorder. ARRP could be associated with extraocular manifestations that define specific syndromes such as Usher syndrome (USH) characterized by retinal degeneration and congenital hearing loss (HL). The USH type II (USH2) associates RP and mild-to-moderate HL with preserved vestibular function. At least three genes USH2A, the very large G-protein-coupled receptor, GPR98, and DFNB31 are responsible for USH2 syndrome. Here, we report on the segregation of non-syndromic ARRP and USH2 syndrome in a consanguineous Tunisian family, which was previously used to define USH2B locus. With regard to the co-occurrence of these two different pathologies, clinical and genetic reanalysis of the extended family showed (i) phenotypic heterogeneity within USH2 patients and (ii) excluded linkage to USH2B locus. Indeed, linkage analysis disclosed the cosegregation of the USH2 phenotype with the USH2C locus markers, D5S428 and D5S618, whereas the ARRP perfectly segregates with PDE6B flanking markers D4S3360 and D4S2930. Molecular analysis revealed two new missense mutations, p.Y6044C and p.W807R, occurring in GPR98 and PDE6B genes, respectively. In conclusion, our results show that the USH2B locus at chromosome 3p23-24.2 does not exist, and we therefore withdraw this locus designation. The combination of molecular findings for GPR98 and PDE6B genes enable us to explain the phenotypic heterogeneity and particularly the severe ocular affection first observed in one USH2 patient. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family.

  1. Adaptive observer for the joint estimation of parameters and input for a coupled wave PDE and infinite dimensional ODE system

    KAUST Repository

    Belkhatir, Zehor

    2016-08-05

    This paper deals with joint parameters and input estimation for coupled PDE-ODE system. The system consists of a damped wave equation and an infinite dimensional ODE. This model describes the spatiotemporal hemodynamic response in the brain and the objective is to characterize brain regions using functional Magnetic Resonance Imaging (fMRI) data. For this reason, we propose an adaptive estimator and prove the asymptotic convergence of the state, the unknown input and the unknown parameters. The proof is based on a Lyapunov approach combined with a priori identifiability assumptions. The performance of the proposed observer is illustrated through some simulation results.

  2. Chronic Inhibition of PDE5 Limits Pro-Inflammatory Monocyte-Macrophage Polarization in Streptozotocin-Induced Diabetic Mice.

    Directory of Open Access Journals (Sweden)

    Mary Anna Venneri

    Full Text Available Diabetes mellitus is characterized by changes in endothelial cells that alter monocyte recruitment, increase classic (M1-type tissue macrophage infiltration and lead to self-sustained inflammation. Our and other groups recently showed that chronic inhibition of phosphodiesterase-5 (PDE5i affects circulating cytokine levels in patients with diabetes; whether PDE5i also affects circulating monocytes and tissue inflammatory cell infiltration remains to be established. Using murine streptozotocin (STZ-induced diabetes and in human vitro cell-cell adhesion models we show that chronic hyperglycemia induces changes in myeloid and endothelial cells that alter monocyte recruitment and lead to self-sustained inflammation. Continuous PDE5i with sildenafil (SILD expanded tissue anti-inflammatory TIE2-expressing monocytes (TEMs, which are known to limit inflammation and promote tissue repair. Specifically, SILD: 1 normalizes the frequency of circulating pro-inflammatory monocytes triggered by hyperglycemia (53.7 ± 7.9% of CD11b+Gr-1+ cells in STZ vs. 30.4 ± 8.3% in STZ+SILD and 27.1 ± 1.6% in CTRL, P<0.01; 2 prevents STZ-induced tissue inflammatory infiltration (4-fold increase in F4/80+ macrophages in diabetic vs. control mice by increasing renal and heart anti-inflammatory TEMs (30.9 ± 3.6% in STZ+SILD vs. 6.9 ± 2.7% in STZ, P <0.01, and 11.6 ± 2.9% in CTRL mice; 3 reduces vascular inflammatory proteins (iNOS, COX2, VCAM-1 promoting tissue protection; 4 lowers monocyte adhesion to human endothelial cells in vitro through the TIE2 receptor. All these changes occurred independently from changes of glycemic status. In summary, we demonstrate that circulating renal and cardiac TEMs are defective in chronic hyperglycemia and that SILD normalizes their levels by facilitating the shift from classic (M1-like to alternative (M2-like/TEM macrophage polarization. Restoration of tissue TEMs with PDE5i could represent an additional pharmacological tool to prevent

  3. Decay Rates of Interactive Hyperbolic-Parabolic PDE Models with Thermal Effects on the Interface

    International Nuclear Information System (INIS)

    Lasiecka, I.; Lebiedzik, C.

    2000-01-01

    We consider coupled PDE systems comprising of a hyperbolic and a parabolic-like equation with an interface on a portion of the boundary. These models are motivated by structural acoustic problems. A specific prototype consists of a wave equation defined on a three-dimensional bounded domain Ω coupled with a thermoelastic plate equation defined on Γ 0 -a flat surface of the boundary Ω. Thus, the coupling between the wave and the plate takes place on the interface Γ 0 . The main issue studied here is that of uniform stability of the overall interactive model. Since the original (uncontrolled) model is only strongly stable, but not uniformly stable, the question becomes: what is the 'minimal amount' of dissipation necessary to obtain uniform decay rates for the energy of the overall system? Our main result states that boundary nonlinear dissipation placed only on a suitable portion of the part of the boundary which is complementary to Γ 0 , suffices for the stabilization of the entire structure. This result is new with respect to the literature on several accounts: (i) thermoelasticity is accounted for in the plate model; (ii) the plate model does not account for any type of mechanical damping, including the structural damping most often considered in the literature; (iii) there is no mechanical damping placed on the interface Γ 0 ; (iv) the boundary damping is nonlinear without a prescribed growth rate at the origin; (v) the undamped portions of the boundary partial Ω are subject to Neumann (rather than Dirichlet) boundary conditions, which is a recognized difficulty in the context of stabilization of wave equations, due to the fact that the strong Lopatinski condition does not hold. The main mathematical challenge is to show how the thermal energy is propagated onto the hyperbolic component of the structure. This is achieved by using a recently developed sharp theory of boundary traces corresponding to wave and plate equations, along with the analytic

  4. Combination of 2D/3D ligand-based similarity search in rapid virtual screening from multimillion compound repositories. Selection and biological evaluation of potential PDE4 and PDE5 inhibitors.

    Science.gov (United States)

    Dobi, Krisztina; Hajdú, István; Flachner, Beáta; Fabó, Gabriella; Szaszkó, Mária; Bognár, Melinda; Magyar, Csaba; Simon, István; Szisz, Dániel; Lőrincz, Zsolt; Cseh, Sándor; Dormán, György

    2014-05-28

    Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost effective approach. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compound databases but the generated library requires further focusing by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase of the hit rate from 8.5% (1st round, 47% inhibition at 10 µM) to 28.5% (2nd round at 50% inhibition at 10 µM) and the best two hits had 53 nM inhibitory activities.

  5. Repercussão cardiovascular, com e sem álcool, do carbonato de lodenafila, um novo inibidor da PDE5 Repercusión cardiovascular, con y sin alcohol, del carbonato de lodenafila, un nuevo inhibidor de la PDE5 Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption

    Directory of Open Access Journals (Sweden)

    Adauto Carvalho Silva

    2010-02-01

    Full Text Available FUNDAMENTO: A disfunção erétil afeta um grande número de homens no mundo e os inibidores de PDE 5 (iPDE5 estão entre os principais métodos de tratamento desses pacientes. O consumo social de álcool e o ato sexual apresentam uma relação considerável. Portanto, a associação entre álcool e iPDE5 pode ocorrer. O carbonato de lodenafila é um novo iPDE5 desenvolvido por uma empresa brasileira. OBJETIVO: Avaliar a repercussão cardiovascular do carbonato de lodenafila, associado ou não ao álcool, assim como as alterações na farmacocinética que esta associação possa determinar. MÉTODOS: Estudo realizado com 15 voluntários sadios que receberam em momentos diferentes o carbonato de lodenafila (CL na dose de 160 mg em jejum, CL (160 mg com álcool, ou somente placebo. Esses pacientes foram monitorados por 24 horas, sendo avaliado o quadro clínico, a pressão arterial (PA, a frequência cardíaca (FC, o intervalo QT e também os dados de farmacocinética. RESULTADOS: O carbonato de lodenafila, isoladamente ou associado com álcool, não determinou alterações clínicas significativas na PA ou FC, embora tenha ocorrido diminuição da PA estatisticamente significativa após 4 horas, nos voluntários que receberam medicamento e álcool, assim como um aumento da FC após 6 horas nos pacientes que receberam o CL. A análise do intervalo QT corrigido não mostrou alteração significativa. O álcool aumentou a biodisponibilidade do medicamento em 74%. Houve somente 2 queixas de cefaleia leve, possivelmente associada ao medicamento. CONCLUSÃO: O carbonato de lodenafila, mesmo associado ao álcool, não determinou repercussões clínicas importantes na PA, FC, ou alterações no intervalo QTc; a ingestão com álcool, por sua vez, aumentou significativamente sua biodisponibilidade.FUNDAMENTO: La disfunción eréctil afecta a un gran número de hombres en el mundo y los inhibidores de PDE5 (iPDE5 están entre los principales métodos de

  6. PKA and PDE4D3 anchoring to AKAP9 provides distinct regulation of cAMP signals at the centrosome

    Science.gov (United States)

    Terrin, Anna; Monterisi, Stefania; Stangherlin, Alessandra; Zoccarato, Anna; Koschinski, Andreas; Surdo, Nicoletta C.; Mongillo, Marco; Sawa, Akira; Jordanides, Niove E.; Mountford, Joanne C.

    2012-01-01

    Previous work has shown that the protein kinase A (PKA)–regulated phosphodiesterase (PDE) 4D3 binds to A kinase–anchoring proteins (AKAPs). One such protein, AKAP9, localizes to the centrosome. In this paper, we investigate whether a PKA–PDE4D3–AKAP9 complex can generate spatial compartmentalization of cyclic adenosine monophosphate (cAMP) signaling at the centrosome. Real-time imaging of fluorescence resonance energy transfer reporters shows that centrosomal PDE4D3 modulated a dynamic microdomain within which cAMP concentration selectively changed over the cell cycle. AKAP9-anchored, centrosomal PKA showed a reduced activation threshold as a consequence of increased autophosphorylation of its regulatory subunit at S114. Finally, disruption of the centrosomal cAMP microdomain by local displacement of PDE4D3 impaired cell cycle progression as a result of accumulation of cells in prophase. Our findings describe a novel mechanism of PKA activity regulation that relies on binding to AKAPs and consequent modulation of the enzyme activation threshold rather than on overall changes in cAMP levels. Further, we provide for the first time direct evidence that control of cell cycle progression relies on unique regulation of centrosomal cAMP/PKA signals. PMID:22908311

  7. Effect of PDE5 inhibition on the modulation of sympathetic α-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Piil, Peter Bergmann; Egelund, Jon

    2015-01-01

    Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not you...

  8. Investigation of a Putative Estrogen-Imprinting Gene, Phosphodiesterase Type IV Variant (Pde4d4), in Determining Prostate Cancer Risk

    Science.gov (United States)

    2008-04-01

    arrays. Methods Mol Biol 2002;200:87–100. [78] Craig JM, Kraus J, Cremer T. Removal of repetitive sequences from FISH probes using PCR-assisted affinity...Worcester, MA), David Hepps, MD, and Lynn Birch for technical contributions. Figure 5. Alterations in PDE4D4 CpG methylation and gene expression in NbE-1

  9. In Silico Investigations of Chemical Constituents of Clerodendrum colebrookianum in the Anti-Hypertensive Drug Targets: ROCK, ACE, and PDE5.

    Science.gov (United States)

    Arya, Hemant; Syed, Safiulla Basha; Singh, Sorokhaibam Sureshkumar; Ampasala, Dinakar R; Coumar, Mohane Selvaraj

    2017-06-16

    Understanding the molecular mode of action of natural product is a key step for developing drugs from them. In this regard, this study is aimed to understand the molecular-level interactions of chemical constituents of Clerodendrum colebrookianum Walp., with anti-hypertensive drug targets using computational approaches. The plant has ethno-medicinal importance for the treatment of hypertension and reported to show activity against anti-hypertensive drug targets-Rho-associated coiled-coil protein kinase (ROCK), angiotensin-converting enzyme, and phosphodiesterase 5 (PDE5). Docking studies showed that three chemical constituents (acteoside, martinoside, and osmanthuside β6) out of 21 reported from the plant to interact with the anti-hypertensive drug targets with good glide score. In addition, they formed H-bond interactions with the key residues Met156/Met157 of ROCK I/ROCK II and Gln817 of PDE5. Further, molecular dynamics (MD) simulation of protein-ligand complexes suggest that H-bond interactions between acteoside/osmanthuside β6 and Met156/Met157 (ROCK I/ROCK II), acteoside and Gln817 (PDE5) were stable. The present investigation suggests that the anti-hypertensive activity of the plant is due to the interaction of acteoside and osmanthuside β6 with ROCK and PDE5 drug targets. The identified molecular mode of binding of the plant constituents could help to design new drugs to treat hypertension.

  10. Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease

    Science.gov (United States)

    Su, Tao; Zhang, Tianhua; Xie, Shishun; Yan, Jun; Wu, Yinuo; Li, Xingshu; Huang, Ling; Luo, Hai-Bin

    2016-02-01

    Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer’s disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ1-42 aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu2+-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.

  11. Radiosynthesis and initial characterization of a PDE10A specific PET tracer [18 F]AMG 580 in non-human primates

    International Nuclear Information System (INIS)

    Hwang, Dah-Ren; Hu, Essa; Allen, Jennifer R.; Davis, Carl; Treanor, James; Miller, Silke; Chen, Hang; Shi, Bingzhi; Narayanan, Tanjorie K.; Barret, Olivier; Alagille, David; Yu, Zhigang; Slifstein, Mark

    2015-01-01

    Introduction: Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [ 18 F]AMG 580 and in vitro and in vivo characterization results. Methods: The potency and selectivity were determined by in vitro assay using [ 3 H]AMG 580 and baboon brain tissues. [ 18 F]AMG 580 was prepared by a 1-step [ 18 F]fluorination procedure. Dynamic brain PET scans were performed in non-human primates. Regions-of-interest were defined on individuals’ MRIs and transferred to the co-registered PET images. Data were analyzed using two tissue compartment analysis (2TC), Logan graphical (Logan) analysis with metabolite-corrected input function and the simplified reference tissue model (SRTM) method. A PDE10A inhibitor and unlabeled AMG 580 were used to demonstrate the PDE10A specificity. K D was estimated by Scatchard analysis of high and low affinity PET scans. Results: AMG 580 has an in vitro K D of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121 ± 18 MBq was used in PET studies. In Rhesus, the baseline BP ND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BP ND was observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24 mg/kg dose of AMG 580 resulted in about 70% decrease of BP ND . The in vivo K D of [ 18 F]AMG 580 was estimated to be around 0.44 nM in baboons. Conclusion: [ 18 F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans

  12. Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.

    Directory of Open Access Journals (Sweden)

    Carmela Giampà

    2010-10-01

    Full Text Available Huntington's disease is a devastating neurodegenerative condition for which there is no therapy to slow disease progression. The particular vulnerability of striatal medium spiny neurons to Huntington's pathology is hypothesized to result from transcriptional dysregulation within the cAMP and CREB signaling cascades in these neurons. To test this hypothesis, and a potential therapeutic approach, we investigated whether inhibition of the striatal-specific cyclic nucleotide phosphodiesterase PDE10A would alleviate neurological deficits and brain pathology in a highly utilized model system, the R6/2 mouse.R6/2 mice were treated with the highly selective PDE10A inhibitor TP-10 from 4 weeks of age until euthanasia. TP-10 treatment significantly reduced and delayed the development of the hind paw clasping response during tail suspension, deficits in rotarod performance, and decrease in locomotor activity in an open field. Treatment prolonged time to loss of righting reflex. These effects of PDE10A inhibition on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal and cortical cell loss, the formation of striatal neuronal intranuclear inclusions, and the degree of microglial activation that occurs in response to the mutant huntingtin-induced brain damage. Striatal and cortical levels of phosphorylated CREB and BDNF were significantly elevated.Our findings provide experimental support for targeting the cAMP and CREB signaling pathways and more broadly transcriptional dysregulation as a therapeutic approach to Huntington's disease. It is noteworthy that PDE10A inhibition in the R6/2 mice reduces striatal pathology, consistent with the localization of the enzyme in medium spiny neurons, and also cortical pathology and the formation of neuronal nuclear inclusions. These latter findings suggest that striatal pathology may be a primary driver of these secondary pathological events. More

  13. Development of two fluorine-18 labeled PET radioligands targeting PDE10A and in vivo PET evaluation in nonhuman primates.

    Science.gov (United States)

    Stepanov, Vladimir; Takano, Akihiro; Nakao, Ryuji; Amini, Nahid; Miura, Shotaro; Hasui, Tomoaki; Kimura, Haruhide; Taniguchi, Takahiko; Halldin, Christer

    2018-02-01

    Phosphodiesterase 10A (PDE10A) is a member of the PDE enzyme family that degrades cyclic adenosine and guanosine monophosphates (cAMP and cGMP). Based on the successful development of [ 11 C]T-773 as PDE10A positron emission tomography (PET) radioligand, in this study our aim was to develop and evaluate fluorine-18 analogs of [ 11 C]T-773. [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 were synthesized from the same precursor used for 11 C-labeling of T-773 in a two-step approach via 18 F-fluoromethylation and 18 F-fluoroethylation, respectively, using corresponding deuterated synthons. A total of 12 PET measurements were performed in seven non-human primates. First, baseline PET measurements were performed using High Resolution Research Tomograph system with both [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 ; the uptake in whole brain and separate brain regions, as well as the specific binding and tissue ratio between putamen and cerebellum, was examined. Second, baseline and pretreatment PET measurements using MP-10 as the blocker were performed for [ 18 F]FM-T-773-d 2 including arterial blood sampling with radiometabolite analysis in four NHPs. Both [ 18 F]FM-T-773-d 2 and [ 18 F]FE-T-773-d 4 were successfully radiolabeled with an average molar activity of 293 ± 114 GBq/μmol (n=8) for [ 18 F]FM-T-773-d 2 and 209 ± 26 GBq/μmol (n=4) for [ 18 F]FE-T-773-d 4 , and a radiochemical yield of 10% (EOB, n=12, range 3%-16%). Both radioligands displayed high brain uptake (~5.5% of injected radioactivity for [ 18 F]FM-T-773-d 2 and ~3.5% for [ 18 F]FE-T-773-d 4 at the peak) and a fast washout. Specific binding reached maximum within 30 min for [ 18 F]FM-T-773-d 2 and after approximately 45 min for [ 18 F]FE-T-773-d 4 . [ 18 F]FM-T-773-d 2 data fitted well with kinetic compartment models. BP ND values obtained indirectly through compartment models were correlated well with those obtained by SRTM. BP ND calculated with SRTM was 1.0-1.7 in the putamen. The occupancy with 1

  14. Moving-Horizon Modulating Functions-Based Algorithm for Online Source Estimation in a First Order Hyperbolic PDE

    KAUST Repository

    Asiri, Sharefa M.; Elmetennani, Shahrazed; Laleg-Kirati, Taous-Meriem

    2017-01-01

    In this paper, an on-line estimation algorithm of the source term in a first order hyperbolic PDE is proposed. This equation describes heat transport dynamics in concentrated solar collectors where the source term represents the received energy. This energy depends on the solar irradiance intensity and the collector characteristics affected by the environmental changes. Control strategies are usually used to enhance the efficiency of heat production; however, these strategies often depend on the source term which is highly affected by the external working conditions. Hence, efficient source estimation methods are required. The proposed algorithm is based on modulating functions method where a moving horizon strategy is introduced. Numerical results are provided to illustrate the performance of the proposed estimator in open and closed loops.

  15. Moving-Horizon Modulating Functions-Based Algorithm for Online Source Estimation in a First Order Hyperbolic PDE

    KAUST Repository

    Asiri, Sharefa M.

    2017-08-22

    In this paper, an on-line estimation algorithm of the source term in a first order hyperbolic PDE is proposed. This equation describes heat transport dynamics in concentrated solar collectors where the source term represents the received energy. This energy depends on the solar irradiance intensity and the collector characteristics affected by the environmental changes. Control strategies are usually used to enhance the efficiency of heat production; however, these strategies often depend on the source term which is highly affected by the external working conditions. Hence, efficient source estimation methods are required. The proposed algorithm is based on modulating functions method where a moving horizon strategy is introduced. Numerical results are provided to illustrate the performance of the proposed estimator in open and closed loops.

  16. The dynamics of p53 in single cells: physiologically based ODE and reaction–diffusion PDE models

    International Nuclear Information System (INIS)

    Eliaš, Ján; Clairambault, Jean; Dimitrio, Luna; Natalini, Roberto

    2014-01-01

    The intracellular signalling network of the p53 protein plays important roles in genome protection and the control of cell cycle phase transitions. Recently observed oscillatory behaviour in single cells under stress conditions has inspired several research groups to simulate and study the dynamics of the protein with the aim of gaining a proper understanding of the physiological meanings of the oscillations. We propose compartmental ODE and PDE models of p53 activation and regulation in single cells following DNA damage and we show that the p53 oscillations can be retrieved by plainly involving p53–Mdm2 and ATM–p53–Wip1 negative feedbacks, which are sufficient for oscillations experimentally, with no further need to introduce any delays into the protein responses and without considering additional positive feedback. (paper)

  17. GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses.

    Science.gov (United States)

    Bruno, O; Fedele, E; Prickaerts, J; Parker, L A; Canepa, E; Brullo, C; Cavallero, A; Gardella, E; Balbi, A; Domenicotti, C; Bollen, E; Gijselaers, H J M; Vanmierlo, T; Erb, K; Limebeer, C L; Argellati, F; Marinari, U M; Pronzato, M A; Ricciarelli, R

    2011-12-01

    Strategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3-cyclopentyloxy-4-methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR-7b, on memory performance, nausea, hippocampal cAMP and amyloid-β (Aβ) levels. To measure memory performance, we performed object recognition tests on rats and mice treated with GEBR-7b or rolipram. The emetic potential of the drug, again compared with rolipram, was evaluated in rats using the taste reactivity test and in mice using the xylazine/ketamine anaesthesia test. Extracellular hippocampal cAMP was evaluated by intracerebral microdialysis in freely moving rats. Levels of soluble Aβ peptides were measured in hippocampal tissues and cultured N2a cells by elisa. GEBR-7b increased hippocampal cAMP, did not influence Aβ levels and improved spatial, as well as object memory performance in the object recognition tests. The effect of GEBR-7b on memory was 3 to 10 times more potent than that of rolipram, and its effective doses had no effect on surrogate measures of emesis in rodents. Our results demonstrate that GEBR-7b enhances memory functions at doses that do not cause emesis-like behaviour in rodents, thus offering a promising pharmacological perspective for the treatment of memory impairment. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  18. On the deflagration-to-detonation transition (DDT) process with added energetic solid particles for pulse detonation engines (PDE)

    Science.gov (United States)

    Nguyen, V. B.; Li, J.; Chang, P.-H.; Phan, Q. T.; Teo, C. J.; Khoo, B. C.

    2018-01-01

    In this paper, numerical simulations are performed to study the dynamics of the deflagration-to-detonation transition (DDT) in pulse detonation engines (PDE) using energetic aluminum particles. The DDT process and detonation wave propagation toward the unburnt hydrogen/air mixture containing solid aluminum particles is numerically studied using the Eulerian-Lagrangian approach. A hybrid numerical methodology combined with appropriate sub-models is used to capture the gas dynamic characteristics, particle behavior, combustion characteristics, and two-way solid-particle-gas flow interactions. In our approach, the gas mixture is expressed in the Eulerian frame of reference, while the solid aluminum particles are tracked in the Lagrangian frame of reference. The implemented computer code is validated using published benchmark problems. The obtained results show that the aluminum particles not only shorten the DDT length but also reduce the DDT time. The improvement of DDT is primarily attributed to the heat released from surface chemical reactions on the aluminum particles. The temperatures associated with the DDT process are greater than the case of non-reacting particles added, with an accompanying rise in the pressure. For an appropriate range of particle volume fraction, particularly in this study, the higher volume fraction of the micro-aluminum particles added in the detonation chamber can lead to more heat energy released and more local instabilities in the combustion process (caused by the local high temperature), thereby resulting in a faster DDT process. In essence, the aluminum particles contribute to the DDT process of successfully transitioning to detonation waves for (failure) cases in which the fuel gas mixture can be either too lean or too rich. With a better understanding of the influence of added aluminum particles on the dynamics of the DDT and detonation process, we can apply it to modify the geometry of the detonation chamber (e.g., the length of

  19. Restoration of vision in the pde6β-deficient dog, a large animal model of rod-cone dystrophy.

    Science.gov (United States)

    Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

    2012-11-01

    Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment.

  20. Exercise training improves erectile dysfunction (ED) in patients with metabolic syndrome on phosphodiesterase-5 (PDE-5) inhibitors.

    Science.gov (United States)

    Maresca, Luigi; D'Agostino, Mariantonietta; Castaldo, Luigi; Vitelli, Alessandra; Mancini, Maria; Torella, Giorgio; Lucci, Rosa; Albano, Giovanna; Del Forno, Domenico; Ferro, Matteo; Altieri, Vincenzo; Giallauria, Francesco; Vigorito, Carlo

    2013-12-01

    Erectile dysfunction (ED) affects about 50% of males aged 40-70 years old. ED shares with atherosclerotic disease several common risk factors; therefore, it may be considered a surrogate marker of atherosclerosis. Since phosphodiesterase-5 inhibitors are well known pharmacologic agents capable of significant improvement in ED, we designed this study to evaluate whether exercise training is of added value in patients with ED who are already on PDE-5 inhibitors. We recruited 20 male patients affected by ED with metabolic syndrome. At baseline, all patients underwent Cardio-Pulmonary Exercise Testing (CPET) and the International Index of Erectile Function (IIEF) test. After the initial evaluation, patients were subdivided into two groups: tadalafil group (group T, n = 10), who were maintained only on tadalafil therapy, and a tadalafil/exercise training group (T/E group, n = 10) who continued tadalafil but in addition underwent a2-month structured exercise training program. Basal anthropometric characteristics of study population showed no significant differences. Although both-groups showed at 2 months an improvement of the IIEF score, this was more evident in the T/E group (T group: 11.2 vs 14.2, P = 0.02; T/E group: 10.8 vs 20.1, P exercise (VO(2peak)) only in the T/E group patients (T group: 13.63 +/- 2.03 vs 14.24 +/- 2.98 mL/kg/min; P = 0.521; T/E group: 13.41 +/- 2.97 vs 16.58 +/- 3.17 mL/kg/min; P = 0.006). A significant correlation was found between the changes in VO(2peak) and the modifications in IIEF score (r = 0.575; P = 0.001). Exercise training in ED patients treated with PDE-5 inhibitors is of added value since further improves ED, as evaluated by IIEF score, and increases functional capacity.

  1. The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents.

    Science.gov (United States)

    Gentzel, Renee C; Toolan, Dawn; Roberts, Rhonda; Koser, Amy Jo; Kandebo, Monika; Hershey, James; Renger, John J; Uslaner, Jason; Smith, Sean M

    2015-12-01

    Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor. Copyright © 2015. Published by Elsevier Ltd.

  2. PDE5 inhibitor treatment persistence and adherence in Brazilian men: post-hoc analyses from a 6-month, prospective, observational study.

    Science.gov (United States)

    Cairoli, Carlos; Reyes, Luis Antonio; Henneges, Carsten; Sorsaburu, Sebastian

    2014-01-01

    Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED). Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence. 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment.

  3. PDE5 Inhibitor Treatment Persistence and Adherence in Brazilian Men: Post-hoc Analyses from a 6-Month, Prospective, Observational Study

    Directory of Open Access Journals (Sweden)

    Carlos Cairoli

    2014-06-01

    Full Text Available Purpose Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED. Materials and Methods Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR Questionnaire, and International Index of Erectile Function (IIEF. Multivariate logistic regression was used to identify factors associated with persistence/adherence. Results 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%. The prescribed PDE5I was sildenafil citrate for 50 (48.1%, tadalafil for 36 (34.6%, vardenafil for 15 (14.4%, and lodenafil for 3 patients (2.9%. Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0% versus sildenafil or vardenafil (range 60.0% to 68.0%. Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. Conclusion Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment.

  4. Empirical Productivity Indices and Indicators

    NARCIS (Netherlands)

    B.M. Balk (Bert)

    2016-01-01

    textabstractThe empirical measurement of productivity change (or difference) by means of indices and indicators starts with the ex post profit/loss accounts of a production unit. Key concepts are profit, leading to indicators, and profitability, leading to indices. The main task for the productivity

  5. Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases.

    Science.gov (United States)

    Kalash, Leen; Val, Cristina; Azuaje, Jhonny; Loza, María I; Svensson, Fredrik; Zoufir, Azedine; Mervin, Lewis; Ladds, Graham; Brea, José; Glen, Robert; Sotelo, Eddy; Bender, Andreas

    2017-12-30

    Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A 1 and A 2A receptors (A 1 R and A 2A R) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A 1 and A 2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes. This approach has identified 2-aminopyridine-3-carbonitriles as the first multi-target ligands at A 1 R, A 2A R and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efficient one-pot scheme and validated pharmacologically as A 1 R/A 2A R-PDE10A ligands, with IC 50 values of 2.4-10.0 μM at PDE10A and K i values of 34-294 nM at A 1 R and/or A 2A R. Furthermore, selectivity profiling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested off-targets. In addition, both compounds 8 and 16 exhibited the desired multi-target profile, which could be considered for further functional efficacy assessment, analog modification for the improvement of selectivity towards A 1 R, A 2A R and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels.

  6. A 6 month, prospective, observational study of PDE5 inhibitor treatment persistence and adherence in Latin American men with erectile dysfunction.

    Science.gov (United States)

    Rubio-Aurioles, Eusebio; Reyes, Luis Antonio; Borregales, Leonardo; Cairoli, Carlos; Sorsaburu, Sebastian

    2013-06-01

    To assess persistence/adherence rates of phosphodiesterase type-5 inhibitor (PDE5I) on-demand dosing in Latin American men with erectile dysfunction (ED), and explore patient characteristics and treatment factors that may be predictive for PDE5I persistence and adherence. Men from Brazil, Mexico, and Venezuela with ED who were naïve to PDE5Is were prescribed sildenafil, tadalafil, vardenafil, or lodenafil on-demand dosing and asked to provide information about PDE5I use at baseline and at 1, 3, and 6 months. Patients were persistent if they used ≥1 dose during the 4 week period prior to each evaluation. Patients were adherent if they complied with dosing instructions during most recent dose. Main outcome measures included Persistence and Adherence Questionnaire (PAQ), Partner Relationship Questionnaire (PRQ), Self-Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence and adherence. A total of 511 men were enrolled; most had mild to moderate ED (77.1%); 317 patients (62.0%) were prescribed tadalafil, 116 (22.7%) sildenafil, 75 (14.7%) vardenafil, and 3 (0.6%) lodenafil (not further analyzed). A total of 340 patients (66.5%) were 'persistent' at 6 months; 345 (67.5%) were 'adherent'. Persistence and adherence were associated with age, education level, and ED duration. Reasons for non-persistence included medication cost and lack of efficacy. Study limitations included its design, brief observation period, its bias observed toward tadalafil selection; its dependence on patient self-reporting, limited number of factors that were analyzed for persistence/adherence association, its small number of participating patients and Latin American countries, and inherent differences in PDE5I preference and medical practices. Approximately two-thirds of PDE5I-naïve, Latin American men with ED were persistent and adherent after 6 months of

  7. Waste indicators

    Energy Technology Data Exchange (ETDEWEB)

    Dall, O.; Lassen, C.; Hansen, E. [Cowi A/S, Lyngby (Denmark)

    2003-07-01

    The Waste Indicator Project focuses on methods to evaluate the efficiency of waste management. The project proposes the use of three indicators for resource consumption, primary energy and landfill requirements, based on the life-cycle principles applied in the EDIP Project. Trial runs are made With the indicators on paper, glass packaging and aluminium, and two models are identified for mapping the Danish waste management, of which the least extensive focuses on real and potential savings. (au)

  8. Waste indicators

    International Nuclear Information System (INIS)

    Dall, O.; Lassen, C.; Hansen, E.

    2003-01-01

    The Waste Indicator Project focuses on methods to evaluate the efficiency of waste management. The project proposes the use of three indicators for resource consumption, primary energy and landfill requirements, based on the life-cycle principles applied in the EDIP Project. Trial runs are made With the indicators on paper, glass packaging and aluminium, and two models are identified for mapping the Danish waste management, of which the least extensive focuses on real and potential savings. (au)

  9. Quality indicators

    DEFF Research Database (Denmark)

    Hjorth-Andersen, Christian

    1991-01-01

    In recent literature it has been suggested that consumers need have no knowledge of product quality as a number of quality indicators (or signals) may be used as substitutes. Very little attention has been paid to the empirical verification of these studies. The present paper is devoted...... to the issue of how well these indicators perform, using market data provided by consumer magazines from 3 countries. The results strongly indicate that price is a poor quality indicator. The paper also presents some evidence which suggests that seller reputation and easily observable characteristics are also...

  10. General indicators

    International Nuclear Information System (INIS)

    2003-01-01

    This document summarizes the main 2002 energy indicators for France. A first table lists the evolution of general indicators between 1973 and 2002: energy bill, price of imported crude oil, energy independence, primary and final energy consumption. The main 2002 results are detailed separately for natural gas, petroleum and coal (consumption, imports, exports, production, stocks, prices). (J.S.)

  11. Phenotypic Variability in a Family with Acrodysostosis Type 2 Caused by a Novel PDE4D Mutation Affecting the Serine Target of Protein Kinase-A Phosphorylation

    Science.gov (United States)

    Hoppmann, Julia; Gesing, Julia; Silve, Caroline; Leroy, Chrystel; Bertsche, Astrid; Hirsch, Franz Wolfgang; Kiess, Wieland; Pfäffle, Roland; Schuster, Volker

    2017-01-01

    Acrodysostosis is a very rare congenital multisystem condition characterized by skeletal dysplasia with severe brachydactyly, midfacial hypoplasia, and short stature, varying degrees of intellectual disability, and possible resistance to multiple G protein-coupled receptor signalling hormones. Two distinct subtypes are differentiated: acrodysostosis type 1 resulting from defects in protein kinase type 1-α regulatory subunit and acrodysostosis type 2 caused by mutations in phosphodiesterase 4D (PDE4D). Most cases are sporadic. We report on a rare multigenerational familial case of acrodysostosis type 2 due to a novel autosomal dominantly inherited PDE4D mutation. A 3.5-year-old boy presented with short stature, midfacial hypoplasia, severe brachydactyly, developmental delay, and behavioural problems. Laboratory investigations revealed mild thyrotropin resistance. His mother shared some characteristic features, such as midfacial hypoplasia and severe brachydactyly, but did not show short stature, intellectual disability or hormonal resistance. Genetic analysis identified the identical, novel heterozygous missense mutation of the PDE4D gene c.569C>T (p.Ser190Phe) in both patients. This case illustrates the significant phenotypic variability of acrodysostosis even within one family with identical mutations. Hence, a specific clinical diagnosis of acrodysostosis remains challenging because of great interindividual variability and a substantial overlap of the two subtypes as well as with other related Gsα-cAMP-signalling-linked disorders. PMID:28515031

  12. Assessment of sperm quality, oxidative stress injury as well as ACP, AC and PDE expression in patients with oligoasthenozoospermia before and after qilin pill treatment

    Directory of Open Access Journals (Sweden)

    Shi-Jun Zhang

    2016-09-01

    Full Text Available Objective: To analyze the sperm quality, oxidative stress injury as well as ACP, AC and PDE expression in patients with oligoasthenozoospermia before and after qilin pill treatment. Methods: A total of 60 patients with oligoasthenozoospermia were randomly divided into observation group and control group, control group received routine western medicine treatment, observation group received qilin pill + conventional western medicine treatment, and then differences in sperm quality, oxidative stress injury, ACP, AC and PDE expression, etc. were compared between two groups after treatment. Results: Semen volume and sperm density in semen samples of observation group after qilin pill treatment were higher than those of control group; serum FSH and LH levels were lower than those of control group, and the T level was higher than that of control group; ROS and MDA levels in seminal plasma were lower than those of control group, and SOD level was higher than that of control group; ACP, AC, α-Glu and Fru levels in seminal plasma were higher than those of control group, and PDE level was lower than that of control group. Conclusion: Qilin pill can improve sperm quality and optimize testicular internal environment in patients with oligoasthenozoospermia, and it has positive clinical significance.

  13. The NO/cGMP pathway inhibits transient cAMP signals through the activation of PDE2 in striatal neurons

    Directory of Open Access Journals (Sweden)

    Marina ePolito

    2013-11-01

    Full Text Available The NO-cGMP signaling plays an important role in the regulation of striatal function although the mechanisms of action of cGMP specifically in medium spiny neurons (MSNs remain unclear. Using genetically encoded fluorescent biosensors, including a novel Epac-based sensor (EPAC-SH150 with increased sensitivity for cAMP, we analyze the cGMP response to NO and whether it affected cAMP/PKA signaling in MSNs. The Cygnet2 sensor for cGMP reported large responses to NO donors in both striatonigral and striatopallidal MSNs, and this cGMP signal was controlled partially by PDE2. At the level of cAMP brief forskolin stimulations produced transient cAMP signals which differed between D1 and D2 medium spiny neurons. NO inhibited these cAMP transients through cGMP-dependent PDE2 activation, an effect that was translated and magnified downstream of cAMP, at the level of PKA. PDE2 thus appears as a critical effector of NO which modulates the post-synaptic response of MSNs to dopaminergic transmission.

  14. Performance optimization of Sparse Matrix-Vector Multiplication for multi-component PDE-based applications using GPUs

    KAUST Repository

    Abdelfattah, Ahmad

    2016-05-23

    Simulations of many multi-component PDE-based applications, such as petroleum reservoirs or reacting flows, are dominated by the solution, on each time step and within each Newton step, of large sparse linear systems. The standard solver is a preconditioned Krylov method. Along with application of the preconditioner, memory-bound Sparse Matrix-Vector Multiplication (SpMV) is the most time-consuming operation in such solvers. Multi-species models produce Jacobians with a dense block structure, where the block size can be as large as a few dozen. Failing to exploit this dense block structure vastly underutilizes hardware capable of delivering high performance on dense BLAS operations. This paper presents a GPU-accelerated SpMV kernel for block-sparse matrices. Dense matrix-vector multiplications within the sparse-block structure leverage optimization techniques from the KBLAS library, a high performance library for dense BLAS kernels. The design ideas of KBLAS can be applied to block-sparse matrices. Furthermore, a technique is proposed to balance the workload among thread blocks when there are large variations in the lengths of nonzero rows. Multi-GPU performance is highlighted. The proposed SpMV kernel outperforms existing state-of-the-art implementations using matrices with real structures from different applications. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  15. A PDE-constrained SQP algorithm for optical tomography based on the frequency-domain equation of radiative transfer

    International Nuclear Information System (INIS)

    Kim, Hyun Keol; Hielscher, Andreas H

    2009-01-01

    It is well acknowledged that transport-theory-based reconstruction algorithm can provide the most accurate reconstruction results especially when small tissue volumes or high absorbing media are considered. However, these codes have a high computational burden and are often only slowly converging. Therefore, methods that accelerate the computation are highly desirable. To this end, we introduce in this work a partial-differential-equation (PDE) constrained approach to optical tomography that makes use of an all-at-once reduced Hessian sequential quadratic programming (rSQP) scheme. The proposed scheme treats the forward and inverse variables independently, which makes it possible to update the radiation intensities and the optical coefficients simultaneously by solving the forward and inverse problems, all at once. We evaluate the performance of the proposed scheme with numerical and experimental data, and find that the rSQP scheme can reduce the computation time by a factor of 10–25, as compared to the commonly employed limited memory BFGS method. At the same time accuracy and robustness even in the presence of noise are not compromised

  16. Performance optimization of Sparse Matrix-Vector Multiplication for multi-component PDE-based applications using GPUs

    KAUST Repository

    Abdelfattah, Ahmad; Ltaief, Hatem; Keyes, David E.; Dongarra, Jack

    2016-01-01

    Simulations of many multi-component PDE-based applications, such as petroleum reservoirs or reacting flows, are dominated by the solution, on each time step and within each Newton step, of large sparse linear systems. The standard solver is a preconditioned Krylov method. Along with application of the preconditioner, memory-bound Sparse Matrix-Vector Multiplication (SpMV) is the most time-consuming operation in such solvers. Multi-species models produce Jacobians with a dense block structure, where the block size can be as large as a few dozen. Failing to exploit this dense block structure vastly underutilizes hardware capable of delivering high performance on dense BLAS operations. This paper presents a GPU-accelerated SpMV kernel for block-sparse matrices. Dense matrix-vector multiplications within the sparse-block structure leverage optimization techniques from the KBLAS library, a high performance library for dense BLAS kernels. The design ideas of KBLAS can be applied to block-sparse matrices. Furthermore, a technique is proposed to balance the workload among thread blocks when there are large variations in the lengths of nonzero rows. Multi-GPU performance is highlighted. The proposed SpMV kernel outperforms existing state-of-the-art implementations using matrices with real structures from different applications. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  17. PDE-based geophysical modelling using finite elements: examples from 3D resistivity and 2D magnetotellurics

    Science.gov (United States)

    Schaa, R.; Gross, L.; du Plessis, J.

    2016-04-01

    We present a general finite-element solver, escript, tailored to solve geophysical forward and inverse modeling problems in terms of partial differential equations (PDEs) with suitable boundary conditions. Escript’s abstract interface allows geoscientists to focus on solving the actual problem without being experts in numerical modeling. General-purpose finite element solvers have found wide use especially in engineering fields and find increasing application in the geophysical disciplines as these offer a single interface to tackle different geophysical problems. These solvers are useful for data interpretation and for research, but can also be a useful tool in educational settings. This paper serves as an introduction into PDE-based modeling with escript where we demonstrate in detail how escript is used to solve two different forward modeling problems from applied geophysics (3D DC resistivity and 2D magnetotellurics). Based on these two different cases, other geophysical modeling work can easily be realized. The escript package is implemented as a Python library and allows the solution of coupled, linear or non-linear, time-dependent PDEs. Parallel execution for both shared and distributed memory architectures is supported and can be used without modifications to the scripts.

  18. PDE-based geophysical modelling using finite elements: examples from 3D resistivity and 2D magnetotellurics

    International Nuclear Information System (INIS)

    Schaa, R; Gross, L; Du Plessis, J

    2016-01-01

    We present a general finite-element solver, escript, tailored to solve geophysical forward and inverse modeling problems in terms of partial differential equations (PDEs) with suitable boundary conditions. Escript’s abstract interface allows geoscientists to focus on solving the actual problem without being experts in numerical modeling. General-purpose finite element solvers have found wide use especially in engineering fields and find increasing application in the geophysical disciplines as these offer a single interface to tackle different geophysical problems. These solvers are useful for data interpretation and for research, but can also be a useful tool in educational settings. This paper serves as an introduction into PDE-based modeling with escript where we demonstrate in detail how escript is used to solve two different forward modeling problems from applied geophysics (3D DC resistivity and 2D magnetotellurics). Based on these two different cases, other geophysical modeling work can easily be realized. The escript package is implemented as a Python library and allows the solution of coupled, linear or non-linear, time-dependent PDEs. Parallel execution for both shared and distributed memory architectures is supported and can be used without modifications to the scripts. (paper)

  19. Protective effect of sulforaphane against retinal degeneration in the Pde6rd10 mouse model of retinitis pigmentosa.

    Science.gov (United States)

    Kang, Kai; Yu, Minzhong

    2017-12-01

    Retinitis pigmentosa (RP) is a group of inherited diseases characterized by the death of rod photoreceptors, followed by the death of cone photoreceptors, progressively leading to partial or complete blindness. Currently no specific treatment is available for RP patients. Sulforaphane (SFN) has been confirmed to be an effective antioxidant in the treatment of many diseases. In this study, we tested the therapeutic effects of SFN against photoreceptor degeneration in Pde6b rd10 mice. rd10 mice and C57/BL6 wild-type (WT) mice were treated with SFN and saline, respectively, from P6 to P20. Electroretinography (ERG), terminal deoxynucleotidyl transferase dUTP nick end labeling and western blot were tested, respectively, at P21 for the analysis of retinal function, retinal cell apoptosis or death and the protein express of GRP78/BiP (TUNEL) as a marker of endoplasmic reticulum (ER) stress. Compared with the saline group, the SFN-treated group showed significantly higher ERG a-wave and b-wave amplitudes, less photoreceptor death, and the downregulation of GRP78/BiP. Our data showed that SFN ameliorated the retinal degeneration of rd10 mice, which is possibly related to the downregulation of GRP78 expression.

  20. Solar Indices

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection includes a variety of indices related to solar activity contributed by a number of national and private solar observatories located worldwide. This...

  1. Operational indicators

    International Nuclear Information System (INIS)

    2010-01-01

    The chapter presents the operational indicators related to budget, travel costs and tickets, the evolution of the annual program for regulatory inspection, the scientific production, requested patents and the numbers related to the production of the services offered by the Institution

  2. ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2.

    Directory of Open Access Journals (Sweden)

    Matthew J Girgenti

    Full Text Available ZNF804a was identified by a genome-wide association study (GWAS in which a single nucleotide polymorphism (SNP rs1344706 in ZNF804a reached genome-wide statistical significance for association with a combined diagnosis of schizophrenia (SZ and bipolar disorder. Although the molecular function of ZNF804a is unknown, the amino acid sequence is predicted to contain a C2H2-type zinc-finger domain and suggests ZNF804a plays a role in DNA binding and transcription. Here, we confirm that ZNF804a directly contributes to transcriptional control by regulating the expression of several SZ associated genes and directly interacts with chromatin proximal to the promoter regions of PRSS16 and COMT, the two genes we find upregulated by ZNF804a. Using immunochemistry we establish that ZNF804a is localized to the nucleus of rat neural progenitor cells in culture and in vivo. We demonstrate that expression of ZNF804a results in a significant increase in transcript levels of PRSS16 and COMT, relative to GFP transfected controls, and a statistically significant decrease in transcript levels of PDE4B and DRD2. Furthermore, we show using chromatin immunoprecipitation assays (ChIP that both epitope-tagged and endogenous ZNF804a directly interacts with the promoter regions of PRSS16 and COMT, suggesting a direct upregulation of transcription by ZNF804a on the expression of these genes. These results are the first to confirm that ZNF804a regulates transcription levels of four SZ associated genes, and binds to chromatin proximal to promoters of two SZ genes. These results suggest a model where ZNF804a may modulate a transcriptional network of SZ associated genes.

  3. Nonsymbolic Gestural Interaction for Ambient Intelligence

    DEFF Research Database (Denmark)

    Rehm, Matthias

    2010-01-01

    the addressee with subtle clues about personality or cultural background. Gestures are an extremly rich source of communication-specific and contextual information for interactions in ambient intelligence environments. This chapter reviews the semantic layers of gestural interaction, focusing on the layer...

  4. PDK1/Akt/PDE4D axis identified as a target for asthma remedy synergistic with β2 AR agonists by a natural agent arctigenin.

    Science.gov (United States)

    Fang, R; Cui, Q; Sun, J; Duan, X; Ma, X; Wang, W; Cheng, B; Liu, Y; Hou, Y; Bai, G

    2015-12-01

    Asthma is a heterogenetic disorder characterized by chronic inflammation with variable airflow obstruction and airway hyper-responsiveness. As the most potent and popular bronchodilators, β2 adrenergic receptor (β2 AR) agonists bind to the β2 ARs that are coupled via a stimulatory G protein to adenylyl cyclase, thereby improving cAMP accumulation and resulting in airway smooth muscle relaxation. We previously demonstrated arctigenin had a synergistic function with the β2 AR agonist, but the target for this remained elusive. Chemical proteomics capturing was used to enrich and uncover the target of arctigenin in human bronchial smooth muscle cells, and reverse docking and molecular dynamic stimulation were performed to evaluate the binding of arctigenin and its target. In vitro enzyme activities and protein levels were demonstrated with special kits and Western blotting. Finally, guinea pig tracheal muscle segregation and ex vivo function were analysed. Arctigenin bound to PDK1 with an ideal binding free energy -25.45 kcal/mol and inhibited PDK1 kinase activity without changing its protein level. Additionally, arctigenin reduced PKB/Akt-induced phosphorylation of PDE4D, which was first identified in this study. Attenuation of PDE4D resulted in cAMP accumulation in human bronchial smooth muscle. The inhibition of PDK1 showed a synergistic function with β2 AR agonists and relaxed the constriction of segregated guinea pig tracheal muscle. The PDK1/Akt/PDE4D axis serves as a novel asthma target, which may benefit airflow obstruction. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D)

    OpenAIRE

    Gurney, Mark E.; Cogram, Patricia; Deacon, Robert M; Rex, Christopher; Tranfaglia, Michael

    2017-01-01

    Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment o...

  6. Luteinizing hormone signaling phosphorylates and activates the cyclic GMP phosphodiesterase PDE5 in mouse ovarian follicles, contributing an additional component to the hormonally induced decrease in cyclic GMP that reinitiates meiosis.

    Science.gov (United States)

    Egbert, Jeremy R; Yee, Siu-Pok; Jaffe, Laurinda A

    2018-03-01

    Prior to birth, oocytes within mammalian ovarian follicles initiate meiosis, but then arrest in prophase until puberty, when with each reproductive cycle, one or more follicles are stimulated by luteinizing hormone (LH) to resume meiosis in preparation for fertilization. Within preovulatory follicles, granulosa cells produce high levels of cGMP, which diffuses into the oocyte to maintain meiotic arrest. LH signaling restarts meiosis by rapidly lowering the levels of cGMP in the follicle and oocyte. Part of this decrease is mediated by the dephosphorylation and inactivation the NPR2 guanylyl cyclase in response to LH, but the mechanism for the remainder of the cGMP decrease is unknown. At least one cGMP phosphodiesterase, PDE5, is activated by LH signaling, which would contribute to lowering cGMP. PDE5 exhibits increased cGMP-hydrolytic activity when phosphorylated on serine 92, and we recently demonstrated that LH signaling phosphorylates PDE5 on this serine and increases its activity in rat follicles. To test the extent to which this mechanism contributes to the cGMP decrease that restarts meiosis, we generated a mouse line in which serine 92 was mutated to alanine (Pde5-S92A), such that it cannot be phosphorylated. Here we show that PDE5 phosphorylation is required for the LH-induced increase in cGMP-hydrolytic activity, but that this increase has only a modest effect on the LH-induced cGMP decrease in mouse follicles, and does not affect the timing of meiotic resumption. Though we show that the activation of PDE5 is among the mechanisms contributing to the cGMP decrease, these results suggest that another cGMP phosphodiesterase is also activated by LH signaling. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Synergistic interaction between a PDE5 inhibitor (sildenafil) and a new adenosine A2A receptor agonist (LASSBio-1359) improves pulmonary hypertension in rats.

    Science.gov (United States)

    Alencar, Allan K; Carvalho, Fábio I; Silva, Ananssa M; Martinez, Sabrina T; Calasans-Maia, Jorge A; Fraga, Carlos M; Barreiro, Eliezer J; Zapata-Sudo, Gisele; Sudo, Roberto T

    2018-01-01

    Pulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats. An in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured. Isobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats. The combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.

  8. Inhibition of PAF-induced expression of CD11b and shedding of L-selectin on human neutrophils and eosinophils by the type IV selective PDE inhibitor, rolipram

    NARCIS (Netherlands)

    Dijkhuizen, B; deMonchy, JGR; Dubois, AEJ; Gerritsen, J; Kauffman, HF

    We quantitatively determined whether the selective phosphodiesterase (PDE) inhibitor, rolipram, inhibits changes in the adhesion molecules CD11b and L-selectin on platelet-activating factor (PAF)-stimulated human neutrophils and eosinophils in vitro. Incubations were performed in human whole blood

  9. Decision tree analyses of key patient characteristics in Middle Eastern/North African and Latin American men treated with long-acting and short-acting PDE5 inhibitors for erectile dysfunction.

    Science.gov (United States)

    Rubio-Aurioles, Eusebio; El-Meliegy, Amr; Abdulwahed, Samer; Henneges, Carsten; Sorsaburu, Sebastian; Gurbuz, Sirel

    2015-02-01

    Phosphodiesterase type 5 (PDE5) inhibitors have discontinuation rates as high as 60% in men with erectile dysfunction. Treatment satisfaction has been significantly associated with treatment continuation. Understanding key characteristics in terms of treatment preference, relationship, and lifestyle issues could provide direction on how to improve compliance with PDE5 inhibitor treatment globally. The objective was to identify subgroups of interest in the pooled database of two observational studies conducted in Latin America (LA) and Middle East/North Africa (MENA) exploring patient characteristics and prescription of either a long- or short-acting PDE5 inhibitor at baseline. Two identical prospective, non-interventional, observational, studies in MENA (N = 493) and LA (N = 511) treated men with an 'on demand' (pro re nata, PRN) PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or lodenafil) during 6 months. In this post-hoc meta-analysis of two observational studies with equal design, pooled data were analyzed to determine patient characteristics and PDE5 inhibitor prescribed/used most likely to be associated with patient expectations, satisfaction, self-esteem, and patient-partner relationships. Decision tree analyses, with and without weighting, were used to identify and describe key features. In each analysis of patient expectations, patient-partner relationship, and self-esteem, we describe the two major subgroups at baseline for each decision tree. Analyses of patient expectations and sexual self-esteem revealed that patients prescribed long-acting PDE5 inhibitors (59%) highlighted the importance of treatment effect duration, second to partner satisfaction with treatment, while patients prescribed short-acting PDE5 inhibitors (32%) placed less importance on treatment effect duration but considerable importance on treatment effect lasting until intercourse completion. Further insights regarding patients, partner relationship characteristics, and

  10. Estudo clínico fase I de carbonato de lodenafila, um novo tipo de inibidor de fosfodiesterase 5 (PDE5), em voluntários saudáveis do sexo masculino = : A phase I clinical trial of lodenafil carbonate, a new phosphodiesterase type 5 (PDE5) inhibitor, in healthy male volunteers

    OpenAIRE

    Hilton Oliveira dos Santos Filho

    2013-01-01

    Resumo: Carbonato de Lodenafila é um novo tipo de inibidor de fosfodiesterase 5 (PDE5) utilizado no tratamento da disfunção erétil. O presente estudo foi realizado para avaliar a segurança, tolerabilidade e farmacocinética do carbonato de lodenafila após a administração de doses orais únicas ascendentes (de 1 a 100 mg) a voluntários saudáveis do sexo masculino (n = 33). O estudo foi um estudo clínico fase I, aberto, de escalonamento de dose, utilizando a administração de doses orais únicas de...

  11. Comparison of efficacy and satisfaction profile, between penile prosthesis implantation and oral PDE5 inhibitor tadalafil therapy, in men with nerve-sparing radical prostatectomy erectile dysfunction.

    Science.gov (United States)

    Megas, Georgios; Papadopoulos, Georgios; Stathouros, Georgios; Moschonas, Dimitrios; Gkialas, Ioannis; Ntoumas, Konstantinos

    2013-07-01

    WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Erectile dysfunction after nerve-sparing radical retropubic prostatectomy constitutes a challenge to the urologist. The mainstay of medical treatment after radical prostatectomy to restore spontaneous erectile function remains phosphodiesterase (PDE5) inhibitors, despite the fact that data from animal studies suggesting that PDE5 inhibitors can prevent smooth muscle apoptosis and fibrosis have not yet been extrapolated to humans because of a lack of standardized protocols. If the above treatment fails, second-line therapies such as intraurethral prostaglandins, penile injection therapy and vacuum devices are offered. When less invasive therapies are ineffective, interventions that preserve sexual function such as penile prosthesis implantation become the treatment of choice. Our study reveals the alternative of penile prosthesis implantation as first-line treatment in erectile dysfunction after nerve-sparing radical prostatectomy. It also highlights its superiority to the oral PDE5 inhibitor treatment, regarding the erection, frequency, firmness, maintenance and penetration ability. This suggests that a concept of an early penile intervention in the future would be promising for those patients who wish to remain sexually active without depending on oral formulations with doubtful and delayed results. To evaluate the outcome of penile prosthesis surgery in comparison to oral phosphodiesterase type 5 (PDE5) inhibitor administration, in men with erectile dysfunction after nerve-sparing radical prostatectomy, as early penile intervention therapy. A total of 174 patients treated by nerve-sparing retropubic radical prostatectomy (RRP) for clinically localized prostate cancer, between January 2006 and September 2009 enrolled in the study, 153 patients fulfilled the inclusion criteria, and 69 (45%) patients presented with post-RRP erectile dysfunction 6 months after primary surgery. Fifty-four patients were disease

  12. Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors.

    Science.gov (United States)

    Varnes, Jeffrey G; Geschwindner, Stefan; Holmquist, Christopher R; Forst, Janet; Wang, Xia; Dekker, Niek; Scott, Clay W; Tian, Gaochao; Wood, Michael W; Albert, Jeffrey S

    2016-01-01

    Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen led to prioritized fragment hits (IC50's ∼500μM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4μM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D).

    Science.gov (United States)

    Gurney, Mark E; Cogram, Patricia; Deacon, Robert M; Rex, Christopher; Tranfaglia, Michael

    2017-11-07

    Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology. There was no decrement in behavioral scores in control C57Bl6 treated with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the drug. Thus, BPN14770 may be useful for the treatment of fragile-X syndrome and other disorders with decreased cAMP signaling.

  14. Genetic heterogeneity and consanguinity lead to a "double hit": homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa.

    Science.gov (United States)

    Goldenberg-Cohen, Nitza; Banin, Eyal; Zalzstein, Yael; Cohen, Ben; Rotenstreich, Ygal; Rizel, Leah; Basel-Vanagaite, Lina; Ben-Yosef, Tamar

    2013-01-01

    Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. THE FAMILY WAS FOUND TO SEGREGATE NOVEL MUTATIONS OF TWO DIFFERENT GENES: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient.

  15. Genetic heterogeneity and consanguinity lead to a “double hit”: Homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa

    Science.gov (United States)

    Goldenberg-Cohen, Nitza; Banin, Eyal; Zalzstein, Yael; Cohen, Ben; Rotenstreich, Ygal; Rizel, Leah; Basel-Vanagaite, Lina

    2013-01-01

    Purpose Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. Methods The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. Results The family was found to segregate novel mutations of two different genes: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. Conclusions This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient. PMID:23882135

  16. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) determination of stimulants, anorectic drugs and phosphodiesterase 5 inhibitors (PDE5I) in food supplements.

    Science.gov (United States)

    Strano-Rossi, Sabina; Odoardi, Sara; Castrignanò, Erika; Serpelloni, Giovanni; Chiarotti, Marcello

    2015-03-15

    The paper describes a liquid chromatography/high resolution mass spectrometry LC/HRMS method for the simultaneous identification and quantification of stimulants (ephedrines, caffeine, anorectic drugs such as phentermine, phendimetrazine, phenmetrazine, fenfluramine, benfluorex, mephentermine, fencanfamine, sibutramine) and PDE5I (sildenafil, vardenafil and tadalafil) in food supplements using a benchtop Orbitrap mass spectrometer. The mass detector, with a nominal resolving power of 100,000 (FWHM at m/z 200), operated in full scan mode in ESI positive ionization mode. Analytes were identified by retention times, accurate masses and correspondence of experimental and calculated isotopic patterns. The limits of detection (LOD) obtained varied from 1 to 25 ng g(-1) and limits of quantification (LOQ) were 50 ng g(-1) for all compounds. The method was linear for all the analytes in the ranges from 50 to 2000 ng g(-1), giving correlation coefficients>0.99. Accuracy (intended as %E) and repeatability (% CV) were always lower than 15%. The method was applied to the analysis of 36 dietary supplements, revealing the presence of ephedrine and/or pseudoephedrine in four of them, caffeine in eight of them and sildenafil in four of them. In one case, ephedrine was not reported on the label of the dietary supplement, as well as for caffeine in other two cases. A further confirmation of the analytes identity in positive samples was obtained through in-source fragmentation and comparison of the obtained fragments and their relative abundances with those from certified standards. As the acquisition mode is full scan, it would be also possible to re-process a previously acquired datafile for the investigation of untargeted analytes. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Geomagnetic Indices Bulletin (GIB)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Geomagnetic Indices Bulletin is a one page sheet containing the magnetic indices Kp, Ap, Cp, An, As, Am and the provisional aa indices. The bulletin is published...

  18. Use of a severity indicator as a predictor of the use of hepatic transplantation resources.

    Science.gov (United States)

    Eiras, Flavia Regina Cocuzza das; Barbosa, Antonio Pires; Leão, Eliseth Ribeiro; Biancolino, César Augusto

    2016-01-01

    To evaluate the use of a severity indicator for end-stage liver disease as a predictor of resource use in a teaching hospital in São Paulo. Descriptive, retrospective study, classifying independent variables in seven key dimensions: identification/risk rating; length of stay/use of advanced life support; imaging; clinical analysis; special procedures; blood products in the intensive care unit; and in the operating room. The frequencies were analyzed by linear regression analysis of variance to detect relevance due to the dependent variable (severity indicator) in 76 cases seen in 2013. Among the variables studied, those that presented relevance due to the functional risk score were laboratory measurements of bilirubin, amylase, transaminase, blood count, creatine phosphokinase (pde gravidade para doenças hepáticas terminais como fator preditivo do uso de recursos em um hospital-escola de São Paulo. Estudo descritivo, retrospectivo, classificando variáveis independentes em sete dimensões principais: identificação/classificação de risco; tempo de permanência/uso de suporte avançado à vida; exames de imagem; análises clínicas; procedimentos especiais; hemoderivados em unidade de terapia intensiva; e em centro cirúrgico. As frequências foram analisadas por regressão linear com análise de variância para detecção de relevâncias face à variável dependente (indicador de gravidade) em 76 casos atendidos em 2013. Dentre as variáveis estudadas, apresentaram relevância em função do escore de risco funcional as dosagens laboratoriais de bilirrubina, amilase, transaminase, hemograma, creatinofosfoquinase (pde plaquetas (ppotencial capacidade preditiva no uso de recursos pós-operatórios de receptores de fígado nas dimensões, análises clínicas, imagens e hemoterapia.

  19. Recent topics in nonlinear PDE

    International Nuclear Information System (INIS)

    Mimura, Masayasu; Nishida, Takaaki

    1984-01-01

    The meeting on the subject of nonlinear partial differential equations was held at Hiroshima University in February, 1983. Leading and active mathematicians were invited to talk on their current research interests in nonlinear pdes occuring in the areas of fluid dynamics, free boundary problems, population dynamics and mathematical physics. This volume contains the theory of nonlinear pdes and the related topics which have been recently developed in Japan. (Auth.)

  20. Indicators and their functions

    DEFF Research Database (Denmark)

    Gudmundsson, Henrik; Joumard, Robert; Aschemann, Ralf

    2010-01-01

    indicators? How can several indicators be jointly considered? And how can indicators be used in planning and decision making? Firstly we provide definition of 'indicator of environmental sustainability in transport'. The functions, strengths and weaknesses of indicators as measurement tools, and as decision...... for indicators and assessments. As the decision making context influences the perceived and actual needs for indicators and methods, we also analysed the dimensions and context of decision making. We derived criteria and methods for the assessment and selection of indicators of environmental sustainability......This report is the final report of the action COST 356 'EST - Towards the definition of a measurable environmentally sustainable transport'. It tries to answer the following questions: How can environmental impacts of transport be measured? How can measurements be transformed into operational...

  1. Geomagnetic aa Indices

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The geomagnetic aa indices are the continuation of the series beginning in the year 1868. A full description of these indices is given in the International...

  2. Coalizões em educação no Brasil: relação com o governo e influência sobre o Plano de Desenvolvimento da Educação (PDE

    Directory of Open Access Journals (Sweden)

    Lara Elena Ramos Simielli

    2013-06-01

    Full Text Available Atualmente, duas coalizões lutam pela melhoria da qualidade da educação no Brasil: a Campanha Nacional pelo Direito à Educação e o Todos pela Educação. Essas duas coalizões diferenciam-se dos movimentos históricos por sua capacidade de agregar atores provenientes de instituições governamentais e não governamentais, de diversos níveis, que possuem valores e crenças comuns em uma aliança única, aproximando-se do conceito de coalizões advocatórias proposto por Sabatier e Jenkins-Smith (1993. Apesar da bandeira comum, elas possuem origens, composições, metas e formas de atuação completamente diferentes - a relação com o governo é um dos pontos que mais as diferencia. O lançamento do Plano de Desenvolvimento da Educação (PDE, com uma das medidas intitulada "Plano de Metas Compromisso Todos pela Educação", gerou questionamentos com relação à similaridade dos nomes entre um plano de governo e uma das coalizões. Neste artigo, apresentaremos as duas coalizões e a relação de ambas com o governo, utilizando o PDE como estudo de caso.

  3. NRC performance indicator program

    International Nuclear Information System (INIS)

    Singh, R.N.

    1987-01-01

    The performance indicator development work of the US Nuclear Regulatory Commission (NRC) interoffice task group involved several major activities that included selection of candidate indicators for a trial program, data collection and review, validation of the trial indicators, display method development, interactions with the industry, and selection of an optimum set of indicators for the program. After evaluating 27 potential indicators against certain ideal attributes, the task group selected 17 for the trial program. The pertinent data for these indicators were then collected from 50 plants at 30 sites. The validation of the indicators consisted of two primary processes: logical validity and statistical analysis. The six indicators currently in the program are scrams, safety system actuations, significant events, safety system failures, forced outage rate, and equipment forced outages per 100 critical hours. A report containing data on the six performance indicators and some supplemental information is issued on a quarterly basis. The NRC staff is also working on refinements of existing indicators and development of additional indicators as directed by the commission

  4. eHealth indicators

    DEFF Research Database (Denmark)

    HYPPÖNEN, Hannele; AMMENWERTH, Elske; Nøhr, Christian

    2012-01-01

    eHealth indicators are needed to measure defined aspects of national eHealth implementations. However, until now, eHealth indicators are ambiguous or unclear. Therefore, an expert workshop "Towards an International Minimum Dataset for Monitoring National Health Information System Implementations......" was organized. The objective was to develop ideas for a minimum eHealth indicator set. The proposed ideas for indicators were classified based on EUnetHTA and De-Lone & McClean, and classification was compared with health IT evaluation criteria classification by Ammenwerth & Keizer. Analysis of the workshop...... results emphasized the need for a common methodological framework for defining and classifying eHealth indicators. It also showed the importance of setting the indicators into context. The results will benefit policy makers, developers and researchers in pursuit of provision and use of evidence...

  5. Float level indicator

    International Nuclear Information System (INIS)

    Grishchuk, M.Kh.; Laptev, A.G.; Pashkov, V.A.

    1980-01-01

    Specially developed level indicator is suggested with differential to-transformer converter of the float motion, operating in line with a movable electronic block, intended for indicating the level of the dissociating nitrogen tetroxide liquid phase. On the basis of the indicator elements the device is realized to measure the time of calibrated volume fillino. in by liquid nitrogen tetroxide in steady state operation of the experimental bench-marks [ru

  6. Climate Change Indicators

    Science.gov (United States)

    Presents information, charts and graphs showing measured climate changes across 40 indicators related to greenhouse gases, weather and climate, oceans, snow and ice, heath and society, and ecosystems.

  7. VP Ellipsis without Indices

    DEFF Research Database (Denmark)

    Hardt, Daniel; Asher, Nicholas; Hunter, Julie

    2013-01-01

    This paper compares two views on the status of indices in syntactic and logical representations. On a structural view, indices are syntactic formants on a par with node labels and phrase bracketings, and are thus a part of the logical forms that are derived from syntactic representations. On the ......This paper compares two views on the status of indices in syntactic and logical representations. On a structural view, indices are syntactic formants on a par with node labels and phrase bracketings, and are thus a part of the logical forms that are derived from syntactic representations...

  8. Quality indicators in radiotherapy

    International Nuclear Information System (INIS)

    Cionini, Luca; Gardani, Gianstefano; Gabriele, Pietro; Magri, Secondo; Morosini, Pier Luigi; Rosi, Antonella; Viti, Vincenza

    2007-01-01

    Background and purpose: There is a widespread and increasing tendency to develop hospital performance indicators in the field of accreditation/certification systems and quality benchmarking. A study has been undertaken to develop a set of performance indicators for a typical radiotherapy Centre and to evaluate their ability to provide a continuous quality improvement. Materials and methods: A working group consisting of radiation oncologists, medical physicists and radiation technologists under the coordination of experts in health technology assessment has elaborated a set of general indicators able to monitor performances and the quality level of a typical radiotherapy Centre. The work has been carried out through four steps: a preliminary set of indicators was selected; data on these indicators were collected in a number of Italian radiotherapy Centres and medical physics Services; problems in collection and analysis of data were discussed; a final set of indicators was developed. Results: A final set of 13 indicators is here presented. They concern general structural and/or operational features, health physics activities and accuracy and technical complexity of the treatment. Conclusions: The indicators tested in a few Italian Centres of radiotherapy and medical physics Services are now ready to be utilized by a larger community

  9. Indicators of sustainable tourism

    Directory of Open Access Journals (Sweden)

    Jovičić Dobrica

    2010-01-01

    Full Text Available The indicators, precisely describing the linkages between tourism and the environment, social and cultural base, are not easily available. How ever, some relevant organizations (WTO, EU, OECD, etc., institutions and experts, have been hardly working to create the indicators of sustainable tourism. Whereas the economic objectives are easily defined by the use of the traditional indicators used in national and business economics, it is very difficult to identify widely applicable environmental, social and cultural indicators. In order to stimulate and alleviate the process of sustainable tourism development, EU created the list of comparative indicators of sustainable tourism. In preparing this list, special attention is paid to identification of valid indicators of real tourism impacts on the social and cultural environment (the entire set of traditions, customs, history, hospitality and culture that characterize a given area, that is a very complex task. Assuming the fact that the related indicators have been analyzed in many European countries, this paper is focused on applying the related indicators in research of tourism development in villages of the Kosjerić community. .

  10. Key performance indicators

    NARCIS (Netherlands)

    Zwetsloot, G.I.J.M.

    2014-01-01

    This paper addresses how organisations can use OSH performance indicators. This is an important way to mainstream OSH into business management. Key performance indicators (KPIs) should provide objective data on the OSH situation. It is often said that ‘what gets measured gets managed’. Without

  11. Indicators for environmental sustainability

    DEFF Research Database (Denmark)

    Dong, Yan; Hauschild, Michael Zwicky

    2017-01-01

    . In this study, we reviewed indicators applied in life cycle assessment (LCA), planetary boundary framework (PB), and Sustainable Development Goals (SDGs) developed under United Nation. The aim is to 1) identify their applications and relevant decision context; 2) Review their indicators and categorize them...

  12. Evaluating Living Standard Indicators

    Directory of Open Access Journals (Sweden)

    Birčiaková Naďa

    2015-09-01

    Full Text Available This paper deals with the evaluation of selected available indicators of living standards, divided into three groups, namely economic, environmental, and social. We have selected six countries of the European Union for analysis: Bulgaria, the Czech Republic, Hungary, Luxembourg, France, and Great Britain. The aim of this paper is to evaluate indicators measuring living standards and suggest the most important factors which should be included in the final measurement. We have tried to determine what factors influence each indicator and what factors affect living standards. We have chosen regression analysis as our main method. From the study of factors, we can deduce their impact on living standards, and thus the value of indicators of living standards. Indicators with a high degree of reliability include the following factors: size and density of population, health care and spending on education. Emissions of carbon dioxide in the atmosphere also have a certain lower degree of reliability.

  13. Core damage risk indicators

    International Nuclear Information System (INIS)

    Szikszai, T.

    1994-01-01

    The purpose of this document is to show a method for the fast recalculation of the PSA. To avoid the information loose, it is necessary to simplify the PSA models, or at least reorganize them. The method, introduced in this document, require that preparation, so we try to show, how to do that. This document is an introduction. This is the starting point of the work related to the development of the risk indicators. In the future, with the application of this method, we are going to show an everyday use of the PSA results to produce the indicators of the core damage risk. There are two different indicators of the plant safety performance, related to the core damage risk. The first is the core damage frequency indicator (CDFI), and the second is the core damage probability indicator (CDPI). Of course, we cannot describe all of the possible ways to use these indicators, rather we will try to introduce the requirements to establish such an indicator system and the calculation process

  14. Safety performance indicators program

    International Nuclear Information System (INIS)

    Vidal, Patricia G.

    2004-01-01

    In 1997 the Nuclear Regulatory Authority (ARN) initiated a program to define and implement a Safety Performance Indicators System for the two operating nuclear power plants, Atucha I and Embalse. The objective of the program was to incorporate a set of safety performance indicators to be used as a new regulatory tool providing an additional view of the operational performance of the nuclear power plants, improving the ability to detect degradation on safety related areas. A set of twenty-four safety performance indicators was developed and improved throughout pilot implementation initiated in July 1998. This paper summarises the program development, the main criteria applied in each stage and the results obtained. (author)

  15. Solar Indices - Solar Flares

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection includes a variety of indices related to solar activity contributed by a number of national and private solar observatories located worldwide. This...

  16. NOHSS Child Indicators

    Data.gov (United States)

    U.S. Department of Health & Human Services — Data for School year-end 1994 through year-end 2016. State oral health surveys are the data sources for these indicators. States periodically conduct independent...

  17. NOHSS Adult Indicators

    Data.gov (United States)

    U.S. Department of Health & Human Services — 2012-2014 (even years). Data from BRFSS for indicators of adult oral health for even years from 2012 through 2014. National estimates are represented by the median...

  18. Environmental indicators for buildings

    DEFF Research Database (Denmark)

    Dammann, Sven

    Environmental Indicators for Buildings are studied using two different perspectives: with a technological, environmental scientific departing point and with a social scientific departing point. Different relevant groups in the building sector are identified and analysed, using the Social...

  19. Solar Indices - Sunspot Numbers

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection includes a variety of indices related to solar activity contributed by a number of national and private solar observatories located worldwide. This...

  20. Solar Indices Bulletin

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Solar Indices Bulletin is a prompt monthly information product that is distributed within two weeks after the observation month closes. For the month just ended,...

  1. Indicators and SEA

    DEFF Research Database (Denmark)

    Gao, Jingjing; Kørnøv, Lone; Christensen, Per

    Abstract: Indicators are widely used in SEA to measure, communicate and monitor impacts from a proposed policy, plan or programme, and can improve the effectiveness for the SEA by simplifying the complexity of both assessment and presentation. Indicators can be seen as part of the implementation...... and if the information requirement for different target groups is not addressed. Indicators are widely used in SEA to measure, communicate and monitor impacts from a proposed policy, plan or programme, and can improve the effectiveness for the SEA by simplifying the complexity of both assessment and presentation...... process helping to understand, communicate and, integrate important environmental issues in planning and decision-making. On the other hand, use of indicators can also limit SEA effectiveness, if the ones chosen are biased or limited, if the aggregation gives incorrect interpretation...

  2. Fishery Performance Indicators

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Performance indicators for landings, effort, revenue and distribution of revenue are collected for various fisheries nation-wide. The fisheries include catch and...

  3. Indicators: Sediment Enzymes

    Science.gov (United States)

    Sediment enzymes are proteins that are produced by microorganisms living in the sediment or soil. They are indicators of key ecosystem processes and can help determine which nutrients are affecting the biological community of a waterbody.

  4. Solar Indices - Plage Regions

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection includes a variety of indices related to solar activity contributed by a number of national and private solar observatories located worldwide. This...

  5. Solar Indices - Solar Ultraviolet

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection includes a variety of indices related to solar activity contributed by a number of national and private solar observatories located worldwide. This...

  6. Solar Indices - Solar Corona

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection includes a variety of indices related to solar activity contributed by a number of national and private solar observatories located worldwide. This...

  7. Solar Indices - Solar Irradiance

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection includes a variety of indices related to solar activity contributed by a number of national and private solar observatories located worldwide. This...

  8. NOHSS Child Indicators

    Data.gov (United States)

    U.S. Department of Health & Human Services — Data for School year-end 1994 through year-end 2017. State oral health surveys are the data sources for these indicators. States periodically conduct independent...

  9. Indicators of Ecological Change

    Science.gov (United States)

    2005-03-01

    H. 1990. Strategy for monitoring the effects of land use change on atmospheric CO2 concentrations . In Proceedings of “Global Natural Resource...Working Group in Santiago , Chile , February 1995, ten nations agreed to a comprehensive set of criteria and indicators for forest conservation and...chemistry variables, the concentrations of total and inorganic suspended sediments during baseflow and storm periods were excellent indicators of

  10. A new method for extracting near-surface mass-density anomalies from land-based gravity data, based on a special case of Poisson's PDE at the Earth's surface: A case study of salt diapirs in the south of Iran

    Science.gov (United States)

    AllahTavakoli, Y.; Safari, A.; Ardalan, A.; Bahroudi, A.

    2015-12-01

    The current research provides a method for tracking near-surface mass-density anomalies via using only land-based gravity data, which is based on a special version of Poisson's Partial Differential Equation (PDE) of the gravitational field at Earth's surface. The research demonstrates how the Poisson's PDE can provide us with a capability to extract the near-surface mass-density anomalies from land-based gravity data. Herein, this version of the Poisson's PDE is mathematically introduced to the Earth's surface and then it is used to develop the new method for approximating the mass-density via derivatives of the Earth's gravitational field (i.e. via the gradient tensor). Herein, the author believes that the PDE can give us new knowledge about the behavior of the Earth's gravitational field at the Earth's surface which can be so useful for developing new methods of Earth's mass-density determination. In a case study, the proposed method is applied to a set of gravity stations located in the south of Iran. The results were numerically validated via certain knowledge about the geological structures in the area of the case study. Also, the method was compared with two standard methods of mass-density determination. All the numerical experiments show that the proposed approach is well-suited for tracking near-surface mass-density anomalies via using only the gravity data. Finally, the approach is also applied to some petroleum exploration studies of salt diapirs in the south of Iran.

  11. Air quality indicators

    International Nuclear Information System (INIS)

    Clench-Aas, Jocelyn; Guerreiro, Cristina; Bartonova, Alena

    1999-06-01

    This report proposes and describes in detail several air quality indicators that may be used to describe population exposure. The suggested indicators account for temporal and spatial patterns of pollution and movements of individuals between different micro-environments. The Air Quality Indicator /AQI) should represent both the spatial and temporal aspects of pollution exposure that may have important effects on health. Two indicators are needed, the Population Air Quality Indicator and the Individual Air Quality Indicator. Mean concentrations, 98th percentile and maximum values are the traditional indicators for estimating exposure. the temporal variability of PM-10 and NO 2 , however, is here described by means of: 1) The rate of change of pollution as the difference between two consecutive hourly values and of 2) episodes, described in terms of number, duration and winter episode period, maximum concentration in the episode and integrated episode exposure (episode AOT50/100). The spatial variation of AQIs can be described in several ways, e.g.: 1) Concentrations in neighbouring grid squares can be compared as an indication of spatial variation and 2) point estimates can be compared to grid values for a description of variation within a grid. Both methods are presented here. A test of the representativity of static point estimates for pollution exposure is to compare them to an estimate of air pollution exposure accounting for movements between different locations, obtained using diaries. The ultimate aim of AQIs is to describe the population exposure to ambient pollution. This is done by estimating the number of people exposed using different characteristics of AQIs. The data used to describe these indicators originates from dispersion modelling of short-term air pollution concentrations in Oslo. Two series of data are used. One represents hour-for hour concentrations in the 1 km 2 grid system covering the city of Oslo, winter 1994/95, calculated by the grid

  12. Indicators for energy security

    International Nuclear Information System (INIS)

    Kruyt, Bert; Van Vuuren, D.P.; De Vries, H.J.M.; Groenenberg, H.

    2009-01-01

    The concept of energy security is widely used, yet there is no consensus on its precise interpretation. In this research, we have provided an overview of available indicators for long-term security of supply (SOS). We distinguished four dimensions of energy security that relate to the availability, accessibility, affordability and acceptability of energy and classified indicators for energy security according to this taxonomy. There is no one ideal indicator, as the notion of energy security is highly context dependent. Rather, applying multiple indicators leads to a broader understanding. Incorporating these indicators in model-based scenario analysis showed accelerated depletion of currently known fossil resources due to increasing global demand. Coupled with increasing spatial discrepancy between consumption and production, international trade in energy carriers is projected to have increased by 142% in 2050 compared to 2008. Oil production is projected to become increasingly concentrated in a few countries up to 2030, after which production from other regions diversifies the market. Under stringent climate policies, this diversification may not occur due to reduced demand for oil. Possible benefits of climate policy include increased fuel diversity and slower depletion of fossil resources. (author)

  13. CREDIT Performance Indicator Framework

    DEFF Research Database (Denmark)

    Frandsen, Anne Kathrine; Bertelsen, Niels Haldor; Haugbølle, Kim

    2010-01-01

    During the past two years the Nordic Baltic research project CREDIT (Construction and Real Estate – Developing Indicators for Transparency) has worked with the aim to improve transparency of value creation in building and real estate. One of the central deliverables of the CREDIT project was a fr......During the past two years the Nordic Baltic research project CREDIT (Construction and Real Estate – Developing Indicators for Transparency) has worked with the aim to improve transparency of value creation in building and real estate. One of the central deliverables of the CREDIT project...... was a framework of indicators relevant in building and real estate and applicable in the Nordic and Baltic countries as well as a proposal for a set of key indicators. The study resulting in CREDIT Performance Indicator Framework has been based on 28 case studies of evaluation practises in the building and real...... estate sector each addressing three interlinked levels: building/ projects level, company or enterprise level and benchmarking system level. Additionally it has been based on dialogue with researchers and professional organisation, international research and standardisation work and national building...

  14. Publication point indicators

    DEFF Research Database (Denmark)

    Elleby, Anita; Ingwersen, Peter

    2010-01-01

    ; the Cumulated Publication Point Indicator (CPPI), which graphically illustrates the cumulated gain of obtained vs. ideal points, both seen as vectors; and the normalized Cumulated Publication Point Index (nCPPI) that represents the cumulated gain of publication success as index values, either graphically......The paper presents comparative analyses of two publication point systems, The Norwegian and the in-house system from the interdisciplinary Danish Institute of International Studies (DIIS), used as case in the study for publications published 2006, and compares central citation-based indicators...... with novel publication point indicators (PPIs) that are formalized and exemplified. Two diachronic citation windows are applied: 2006-07 and 2006-08. Web of Science (WoS) as well as Google Scholar (GS) are applied to observe the cite delay and citedness for the different document types published by DIIS...

  15. Minimum risk trigger indices

    International Nuclear Information System (INIS)

    Tingey, F.H.

    1979-01-01

    A viable safeguards system includes among other things the development and use of indices which trigger various courses of action. The usual limit of error calculation provides such an index. The classical approach is one of constructing tests which, under certain assumptions, make the likelihood of a false alarm small. Of concern also is the test's failure to indicate a loss (diversion) when in fact one has occurred. Since false alarms are usually costly and losses both costly and of extreme strategic sinificance, there remains the task of balancing the probability of false alarm and its consequences against the probability of undetected loss and its consequences. The application of other than classical hypothesis testing procedures are considered in this paper. Using various consequence models, trigger indices are derived which have certain optimum properties. Application of the techniques would enhance the material control function

  16. Temperature indicating device

    International Nuclear Information System (INIS)

    Angus, J.P.; Salt, D.

    1988-01-01

    A temperature indicating device comprises a plurality of planar elements some undergoing a reversible change in appearance at a given temperature the remainder undergoing an irreversible change in appearance at a given temperature. The device is useful in indicating the temperature which an object has achieved as well as its actual temperature. The reversible change is produced by liquid crystal devices. The irreversible change is produced by an absorbent surface carrying substances e.g. waxes which melt at predetermined temperatures and are absorbed by the surface; alternatively paints may be used. The device is used for monitoring processes of encapsulation of radio active waste. (author)

  17. Injector of solid indicator

    Energy Technology Data Exchange (ETDEWEB)

    Chernyshev, G.I.; Luk' yanov, E.P.; Pruslin, Y.A.; Zabrodin, P.I.

    1981-04-25

    The injector can be used with remote introduction of indicators into a borehole for study in an oil well of the parameters of movement of fluid currents, control of the state of the equipment, and study of the properties of the rocks. Proposed is a method of increasing the reliability of operation of the injector by stabilizing the rate of its dispersing. Introduced to the injector of a solid indicator are auxiliary brackets and a cathode made from nonmetallic electrical conducting material and reinforced at the end by an elastic bracket. The auxillary cathode is attached to the end surface of the anode and cathode.

  18. Economic Indicators Selected Countries.

    Science.gov (United States)

    1987-12-01

    DEFENCE I ECONOMIC INDICATORS SELECTED COUNTRIES DECEMBER QUARTER 1987 . ’-H ISSUED BY MANPOWER POLICY & STRATEGIES BRANCH " "’ :.S S ’,1l f ,am -m mW...100 Sour:e: Main Economic Indicators (OECD) Manufactured Basic Metal Year Goods Chemicals Metals Products 1980 100 100 100 100 1981 110 117 102 107...Earnings of all 1982 1986 7.4 Male Employees (a) Aug 1986 Aug 1987 4.8 Hourly Wace Rates 3 1979 1987 lt.2 Garden Island 1983 1987 6.7 Dockyards Dec

  19. Indications for coronary angiography

    International Nuclear Information System (INIS)

    Kaltenbach, M.; Vallbracht, C.

    1985-01-01

    Today selective coronary angiography, introduced by Sones in 1957, is used as clinical routine for diagnosing morphological changes in the coronary arteries. Hitherto, more recent techniques such as digital subtraction angiography cannot provide comparable information. Strict criteria for its indication depending on possible therapeutic consequences, have to be applied, although the risk is low with a letality of 0.01 to 0.05 percent. Radionuclear investigations can be used as additional tool in selected cases. The careful indication for coronary angiography usually implies the possible need for coronary bypass graft surgery of balloon angioplasty. (orig./MG) [de

  20. The logarithmic hypervolume indicator

    DEFF Research Database (Denmark)

    Friedrich, Tobias; Bringmann, Karl; Voß, Thomas

    2011-01-01

    It was recently proven that sets of points maximizing the hypervolume indicator do not give a good multiplicative approximation of the Pareto front. We introduce a new “logarithmic hypervolume indicator” and prove that it achieves a close-to-optimal multiplicative approximation ratio. This is exp...

  1. Maslov indices and monodromy

    International Nuclear Information System (INIS)

    Dullin, H R; Robbins, J M; Waalkens, H; Creagh, S C; Tanner, G

    2005-01-01

    We prove that for a Hamiltonian system on a cotangent bundle that is Liouville-integrable and has monodromy the vector of Maslov indices is an eigenvector of the monodromy matrix with eigenvalue 1. As a corollary, the resulting restrictions on the monodromy matrix are derived. (letter to the editor)

  2. Lichen indicator [Section 4

    Science.gov (United States)

    Paul L. Patterson; Susan Will-Wolf; Marie T. Trest

    2009-01-01

    Lichens are very responsive to environmental stressors in forests, including changes in forest structure, air quality, and climate. Each lichen species on a plot is an indicator of how lichen communities respond to ecological conditions. Individual lichen species occur erratically and even common species are often absent from plots with suitable habitat. The combined...

  3. LEADING WITH LEADING INDICATORS

    International Nuclear Information System (INIS)

    PREVETTE, S.S.

    2005-01-01

    This paper documents Fluor Hanford's use of Leading Indicators, management leadership, and statistical methodology in order to improve safe performance of work. By applying these methods, Fluor Hanford achieved a significant reduction in injury rates in 2003 and 2004, and the improvement continues today. The integration of data, leadership, and teamwork pays off with improved safety performance and credibility with the customer. The use of Statistical Process Control, Pareto Charts, and Systems Thinking and their effect on management decisions and employee involvement are discussed. Included are practical examples of choosing leading indicators. A statistically based color coded dashboard presentation system methodology is provided. These tools, management theories and methods, coupled with involved leadership and employee efforts, directly led to significant improvements in worker safety and health, and environmental protection and restoration at one of the nation's largest nuclear cleanup sites

  4. Environmental indicators for buildings

    DEFF Research Database (Denmark)

    Dammann, S.

    Whenever we shop, the products we consider buying are labelled with the economical price we have to pay if we want to purchase them - an important parameter in our decisions as purchasers. The increrasing awareness for environmental limits and backlashes of human activities also in the building...... sector have fostered the wish to define 'the ecological price' of a building as a help for environmental conscious decision-making. In a social constructivist approach this Ph.D. thesis looks across and beyond the manifold existing approaches for environmental indicators for buildings. It acknowledges...... in the Netherlands. It identifies lines of conflict and areas of consent betweeen the relevant actors and elaborates scenarios for a possible closure of ongoing debate about environmental indicators for buildings....

  5. 15. Basic economic indicators

    International Nuclear Information System (INIS)

    Carless, J.; Dow, B.; Farivari, R.; O'Connor, J.; Fox, T.; Tunstall, D.; Mentzingen, M.

    1992-01-01

    The clear value of economic data and analysis to decisionmakers has motivated them to mandate the creation of extensive global economic data sets. This chapter contains a set of these basic economic data, which provides the context for understanding the causes and the consequences of many of the decisions that affect the world's resources. Many traditional economic indicators fail to account for the depletion or deterioration of natural resources, the long-term consequences of such depletion, the equitable distribution of income within a country, or the sustainability of current economic practices. The type of measurement shown here, however, is still useful in showing the great differences between the wealthiest and the poorest countries. Tables are given on the following: Gross national product and official development assistance 1969-89; External debt indicators 1979-89; Central government expenditures; and World commodity indexes and prices 1975-89

  6. Trochleoplasty: Indications and Technique.

    Science.gov (United States)

    Nolan, John E; Schottel, Patrick C; Endres, Nathan K

    2018-05-09

    Trochlear dysplasia is a well-described risk factor for patellar instability. Trochleoplasty has emerged as a procedure within the surgical armamentarium for patellar instability, yet its role is unclear. A variety of trochleoplasty procedures have emerged. The purpose of this review is to clarify indications for trochleoplasty, outline the technical steps involved in performing common trochleoplasties and report the published outcomes and potential complications of these procedures. Patellar instability with severe trochlear dysplasia is the main indication for trochleoplasty. Three types of trochleoplasty have emerged: (1) lateral facet elevation; (2) sulcus deepening; and (3) recession wedge. Deepening and recession wedge trochleoplasties are the most commonly performed. Trochleoplasty is a surgical option for addressing patellar instability in patients with severe trochlear dysplasia. Deepening and recession wedge trochleoplasties that address Dejour B and D dysplastic trochleas are the most studied, with both short- and midterm outcomes reported. Long-term outcomes are lacking and comparative studies are needed.

  7. Lichens as bio indicators

    International Nuclear Information System (INIS)

    2003-01-01

    This publication discusses the use of lichens as biological indicators. Perennial growth, long life, efficient take-up of mineral nutrients from air and rain and small loss of nutrition are properties that make lichens suitable as biological indicators. In surveys and monitoring, species diversity and coverage by organisms that live as epiphytes on tree trunks have been the most commonly used parameters. A decline in the occurrence of this type of lichen is often related to the content of sulphur compounds in the air and it has been demonstrated that many species are sensitive to sulphur dioxide. It is also known that the growth of many types of lichens increases with a moderate increase in available nitrogen. In South Norway, pollution sensitive species such as Bryoria spp. have advanced strongly, which is probably due to less sulphur in the rain and a higher content of nutrition in the form of nitrate and ammonium

  8. Publication point indicators

    DEFF Research Database (Denmark)

    Elleby, Anita; Ingwersen, Peter

    2010-01-01

    The paper presents comparative analyses of two publication point systems, The Norwegian and the in-house system from the interdiscplinary Danish Institute for International Studies (DIIS), used as case in the study for publications published 2006, and compares central citation-based indicators...... with novel publication point indicators (PPIs) that are formalized and exemplified. Two diachronic citation windows are applied: 2006-07 and 2006-08. Web of Science (WoS) as well as Google Scholar (GS) are applied to observe the cite delay and citedness for the different document types published by DIIS...... for all document types. Statistical significant correlations were only found between WoS and GS and the two publication point systems in between, respectively. The study demonstrates how the nCPPI can be applied to institutions as evaluation tools supplementary to JCI in various combinations...

  9. Radioisotopic indicators in microbiology

    International Nuclear Information System (INIS)

    Isamov, N.N.

    1976-01-01

    The book comprises data obtained by the laboratory of radiobiology (Uzbek Research Veterinary Institute) for 15 years and sums up data of domestic and foreign scientists; it discusses problems of the utilization of radioactive isotopes of sulphur, cadmium, phosphorus and other chemical elements by microorganisms; indicates the specificity of the utilization of radioisotopes in microbiology. The influence is considered of external factors on the inclusion of radioisotopes into microorganisms, methods are discussed of obtaining labelled microorganisms and their antigens, radioactivity of bacteria is considered as affected by the consistency and composition of the nutritive medium and other problems

  10. Health indicators 1991.

    Science.gov (United States)

    Dawson, N

    1991-01-01

    This is the second edition of a database developed by the Canadian Centre for Health Information (CCHI). It features 49 health indicators, under one cover containing the most recent data available from a variety of national surveys. This information may be used to establish health goals for the population and to offer objective measures of their success. The database can be accessed through CANSIM, Statistics Canada's socio-economic electronic database and retrieval system, or through a personal computer package which enables the user to retrieve and analyze the 1.2 million data points in the system.

  11. Main economics indicators

    International Nuclear Information System (INIS)

    1995-11-01

    This monthly publication, based on the most up-to-date techniques of tabular and graphical presentation, is designed to provide at a glance a picture of the most recent changes in the economies of the OECD countries, and a collection of international statistics on the economic developments which have affected the OECD area in the past few years. The indicators selected cover national accounts, industrial production, business surveys, deliveries, stocks and orders, construction, internal trade, labour, wages, prices, domestic and foreign finance, interest rates, trade and payments. (author)

  12. Dialysate bacterial endotoxin as a prognostic indicator of peritoneal dialysis related peritonitis.

    Science.gov (United States)

    Szeto, Cheuk-Chun; Lai, Ka-Bik; Chow, Kai-Ming; Kwan, Bonnie Ching-Ha; Law, Man-Ching; Pang, Wing-Fai; Ma, Terry King-Wing; Leung, Chi-Bon; Li, Philip Kam-Tao

    2016-12-01

    Peritonitis is the major complication of peritoneal dialysis (PD). The aim of our present study is to explore the prognostic value of endotoxin level in PD effluent for the prediction of treatment failure in PD-related peritonitis. We studied 325 peritonitis episodes in 223 patients. PD effluent (PDE) was collected every 5 days for endotoxin level and leukocyte count. Patients were followed for relapsing or recurrent peritonitis. We found 20 episodes (6.2%) had primary treatment failure; 41 (12.6%) developed relapsing, 19 (5.8%) had recurrent, and 22 (6.8%) had repeat episodes. Endotoxin was detectable in the PDE of 19 episodes (24.4%) caused by Gram negative organisms, 4 episodes (6.8%) of mixed bacterial growth, and none of the culture negative episodes or those by Gram positive organisms. For episodes caused by Gram negative bacteria, a detectable endotoxin level in PDE on day 5 had a sensitivity and specificity of 66.7% and 83.3%, respectively, for predicting primary treatment failure. In contrast, PDE leukocyte count > 1000 per mm3 on day 5 had a sensitivity and specificity of 88.9% and 89.1%, respectively; the addition of PDE endotoxin assay did not improve the sensitivity or specificity. We conclude that detectable endotoxin in PDE 5 days after antibiotic therapy might predict primary treatment failure in peritonitis episodes caused by Gram negative organisms. However, the sensitivity and specificity of PDE endotoxin assay was inferior to PDE leukocyte count. © 2016 Asian Pacific Society of Nephrology.

  13. Position indicating device

    International Nuclear Information System (INIS)

    Fellchenfeld, M.M.; Connors, G.R.

    1987-01-01

    This patent describes a position indicating device for producing an indication of the position of a displaceable structure comprising: a position representing member mounted for movement in response to displacement of the structure; sensing elements spaced apart along the defined path such that each element is associated with a respective location along the defined path; means operatively coupling the elements into respective pairs of elements, having, for each pair of elements, an output producing a signal only when a single element of its respective pair is responding to the presence of the member; signal producing members each operative for producing a signal representing a predetermined logic state in response to a predetermined input signal, the number of the signal producing members being smaller than the number of the sensing elements; and circuit means operatively connecting the outputs to the signal producing members for causing a signal at each output to produce a predetermined input signal at a corresponding signal producing member and for causing a predetermined input signal to be produced at least one the signal producing member whenever a signal is present at either one of at least two of the outputs

  14. Tamper indicating packaging

    International Nuclear Information System (INIS)

    Baumann, M.J.; Bartberger, J.C.; Welch, T.D.

    1994-01-01

    Protecting sensitive items from undetected tampering in an unattended environment is crucial to the success of non-proliferation efforts relying on the verification of critical activities. Tamper Indicating Packaging (TIP) technologies are applied to containers, packages, and equipment that require an indication of a tamper attempt. Examples include: the transportation and storage of nuclear material, the operation and shipment of surveillance equipment and monitoring sensors, and the retail storage of medicine and food products. The spectrum of adversarial tampering ranges from attempted concealment of a pin-hole sized penetration to the complete container replacement, which would involve counterfeiting efforts of various degrees. Sandia National Laboratories (SNL) has developed a technology base for advanced TIP materials, sensors, designs, and processes which can be adapted to various future monitoring systems. The purpose of this technology base is to investigate potential new technologies, and to perform basic research of advanced technologies. This paper will describe the theory of TIP technologies and recent investigations of TIP technologies at SNL

  15. Enhanced tamper indicator

    Science.gov (United States)

    Garcia, Anthony R.; Johnston, Roger G.

    2003-07-08

    The present invention provides an apparatus and method whereby the reliability and tamper-resistance of tamper indicators can be improved. A flexible connector may be routed through a latch for an enclosure such as a door or container, and the free ends of the flexible connector may be passed through a first locking member and firmly attached to an insert through the use of one or more attachment members such as set screws. A second locking member may then be assembled in interlocking relation with the first locking member to form an interlocked assembly around the insert. The insert may have one or more sharp projections extending toward the first or second locking member so that any compressive force applied in an attempt to disassemble the interlocked assembly results in permanent, visible damage to the first or second locking member.

  16. Position indication apparatus

    Energy Technology Data Exchange (ETDEWEB)

    Masuda, T

    1964-02-24

    A plurality of magnetically operated switches are spaced equally in the hollow tube of a control rod actuating mechanism. One side of each switch is connected, via a low resistance, to a corresponding tap of a low resistance voltage divider network consisting of an equivalent number of low resistance sections with the opposite side of each switch connected to a common conducting wire A. To both ends of the voltage dividing network are connected, respectively, conducting wires B and C. Wires A, B, and C are further coupled to a fuel rod position indicator comprising a voltmeter and power source external to the control rod actuating member. The control rod actuating member is adapted to slide in the hollow tube so that switches passing a position facing a magnet secured to the lower end of the actuating member are rendered closed. Hence, the position of the control rod may be read by reading the voltage off the meter.

  17. Lichens as pollution indicators

    Energy Technology Data Exchange (ETDEWEB)

    Rose, F

    1970-01-01

    Although lichens are generally considered to be of little use to man, their sensitivity to air pollution makes them good biological indicators. The author describes how this feature can help to establish relative degrees of air pollution. He notes areas where lichens are reduced in number and vigor, and some in which they have disappeared altogether. He challenges the idea that dryness is responsible, since they have also disappeared from damp woodland areas. Experimental work supports the view that sulfur dioxide is the major factor rather than smoke, although there is no definitive proof. Lichen damage correlates best with mean winter levels of air pollution by SO/sub 2/. 16 references, 1 figure.

  18. Cytological indicators: Haematopoetic effects

    International Nuclear Information System (INIS)

    Fliedner, T.M.; Nothdurft, W.

    1986-01-01

    It is the aim of this paper, intended more as a general outline than a comprehensive review, to elucidate the most prominent events in the sequence of radiation induced cytological changes in the hemopoietic system taking its functional organisation and the cytokinetics of blood cell production into consideration. As could be shown, there are about ten different categories of quantitative and qualitative parameters based on methods ranging from stem cell determinations to tests for mature blood cell function that in principle are available for assessment of radiation damage to the bone marrow and that have been applied to men exposed to ionizing radiation. Some of these indicator systems have proven for a long period of time to be of essential value and to be quite feasible in practice under routine conditions. Considerable methodological progress, however, is needed for others before decisions about their practical applicability can be made. (orig.)

  19. International energy indicators

    International Nuclear Information System (INIS)

    Rossi, E. Jr.

    1981-12-01

    Data are tabulated and graphically represented on international energy indicators. The following are presented: world crude oil production, 1974 to October 1981; OPEC crude oil productive capacity; world crude oil and refined product inventory levels, 1975 to October, 1981; oil consumption in OECD countries, 1975 to October 1981; USSR crude oil production and exports, 1975 to October, 1981; free world and US nuclear electricity generation, 1973 to December, 1981 and current capacity. Specific US data presented are: US domestic oil supply, 1977 to June, 1981; US gross imports of crude oil and products, 1973 to October, 1981; landed cost of Saudi crude current and 1974 dollars; US coal trade, 1975 to September, 1981; US natural gas trade, 1975 to October, 1981; summary of US merchandise trade, 1977 to October, 1981; and energy/GNP ratio

  20. Flammability Indices for Refrigerants

    Science.gov (United States)

    Kataoka, Osami

    This paper introduces a new index to classify flammable refrigerants. A question on flammability indices that ASHRAE employs arose from combustion test results of R152a and ammonia. Conventional methods of not only ASHRAE but also ISO and Japanese High-pressure gas safety law to classify the flammability of refrigerants are evaluated to show why these methods conflict with the test results. The key finding of this paper is that the ratio of stoichiometric concentration to LFL concentration (R factor) represents the test results most precisely. In addition, it has excellent correlation with other flammability parameters such as flame speed and pressure rise coefficient. Classification according to this index gives reasonable flammability order of substances including ammonia, R152a and carbon monoxide. Theoretical background why this index gives good correlation is also discussed as well as the insufficient part of this method.

  1. Teriparatide - Indications beyond osteoporosis

    Directory of Open Access Journals (Sweden)

    Marilyn Lee Cheng

    2012-01-01

    Full Text Available Osteoporosis is a condition of impaired bone strength that results in an increased risk of fracture. The current and most popular pharmacological options for the treatment of osteoporosis include antiresorptive therapy, in particular, oral bisphosphonates (alendronate, risedronate, ibandronate. Anabolic agents like teriparatide have widened our therapeutic options. They act by directly stimulating bone formation and improving bone mass quantity and quality. Two forms of recombinant human parathyroid hormone (PTH are available : full-length PTH (PTH 1-84; approved in the EU only and the 1-34 N-terminal active fragment of PTH (teriparatide, US FDA approved. This review aims to discuss the benefits of teriparatide beyond the currently licensed indications like fracture healing, dental stability, osteonecrosis of jaw, hypoparathyroidism, and hypocalcemia.

  2. Fetal Echocardiography and Indications

    Directory of Open Access Journals (Sweden)

    Melih Atahan Güven

    2008-09-01

    Full Text Available Congenital heart diseases are encountered in 0.8% of live births and are among the most frequently diagnosed malformations. At least half of these anomalies end up with death or require surgical interventions and are responsible for 30% of the perinatal mortality. Fetal echocardiography is the sum of knowledge, skill and orientation rather than knowing the embryologic details of the fetal heart. The purpose of fetal echocardiography is to document the presence of normal fetal cardiac anatomy and rhythm in high risk group and to define the anomaly and arrhythmia if present. A certain sequence should be followed during the evaluation of fetal heart. Sequential segmental analysis (SSA and basic definition terminology made it possible to determine a lot of complex cardiac anomalies during prenatal period. By the end of 1970’s, Shinebourne started using sequential segmental analysis for fetal cardiac evaluation and today, prenatal diagnosis of congenital heart disease is possible without any confusion. In this manner, whole fetal heart can be evaluated as the relation of three segments (atria, ventricles and the great arteries with each other, irrelevant of complexity of a possible cardiac anomaly. Presence of increased nuchal thickness during early gestation and abnormal four-chamber-view during ultrasonography by the obstetrician presents a clear indication for fetal echocardiography,however, one should keep in mind that 80-90% of the babies born with a congenital heart disease do not have a familial or maternal risk factor. In addition, it should be remembered that expectant mothers with diabetes mellitus pose an indication for fetal echocardiography.

  3. Precipitation Indices Low Countries

    Science.gov (United States)

    van Engelen, A. F. V.; Ynsen, F.; Buisman, J.; van der Schrier, G.

    2009-09-01

    Since 1995, KNMI published a series of books(1), presenting an annual reconstruction of weather and climate in the Low Countries, covering the period AD 763-present, or roughly, the last millennium. The reconstructions are based on the interpretation of documentary sources predominantly and comparison with other proxies and instrumental observations. The series also comprises a number of classifications. Amongst them annual classifications for winter and summer temperature and for winter and summer dryness-wetness. The classification of temperature have been reworked into peer reviewed (2) series (AD 1000-present) of seasonal temperatures and temperature indices, the so called LCT (Low Countries Temperature) series, now incorporated in the Millennium databases. Recently we started a study to convert the dryness-wetness classifications into a series of precipitation; the so called LCP (Low Countries Precipitation) series. A brief outline is given here of the applied methodology and preliminary results. The WMO definition for meteorological drought has been followed being that a period is called wet respectively dry when the amount of precipitation is considerable more respectively less than usual (normal). To gain a more quantitative insight for four locations, geographically spread over the Low Countries area (De Bilt, Vlissingen, Maastricht and Uccle), we analysed the statistics of daily precipitation series, covering the period 1900-present. This brought us to the following definition, valid for the Low Countries: A period is considered as (very) dry respectively (very) wet if over a continuous period of at least 60 days (~two months) cq 90 days (~three months) on at least two out of the four locations 50% less resp. 50% more than the normal amount for the location (based on the 1961-1990 normal period) has been measured. This results into the following classification into five drought classes hat could be applied to non instrumental observations: Very wet period

  4. Skin cancer associated with commonly prescribed drugs: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and statins -weighing the evidence.

    Science.gov (United States)

    Nardone, Beatrice; Orrell, Kelsey A; Vakharia, Paras P; West, Dennis P

    2018-02-01

    Skin cancers, including both malignant melanoma (MM) and nonmelanoma skin cancer (NMSC), are the most commonly diagnosed cancers in the US. The incidence of both MM and NMSC continues to rise. Areas covered: Current evidence for an association between four of the most commonly prescribed classes of drugs in the U.S. and risk for MM and NMSC is reported. Medline was searched (January 2000 to May 2017) for each drug in the classes and for 'basal cell carcinoma', 'squamous cell carcinoma', 'non-melanoma skin cancer', 'skin cancer' and 'melanoma'. Skin cancer risk information was reported for: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins). Expert opinion: Since skin cancer risk is associated with all four classes of these commonly prescribed drugs that represent nearly 20% of the Top 100 drugs in the U.S., these important findings warrant enhanced education, especially for prescribers and those patients at high risk for skin cancer.

  5. Risk-based safety indicators

    International Nuclear Information System (INIS)

    Szikszai, T.

    1997-01-01

    The presentation discusses the following issues: The objectives of the risk-based indicator programme. The characteristics of the risk-based indicators. The objectives of risk-based safety indicators - in monitoring safety; in PSA applications. What indicators? How to produce the risk based indicators? PSA requirements

  6. Should researchers use single indicators, best indicators, or multiple indicators in structural equation models?

    Directory of Open Access Journals (Sweden)

    Hayduk Leslie A

    2012-10-01

    Full Text Available Abstract Background Structural equation modeling developed as a statistical melding of path analysis and factor analysis that obscured a fundamental tension between a factor preference for multiple indicators and path modeling’s openness to fewer indicators. Discussion Multiple indicators hamper theory by unnecessarily restricting the number of modeled latents. Using the few best indicators – possibly even the single best indicator of each latent – encourages development of theoretically sophisticated models. Additional latent variables permit stronger statistical control of potential confounders, and encourage detailed investigation of mediating causal mechanisms. Summary We recommend the use of the few best indicators. One or two indicators are often sufficient, but three indicators may occasionally be helpful. More than three indicators are rarely warranted because additional redundant indicators provide less research benefit than single indicators of additional latent variables. Scales created from multiple indicators can introduce additional problems, and are prone to being less desirable than either single or multiple indicators.

  7. [Indicator condition guided human immunodeficiency virus requesting in primary health care: results of a collaboration].

    Science.gov (United States)

    Cayuelas-Redondo, Laia; Menacho-Pascual, Ignacio; Noguera-Sánchez, Pablo; Goicoa-Gago, Carmen; Pollio-Peña, Gernónimo; Blanco-Delgado, Rebeca; Barba-Ávila, Olga; Sequeira-Aymar, Ethel; Muns, Mercè; Clusa, Thais; García, Felipe; León, Agathe

    2015-12-01

    The search of HIV infected patients guided by indicator conditions (IC) is a strategy used to increase the early detection of HIV. The objective is to analyze whether a collaboration to raise awareness of the importance of early detection of HIV in 3 primary care centers influenced the proportion of HIV serology requested. Multicenter retrospective study was conducted comparing the baseline and a post-collaboration period. The collaboration consisted of training sessions and participation in the HIDES study (years 2009-2010). Patients between 18 and 64 years old with newly diagnosed herpes zoster, seborrheic eczema, mononucleosis syndrome, and leucopenia/thrombocytopenia in 3 primary care centers in 2008 (baseline period) and 2012 (post-collaboration period). The sociodemographic variables, HIV risk conditions, requests for HIV serology, and outcomes were evaluated. A total of 1,219 ICs were included (558 in 2008 and 661 in 2012). In 2008 the number of HIV tests in patients with an IC was 3.9%, and rose to 11.8% in 2012 (Pde Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  8. Values of Kp Indices, Ap Indices, Cp Indices, C9 Indices, Sunspot Number, and 10.7 cm Flux

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This data file consists of Kp indices, Ap indices, Cp indices, C9 indices, sunspot number, and 10.7 cm flux. The most often requested parameter of this file are the...

  9. Effect of an intervention on quality indicators for improving the treatment of hyperglycemia in patients hospitalized in noncritical areas.

    Science.gov (United States)

    Ena, J; Gómez-Huelgas, R; Zapatero-Gaviria, A; Vázquez-Rodriguez, P; González-Becerra, C; Romero-Sánchez, M; Igúzquiza-Pellejero, M J; Artero-Mora, A; Varela-Aguilar, J M

    2016-10-01

    We evaluated the effect of an intervention on certain quality indicators employed for improving the treatment of hospital hyperglycemia. A multicenter cross-sectional study was conducted on patients with hyperglycemia hospitalized in the internal medicine departments of 44 hospitals evaluated in 2 time periods: 2014 (baseline period) and 2015 (postintervention period). The intervention consisted of the dissemination of the indicators obtained in 2014 and the objectives for improvement. As indicators, we assessed the frequency of glucose monitoring adapted to the patient's dietary intake or medication, the use of basal-bolus or basal-bolus-correction insulin therapy as the preferred control method of hyperglycemia and the recent availability of HbA1c prior to hospital discharge. A total of 506 and 562 patients were assessed in 2014 and 2015, respectively. The results of the indicators in the baseline and postintervention periods were as follows: blood glucose monitoring adapted to the dietary intake or the medication (71.5 vs. 74.1%, P=.33), use of insulin in basal-correction regimen (32 vs. 32.6%, P=.61) or basal-bolo-correction (20.7 vs. 24, P=.20) and recent HbA1c value (54.1 vs. 66.3%, Pde Medicina Interna (SEMI). All rights reserved.

  10. Statistical Indicators for Religious Studies: Indicators of Level and Structure

    Science.gov (United States)

    Herteliu, Claudiu; Isaic-Maniu, Alexandru

    2009-01-01

    Using statistic indicators as vectors of information relative to the operational status of a phenomenon, including a religious one, is unanimously accepted. By introducing a system of statistic indicators we can also analyze the interfacing areas of a phenomenon. In this context, we have elaborated a system of statistic indicators specific to the…

  11. Indicators for Monitoring Soil Biodiversity

    DEFF Research Database (Denmark)

    Bispo, A.; Cluzeau, D.; Creamer, R.

    2009-01-01

    is made for a set of suitable indicators for monitoring the decline in soil biodiversity (Bispo et al. 2007). These indicators were selected both from a literature review and an inventory of national monitoring programmes. Decline in soil biodiversity was defined as the reduction of forms of life living...... indicators are actually measured.   For monitoring application it was considered in ENVASSO that only three key indicators per soil stress were practical. For indicating biodiversity decline it was difficult to arrive at a small set of indicators due to the complexity of soil biota and functions. Therefore...

  12. Risk-based safety indicators

    International Nuclear Information System (INIS)

    Sedlak, J.

    2001-12-01

    The report is structured as follows: 1. Risk-based safety indicators: Typology of risk-based indicators (RBIs); Tools for defining RBIs; Requirements for the PSA model; Data sources for RBIs; Types of risks monitored; RBIs and operational safety indicators; Feedback from operating experience; PSO model modification for RBIs; RBI categorization; RBI assessment; RBI applications; Suitable RBI applications. 2. Proposal for risk-based indicators: Acquiring information from operational experience; Method of acquiring safety relevance coefficients for the systems from a PSA model; Indicator definitions; On-line indicators. 3. Annex: Application of RBIs worldwide. (P.A.)

  13. Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress.

    Science.gov (United States)

    Bivalacqua, Trinity J; Musicki, Biljana; Hsu, Lewis L; Berkowitz, Dan E; Champion, Hunter C; Burnett, Arthur L

    2013-01-01

    Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.

  14. Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress.

    Directory of Open Access Journals (Sweden)

    Trinity J Bivalacqua

    Full Text Available Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.

  15. Tiltmeter Indicates Sense of Slope

    Science.gov (United States)

    Lonborg, J. O.

    1985-01-01

    Tiltmeter indicates sense and magnitude of slope used in locations where incline not visible to operator. Use of direct rather than alternating current greatly simplifies design of instrument capable of indicating sense of slope.

  16. NEFSC Survey Indices of Abundance

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Northeast Fisheries Survey Bottom trawl survey indices of abundance such as stratified mean number per tow or mean weight per tow by species stock. Includes indices...

  17. Divergence Measures as Diversity Indices

    OpenAIRE

    Abou-Moustafa, Karim T.

    2014-01-01

    Entropy measures of probability distributions are widely used measures in ecology, biology, genetics, and in other fields, to quantify species diversity of a community. Unfortunately, entropy-based diversity indices, or diversity indices for short, suffer from three problems. First, when computing the diversity for samples withdrawn from communities with different structures, diversity indices can easily yield non-comparable and hard to interpret results. Second, diversity indices impose weig...

  18. Nordic eHealth Indicators

    DEFF Research Database (Denmark)

    Hyppönen, Hannele; Faxvaag, Arild; Gilstad, Heidi

    2013-01-01

    eHealth indicator and benchmarking activities are rapidly increasing nationally and internationally. The work is rarely based on a transparent methodology for indicator definition. This article describes first results of testing an indicator methodology for defining eHealth indicators, which...... was reported at the Medical Informatics Europe conference in 2012. The core elements of the methodology are illustrated, demonstrating validation of each of them in the context of Nordic eHealth Indicator work. Validation proved the importance of conducting each of the steps of the methodology, with several...

  19. Performance indicators of work activity.

    Science.gov (United States)

    Lahoz, Manoela de Assis; Camarotto, João Alberto

    2012-01-01

    The measurement of performance is a current topic in the management of people in companies, used as a parameter of effectiveness of processes and operations of production. The methods and models of the indicators of current use in the production have concentrated in the assessment of people's performance as determinative resource of the organizational success in the search for the competitiveness. Associated with the classic indicators of performance assessment of the production proceeding, other indicators are used in the assessment of risks and hazards, however with methods focused in the tasks, without connection with the real work activity. The present article explores literature on the models of performance measurement in use in companies and a field research to understand how companies interpret and use indicators that relate health and work, to direct future studies on the subject. Regarding the literature review, one can see that health indicators can be basically divided into two major groups: the legal and managerial indicators. When conducting case studies, it can be realized that companies do not have precisely the concept of health indicator, or were unable to define which of the indicators could be considered indicators of health, considering that absenteeism was the indicator mentioned by the four companies.

  20. New formulae for Zagreb indices

    Science.gov (United States)

    Cangul, Ismail Naci; Yurttas, Aysun; Togan, Muge; Cevik, Ahmet Sinan

    2017-07-01

    In this paper, we study with some graph descriptors also called topological indices. These descriptors are useful in determination of some properties of chemical structures and preferred to some earlier descriptors as they are more practical. Especially the first and second Zagreb indices together with the first and second multiplicative Zagreb indices are considered and they are calculated in terms of the smallest and largest vertex degrees and vertex number for some well-known classes of graphs.

  1. Craniometric Indices of Nigeria Skulls

    OpenAIRE

    Orish CN; Ibeachu PC

    2016-01-01

    Introduction: Craniometric indices show the percentage relationship between different dimensions. It is an important parameter for classification of race and sex of individuals of unknown identity. This study was undertaken to determine the craniometric indices of gnathic, palatal, orbital, cranial and nasal indices of Nigerian skulls. Materials and Methods: One hundred adult dry skulls, (78 males, and 22 females) free from damage and deformities from eleven Departments of Anatomy in Nige...

  2. The politics of SEA indicators

    DEFF Research Database (Denmark)

    Gao, Jingjing; Kørnøv, Lone; Christensen, Per

    2013-01-01

    The use of indicators is not only technical and science-led, but also a value-laden social process, and thus concerns public participation, political judgment and decision-making. This article approaches the Chinese SEA indicator system from a science-policy interface and aims at: 1) contributing...

  3. Wacky Patents Meet Economic Indicators

    DEFF Research Database (Denmark)

    Czarnitzki, Dirk; Hussinger, Katrin; Schneider, Cédric

    2011-01-01

    We investigate whether standard indicators can distinguish between “wacky” patents and a control group. Forward citations are good predictors of importance. However, “wacky” patents have higher originality, generality and citation lags, suggesting that these indicators should be interpreted...

  4. Performance indicators for power reactors

    International Nuclear Information System (INIS)

    Gillies, C.; White, M.

    1995-11-01

    A review of Canadian and worldwide performance indicator definitions and data was performed to identify a set of indicators that could be used for comparison of performance among nuclear power plants. The results of this review are to be used as input to an AECB team developing a consistent set of performance indicators for measuring Canadian power reactor safety performance. To support the identification of performance indicators, a set of criteria was developed to assess the effectiveness of each indicator for meaningful comparison of performance information. The project identified a recommended set of performance indicators that could be used by AECB staff to compare the performance of Canadian nuclear power plants among themselves, and with international performance. The basis for selection of the recommended set and exclusion of others is provided. This report provides definitions and calculation methods for each recommended performance indicator. In addition, a spreadsheet has been developed for comparison and trending for the recommended set of indicators. Example trend graphs are included to demonstrate the use of the spreadsheet. (author). 50 refs., 11 tabs., 3 figs

  5. Quality Indicators for Learning Analytics

    Science.gov (United States)

    Scheffel, Maren; Drachsler, Hendrik; Stoyanov, Slavi; Specht, Marcus

    2014-01-01

    This article proposes a framework of quality indicators for learning analytics that aims to standardise the evaluation of learning analytics tools and to provide a mean to capture evidence for the impact of learning analytics on educational practices in a standardised manner. The criteria of the framework and its quality indicators are based on…

  6. EJSCREEN Demographic Indicators 2015 Public

    Science.gov (United States)

    EJSCREEN uses demographic factors as very general indicators of a community's potential susceptibility to the types of environmental factors included in this screening tool. There are six demographic indicators: Demographic Index, Supplementary Demographic Index, Individuals under Age 5, Individuals over Age 64, Percent Low-Income, Linguistic Isolation, Percent Minority, and Less than High School Education.

  7. Bayesian Sampling using Condition Indicators

    DEFF Research Database (Denmark)

    Faber, Michael H.; Sørensen, John Dalsgaard

    2002-01-01

    of condition indicators introduced by Benjamin and Cornell (1970) a Bayesian approach to quality control is formulated. The formulation is then extended to the case where the quality control is based on sampling of indirect information about the condition of the components, i.e. condition indicators...

  8. AREVA sustainable development indicators guidelines

    International Nuclear Information System (INIS)

    2003-12-01

    These guidelines set out the procedures used to measure and report the sustainable development and continuous progress data and indicators used within the Areva Group. It defines the scope of the guide, the list of indicators, the measurement and calculation procedures, the internal and external audits. (A.L.B.)

  9. Geomagnetic Kn, Ks, Km Indices

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — A full description of the indices Kn, Ks, Km is given in a monography,"Indices Kn, Ks et Km, 1964-1967", edited in 1968 by the Centre National de la Recherche...

  10. Cancer rehabilitation indicators for Europe

    NARCIS (Netherlands)

    Baili, Paolo; Hoekstra-Weebers, Josette; Van Hoof, Elke; Bartsch, Hans Helge; Travado, Luzia; Garami, Miklos; Di Salvo, Francesca; Micheli, Andrea; Veerus, Piret

    Little is known of cancer rehabilitation needs in Europe. EUROCHIP-3 organised a group of experts to propose a list of population-based indicators used for describing cancer rehabilitation across Europe. The aim of this study is to present and discuss these indicators. A EUROCHIP-3 expert panel

  11. Indicator Based and Indicator - Free Electrochemical DNA Biosensors

    National Research Council Canada - National Science Library

    Kerman, Kagan

    2001-01-01

    The utility and advantages of an indicator free and MB based sequence specific DNA hybridization biosensor based on guanine and adenine oxidation signals and MB reduction signals have been demonstrated...

  12. Cancer rehabilitation indicators for Europe

    DEFF Research Database (Denmark)

    Baili, Paolo; Hoekstra-Weebers, Josette; Van Hoof, Elke

    2013-01-01

    , but to obtain comparable data across European countries it will be necessary to administer a questionnaire to randomly selected samples of patients from population-based cancer registry databases. However, three factors complicate questionnaire studies: patients may not be aware that they have cancer......Little is known of cancer rehabilitation needs in Europe. EUROCHIP-3 organised a group of experts to propose a list of population-based indicators used for describing cancer rehabilitation across Europe. The aim of this study is to present and discuss these indicators. A EUROCHIP-3 expert panel...... reached agreement on two types of indicators. (a) Cancer prevalence indicators. These were proposed as a means of characterising the burden of cancer rehabilitation needs by time from diagnosis and patient health status. These indicators can be estimated from cancer registry data or by collecting data...

  13. Decision making with environmental indices

    Science.gov (United States)

    Hoag, Dana L.; Ascough, James C.; Keske-Handley, C.; Koontz, Lynne; Burk, A.R.

    2005-01-01

    Since Ott's seminal book on environmental indices (1978), the use of indices has expanded into several natural resource disciplines, including ecological studies, environmental policymaking, and agricultural economics. However, despite their increasing use in natural resource disciplines, researchers and public decision makers continue to express concern about validity of these instruments to capture and communicate multidimensional, and sometimes disparate, characteristics of research data and stakeholder interests. Our purpose is to demonstrate how useful indices can be for communicating environmental information to decision makers. We discuss how environmental indices have evolved over four stages: 1) simple; 2) compound multicriteria; 3) the impact matrix and 4) disparate stakeholder management. We provide examples of simple and compound indices that were used by policy decision makers. We then build a framework, called an Impact Matrix (IM), that comprehensively accounts for multiple indices but lets the user decide how to integrate them. The IM was shaped from the concept of a financial risk payoff matrix and applied to ecosystem risk. While the IM offers flexibility, it does not address stakeholder preferences about which index to use. Therefore, the last phase in our evolutionary ladder includes stakeholder indices to specifically address disparate stakeholder preferences. Finally, we assert that an environmental index has the potential to increase resource efficiency, since the number of decision making resources may be reduced, and hence improve upon resource productivity

  14. Quality indicators for eye bank

    Directory of Open Access Journals (Sweden)

    Manisha Acharya

    2018-01-01

    Full Text Available Purpose: The aim of this study is to identify quality indicators of the eye bank and validate their effectivity. Methods: Adverse reaction rate, discard rate, protocol deviation rate, and compliance rate were defined as Quality Indicators of the eye bank. These were identified based on definition of quality that captures two dimensions – “result quality” and “process quality.” The indicators were measured and tracked as part of quality assurance (QA program of the eye bank. Regular audits were performed to validate alignment of standard operating procedures (SOP with regulatory and surgeon acceptance standards and alignment of activities performed in the eye bank with the SOP. Prospective study of the indicators was performed by comparing their observed values over the period 2011–2016. Results: Adverse reaction rate decreased more than 8-fold (from 0.61% to 0.07%, discard rate decreased and stabilized at 30%, protocol deviation rate decreased from 1.05% to 0.08%, and compliance rate reported by annual quality audits improved from 59% to 96% at the same time. In effect, adverse reaction rate, discard rate, and protocol deviation rate were leading indicators, and compliance rate was the trailing indicator. Conclusion: These indicators fulfill an important gap in available literature on QA in eye banking. There are two ways in which these findings can be meaningful. First, eye banks which are new to quality measurement can adopt these indicators. Second, eye banks which are already deeply engaged in quality improvement can test these indicators in their eye bank, thereby incorporating them widely and improving them over time.

  15. Quality indicators for eye bank.

    Science.gov (United States)

    Acharya, Manisha; Biswas, Saurabh; Das, Animesh; Mathur, Umang; Dave, Abhishek; Singh, Ashok; Dubey, Suneeta

    2018-03-01

    The aim of this study is to identify quality indicators of the eye bank and validate their effectivity. Adverse reaction rate, discard rate, protocol deviation rate, and compliance rate were defined as Quality Indicators of the eye bank. These were identified based on definition of quality that captures two dimensions - "result quality" and "process quality." The indicators were measured and tracked as part of quality assurance (QA) program of the eye bank. Regular audits were performed to validate alignment of standard operating procedures (SOP) with regulatory and surgeon acceptance standards and alignment of activities performed in the eye bank with the SOP. Prospective study of the indicators was performed by comparing their observed values over the period 2011-2016. Adverse reaction rate decreased more than 8-fold (from 0.61% to 0.07%), discard rate decreased and stabilized at 30%, protocol deviation rate decreased from 1.05% to 0.08%, and compliance rate reported by annual quality audits improved from 59% to 96% at the same time. In effect, adverse reaction rate, discard rate, and protocol deviation rate were leading indicators, and compliance rate was the trailing indicator. These indicators fulfill an important gap in available literature on QA in eye banking. There are two ways in which these findings can be meaningful. First, eye banks which are new to quality measurement can adopt these indicators. Second, eye banks which are already deeply engaged in quality improvement can test these indicators in their eye bank, thereby incorporating them widely and improving them over time.

  16. Variational PDE Models in Image Processing

    National Research Council Canada - National Science Library

    Chan, Tony F; Shen, Jianhong; Vese, Luminita

    2002-01-01

    .... These include astronomy and aerospace exploration, medical imaging, molecular imaging, computer graphics, human and machine vision, telecommunication, auto-piloting, surveillance video, and biometric...

  17. Terascale Optimal PDE Simulations (TOPS) Center

    Energy Technology Data Exchange (ETDEWEB)

    Professor Olof B. Widlund

    2007-07-09

    Our work has focused on the development and analysis of domain decomposition algorithms for a variety of problems arising in continuum mechanics modeling. In particular, we have extended and analyzed FETI-DP and BDDC algorithms; these iterative solvers were first introduced and studied by Charbel Farhat and his collaborators, see [11, 45, 12], and by Clark Dohrmann of SANDIA, Albuquerque, see [43, 2, 1], respectively. These two closely related families of methods are of particular interest since they are used more extensively than other iterative substructuring methods to solve very large and difficult problems. Thus, the FETI algorithms are part of the SALINAS system developed by the SANDIA National Laboratories for very large scale computations, and as already noted, BDDC was first developed by a SANDIA scientist, Dr. Clark Dohrmann. The FETI algorithms are also making inroads in commercial engineering software systems. We also note that the analysis of these algorithms poses very real mathematical challenges. The success in developing this theory has, in several instances, led to significant improvements in the performance of these algorithms. A very desirable feature of these iterative substructuring and other domain decomposition algorithms is that they respect the memory hierarchy of modern parallel and distributed computing systems, which is essential for approaching peak floating point performance. The development of improved methods, together with more powerful computer systems, is making it possible to carry out simulations in three dimensions, with quite high resolution, relatively easily. This work is supported by high quality software systems, such as Argonne's PETSc library, which facilitates code development as well as the access to a variety of parallel and distributed computer systems. The success in finding scalable and robust domain decomposition algorithms for very large number of processors and very large finite element problems is, e.g., illustrated in [24, 25, 26]. This work is based on [29, 31]. Our work over these five and half years has, in our opinion, helped advance the knowledge of domain decomposition methods significantly. We see these methods as providing valuable alternatives to other iterative methods, in particular, those based on multi-grid. In our opinion, our accomplishments also match the goals of the TOPS project quite closely.

  18. An Elliptic PDE Approach for Shape Characterization

    Science.gov (United States)

    Haidar, Haissam; Bouix, Sylvain; Levitt, James; McCarley, Robert W.; Shenton, Martha E.; Soul, Janet S.

    2009-01-01

    This paper presents a novel approach to analyze the shape of anatomical structures. Our methodology is rooted in classical physics and in particular Poisson's equation, a fundamental partial differential equation [1]. The solution to this equation and more specifically its equipotential surfaces display properties that are useful for shape analysis. We present a numerical algorithm to calculate the length of streamlines formed by the gradient field of the solution to this equation for 2D and 3D objects. The length of the streamlines along the equipotential surfaces was used to build a new function which can characterize the shape of objects. We illustrate our method on 2D synthetic and natural shapes as well as 3D medical data. PMID:17271986

  19. Sustainable development and energy indicators

    International Nuclear Information System (INIS)

    Pop-Jordanov, Jordan

    2002-01-01

    Starting from the basic definition of sustainable development and its four dimensions, the role of indicators for sustainable energy development is analysed. In particular, it is shown that important energy efficiency indicators belong in fact to energy supply efficiency, while the end-use energy efficiency could be more pertinently represented by energy intensity indicators. Furthermore, the negentropic effects of science and technology related sustainable energy scenarios are pointed out. Finally, the sustainable development is related to wisdom, interpreted as a sum of knowledge, morality and timing. (Author)

  20. Sustainable Transport and Performance Indicators

    DEFF Research Database (Denmark)

    Gudmundsson, H.

    2004-01-01

    ustainable transport has become a major policy concern in recent years. The term suggests a need to consider transport in a comprehensive perspective including the well-being of both present and future generations, and taking environmental, social and economic issues into account. Indicators...... in forecasting and tracking the performance of transport systems increasingly guide sustainable transport policy making. This review explores the implications of the "sustainable transport" concept and how it can be made operational with indicators. A number of indicator systems are reviewed, and some strengths...... and weaknesses are highlighted with regard to the support they provide for sustainable transport development....

  1. Sustainable Transport and Performance Indicators

    DEFF Research Database (Denmark)

    Gudmundsson, Henrik

    2004-01-01

    Sustainable transport has become a major policy concern in recent years. The term suggests a need to consider transport in a comprehensive perspective including the well-being of both present and future generations, and taking environmental, social and economic issues into account. Indicators...... in forecasting and tracking the performance of transport systems increasingly guide sustainable transport policy making. This review explores the implications of the sustainable transport” concept and how it can be made operational with indicators. A number of indicator systems are reviewed, and some strengths...

  2. From lagging indicators to leading indicators : design of a leading indicator dashboard for Philips Lighting

    NARCIS (Netherlands)

    Cai, Yongjian

    2011-01-01

    KPI (Key Performance Indicators) such as customer service level and stock level are commonly used in industry to measure the supply chain performance. Supply chain managers have a decided preference for these "lagging" indicators since they only measure the final outcomes that result from their

  3. Atlantic Coast Environmental Indicators Consortium

    Data.gov (United States)

    Federal Laboratory Consortium — n 2000, the US EPA granted authority to establish up to five Estuarine Indicator Research Programs. These Programs were designed to identify, evaluate, recommend and...

  4. Indicators of Indiscipline. Phase 2

    National Research Council Canada - National Science Library

    Owens, S

    1991-01-01

    .... Phase 2 research was conducted to determine which of the indicators identified by the phase 1 study could successfully identify soldiers who cause accidents due to indiscipline and to field test...

  5. Sustainable development indicators for territories

    International Nuclear Information System (INIS)

    Moreau; Sylvain; Bottin, Anne; Bovar, Odile; Nirascou, Francoise; Albecker, Marie-Fleur; Bardou, Magali; Barret, Christophe; Berger, Emmanuel; Blanc, Christophe; Bovar, Odile; Briquel, Vincent; Chery, Jean-Pierre; Deshayes, Michel; Firdion, Laetitia; Fluxa, Christine; Girault, Maurice; Guerrero, David; Hassaine, Zahida; Hilal, Mohamed; Imbert, Frederic; Kerouanton, Marie-Helene; Lacroix, Steve; Magnier, Celine; Moreau, Jacques; Nirascou, Francoise; Pageaud, Dorothee; Schaeffer, Yves; Thienard, Helene; Vinet, Loic; Wemelbeke, Guillaume; Wichmann, Martine; Boitard, Corinne; Bird, Geoffrey

    2011-11-01

    For different themes (Sustainable consumption and production, Knowledge and social and economic development society, governance, climate change and energy management, sustainable transport and modality, conservation and sustainable management of biodiversity and natural resources, public health, risk prevention and management, social and territorial cohesion), this study proposes a set of axis, and several indicators for each axis. Indicators correspond to different geographical scale and are determined from different sources. These indicators are for example: production of aggregates, proportion of organic agriculture in usable agricultural area, evolution in quantity of household waste collected per inhabitant, employment rate, research spending in relation to GDP, coverage of population by local Agenda 21, and so on. Thus, each indicator is discussed, commented and analysed

  6. Radar Plan Position Indicator Scope

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Radar Plan Position Indicator Scope is the collection of weather radar imagery for the period prior to the beginning of the Next Generation Radar (NEXRAD) system...

  7. EJSCREEN Environmental Indicators 2015 Public

    Data.gov (United States)

    U.S. Environmental Protection Agency — There are eight EJ Indexes in EJSCREEN reflecting the 8 environmental indicators. The eight EJ Index names are: Particulate Matter (PM2.5), Ozone Traffic Proximity...

  8. EJSCREEN Demographic Indicators 2015 Public

    Data.gov (United States)

    U.S. Environmental Protection Agency — EJSCREEN uses demographic factors as very general indicators of a community's potential susceptibility to the types of environmental factors included in this...

  9. Developing macroeconomic energy cost indicators

    International Nuclear Information System (INIS)

    Oberndorfer, Ulrich

    2012-01-01

    Indicators are more and more drawn on for policy making and assessment. This is also true for energy policy. However, while numerous different energy price figures are available, subordinate energy cost indicators are lacking. This paper lays out a general concept for such indicator sets and presents a flexible framework for representative and consistent energy cost indicators with an underlying weighting principle based on consumption shares. Their application would provide interesting new insights into the relationship between energy cost burdens of different sectors and countries. It would allow for more rigorous analysis in the field of energy economics and policy, particularly with regard to market monitoring and impact assessment as well as ex-post-policy analysis.

  10. EJSCREEN Environmental Indicators 2016 Public

    Data.gov (United States)

    U.S. Environmental Protection Agency — There are eleven EJ Indexes in EJSCREEN reflecting the 11 environmental indicators. The EJ Index names are: Particulate Matter (PM2.5), Ozone, NATA Diesel PM, NATA...

  11. Radioisotope indicator, type BETA 2

    International Nuclear Information System (INIS)

    Duszanski, M.; Pankow, A.; Skwarczynski, B.

    1975-01-01

    The authors describe a radioisotope indicator, type BETA 2, constructed in the ZKMPW Works to be employed in mines for counting, checking, signalling the presence and positioning of cars, as well as monitoring the state of some other equipment. (author)

  12. Solar Indices - Solar Radio Flux

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Collection includes a variety of indices related to solar activity contributed by a number of national and private solar observatories located worldwide. This...

  13. Performance Indicators of Operating Reactors

    Data.gov (United States)

    Nuclear Regulatory Commission — A list of Performance Indicators (PI) that are reported to the NRC by licensees at the end of each quarter in accordance with Inspection Manual Chapters (IMC) 0608,...

  14. EJSCREEN Demographic Indicators 2016 Public

    Data.gov (United States)

    U.S. Environmental Protection Agency — EJSCREEN uses demographic factors as very general indicators of a community's potential susceptibility to the types of environmental factors included in this...

  15. Renewable Energy Country Attractiveness Indices

    International Nuclear Information System (INIS)

    2011-02-01

    Since 2003 Ernst and Young team has been releasing quarterly data that ranks national renewable energy markets, and their suitability for individual technologies. The Country Attractiveness Indices now track the relative attractiveness of 30 countries' renewable energy markets across a selection of technologies each quarter. The Renewable Energy Country Attractiveness Indices publication scores and comments on various technologies, including: on-shore wind, off-shore wind, solar PV, solar CSP, biomass, and geothermal.

  16. Performance indicators for roadway bridges

    OpenAIRE

    Strauss, A.; Vidovic, A.; Zambon, I.; Dengg, F.; Tanasic, N.; Matos, José C.

    2016-01-01

    Publicado em "Maintenance, monitoring, safety, risk and resilience of bridges and bridge networks". ISBN 978-1-138-02851-7 The performance indicators should, by its definition, allow capturing the life-cycle degradation processes affecting maintenance plans or the remaining lifetime. The qualitative or quantitative performance indicators are obtained through visual inspections, non-destructive tests or monitoring systems. After their quantification and the comparison with the resp...

  17. Cycling indices for ecosystem models

    International Nuclear Information System (INIS)

    Carney, J.H.; Gardner, R.H.; Mankin, J.B.; DeAngelis, D.L.

    1979-01-01

    The study of ecosystems is aided by representing structural and functional groups of organisms or processes as discrete components. A complex compartment model will explicitly map pathways from one compartment to another and specify transfer rates. This quantitative description allows insight into the dynamics of flow of nutrients, toxic chemicals, radionuclides, or energy. Three new indices that calculate compartment-specific probabilities of occurrence and recycling and illustrate the problem of applying these indices to ecosystem models are presented

  18. Indicators of Information Society Measurement :

    Directory of Open Access Journals (Sweden)

    Hind Elwy

    2006-09-01

    Full Text Available The indicator of information society describe the infrastructure of information and communication technology ; as well as it’s use and it’s production in different estate of society. The importance economic and social of tic is crescent in modern society. and the presentation of tendency inform above the situation of information society . in this article we want to describe the indicator of tic in Algeria according to librarian’s vision in Mentouri university

  19. Cognitive Value of Financial Indicators

    Directory of Open Access Journals (Sweden)

    Gabriela Cristina FLOREA

    2012-11-01

    Full Text Available Economic and Financial indicators are very important tools in the assessment of the economic entity's well-being. They Provide permanent monitoring of the significance of the issues related to the economic activity's deployment. The main Objectives tracked by the process of managing the company with the help of Economic and Financial indicators is the activity's continuity, ensuring liquidity and Achieving positive results.

  20. Energy Efficiency Indicators Methodology Booklet

    Energy Technology Data Exchange (ETDEWEB)

    Sathaye, Jayant; Price, Lynn; McNeil, Michael; de la rue du Can, Stephane

    2010-05-01

    This Methodology Booklet provides a comprehensive review and methodology guiding principles for constructing energy efficiency indicators, with illustrative examples of application to individual countries. It reviews work done by international agencies and national government in constructing meaningful energy efficiency indicators that help policy makers to assess changes in energy efficiency over time. Building on past OECD experience and best practices, and the knowledge of these countries' institutions, relevant sources of information to construct an energy indicator database are identified. A framework based on levels of hierarchy of indicators -- spanning from aggregate, macro level to disaggregated end-use level metrics -- is presented to help shape the understanding of assessing energy efficiency. In each sector of activity: industry, commercial, residential, agriculture and transport, indicators are presented and recommendations to distinguish the different factors affecting energy use are highlighted. The methodology booklet addresses specifically issues that are relevant to developing indicators where activity is a major factor driving energy demand. A companion spreadsheet tool is available upon request.

  1. Performance Indicators in Spine Surgery.

    Science.gov (United States)

    St-Pierre, Godefroy Hardy; Yang, Michael H; Bourget-Murray, Jonathan; Thomas, Ken C; Hurlbert, Robin John; Matthes, Nikolas

    2018-02-15

    Systematic review. To elucidate how performance indicators are currently used in spine surgery. The Patient Protection and Affordable Care Act has given significant traction to the idea that healthcare must provide value to the patient through the introduction of hospital value-based purchasing. The key to implementing this new paradigm is to measure this value notably through performance indicators. MEDLINE, CINAHL Plus, EMBASE, and Google Scholar were searched for studies reporting the use of performance indicators specific to spine surgery. We followed the Prisma-P methodology for a systematic review for entries from January 1980 to July 2016. All full text articles were then reviewed to identify any measure of performance published within the article. This measure was then examined as per the three criteria of established standard, exclusion/risk adjustment, and benchmarking to determine if it constituted a performance indicator. The initial search yielded 85 results among which two relevant studies were identified. The extended search gave a total of 865 citations across databases among which 15 new articles were identified. The grey literature search provided five additional reports which in turn led to six additional articles. A total of 27 full text articles and reports were retrieved and reviewed. We were unable to identify performance indicators. The articles presenting a measure of performance were organized based on how many criteria they lacked. We further examined the next steps to be taken to craft the first performance indicator in spine surgery. The science of performance measurement applied to spine surgery is still in its infancy. Current outcome metrics used in clinical settings require refinement to become performance indicators. Current registry work is providing the necessary foundation, but requires benchmarking to truly measure performance. 1.

  2. Vegetation indices as indicators of damage by the sunn pest ...

    African Journals Online (AJOL)

    SERVER

    2008-01-18

    Jan 18, 2008 ... nylon cloth cage experiments were conducted to determine the feasibility of using remote sensing techniques to ... conventionally used method for the sunn pest manage- ... Study area and sunn pest experiment design ... graphy is nearly flat. .... for determination of indices showed an increasing pattern.

  3. Fluctuations of indicator and index microbes as indication of ...

    African Journals Online (AJOL)

    2013-07-04

    Jul 4, 2013 ... The Plankenburg and Eerste Rivers (Western Cape) have been reported to be contaminated with faecal coliforms. Water is drawn from both rivers for irrigation of fresh produce. The potential risk in the use of these rivers as irrigation sources was assessed by determining the fluctuations of 'indicator' and ...

  4. Climate indices for vulnerability assessments

    Energy Technology Data Exchange (ETDEWEB)

    Persson, Gunn; Baerring, Lars; Kjellstroem, Erik; Strandberg, Gustav; Rummuk ainen, Markku

    2007-08-15

    The demand is growing for practical information on climate projections and the impacts expected in different geographical regions and different sectors. It is a challenge to transform the vast amount of data produced in climate models into relevant information for climate change impact studies. Climate indices based on climate model data can be used as means to communicate climate change impact relations. In this report a vast amount of results is presented from a multitude of indices based on different regional climate scenarios. The regional climate scenarios described in this report show many similarities with previous scenarios in terms of general evolution and amplitude of future European climate change. The broad features are manifested in increases in warm and decreases in cold indices. Likewise are presented increases in wet indices in the north and dry indices in the south. Despite the extensive nature of the material presented, it does not cover the full range of possible climate change. We foresee a continued interactive process with stakeholders as well as continued efforts and updates of the results presented in the report.

  5. Jordan Banks Financial Soundness Indicators

    Directory of Open Access Journals (Sweden)

    Imad Kutum

    2015-09-01

    Full Text Available The aim of this research paper is to examine the Jordanian banks using financial soundness indicators. This is to establish if Jordanian banks were affected because of the 2007/2008 financial crisis and determine the underlying reasons. The research paper was conducted on 25 banks in Jordan listed in the countries securities exchange. The research methodology used consisted of examining the banks financial records in order to derive four crucial Basel III ratio such as the capital adequacy ratio, the leverage ratio, the liquidity ratio and finally the Total Provisions (As % Of Non-Performing Loans %. The results revealed that out of the four hypotheses under examination Jordan Banks do not meet Basel financial Indicators for Capital Adequacy Ratio, Jordan Banks does not meet Basel financial Indicators for Liquidity Ratio , Jordan Banks do not meet Basel financial Indicators for Leverage Ratio and Jordan Banks do not meet Basel financial Indicators for Total Provisions (As % Of Non-Performing Loans ratio. Only one hypothesis was accepted based on the research outcomes. The rest of the hypothesis was rejected since the average trend line did not go below the Basel III required ratio level. The general outcome of the research revealed that Jordanian banks were not affected significantly by the financial crisis.

  6. Indicators for Nuclear Power Development

    International Nuclear Information System (INIS)

    2015-01-01

    Considering the scale of nuclear power aspirations, the number of planned nuclear new builds and the prospects of a number of countries constructing their first nuclear power plants, there is a need to assess the broader context of nuclear energy programmes in areas of macro-and socioeconomic conditions, energy systems and nuclear power, and the environment. It is important to assess the degree to which introduction or expansion of nuclear power is beneficial under these specific circumstances. This publication provides a set of indicators for nuclear power development that can serve as a tool to help explore these issues. The indicators are meant to provide a first order assessment of the situation and identify the issues that present the benefits and challenges in a balanced and objective manner and thereby help guide more detailed evaluations in the next stage of planning and preparations. Methodology sheets are provided to help users in data collection, quantification and interpretation of the indicators. The application of the indicators set is flexible. Users can select a subset of indicators that are most relevant for the questions they wish to explore in a given study or decision making process

  7. Design of energy management indicator.

    Directory of Open Access Journals (Sweden)

    Ernesto Tomás Dalmau García

    2010-10-01

    Full Text Available This work has as a main goal to demostrate the viability of the energy management indicator, that will be a part of the Balanced Scorecard in the organization and the own process of calculation allows to obtain a Balanced Scorecard of energy management. It describes the executive order of the actions that have to be done to reach to the mentioned indicator, based on the selection of the selected period of time; the types of power carriers, the weight of each carrier in the structure of the consumption and the activities where they are used. With these elements several tools are used to reach to the expected results, as the bar charts, comparative tables and indices of power intensity. The indices of energy intensity are recommended as comparative elements for the contribution to the operativity and information level, meaning that not always is necessary to tie them , if not, in some cases, may be other selected indicators that may result as qualitatives type, The Cuban enterprise system uses the model Control of Consumption and Catchment Demand of fuels and lubricants (CDA 002 of the Ministry of Economy and Planning (MEP that is used in the work and it is recommended for the organizations who apply it. The study and application of this method were made in the Company of Raw materials Recovery in an experimental form.

  8. Some indicators of (unsuccessful reading

    Directory of Open Access Journals (Sweden)

    Vuksanović Jasmina

    2008-01-01

    Full Text Available In the paper we set the aim to determine whether phonological awareness and short-term verbal memory are indicators of a subsequent reading acquisition. The sample consisted of 194 first graders from two primary schools in Belgrade. The results of our research showed that the most significant indicator of the subsequent (unsuccessful reading was phonological awareness. The short-term verbal memory is, to a lesser extent, an indicator of the subsequent reading acquisition defined by the time needed for reading the text and by the text comprehension. Our findings offer basis for proposing that the phonological awareness assessment should be implemented into the regular procedure of assessing child's readiness for school. In this way children in need for preventive stimulation within the inclusive programme in primary schools could be identified.

  9. Geophysical and solar activity indices

    Science.gov (United States)

    Bossy, L.; Lemaire, J.

    1984-04-01

    A large number of geophysicists try to correlate their observations with one or even a series of different geophysical or solar activity indices. Yet the right choice of the most appropriate index with which to correlate depends mainly on our understanding of the physical cause-effect relationship between the new set of observations and the index chosen. This best choice will therefore depend on our good understanding of the methods of measurement and derivation of the adopted index in such correlative studies. It relies also on our awareness of the range of applicability of the indices presently available as well as on our understanding of their limitations. It was to achieve these goals that a series of general lectures on geophysical and solar activity indices was organized by L. Bossy and J. Lemaire (Institut d'Aeronomie Spatiale de Belgique (IASB), Brussels), March 26-29, 1984 at Han-sur-Lesse, Belgium.

  10. Instrumental Landing Using Audio Indication

    Science.gov (United States)

    Burlak, E. A.; Nabatchikov, A. M.; Korsun, O. N.

    2018-02-01

    The paper proposes an audio indication method for presenting to a pilot the information regarding the relative positions of an aircraft in the tasks of precision piloting. The implementation of the method is presented, the use of such parameters of audio signal as loudness, frequency and modulation are discussed. To confirm the operability of the audio indication channel the experiments using modern aircraft simulation facility were carried out. The simulated performed the instrument landing using the proposed audio method to indicate the aircraft deviations in relation to the slide path. The results proved compatible with the simulated instrumental landings using the traditional glidescope pointers. It inspires to develop the method in order to solve other precision piloting tasks.

  11. Hearing Aid with Visual Indicator

    DEFF Research Database (Denmark)

    2004-01-01

    The invention comprises a hearing aid, which has a casing containing a signal receiving part for receiving an audio signal, an audio transducer for providing an audio signal to the user, a signal transmission path between the signal receiving part and the audio transducer, whereby a battery...... is provided for powering the signal receiving part, the signal path and the audio transducer, and where further means are provided for assessing the function of the hearing aid and for generating an electrical indication signal which indicates the function of the hearing aid and where further means...... are provided for intermittently generating a power signal in response to the electrical indication signal and where means are provided for converting the power signal into a light signal, such that the light signal is visible from outside the hearing aid....

  12. Website quality indicators for consumers.

    Science.gov (United States)

    Griffiths, Kathleen M; Christensen, Helen

    2005-11-15

    The rating tool DISCERN was designed for use by consumers without content expertise to evaluate the quality of health information. There is some evidence that DISCERN may be a valid indicator of evidence-based website quality when applied by health professionals. However, it is not known if the tool is a valid measure of evidence-based quality when used by consumers. Since it is a lengthy instrument requiring training in its use, DISCERN may prove impractical for use by the typical consumer. It is therefore important to explore the validity of other simpler potential indicators of site quality such as Google PageRank. This study aimed to determine (1) whether the instrument DISCERN is a valid indicator of evidence-based Web content quality for consumers without specific mental health training, and (2) whether Google PageRank is an indicator of website content quality as measured by an evidence-based gold standard. This was a cross-sectional survey of depression websites using consumer and health professional raters. The main outcome measures were (1) site characteristics, (2) evidence-based quality of content as measured by evidence-based depression guidelines, (3) DISCERN scores, (4) Google PageRank, and (5) user satisfaction. There was a significant association between evidence-based quality ratings and average DISCERN ratings both for consumers (r = 0.62, P = .001) and health professionals (r = 0.80, P PageRank (r = 0.59, P = .002). However, the correlation between DISCERN scores and user satisfaction was higher than the correlation between Google PageRank and user satisfaction. DISCERN has potential as an indicator of content quality when used either by experts or by consumers. Google PageRank shows some promise as an automatic indicator of quality.

  13. Canadian environmental sustainability indicators 2006

    International Nuclear Information System (INIS)

    2006-01-01

    In 2004, the Canadian government committed to reporting annual national indicators of air quality, greenhouse gas (GHG) emissions and freshwater quality in order to provide Canadians with more regular and consistent information on the state of the environment and how it is linked with human activities. The national air quality indicators in this report focused on human exposure to ground-level ozone and fine particulate matter (PM 2.5 ). The report showed that from 1990 to 2004, the ozone indicator showed year-to-year variability, with an averaged increase of 0.9 per cent per year. Stations in southern Ontario reported the highest levels of ozone and PM 2.5 in the country in 2004. There was no discernible upward or downward trend in PM 2.5 levels at the national level for the 2000 to 2004 period, and GHG emissions rose 27 per cent from 1990 to 2004. In 2004, emissions were 35 per cent above the target to which Canada committed under the Kyoto Protocol. However, while total emissions rose, emissions per unit of gross domestic product (GDP) fell by 14 per cent from 1990 to 2004. GHG emissions also grew faster than the Canadian population, resulting in a 10 per cent rise in emissions per person. The freshwater quality indicator presented in this report covered the period from 2002 to 2004, and focused on the ability of Canada's surface waters to support aquatic life. For the 340 sites selected across southern Canada, water quality was rated as good or excellent at 44 per cent of sites, fair at 34 per cent of sites, and marginal or poor at 22 per cent of sites. The report included a chapter which attempted to integrate the indicators with other environmental impacts, measures of economic performance, and indices of social progress to improve the ability of the report to influence decision-making that fully accounts for environmental sustainability. 63 refs., 18 figs

  14. Nordic eHealth Indicators

    DEFF Research Database (Denmark)

    Hyppönen, Hannele; Faxvaag, Arild; Gilstad, Heidi

    This report describes first results of the Network: eHealth policy analysis and first common Nordic eHealth indicators. The results show similarities and also some differences in the eHealth policies, priorities and implementation. Interesting similarities and differences in availability and use...... of eHealth services in the Nordic countries were found with the first comparable eHealth indicators. The results create a basis for Evidence-based policy making as well as benchmarking and learning best practices from each other....

  15. Stereotactic radiotherapy in pediatric indications

    International Nuclear Information System (INIS)

    Bernier-Chastagner, V.; Supiot, S.; Carrie, C.; Helfre, S.

    2012-01-01

    Stereotactic radiotherapy is a very high precision procedure, which has been limited to radiosurgery for a long time. Technological improvements allowed the development of radiotherapy in stereotactic conditions, leading to a lot of innovations. Previously indicated for cerebral pathologies, this procedure is now developed for extra-cerebral locations. In paediatrics, stereotactic radiotherapy is still limited, delivered precociously, due to the possibility of long-term late effects that needs to be addressed. This review reports the different useful conditions, technical evolutions, and the current validated paediatric indications, with differences from adults, and future directions. (authors)

  16. CHALLENGES WHEN DEVELOPING PERFORMANCE INDICATORS

    Directory of Open Access Journals (Sweden)

    Brindusa Maria POPA

    2015-04-01

    Full Text Available Abstract Developing key performance indicators (KPIs represents one step closer to the achievement of objectives and strategic vision of the organization. They are important elements of the pathway towards performance, they evaluate and indicate the level of progress, guide the organizational strategy, they can be considered even the qualitative or quantitative expression of the execution of the strategy. Building reliable and appropriate measurement systems is one of the most difficult stage in the performance evaluation process. Such systems of management will help the executives and the management teams identify and build upon the elements that create competitive advantage and opportunities for better results.

  17. Indicators for knowledge transfer analysis

    International Nuclear Information System (INIS)

    Plaza, L. M.

    2007-01-01

    Understanding by knowledge transfer, the process by which the scientific knowledge generated by the R+Ds Spanish public system investigators is finally harnessed and officially used by the agents that make up the productive system, or by the administration; this project aims to offer a global view of the main scientific indicators by which said process can be analysed and in particular, of the way that some of these indicators allow us to evaluate this transfer in the case of the Spanish I+D system and in that concerning the Biotechnology sector. (Author) 12 refs

  18. Academic appropriation and Impact Indicators

    Directory of Open Access Journals (Sweden)

    Wilson López López

    2012-06-01

    Full Text Available The role of appropriation of scientific knowledge and the indicators designed to measure its impact is being hotly debated in Iberoamerica right now. I will separate what I call academic appropriation of knowledge from what many authors have called social appropriation of knowledge. The former isrelated to knowledge communication and transference practices in scientific communities, and the latter has to do with the multiple ways in which knowledge goes to society. This editorial will address academic appropriation.Academic appropriations are found in many levels: the first is that performed by colleagues (peers who use this knowledge, and citations are the indicators of usage. This is a sensitive indicator, and thus vulnerable to citation dynamics in academic communities. For example, communities with low levels of knowledge use are generally endogamic and have low international collaboration.They are also characterised by not easily modifying their citation habits. In this sense, a part of these citations generally make themselves invisible, this is, they do not acknowledge neither their own efforts, not those made by local peer groups (regional, and are negatively paradoxical, even when proclaimed in an anti-mainstream science discourse. At the same time, they downplay their own production or the regional production, and ground their work on the production that they claim to go beyond.On the other hand, research groups with an important output can improve or decrease the visibility of other groups and journals, since the amount of work ends up concentrating citations in particular works or journals, which affects themeasures derived from citation-expressed impacts. In this sense, and as a response with additional elements for assessing academic production, it is suggested that: 1. The quartile of the journal be used, since it gives a more accurate idea of its dynamics and shows the journal in relation to other journals with its variability

  19. Maternal health Indicators Signal Optimism

    African Journals Online (AJOL)

    user

    Maternal health Indicators Signal Optimism. Abraham Haileamlak, MD, Professor of Pediatrics and Child Health. Maternal health is a major health priority for international agencies and the Ethiopian. Government. Many low income countries including. Ethiopia, made substantial improvements in maternal health achieving ...

  20. Participatory evaluation for environmental indicators

    NARCIS (Netherlands)

    Goma, H.C.; Rahim, K.; Nangendo, G.; Riley, J.; Stein, A.

    2001-01-01

    Participatory research has emerged as a powerful tool to identify agro-ecosystem indicators in developing countries. Indigenous knowledge, thus generated complements scientific information to the benefit of all stakeholders. This paper demonstrates the value of participating with farmers and hunters

  1. Multimetric indices: How many metrics?

    Science.gov (United States)

    Multimetric indices (MMI’s) often include 5 to 15 metrics, each representing a different attribute of assemblage condition, such as species diversity, tolerant taxa, and nonnative taxa. Is there an optimal number of metrics for MMIs? To explore this question, I created 1000 9-met...

  2. 5 Indicators of Decimal Understandings

    Science.gov (United States)

    Cramer, Kathleen; Monson, Debra; Ahrendt, Sue; Colum, Karen; Wiley, Bethann; Wyberg, Terry

    2015-01-01

    The authors of this article collaborated with fourth-grade teachers from two schools to support implementation of a research-based fraction and decimal curriculum (Rational Number Project: Fraction Operations and Initial Decimal Ideas). Through this study, they identified five indicators of rich conceptual understanding of decimals, which are…

  3. Constitutive Effects of Performance Indicators

    DEFF Research Database (Denmark)

    Dahler-Larsen, Peter

    2014-01-01

    that are demonstrably problematic. Based on a distinction between trivial and advanced measure fixation, an argument is made for constitutive effects that are based on less problematic assumptions. Through this conceptual move, the political dimension of performance indicators is appreciated. The conceptual dimensions...... of constitutive effects are carved out, empirical illustrations of their applicability are offered and implications discussed....

  4. Automated evaluation of ultrasonic indications

    International Nuclear Information System (INIS)

    Hansch, M.K.T.; Stegemann, D.

    1994-01-01

    Future requirements of reliability and reproducibility in quality assurance demand computer evaluation of defect indications. The ultrasonic method with its large field of applications and a high potential for automation provides all preconditions for fully automated inspection. The survey proposes several desirable hardware improvements, data acquisition requirements and software configurations. (orig.) [de

  5. Environmental indicators for evaluating properties

    Directory of Open Access Journals (Sweden)

    Mario Grosso

    2015-06-01

    Full Text Available Property evaluation for tax purposes has traditionally relied on urban and building criteria, mostly resulting from concepts driven by the commercial attractiveness of the property under evaluation, its building and the site itself. Due to the world climate and ecological crisis, awareness has risen about the need for other indicators, which can evaluate the quality of a property, even referring to its potential environmental impact. Technical standards for the evaluation of buildings’ environmental sustainability, which have been developed since the first years of this century, both nationally and internationally, take into account the impact of the building and its relevance for the life-cycle of materials and elements, with reference to the three sectors of sustainability: environmental, economic and social. The social sector includes indicators referring to the user’s health and comfort, which also interact with the morphological and spatial characteristics of the building. However, there is a lack of methodological tools for the evaluation of said indicators and existing ones are mainly of a qualitative type. This paper suggests a methodological approach for the quantitative evaluation of sustainability indicators, relying on the accessibility of a site’s climate resources by the property, as a criterion to evaluate the potential for the reduction of negative environmental impact, as well as a criterion to improve users’ life quality.

  6. Monitoring indicators in a dismantling

    International Nuclear Information System (INIS)

    Soto Lanuza, A.

    2013-01-01

    Knowing yourself know the processes (Manual process), knows as the more quantitative possible, as are things (table of indicators), document and manage incidents and finds (integrated system of improvements), will allow us to carry to term two important tasks: the tracking and the continuous improvement of the project.

  7. Indicators of Malicious SSL Connections

    NARCIS (Netherlands)

    Bortolameotti, Riccardo; Peter, Andreas; Everts, Maarten Hinderik; Bolzoni, D.

    2015-01-01

    Internet applications use SSL to provide data confidential- ity to communicating entities. The use of encryption in SSL makes it impossible to distinguish between benign and malicious connections as the content cannot be inspected. Therefore, we propose and evaluate a set of indicators for malicious

  8. Indicators of malicious SSL connections

    NARCIS (Netherlands)

    Bortolameotti, R.; Peter, A.; Everts, M.H.; Bolzoni, D.

    2015-01-01

    Internet applications use SSL to provide data confidentiality to communicating entities. The use of encryption in SSL makes it impossible to distinguish between benign and malicious connections as the content cannot be inspected. Therefore, we propose and evaluate a set of indicators for malicious

  9. Sound construction of risk indicators

    DEFF Research Database (Denmark)

    Sørensen, Peter Borgen; Kjær, Christian; Thomsen, Marianne

      In spite of the great effort in the area of environmental risk assessment of chemicals, a critical amount of uncertainty is still a reality due to high complexity of the governing risk problem. Unexpected adverse effects may thus take place event though the risk assessment predicts no-risk. Some...... chemicals are even lacking risk assessment due to a priori judgment based on risk screening methods that bypass further risk assessment activity. It is thus advisable to set up a safety net under the risk assessment of chemicals and this poster suggests a supporting paradigm using risk indicators...... that governs the method: HotSpot Driven Aggregation of Risk Indicators (HoSDARI) as described in Sørensen et al. (2008). The purpose of the risk assessment is to protect a defined target that has some value for protection. The target has a number of realizations each defined as a Protection Unit (PU...

  10. Human Resources Key Performance Indicators

    Directory of Open Access Journals (Sweden)

    Gabčanová Iveta

    2012-03-01

    Full Text Available The article brings out a proposed strategy map and respective key performance indicators (KPIs in human resources (HR. The article provides an overview of how HR activities are supported in order to reach the partial goals of HR as defined in the strategic map. Overall the aim of the paper is to show the possibilities of using the modern Balanced Scorecard method in human capital.

  11. Intravitreal Bevacizumab: Indications and Complications

    International Nuclear Information System (INIS)

    Jan, S.; Nazim, M.; Karim, S.; Hussain, Z.

    2016-01-01

    Background: Bevacizmab is still an unlicensed drug for intraocular use in spite of the fact that it has shown comparable efficacy to other anti-vascular endothelial growth factors (anti-VEGF) medications in some large sample randomized control trails. Although repackaged bevacizumab has got safety concerns but its use is growing because of easy availability and low cost. Our study focuses on the diverse and growing indications of intravitreal bevacizumab (IVB) and its ocular complications in our geographical setting. Method: This interventional case series was carried out at my private practice in Said Anwar Medical Complex, Dabgari, Peshawar, from January 2008 to July 2015. Total of 6107 injections were given to 4352 eyes. Intravitreal bevacizumab was injected in proper operating room setting. Bevacizumab injections were prepared from same vial by multiple withdrawals taking care of aseptic precautions. Follow up was done at 1 week and 20 days and adverse effects were noted. Results: Diabetic macular oedema (36 percent), central retinal vein occlusion (17.6 percent) and branched retinal vein occlusion (11 percent) were the top three indications of IVB. Other common indications were proliferative diabetic retinopathy (9.6 percent), neo-vascular glaucoma (5.9 percent), proliferative diabetic retinopathy with vitreous bleed (4.4 percent), proliferative diabetic retinopathy with tractional retinal detachment (3.7 percent), neo-vascular age related macular degeneration (2.9 percent), central serous retinopathy (1.48 percent) and Eale disease (1.48 percent). Endohthalmitis occurred in 3 eyes (0.069 percent) while retinal detachment was found in only 2 eyes (0.046 percent).Conclusion: Common indications of bevacizumab are diabetic macular oedema, central retinal vein occlusion and branched retinal vein occlusion. Complications like endophthalmitis and retinal detachment are rare. (author)

  12. Polychaetes as environmental indicators revisited

    International Nuclear Information System (INIS)

    Giangrande, Adriana; Licciano, Margherita; Musco, Luigi

    2005-01-01

    The utilization of polychaetes in descriptive ecology is reviewed in the light of recent research especially concerning the biota hard bottom environments. Polychaetes, often linked in the past to the concept of opportunistic species able to proliferate after an increase in organic matter, have played an important role especially with regard to impacted soft-bottom habitats. Increased knowledge of the group, suggests that not only opportunistic species can be utilised as indicators, so that these organisms can be disengaged from the old concept of opportunistic taxa. Moreover, recent researches conducted on this group allowed demonstrating as surrogacy is not always applicable. Among polychaetes inhabiting hard bottom environment, the analysis of family Syllidae appears particularly promising. Studied conducted in our laboratory demonstrated as syllid species decrease in abundance or completely disappear under varying sources of negative impact. The distribution of species also appeared indicative in underlying effects of marine protected areas (MPA) functioning, or in describing different climatic areas within biogeographical sectors. It is obvious that good results can only be obtained on the basis of good taxonomic resolution. We suggested that, in monitoring studies, operational time could be optimized not only by working at a higher-level on the whole invertebrate data set, but by also selecting a particularly indicative group and working at fine level

  13. Polychaetes as environmental indicators revisited

    Energy Technology Data Exchange (ETDEWEB)

    Giangrande, Adriana [Department of Biological and Environmental Sciences and Technology, University of Lecce, Marine Biological Station, 73100 Lecce (Italy)]. E-mail: gianadri@ilenic.unile.it; Licciano, Margherita [Department of Biological and Environmental Sciences and Technology, University of Lecce, Marine Biological Station, 73100 Lecce (Italy); Musco, Luigi [Department of Biological and Environmental Sciences and Technology, University of Lecce, Marine Biological Station, 73100 Lecce (Italy)

    2005-11-15

    The utilization of polychaetes in descriptive ecology is reviewed in the light of recent research especially concerning the biota hard bottom environments. Polychaetes, often linked in the past to the concept of opportunistic species able to proliferate after an increase in organic matter, have played an important role especially with regard to impacted soft-bottom habitats. Increased knowledge of the group, suggests that not only opportunistic species can be utilised as indicators, so that these organisms can be disengaged from the old concept of opportunistic taxa. Moreover, recent researches conducted on this group allowed demonstrating as surrogacy is not always applicable. Among polychaetes inhabiting hard bottom environment, the analysis of family Syllidae appears particularly promising. Studied conducted in our laboratory demonstrated as syllid species decrease in abundance or completely disappear under varying sources of negative impact. The distribution of species also appeared indicative in underlying effects of marine protected areas (MPA) functioning, or in describing different climatic areas within biogeographical sectors. It is obvious that good results can only be obtained on the basis of good taxonomic resolution. We suggested that, in monitoring studies, operational time could be optimized not only by working at a higher-level on the whole invertebrate data set, but by also selecting a particularly indicative group and working at fine level.

  14. Indicators System for Poverty Measurement

    Directory of Open Access Journals (Sweden)

    Constantin Mitrut

    2006-10-01

    Full Text Available Poverty represents a life aspect which is focusing the attention of both the macroeconomic analysis and the international comparisons. In order to measure the level being recorded by this phenomenon, there is a system of indicators which are used in order to underline, in a correlated manner, a number of aspects which are characterizing, quality and quantity wise, the evolution of the poverty in a specific country or, to a larger extent, through comparative surveys, at international level. Despite the fact that they are not the only instrument being used within the process of comparison of the stages of social and economic development at the international level, however the poverty indicators are providing a clear significance to the worked out surveys. In fact, the very purpose of the economic activity consists of increasing welfare and, as much as possible, at least reducing, if not eradicating, the poverty. The present work is broadly presenting the methodology as well as, both theoretical and practical, the way of computing the poverty, making a synthesis of the specific used indicators.

  15. Transportable type neutron level indicators

    International Nuclear Information System (INIS)

    Khatskevich, M.V.; Kalinin, O.V.; Moskovkin, V.N.; Molchanov, A.V.; Bobkov, A.D.; Rabotnov, Yu.A.

    1979-01-01

    Some peculiarities of designing level neutron converters (LNC) for portable indicators or level neutron relays are considered. The effect of the LNC geometry and other factors on measurement errors has been studied. Calibration results of the LNC with a neutron reflector and without it are presented. It is shown that the problem of level monitoring with the help of portable indicators can be solved practically for any volume, provided two LNC modifications with reflectors are available: the NPU-G modification with horizontal location of a counter for large volumes and the NPU-V with vertical location of a counter for lesser volumes. A possibility of perfecting LNC performances by shielding the counter with thermal neutron absorbers has been studied. The design of the NPU-V modification for the NIUP-2 level indicator is described. It is intended for tubes and cylinders 30-100 mm in diameter. Measurements carried out on different steel and aluminium vessels with a diameter ranging from 300 to 100 mm and a wall thickness of up to 16 mm with the help of the NPU-V and NPU-G modifications proved the efficiency of the LNC to control a variety of products (kerosine, gasoline, oils, acids, alkalis) [ru

  16. Allograft Pancreatectomy: Indications and Outcomes.

    Science.gov (United States)

    Nagai, S; Powelson, J A; Taber, T E; Goble, M L; Mangus, R S; Fridell, J A

    2015-09-01

    This study evaluated the indications, surgical techniques, and outcomes of allograft pancreatectomy based on a single center experience. Between 2003 and 2013, 47 patients developed pancreas allograft failure, excluding mortality with a functioning pancreas allograft. Early graft loss (within 14 days) occurred in 16, and late graft loss in 31. All patients with early graft loss eventually required allograft pancreatectomy. Nineteen of 31 patients (61%) with late graft loss underwent allograft pancreatectomy. The main indication for early allograft pancreatectomy included vascular thrombosis with or without severe pancreatitis, whereas one recipient required urgent allograft pancreatectomy for gastrointestinal hemorrhage secondary to an arterioenteric fistula. In cases of late allograft pancreatectomy, graft failure with clinical symptoms such as abdominal discomfort, pain, and nausea were the main indications (13/19 [68%]), simultaneous retransplantation without clinical symptoms in 3 (16%), and vascular catastrophes including pseudoaneurysm and enteric arterial fistula in 3 (16%). Postoperative morbidity included one case each of pulmonary embolism leading to mortality, formation of pseudoaneurysm requiring placement of covered stent, and postoperative bleeding requiring relaparotomy eventually leading to femoro-femoral bypass surgery 2 years after allograftectomy. Allograft pancreatectomy can be performed safely, does not preclude subsequent retransplantation, and may be lifesaving in certain instances. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  17. Energy indicators for sustainable development

    International Nuclear Information System (INIS)

    Vera, Ivan; Langlois, Lucille

    2007-01-01

    Energy is an essential factor in overall efforts to achieve sustainable development. Countries striving to this end are seeking to reassess their energy systems with a view toward planning energy programmes and strategies in line with sustainable development goals and objectives. This paper summarizes the outcome of an international partnership initiative on indicators for sustainable energy development that aims to provide an analytical tool for assessing current energy production and use patterns at a national level. The proposed set of energy indicators represents a first step of a consensus reached on this subject by five international agencies-two from the United Nations system (the Department of Economic and Social Affairs and the International Atomic Energy Agency), two from the European Union (Eurostat and the European Environment Agency) and one from the Organization for Economic Cooperation and Development (the International Energy Agency). Energy and environmental experts including statisticians, analysts, policy makers and academics have started to implement general guidelines and methodologies in the development of national energy indicators for use in their efforts to monitor the effects of energy policies on the social, economic and environmental dimensions of sustainable development

  18. Risk-based performance indicators

    International Nuclear Information System (INIS)

    Azarm, M.A.; Boccio, J.L.; Vesely, W.E.; Lofgren, E.

    1987-01-01

    The purpose of risk-based indicators is to monitor plant safety. Safety is measured by monitoring the potential for core melt (core-melt frequency) and the public risk. Targets for these measures can be set consistent with NRC safety goals. In this process, the performance of safety systems, support systems, major components, and initiating events can be monitored using measures such as unavailability, failure or occurrence frequency. The changes in performance measures and their trends are determined from the time behavior of monitored measures by differentiation between stochastical and actual variations. Therefore, degradation, as well as improvement in the plant safety performance, can be determined. The development of risk-based performance indicators will also provide the means to trace a change in the safety measures to specific problem areas which are amenable to root cause analysis and inspection audits. In addition, systematic methods will be developed to identify specific improvement policies using the plant information system for the identified problem areas. The final product of the performance indicator project will be a methodology, and an integrated and validated set of software packages which, if properly interfaced with the logic model software of a plant, can monitor the plant performance as plant information is provided as input

  19. Tamper indicating radiation surveillance instrumentation

    International Nuclear Information System (INIS)

    Chambers, W.H.; Ney, J.F.

    1975-01-01

    Prototype personnel and shipping dock portal monitors suitable for unattended use were fabricated and tested. The requirement for continuous operation with only periodic inspection along with a desire for minimum costs and minimum interference with normal plant operation imposed unique design constraints. The design, operation, and performance of the detection and data recording instrumentation are described, as well as the tamper indicating techniques required to protect the collected data. The essential elements of either of the two instruments include a gamma detector array, signal conditioning electronics, digital alarm logic circuitry, power supplies, a microwave occupancy monitor, surveillance camera, irreversible electromechanical counters, and the appropriate tamper indicating envelope protecting these elements. Attempts to penetrate the tamper indicating envelope require material removal, and undetectable repair is very difficult, if not impossible. The techniques for joining major subassemblies and providing unique seals are also described. The personnel doorway uses a double pole array of NaI(Tl) detectors, and outputs are taken from a single channel pulse height analyzer with a window set at 60 to 250 keV and the lower level discriminator at greater than 60 keV. A sliding interval counter is used to make comparisons to an accumulated background at the 4sigma level. Logic design, sensitivity for special nuclear materials, false alarm data, and test procedures are described in detail. The shipping dock monitor had different design constraints and therefore uses a single, long, cylindrical plastic scintillator. Some differences in signal conditioning and processing are also described. (auth)

  20. Construction and demolition waste indicators.

    Science.gov (United States)

    Mália, Miguel; de Brito, Jorge; Pinheiro, Manuel Duarte; Bravo, Miguel

    2013-03-01

    The construction industry is one of the biggest and most active sectors of the European Union (EU), consuming more raw materials and energy than any other economic activity. Furthermore, construction waste is the commonest waste produced in the EU. Current EU legislation sets out to implement construction and demolition waste (CDW) prevention and recycling measures. However it lacks tools to accelerate the development of a sector as bound by tradition as the building industry. The main objective of the present study was to determine indicators to estimate the amount of CDW generated on site both globally and by waste stream. CDW generation was estimated for six specific sectors: new residential construction, new non-residential construction, residential demolition, non-residential demolition, residential refurbishment, and non-residential refurbishment. The data needed to develop the indicators was collected through an exhaustive survey of previous international studies. The indicators determined suggest that the average composition of waste generated on site is mostly concrete and ceramic materials. Specifically for new residential and new non-residential construction the production of concrete waste in buildings with a reinforced concrete structure lies between 17.8 and 32.9 kg m(-2) and between 18.3 and 40.1 kg m(-2), respectively. For the residential and non-residential demolition sectors the production of this waste stream in buildings with a reinforced concrete structure varies from 492 to 840 kg m(-2) and from 401 to 768 kg/m(-2), respectively. For the residential and non-residential refurbishment sectors the production of concrete waste in buildings lies between 18.9 and 45.9 kg/m(-2) and between 18.9 and 191.2 kg/m(-2), respectively.

  1. Performance indicators for rinderpest surveillance

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-12-01

    In 1986, the Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture initiated a programme of assistance to FAO and IAEA Member States for the development of effective, quality assured veterinary laboratory diagnostic services. This programme introduced the use of standardized and internationally validated ELISA-based systems for the diagnosis and surveillance of the major transboundary diseases that affect livestock. This approach has proved of immense value in the monitoring of national, regional and global animal disease control and eradication programmes. One such programme focuses on the global elimination of rinderpest. Co-ordinated by FAO through the Global Rinderpest Eradication Programme (GREP) the joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture has developed critical diagnostic and epidemiological tools to assist this effort. As the final stages of the global eradication of rinderpest are reached, it is fitting that the Joint Division should again take the lead in providing guidance to Member States on how best to meet the criteria for quality assurance of national disease surveillance programmes - a prerequisite for international acceptance of freedom from a particular disease. This publication is intended to provide countries involved in rinderpest eradication with a detailed protocol for using performance indicators in evaluating their disease surveillance system and making, where necessary, adjustments to meet the criteria for acceptance specified in the OIE Rinderpest Pathway - a pathway that leads to international recognition of freedom from rinderpest. An initial publication (IAEA-TECDOC-1161) described guidelines for the use of performance indicators in rinderpest surveillance programmes. This publication now describes in detail the protocols and the linked indicators which have been developed and field validated through a series of FAO/IAEA meetings and through IAEA expert assignments to countries in Africa.

  2. Performance indicators for rinderpest surveillance

    International Nuclear Information System (INIS)

    2001-12-01

    In 1986, the Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture initiated a programme of assistance to FAO and IAEA Member States for the development of effective, quality assured veterinary laboratory diagnostic services. This programme introduced the use of standardized and internationally validated ELISA-based systems for the diagnosis and surveillance of the major transboundary diseases that affect livestock. This approach has proved of immense value in the monitoring of national, regional and global animal disease control and eradication programmes. One such programme focuses on the global elimination of rinderpest. Co-ordinated by FAO through the Global Rinderpest Eradication Programme (GREP) the joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture has developed critical diagnostic and epidemiological tools to assist this effort. As the final stages of the global eradication of rinderpest are reached, it is fitting that the Joint Division should again take the lead in providing guidance to Member States on how best to meet the criteria for quality assurance of national disease surveillance programmes - a prerequisite for international acceptance of freedom from a particular disease. This publication is intended to provide countries involved in rinderpest eradication with a detailed protocol for using performance indicators in evaluating their disease surveillance system and making, where necessary, adjustments to meet the criteria for acceptance specified in the OIE Rinderpest Pathway - a pathway that leads to international recognition of freedom from rinderpest. An initial publication (IAEA-TECDOC-1161) described guidelines for the use of performance indicators in rinderpest surveillance programmes. This publication now describes in detail the protocols and the linked indicators which have been developed and field validated through a series of FAO/IAEA meetings and through IAEA expert assignments to countries in Africa

  3. Optimization by visualization of indices

    Energy Technology Data Exchange (ETDEWEB)

    Haverkamp, Uwe; Kriz, Jan; Eich, Hans Theodor [University Muenster, Department of Radiotherapy, Muenster (Germany); Norkus, Darius [Vilnius University, Oncology Institute, Vilnius (Lithuania); Mueller Minai, Mariam; Prott, Franz-Josef [RNS Radiotherapy Wiesbaden, Wiesbaden (Germany)

    2014-11-15

    Physical 3D treatment planning provides a pool of parameters describing dose distributions. It is often useful to define conformal indices to enable quicker evaluation. However, the application of individual indices is controversial and not always effective. The aim of this study was to design a quick check of dose distributions based on several indices detecting underdosages within planning target volumes (PTVs) and overdosages in normal tissue. Dose distributions of 215 cancer patients were considered. Treatment modalities used were three-dimensional conformal radiotherapy (3DCRT), radiosurgery, intensity-modulated radiotherapy (IMRT), intensity-modulated arc therapy (IMAT) and tomotherapy. The volumes recommended in ICRU 50 and 83 were used for planning and six conformation and homogeneity indices were selected: CI, CN, C{sub ICRU}, COV, C{sub ∇}, and HI. These were based on the PTV, the partial volume covered by the prescribed isodose (PI; PTV{sub PI}), the treated volume (TV{sub PI}), near maximum D{sub 2} and near minimum D{sub 98}. Results were presented as a hexagon - the corners of which represent the values of the indices - and a modified test function F (Rosenbrock's function) was calculated. Results refer to clinical examples and mean values, in order to allow evaluation of the power of F and hexagon-based decision support procedures in detail and in general. IMAT and tomotherapy showed the best values for the indices and the lowest standard deviation followed by static IMRT. DCRT and radiosurgery (e.g. CN: IMAT 0.85 ± 0.06; tomotherapy 0.84 ± 0.06; IMRT 0.83 ± 0.07; 3DCRT 0.65 ± 0.08; radiosurgery 0.64 ± 0.11). In extreme situations, not all indices reflected the situation correctly. Over- and underdosing of PTV and normal tissue could be qualitatively assessed from the distortion of the hexagon in graphic analysis. Tomotherapy, IMRT, IMAT, 3DCRT and radiosurgery showed increasingly distorted hexagons, the type of distortion indicating

  4. Techniques and indications in radiology

    International Nuclear Information System (INIS)

    Lange, S.

    1987-01-01

    The stated purpose of this book is to review modern radiologic diagnostic techniques as applied to the study of the kidney and urinary tract, and their pertinent indications. This goal is partially accomplished in the first two segments of the book, which consist of about 100 pages. These include a synoptic description of various techniques - including classic uroradiologic studies such as excretory urography and retrograde pyelography, plus sonography, computed tomography, angiography, and nuclear medicine. The diagnostic signs and the differential diagnoses are fairly well described, aided by a profusion of tables and diagrams. The overall quality of the reproduction of the illustrations is good

  5. Biological indicators of radiation quality

    International Nuclear Information System (INIS)

    Bender, M.A.; Wong, R.M.A.

    1982-01-01

    The induction of many biological effects by high linear energy transfer (LET) radiation is strikingly different in one or two respects from the induction by acute low-LET radiation. If the acute low-LET dose-effect curve is of the usual quadratic form, it becomes linear as LET increases. In any case the linear slope increases as LET increases; that is, the relative biological effectiveness (RBE) increases. Both changes might be exploited as biological indicators of whether or not the recent recalculations of dose and of neutron contribution to dose at Hiroshima and Nagasaki seem consistent with the epidemiological observations. The biological end points that have been extensively studied in survivors include acute effects, growth and development after in utero or childhood exposure, genetic and cytogenetic effects in offspring, somatic chromosomal aberrations in survivors, and, of course, cancers, including leukemia. No significant indication among offspring of genetic or cytogenetic effects attributable to parental exposure has been found. Among the remaining end points, only the data on somatic chromosomal aberrations and on cancers appear robust enough to allow one to draw definite inferences by comparing experiences at the two cities

  6. Morphological Indices in Mangalitsa Breed

    Directory of Open Access Journals (Sweden)

    Eleonora Nistor

    2012-10-01

    Full Text Available Observations were made in several Mangalitsa farm from Hungary and Romania on Red, Blonde and Swallowbelliedvarieties. Body measurements were performed on a total of 175 individuals of Mangalitsa and Mangalitsa xDuroc hybrids. There are differences in physical development among Mangalitsa varieties: blond variety has the bestbody development followed by red and swallow-bellied varieties. The average body weight for Mangalitsa pigs was109.031.4 kg and the thoracic perimeter 115.180.95 cm. Results obtained indicate that body development ofMangalitsa pigs from Hungary area, are close to the breed standard. In average height at withers was 65.872.09 cm,while height at back was 72.591.2 cm. Low coefficient of variation for both measurements (CV%=1.83 for withersheigh and 1.52% for back height indicate that pigs populations in which measurements were made are veryhomogeneous.

  7. Simple indicators for Lorentzian causets

    Science.gov (United States)

    Bolognesi, Tommaso; Lamb, Alexander

    2016-09-01

    Several classes of directed acyclic graphs have been investigated in the last two decades, in the context of the causal set program, in search for good discrete models of spacetime. We introduce some statistical indicators that can be used for comparing these graphs and for assessing their closeness to the ideal Lorentzian causal sets (‘causets’)—those obtained by sprinkling points in a Lorentzian manifold. In particular, with the reversed triangular inequality of Special Relativity in mind, we introduce ‘longest/shortest path plots’, an easily implemented tool to visually detect the extent to which a generic causet matches the wide range of path lengths between events of Lorentzian causets. This tool can attribute some degree of ‘Lorentzianity’—in particular ‘non-locality’—also to causets that are not (directly) embeddable and that, due to some regularity in their structure, would not pass the key test for Lorentz invariance: the absence of preferred reference frames. We compare the discussed indicators and use them for assessing causets both of stochastic and of deterministic, algorithmic origin, finding examples of the latter that behave optimally w.r.t. our longest/shortest path plots.

  8. Triboluminescent tamper-indicating device

    Science.gov (United States)

    Johnston, Roger G.; Garcia, Anthony R. E.

    2002-01-01

    A tamper-indicating device is described. The device has a transparent or translucent cylindrical body that includes triboluminescent material, and an outer opaque layer that prevents ambient light from entering. A chamber in the body holds an undeveloped piece of photographic film bearing an image. The device is assembled from two body members. One of the body members includes a recess for storing film and an optical assembly that can be adjusted to prevent light from passing through the assembly and exposing the film. To use the device with a hasp, the body members are positioned on opposite sides of a hasp, inserted through the hasp, and attached. The optical assembly is then manipulated to allow any light generated from the triboluminescent materials during a tampering activity that damages the device to reach the film and destroy the image on the film.

  9. CT colonography: Techniques, indications, findings

    International Nuclear Information System (INIS)

    Mang, Thomas; Graser, Anno; Schima, Wolfgang; Maier, Andrea

    2007-01-01

    Computed tomographic colonography (CTC) is a minimally invasive technique for imaging the entire colon. Based on a helical thin-section CT of the cleansed and air-distended colon, two-dimensional and three-dimensional projections are used for image interpretation. Several clinical improvements in patient preparation, technical advances in CT, and new developments in evaluation software have allowed CTC to develop into a powerful diagnostic tool. It is already well established as a reliable diagnostic tool in symptomatic patients. Many experts currently consider CTC a comparable alternative to conventional colonoscopy, although there is still debate about its sensitivity for the detection of colonic polyps in a screening population. This article summarizes the main indications, the current techniques in patient preparation, data acquisition and data analysis as well as imaging features for common benign and malignant colorectal lesions

  10. Selected Banks Economic Efficiency Indicators

    Directory of Open Access Journals (Sweden)

    Adam Szafarczyk

    2007-04-01

    Full Text Available There are a lot of economic efficiency indicators in theory. It is necessary to choice some of them for concrete purposes. ROA, ROE and C/I play important role due to last experience of polish banks.Cost to Income Ratio plays very important role affecting not only efficiency monitoring process in the banks but also becoming a very important target in strategy or finance plan. There are several methodological approaches to construct this index in detail. Results are differing due to implementing methodology. This article describes trends C/I concerning both polish and foreign banks. It is difficult to compare banks in emerging country and real giants in finance mature economies.

  11. Radon as a hydrological indicator

    Energy Technology Data Exchange (ETDEWEB)

    Komae, Takami [National Research Inst. of Agricultural Engineering, Tsukuba, Ibaraki (Japan)

    1997-02-01

    The radon concentration in water is measured by a liquid scintillation method. After the radioactive equilibrium between radon and the daughter nuclides was attained, the radon concentration was determined by the liquid scintillation analyzer. {alpha}-ray from radon, then two {beta}- and two {alpha}-ray from the daughter nuclei group were released, so that 500% of the apparent counting efficiency was obtained. The detector limit is about 0.03 Bq/l, the low value, which corresponds to about 5.4x10{sup -15} ppm. By determining the radon concentration in groundwater, behavior of radon in hydrological process, the groundwater exchange caused by pumping and exchange between river water and groundwater were investigated. The water circulation analysis by means of radon indicator in the environment was shown. By using the large difference of radon concentration between in river water and in groundwater, arrival of injected water to the sampling point of groundwater was detected. (S.Y.)

  12. Nuclear power indices and safety

    International Nuclear Information System (INIS)

    Bennet, L.L.; Fizher, D.; Nechaev, A.

    1987-01-01

    Problems discussed at the IAEA International Conference on nuclear power indices and safety held in Vienna from 28 September to 2 October, 1987 are considered. Representatives from 40 countries and 12 international organizations participated in the conference. It is marked that by the end of this century nuclear power plant capacities in developing countries will increase by more than twice. In developed countries increase of installed capacity by 65 % is forecasted. It is stressed that competently constructed and operated NPPs will be successfully competing with coal-fueled power plants in the majority of the world regions. Much attention was paid to reports on measures taken after Chernobyl' accident and its radiation effects on people helth. It is shown that parallel with fundamental theoretical studies on NPP safety as a complex engineering system much attention is paid to some problems of designing and operation of such facilities. Fuel cycle problems, radioactive waste and spent fuel storage and disposal in particular, are considered

  13. Quality Indicators in Radiation Oncology

    Energy Technology Data Exchange (ETDEWEB)

    Albert, Jeffrey M. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Das, Prajnan, E-mail: prajdas@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-03-15

    Oncologic specialty societies and multidisciplinary collaborative groups have dedicated considerable effort to developing evidence-based quality indicators (QIs) to facilitate quality improvement, accreditation, benchmarking, reimbursement, maintenance of certification, and regulatory reporting. In particular, the field of radiation oncology has a long history of organized quality assessment efforts and continues to work toward developing consensus quality standards in the face of continually evolving technologies and standards of care. This report provides a comprehensive review of the current state of quality assessment in radiation oncology. Specifically, this report highlights implications of the healthcare quality movement for radiation oncology and reviews existing efforts to define and measure quality in the field, with focus on dimensions of quality specific to radiation oncology within the “big picture” of oncologic quality assessment efforts.

  14. 'Blueberry' Layers Indicate Watery Origins

    Science.gov (United States)

    2004-01-01

    This microscopic image, taken at the outcrop region dubbed 'El Capitan' near the Mars Exploration Rover Opportunity's landing site, reveals millimeter-scale (.04 inch-scale) layers in the lower portion. This same layering is hinted at by the fine notches that run horizontally across the sphere-like grain or 'blueberry' in the center left. The thin layers do not appear to deform around the blueberry, indicating that these geologic features are concretions and not impact spherules or ejected volcanic material called lapilli. Concretions are balls of minerals that form in pre-existing wet sediments. This image was taken by the rover's microscopic imager on the 29th martian day, or sol, of its mission. The observed area is about 3 centimeters (1.2 inches) across.

  15. Quality Indicators in Radiation Oncology

    International Nuclear Information System (INIS)

    Albert, Jeffrey M.; Das, Prajnan

    2013-01-01

    Oncologic specialty societies and multidisciplinary collaborative groups have dedicated considerable effort to developing evidence-based quality indicators (QIs) to facilitate quality improvement, accreditation, benchmarking, reimbursement, maintenance of certification, and regulatory reporting. In particular, the field of radiation oncology has a long history of organized quality assessment efforts and continues to work toward developing consensus quality standards in the face of continually evolving technologies and standards of care. This report provides a comprehensive review of the current state of quality assessment in radiation oncology. Specifically, this report highlights implications of the healthcare quality movement for radiation oncology and reviews existing efforts to define and measure quality in the field, with focus on dimensions of quality specific to radiation oncology within the “big picture” of oncologic quality assessment efforts

  16. Performance indicators of bioethanol distillation

    International Nuclear Information System (INIS)

    Marriaga, Nilson

    2009-01-01

    The increase of biofuels demand accelerates the construction of new production plants and technological improvements in the process so the development of versatile tools for evaluating alternatives becomes an undeniable challenge. It was established through heuristic rules, thermodynamic analysis and simulation computer the energy consumption and performance indicators that govern, from fermented mash (ethanol 8.5 % v/v), the distillation of various capacities for bioethanol production: 20, 60, 100 and 150 KLD (kiloliters / day) through Aspen PlusTM simulator. It was found that the distillation demand nearly 30% of heat that would be obtained by burning alcohol fuel produced thus it is necessary the use of raw materials that generate enough biomass to produce the steam required. In addition, correlations were found to allow for easy diameters of distillation columns in terms of production capacity.

  17. Barium 139 as Fission Indicator

    Energy Technology Data Exchange (ETDEWEB)

    Broda, E.

    1943-07-01

    This report is based on a measurement performed at the Cavendish Laboratory (Cambridge) by E. Broda in December 1943 where a technique has been worked out for measuring the fission density in a uranium containing medium in relative units by determining the amount of a suitable fission product formed. Generally a given fission product will be formed in natural uranium by slow neutron fission of U235 or by fast neutron fission of either U235 or U238. It is intended to translate the relative units into absolute units by comparison of the Ba yield with the indication of UF6 fission chamber in the same medium. This has to be done separately for fast and slow neutron fission as the yields may be different. Another application of the technique developed is the measurement of thermal neutron density in an uraniferous medium without using a detector subject to variations of sensitivity according to the properties of the medium. (nowak)

  18. Kyphoplasty: indications, contraindications and technique

    International Nuclear Information System (INIS)

    Masala, Salvatore; Fiori, Roberto; Massari, Francesco; Simonetti, Giovanni

    2005-01-01

    Purpose. Percutaneous Kyphoplasty is an emerging Interventional Radiology technique consisting in injecting polymethylmethacrylate (PMMA) into collapsed vertebral bodies under fluoroscopic guidance, after compaction of the cancellous bone with two dedicated balloon catheters. The purpose of our study was to assess the indications, contraindications, technique and results of our initial study. Materials and methods. Between January and May 2003 we treated 11 patients (5 men, 6 women) with vertebral collapse occurred up to three months earlier and osteoporosis or myeloma (mean age: 68.9), with pain refractory to medical therapy. All patients underwent treatment on a single vertebra (1 D7; 1 D8; 2 D12; 3 L1; 3 L2; 1 l4). Patient selection was based on clinical and instrumental criteria: conventional radiography, CT and MR were performed on all patients before the procedure. The Visual Analogue scale (VAS) for pain assessment was used to evaluate the post-procedure results. Results. All patients showed an increase in the height of the collapsed vertebral body, associated with partial or complete pain relief (VAS score decreasing from a pre-treatment score of 8 to a score of 2 after treatment). No complications related to the procedure were recorded. Conclusions. The indications for kyphoplasty include recent vertebral compression fractures due to osteoporosis, myeloma, metastasis and vertebral angioma with intractable pain and with no neurological symptoms. The main contraindications are coagulation disorders, unstable fractures or complete vertebral collapse (vertebra plana). Kyphoplasty proved to be a safe and effective method for the treatment of intractable pain due to vertebral collapse that allows for shorter hospital stays and an immediate improvement in the patient's quality of life [it

  19. Stability indicators in network reconstruction.

    Directory of Open Access Journals (Sweden)

    Michele Filosi

    Full Text Available The number of available algorithms to infer a biological network from a dataset of high-throughput measurements is overwhelming and keeps growing. However, evaluating their performance is unfeasible unless a 'gold standard' is available to measure how close the reconstructed network is to the ground truth. One measure of this is the stability of these predictions to data resampling approaches. We introduce NetSI, a family of Network Stability Indicators, to assess quantitatively the stability of a reconstructed network in terms of inference variability due to data subsampling. In order to evaluate network stability, the main NetSI methods use a global/local network metric in combination with a resampling (bootstrap or cross-validation procedure. In addition, we provide two normalized variability scores over data resampling to measure edge weight stability and node degree stability, and then introduce a stability ranking for edges and nodes. A complete implementation of the NetSI indicators, including the Hamming-Ipsen-Mikhailov (HIM network distance adopted in this paper is available with the R package nettools. We demonstrate the use of the NetSI family by measuring network stability on four datasets against alternative network reconstruction methods. First, the effect of sample size on stability of inferred networks is studied in a gold standard framework on yeast-like data from the Gene Net Weaver simulator. We also consider the impact of varying modularity on a set of structurally different networks (50 nodes, from 2 to 10 modules, and then of complex feature covariance structure, showing the different behaviours of standard reconstruction methods based on Pearson correlation, Maximum Information Coefficient (MIC and False Discovery Rate (FDR strategy. Finally, we demonstrate a strong combined effect of different reconstruction methods and phenotype subgroups on a hepatocellular carcinoma miRNA microarray dataset (240 subjects, and we

  20. [Indications for surgery in thyroiditis].

    Science.gov (United States)

    Diaconescu, M R; Glod, M; Costea, I; Grigorovici, M; Diaconescu, S

    2012-01-01

    Inflammatory processes of the thyroid represents a main proportion of the gland's pathology but the majority of them are treated by medical methods, surgery being indicated. In 14 cases (3%) from 464 operations for different thyroid conditions we have encountered authentic inflammatory lesions in 9 cases of Hashimoto's thyroiditis (two associated with papillary thyroid carcinoma and one with malignant lymphoma), two cases of Riedel's thyroiditis and respectively de Quervain thyoiditis, tuberculous thyroiditis and actynomicosis one case each. The common lymphoplasmacytic infiltration in Basedow's disease was not considered likewise as the inflammatory nespecific lesions encountered in benign and malignant pathology of the gland. The clinical and imagistic data, biological evaluation and titer of anticorps but particularly the paraffine examination together with intraoperative estimations are decisive for the diagnosis. Firm diagnosis of thyroiditis was rarely affirmed before operation, surgical indication being formulated on clinical criterions dominated by cancer suspicion. Among these are diffuse or (multi)nodular thyromegaly with a dominant nodule with recent appearance and rapid growing in temporal and geographic proximity of Chemobyl disaster, with hard consistence, celsian or compressive features and adenopathy. More added the imagistic signs but especially suspect aspects of the FNAB (follicular or with Hürthle cells smears) and also of the frozen sections. Certainty diagnosis was established by paraffine examination not always without hesitations or reexamination (Hashimoto's thyroiditis diagnosed in one case was finally a malignant lymphoma). Large removal decided after intraoperative findings induced for the most of patients a definitive hypothyroidism. All the diagnosis resources must be exhausted for the diagnosis of the inflammatory lesions of the thyroid to avoid unnecessary surgery. On the other side the chronic overstimulation by the TSH of the

  1. Indicating anthropogenic effectson urban water system - indicators and extension

    Science.gov (United States)

    Strauch, G.; Ufz-Team

    2003-04-01

    Urban water systems are polluted by diffusive and direct contribution of anthropogenic activities. Besides industrial contaminants like aromatic and chlorinated HC and other persistent organic compounds, the urban aquatic environment is increasingly polluted by low concentrated but high eco-toxic compounds as pharmaceuticals, fragrances, plasticizers which most have disrupt endocrine functions, and trace elements carried in by surface and sub-surface waste water and seeping processes. This contamination could have a longtime impact on the urban ecosystem and on the human health. The interdisciplinary project on risk assessment of water pollution was initiated to explore new methodologies for assessing human activities on the urban water system and processes among urban watersheds. In a first assumption we used a flow model concept with in- and output and surface water transport represented by the city of Halle, Germany, and the river Saale. The river Saale acts as surface water system collecting waste water inputs along the city traverse. We investigated the anthropogenic effect on the urban water system using the indicators hydrological parameters, compound specific pattern of complex organic substances and trace elements, isotopic signatures of water (H, O) and dissolved substances (sulfate, DIC, nitrate), pathogens, and microbiota. A first balance modeling showed that main ions are not very sensitive concerning the direct urban input into the river. Depending on the discharge of the river in high and low flood stages the load of dissolved matter has no specific urban effect. However, the concentration pattern of fragrances (tonalid, galaxolid) and endocrine disrupters (t-nonylphenol) point to a different pollution along the city traverse: downstream of the sewage plant a higher load was observed in comparison to the upstream passage. Furthermore, a degradation ability of fungi and bacteria occurred in the bank sediments could be detected in lab experiments

  2. Geochemical indicators of intrinsic bioremediation

    International Nuclear Information System (INIS)

    Borden, R.C.; Gomez, C.A.; Becker, M.T.

    1995-01-01

    A detailed field investigation has been completed at a gasoline-contaminated aquifer near Rocky Point, NC, to examine possible indicators of intrinsic bioremediation and identify factors that may significantly influence the rae and extent of bioremediation. The dissolved plume of benzene, toluene, ethylbenzene, and xylene (BTEX) in ground water is naturally degrading. Toluene and o-xylene are most rapidly degraded followed by m-, p-xylene, and benzene. Ethylbenzene appears to degrade very slowly under anaerobic conditions present in the center of the plume. The rate and extent of biodegradation appears to be strongly influenced by the type and quantity of electron acceptors present in the aquifer. At the upgradient edge of the plume, nitrate, ferric iron, and oxygen are used as terminal electron acceptors during hydrocarbon biodegradation. The equivalent of 40 to 50 mg/l of hydrocarbon is degraded based on the increase in dissolved CO 2 relative to background ground water. Immediately downgradient of the source area, sulfate and iron are the dominant electron acceptors. Toluene and o-xylene are rapidly removed in this region. Once the available oxygen, nitrate, and sulfate are consumed, biodegradation is limited and appears to be controlled by mixing and aerobic biodegradation at the plume fringes

  3. Reusable, tamper-indicating seal

    International Nuclear Information System (INIS)

    Ryan, M.J.

    1978-01-01

    A reusable, tamper-indicating seal is comprised of a drum confined within a fixed body and rotatable in one direction therewithin, the top of the drum constituting a tray carrying a large number of small balls of several different colors. The fixed body contains parallel holes for looping a seal wire therethrough. The base of the drums carries cams adapted to coact with cam followers to lock the wire within the seal at one angular position of the drum. A channel in the fixed body, visible from outside the seal, adjacent the tray constitutes a segregated location for a small plurality of the colored balls. A spring in the tray forces colored balls into the segregated location at one angular position of the drum, further rotation securing the balls in position and the wires in the seal. A wedge-shaped plough removes the balls from the segregated location, at a different angular position of the drum, the wire being unlocked at the same postion. A new pattern of colored balls will appear in the segregated location when the seal is relocked

  4. Integrated Initiating Event Performance Indicators

    International Nuclear Information System (INIS)

    S. A. Eide; Dale M. Rasmuson; Corwin L. Atwood

    2005-01-01

    The U.S. Nuclear Regulatory Commission Industry Trends Program (ITP) collects and analyses industry-wide data, assesses the safety significance of results, and communicates results to Congress and other stakeholders. This paper outlines potential enhancements in the ITP to comprehensively cover the Initiating Events Cornerstone of Safety. Future work will address other cornerstones of safety. The proposed Tier 1 activity involves collecting data on ten categories of risk-significant initiating events, trending the results, and comparing early performance with prediction limits (allowable numbers of events, above which NRC action may occur). Tier 1 results would be used to monitor industry performance at the level of individual categories of initiating events. The proposed Tier 2 activity involves integrating the information for individual categories of initiating events into a single risk-based indicator, termed the Baseline Risk Index for Initiating Events or BRIIE. The BRIIE would be evaluated yearly and compared against a threshold. BRIIE results would be reported to Congress on a yearly basis

  5. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs.

    Science.gov (United States)

    Zhang, Han-Ting

    2009-01-01

    Phosphodiesterase-4 (PDE4), one of eleven PDE enzyme families, specifically catalyzes hydrolysis of cyclic AMP (cAMP); it has four subtypes (PDE4A-D) with at least 25 splice variants. PDE4 plays a critical role in the control of intracellular cAMP concentrations. PDE4 inhibitors produce antidepressant actions in both animals and humans via enhancement of cAMP signaling in the brain. However, their clinical utility has been hampered by side effects, in particular nausea and emesis. While there is still a long way to go before PDE4 inhibitors with high therapeutic indices are available for treatment of depressive disorders, important advances have been made in the development of PDE4 inhibitors as antidepressants. First, limited, but significant studies point to PDE4D as the major PDE4 subtype responsible for antidepressant-like effects of PDE4 inhibitors, although the role of PDE4A cannot be excluded. Second, PDE4D may contribute to emesis, the major side effect of PDE4 inhibitors. For this reason, identification of roles of PDE4D splice variants in mediating antidepressant activity is particularly important. Recent studies using small interfering RNAs (siRNAs) have demonstrated the feasibility to identify cellular functions of individual PDE4 variants. Third, mixed inhibitors of PDE4 and PDE7 or PDE4 and serotonin reuptake have been developed and may be potential antidepressants with minimized side effects. Finally, relatively selective inhibitors of one or two PDE4 subtypes have been synthesized using structure- and scaffold-based design. This review also discusses the relationship between PDE4 and antidepressant activity based on structures, brain distributions, and pharmacological properties of PDE4 and its isoforms.

  6. Mute swans: Natural (?) environmental indicators

    Science.gov (United States)

    Day, D.; Perry, Matthew C.

    2004-01-01

    The rapid expansion of the Chesapeake Bay's population of feral mute swans (Cygnus olar), coupled with a dramatic Bay-wide decline in submerged aquatic vegetation (SAV), has fueled much of the current debate surrounding the need for a management plan to protect the aquatic food resources that are critical to many species native to the Bay. Crucial to this decision process is a sound understanding of the ecological ramifications of having the year-round presence of a large, nonnative, aquatic herbivore on the Bay. Ultimately, this will require a quantitative assessment of the ecological harm currently posed by mute swans before a biologically defensible management strategy can be developed. Unfortunately, very little new information specific to the Bay's mute swan population has been gathered since Reese first studied them in the late 1960s and 1970s. While the debate over what to do about the rapidly expanding mute swan population continues, there is much that can be gained from study of this beautiful intruder. Several recent studies of the feeding habits of mute swans have shown that mutes can provide a unique barometer, or indicator, of environmental conditions. Because of their reliance on SAV as a primary food source, monitoring the density of swans utilizing a particular area can give some indication of the status of the area's grass beds. This phenomenon was clearly demonstrated during the summer of 1999 when there was a dramatic decline in the number of swans observed around the Eastern Neck NWR, a traditional population stronghold. The shift in bird use was precipitated by a rapid, large-scale collapse of the area's aquatic grass beds, possibly the result of a prolonged drought. During the winter of 2000/2001, a similar ecological assessment was conducted by comparing body weights of swans collected from Tangier Sound, an area with relatively abundant grass beds, and swans from the waters adjacent to Eastern Neck Island. Swans weights tended to reflect the

  7. Extended indications for percutaneous tracheostomy.

    Science.gov (United States)

    Ben Nun, Alon; Altman, Eduard; Best, Lael Anson

    2005-10-01

    In recent years, percutaneous tracheostomy has become a routine practice in many hospitals. In the early publications, most authors considered adverse conditions such as short, fat neck or obesity as relative contraindications whereas cervical injury, coagulopathy, and emergency were regarded as absolute contraindications. More recently, several reports demonstrated the feasibility of percutaneous tracheostomy in patients with some of these contraindications. The aim of this study is to determine the safety and efficacy of percutaneous tracheostomy in conditions commonly referred to as contraindications. Between June 2000 and July 2001, 157 consecutive percutaneous tracheostomy procedures were performed on 154 critically ill adult patients in the general intensive care unit of a major tertiary care facility. The Griggs technique and Portex set were used at the bedside. All procedures were performed by staff thoracic surgeons and anesthesiologists experienced with the technique. Anatomical conditions, presence of coagulopathy and anti-coagulation therapy, demographics, and complication rates were recorded. Five of 157 procedures (154 patients owing to three repeat tracheostomies) had complications. In patients with normal anatomical conditions and coagulation profiles, there was one case of bleeding (50 cc to 120 cc) and one case of mild cellulitis around the stoma. In patients with adverse conditions, there was one case of bleeding (50 cc to 120 cc) and two cases of minor bleeding (< 50 cc). Patients with adverse conditions had a low complication rate similar to patients with normal conditions. For this reason, we believe that percutaneous tracheostomy is indicated in patients with short, fat neck; inability to perform neck extension; enlarged isthmus of thyroid; previous tracheostomy; or coagulopathy and anti-coagulation therapy.

  8. The Indicating FTA Elute Cartridge

    Science.gov (United States)

    de Bie, Roosmarie P.; Schmeink, Channa E.; Bakkers, Judith M.J.E.; Snijders, Peter J.F.; Quint, Wim G.V.; Massuger, Leon F.A.G.; Bekkers, Ruud L.M.; Melchers, Willem J.G.

    2011-01-01

    The clinically validated high-risk human papillomavirus (hrHPV) Hybrid Capture 2 (HC2) and GP5+/6+-PCR assays were analyzed on an Indicating FTA Elute cartridge (FTA cartridge). The FTA cartridge is a solid dry carrier that allows safe transport of cervical samples. FTA cartridge samples were compared with liquid-based samples for hrHPV and high-grade cervical intraepithelial neoplasia (CIN) detection. One cervical sample was collected in a liquid-based medium, and one was applied to the FTA cartridge. DNA was eluted directly from the FTA cartridge by a simple elution step. HC2 and GP5+/6+-PCR assays were performed on both the liquid-based and the FTA-eluted DNA of 88 women. Overall agreement between FTA and liquid-based samples for the presence of hrHPV was 90.9% with GP5+/6+-PCR and 77.3% with HC2. The sensitivity for high-grade CIN of hrHPV testing on the FTA cartridges was 84.6% with GP5+/6+-PCR and only 53.8% with HC2. By comparison, these sensitivities on liquid-based samples were 92.3% and 100% for GP5+/6+-PCR and HC2, respectively. Therefore, the FTA cartridge shows reasonably good overall agreement for hrHPV detection with liquid-based media when using GP5+/6+-PCR but not HC2 testing. Even with GP5+/6+-PCR, the FTA cartridge is not yet capable of detecting all high-grade CIN lesions. PMID:21704269

  9. Gamma radiographic exposure time indicator

    International Nuclear Information System (INIS)

    Risbud, V.H.; Thiagarajan, A.; Gangadharan, P.

    1979-01-01

    In industrial radiography, with the proper selection of source and film, the radiographic quality depends very much on the exposure time, which in turn depends upon the source strength and the source to film distance. Conventional methods to arrive at correct exposure time involve time consuming calculations and in these methods the knowledge of the above mentioned parameters is imperative. An instrument to determine the required exposure time has been developed which indicates exposure times in about 30 secs. This covers two commonly used gamma radiography sources, viz., 192 Ir and 60 Co and six commonly used radiography films of different speeds. Knowledge of source strength and source to film distance is not required with the use of this instrument. With a knowledge of the total exposure required by the film to give the required sensitivity and by the measurement of radiation level at the film location, the correct exposure time is determined. The radiation level is measured by placing a GM counter behind the radiographic specimen at the film location. To match the responses of the film and the GM counter, the counter is incorporated in a suitably designed probe. In this instruments, an integrator to integrate the GM-pulses and a constant current integrator (timer) are started simultaneously. The voltage at the GM-pulse integrator is compared with a preselected voltage, (selected on the basis of film type, source, source strength and order of object thickness) by a comparator. The comparator is so adjusted that when the GM-pulse integrator voltage exceeds the preselected voltage, it switches its state and stops the integration of constant current. The constant current integrator output which is proportional to the time taken for the GM-pulse integrator to reach the preselected voltage, is read on a meter graduated in terms of exposure time. The instrument can measure exposure times from 5 minutes to 10 hours read in two ranges, the range-changing being automatic

  10. Do Scientometric Indices Require Revision?

    Directory of Open Access Journals (Sweden)

    Mozafar Khazaei

    2014-09-01

    that in a scientific domain, more cited articles are in a higher scientific rank, while there are articles that are analyzed and reviewed by researchers due to presenting a contradictory subject, and are frequently cited in spite of their inappropriate scientific value, although these citations are not indicative of their higher quality. The impact factor of journals can also make the comparison and ranking of researchers problematic. It is burdensome to compare two researchers with equal h index but different impact factor of journals in which they have published their papers. However, it should be noted that there are differences between two researchers with similar h index in terms of scientific life, number of publications, total number of citations and impact factor of journals in which their articles have been published. Further, the authors of an article do not have the same role and collaboration in publishing the paper. Imagine a researcher with 100 articles and h=15 has been the corresponding author only in 5 articles, but coauthor in the rest of articles. It seems that scientific index for the corresponding author of each article is more important than allocating similar credits to all authors. Nowadays, h index is extensively used to measure the scientific status of researchers, journals, departments and universities. In some academic centers, however, it is incorrectly used to compare the researchers in different majors. Since the introduction of this index, various variants have been prompted upon it; thereby, pre¬senting different variations such as a, g, m and r indices (3. Although, h index apparently differentiates the prominent researchers from those who have merely published many papers, it cannot reveal a perfect view of the scientific output of a researcher. Application of a scientometric criterion alone cannot determine the precise and valid scientific rank of the researchers. Thus, a proper combination of criteria seems necessary. Furthermore

  11. EFFECTIVE INDICATORS FOR SCIENCE INTERNATIONALIZATION.

    Science.gov (United States)

    Cunha-Melo, José Renan da

    2015-01-01

    To review of concepts and actions that aim to analyze the effects of internationalization of science and education, with emphasis in the medical field and its basement in development policies adopted by nations, exploring the potential for international interdisciplinary cooperation of each laboratory, department, university or institute. Search of indicators to assess the degree of internationalization of universities and research institutes in several interconnected levels: organizational, regional, sectoral and global, and policy-making in science, technology innovation and higher education. Scientific research is still carried out individually, but is now much more closely integrated with other social processes. The scientist is no longer a stranger who is allowed to surrender to his hobby to do what it wants. Internationalization of research and medical education, although it is among the topics of greatest need, as the globalized world, is difficult activity to be assessed. The leaders seem to have understood that the knowledge societies, leading to economic policy based on knowledge, can result in economic and social progress of nations. This fact has motivated increasingly the incentive to actions aimed at addressing global problems (eg health, climate change) by funding research that generates new knowledge. The consensus is that the internationalization of science is desirable and necessary for the sustainable development of nations. However it cannot be done only by encouraging and promoting the outward students and researchers abroad. It is necessary, in addition, offer conditions to foreign researchers and students teachers to work in collaboration with Brazilian and raise the country to international scientific standards. Apresentar revisão dos conceitos e ações que objetivam analisar os efeitos da internacionalização da ciência e da educação, com ênfase na área médica e seu embasamento nas políticas de desenvolvimento adotadas pelas na

  12. Calculation and definition of safety indicators

    International Nuclear Information System (INIS)

    Cristian, I.; Branzeu, N.; Vidican, D.; Vladescu, G.

    1997-01-01

    This paper presents, based on Cernavoda safety indicators proposal, the purpose definition and calculation formulas for each of the selected safety indicators. Five categories of safety indicators for Cernavoda Unit 1 were identified, namely: overall plant safety performance; initiating events; safety system availability, physical barrier integrity; indirect indicators. Definition, calculation and use of some safety indicators are shown in a tabular form. (authors)

  13. The indicators of the sustainable development

    International Nuclear Information System (INIS)

    1996-01-01

    The 132 selected indicators of the sustainable development are described. They are grouped into: (1) The social indicators of the sustainable development; (2) The economic indicators of the sustainable development; (3) The environmental indicators of the sustainable development. (4) The institutional indicators of the sustainable development

  14. Environmental indicators for industrial optimization and design

    NARCIS (Netherlands)

    Konneman, Bram

    2008-01-01

    Companies use standard financial indicators to determine their business success and optimize their business opportunities. However, sustainable development demands for an integrated approach to economic, environmental and social indicators. Although a lot of indicator initiatives are under

  15. Climate change indicators in the United States

    Science.gov (United States)

    2010-04-01

    The U.S. Environmental Protection Agency (EPA) has published this report, Climate Change Indicators in the United States, to help readers interpret a set of important indicators to better understand climate change. The report presents 24 indicators, ...

  16. Wholesale gas market indicators - 4. Quarter 2012

    International Nuclear Information System (INIS)

    2013-01-01

    The wholesale gas market indicators publication aims to provide general monitoring indicators about: wholesale gas prices, gas trade between France and neighboring countries, infrastructures availability and utilisation

  17. Wholesale gas market indicators - December 2013

    International Nuclear Information System (INIS)

    2013-12-01

    The wholesale gas market indicators publication aims to provide general monitoring indicators about: wholesale gas prices, gas trade between France and neighboring countries, infrastructures availability and utilisation

  18. Wholesale gas market indicators - September 2013

    International Nuclear Information System (INIS)

    2013-09-01

    The wholesale gas market indicators publication aims to provide general monitoring indicators about: wholesale gas prices, gas trade between France and neighboring countries, infrastructures availability and utilisation

  19. Measuring educational quality by means of indicators

    NARCIS (Netherlands)

    Scheerens, Jaap; Scheerens, J; Luyten, H.; van Ravens, J.

    2011-01-01

    In this chapter the input-process-outcomes-context framework, introduced in Chapter 1 is used for categorising and describing input indicators, process indicators, outcome indicators and context indicators. The chapter starts out with a review and further illustration of this framework and follows

  20. DC KIDS COUNT e-Databook Indicators

    Science.gov (United States)

    DC Action for Children, 2012

    2012-01-01

    This report presents indicators that are included in DC Action for Children's 2012 KIDS COUNT e-databook, their definitions and sources and the rationale for their selection. The indicators for DC KIDS COUNT represent a mix of traditional KIDS COUNT indicators of child well-being, such as the number of children living in poverty, and indicators of…

  1. Symbolic and Nonsymbolic Equivalence Tasks: The Influence of Symbols on Students with Mathematics Difficulty

    Science.gov (United States)

    Driver, Melissa K.; Powell, Sarah R.

    2015-01-01

    Students often experience difficulty with attaching meaning to mathematics symbols. Many students react to symbols, such as the equal sign, as a command to "do something" or "write an answer" without reflecting upon the proper relational meaning of the equal sign. One method for assessing equal-sign understanding is through…

  2. Symbolic and Nonsymbolic Number Comparison in Children with and without Dyscalculia

    Science.gov (United States)

    Mussolin, Christophe; Mejias, Sandrine; Noel, Marie-Pascale

    2010-01-01

    Developmental dyscalculia (DD) is a pervasive difficulty affecting number processing and arithmetic. It is encountered in around 6% of school-aged children. While previous studies have mainly focused on general cognitive functions, the present paper aims to further investigate the hypothesis of a specific numerical deficit in dyscalculia. The…

  3. Indicators to monitor NPP operational safety performance

    International Nuclear Information System (INIS)

    Gomez-Cobo, Ana

    2002-01-01

    Since December 1995 the IAEA activities on safety performance indicators focused on the elaboration of a framework for the establishment of an operational safety performance indicator programme. The development of this framework began with the consideration of the concept of NPP operational safety performance and the identification of operational safety attributes. For each operational safety attribute, overall indicators, envisioned as providing an overall evaluation of relevant aspects of safety performance, were established. Associated with each overall indicator is a level of strategic indicators intended to provide a bridge from overall to specific indicators. Finally each strategic indicator was supported by a set of specific indicators, which represent quantifiable measures of performance. The programme development was enhanced by pilot plant studies, conducted over a 15 month period from January 1998 to March 1999. The result of all this work is compiled in the IAEA-TECDOC-1141, to be published shortly. This paper presents a summary of this IAEA TECDOC. It describes the operational safety performance indicator framework proposed and discusses the results of and lessons learned from the pilot studies. Despite the efforts described, it is clear that additional research is still necessary in areas such as plant-specific adaptation of proposed frameworks in order to suit individual data collection systems and plant characteristics, indicator selection, indicator definition, goal setting, action thresholds, analysis of trends, indicator display systems, analysis of overall safety performance (i.e., aggregation or combination of indicators), safety culture indicators, qualitative indicators, and use of additional indicators to address issues such as industrial safety attitude and performance, staff welfare, and environmental compliance. This is the rationale for a new IAEA Coordinated Research Project on 'Development and application of indicators to monitor NPP

  4. Estudo da produção de HIS (habitação de interesse social e HMP (habitação de mercado popular nas zeis (zonas especiais de interesse social da subprefeitura da Lapa, município de são paulo a partir do pde (plano diretor estratégico de 2002

    Directory of Open Access Journals (Sweden)

    Denise Falcão Pessoa

    2009-12-01

    Full Text Available Este trabajo analiza la producción de Habitación de Interés Social (HIS y Habitación de Mercado Popular (HMP en la submunicipalidad de Lapa, a partir del Plan Director Estratégico (PDE de 2002, en el que empiezan a vigorar las Zonas Especiales de Interés Social (ZEIS. Se busca dar subsídios a los diversos promotores de viviendas de interés social (gobierno municipal, iniciativa privada, para usar o repensar las ZEIS. Las ZEIS estudiadas en este texto, aunque son áreas ocupadas por" villas miseria", están próximas a áreas valorizadas de la ciudad. Se busca demostrar que las ZEIS localizadas cerca de áreas de mejor infraestructura urbana son codiciadas y muchas veces ocupadas por el mercado inmobiliario que, a pesar de la obligación de construir apenas para la población de baja renta, pretende realizar (y efectivamente ha realizado proyectos para un sector más abastado de la población.

  5. O Ensino de História no século XXI: a perspectiva dos professores participantes do Programa de Desenvolvimento Educacional do Paraná (PDE em relação às Diretrizes Curriculares da Educação Básica de História (DCEs

    Directory of Open Access Journals (Sweden)

    Maria Paula Costa

    2013-12-01

    Full Text Available Este artigo tem por objetivo analisar como os professores que participaram do Programa de Desenvolvimento Educacional do Paraná (PDE mobilizaram seus saberes docentes para a leitura e apropriação na prática do cotidiano escolar das Diretrizes Curriculares da Educação Básica de História do Estado do Paraná (DCEs. Para tanto a principal fonte de pesquisa foram às respostas de um instrumento de investigação que procurou compreender os usos, significados, dificuldades e negação deste texto curricular oficial. A proposta de ensino das DCEs está vinculada as discussões da área de investigação denominada, Educação Histórica, especificamente aos estudos teóricos de Jörn Rüsen sobre consciência histórica. Neste sentido, buscamos desvendar os diferentes significados atribuídos pelos professores e seu impacto no trabalho docente no âmbito escolar.

  6. Radiation indicator options for environmental policy

    CERN Document Server

    Pruppers, M J M

    2002-01-01

    It has proven impossible to create an indicator capable of showing the state of the art in a single figure so as to determine the progress made in the 'radiation component' of environmental policy from the trends indicated. This is the conclusion following an investigation requested by the Ministry of Housing, Spatial Planning and the Environment in the framework of the environmental theme 'dispersion of radioactive substances and ionising radiation' to develop a radiation indicator comparable to the indicators for proprietary substances and pesticides. The most important reasons for failing to develop this indicator lie in the absence of both suitable policy targets and data for the calculations necessary for the indicator. Substituting policy targets with reference emissions, reference concentrations and reference doses would make it possible to define indicators for radiation protection. Here, environmental pressure indicators are proposed for nuclear installations and the process industry. The environment...

  7. Wholesale electricity market indicators - December 2013

    International Nuclear Information System (INIS)

    2013-12-01

    The wholesale electricity markets indicators publication aims to provide general monitoring indicators about: wholesale electricity prices, electricity trade between France and neighboring countries, fuel prices, availability and capacity of power generation means, and grid interconnections

  8. Wholesale electricity markets indicators - September 2013

    International Nuclear Information System (INIS)

    2013-09-01

    The wholesale electricity markets indicators publication aims to provide general monitoring indicators about: wholesale electricity prices, electricity trade between France and neighboring countries, fuel prices, availability and capacity of power generation means, and grid interconnections

  9. School infrastructure performance indicator system (SIPIS)

    CSIR Research Space (South Africa)

    Gibberd, Jeremy T

    2007-05-01

    Full Text Available This paper describes the School Infrastructure Performance Indicator System (SIPIS) project which explores how an indicator system could be developed for school infrastructure in South Africa. It outlines the key challenges faced by the system...

  10. SECURITIES MARKET AS AN INDICATOR OF INNOVATION

    Directory of Open Access Journals (Sweden)

    Victor M. Askinadze

    2014-01-01

    Full Text Available The article presents a potential possibility to use stock market Indices as an indicator of emerging innovative economy. The focal point is the significance of taking into account the stock market Indices’ dynamics and volatility.

  11. SECURITIES MARKET AS AN INDICATOR OF INNOVATION

    OpenAIRE

    Victor M. Askinadze

    2014-01-01

    The article presents a potential possibility to use stock market Indices as an indicator of emerging innovative economy. The focal point is the significance of taking into account the stock market Indices’ dynamics and volatility.

  12. Indications for Oesophagogastroduodenoscopy in Ilorin, Nigeria- A ...

    African Journals Online (AJOL)

    Oesophagogastroduodenoscopy is generally indicated for evaluating upper ... ulcer, upper tract stricture or obstruction, gastrointestinal bleeding, persistent vomiting of unknown cause etc. This study is therefore to review the indications for ...

  13. Study of Dendrimers by Topological Indices

    Directory of Open Access Journals (Sweden)

    Soleimani Najmeh

    2017-12-01

    Full Text Available In this paper, five degree based topological indices, the first Zagreb (M1, second Zagreb (M2, first multiple Zagreb (PM1, second multiple Zagreb (PM2, and the hyper Zagreb (HM indices of two types of dendrimers are studied. In addition, two distance based topological indices, the total eccentricity (θ and eccentric connectivity (ξc indices of these dendrimers are computed.

  14. Review of Urban Sustainability Indicators Assessment

    DEFF Research Database (Denmark)

    Michael, Florianna Lendai; Noor, Zainura Zainon; Figueroa, Maria Josefina

    2015-01-01

    This paper examines and compares the processes, methodologies and resulting sets of indicators for urban sustainability carried out in three of Asia's developing countries; Malaysia, Taiwan and China. The paper analytically discusses the challenges of developing urban sustainability indicators...... among the developing countries. The comparison reveals the urban indicators development's processes, contents and outcomes and whether the resulting set of urban indicators is operational and has changed the way things were....

  15. Entropic Representation and Estimation of Diversity Indices

    OpenAIRE

    Zhang, Zhiyi; Grabchak, Michael

    2014-01-01

    This paper serves a twofold purpose. First, a unified perspective on diversity indices is introduced based on an entropic basis. It is shown that the class of all linear combinations of the entropic basis, referred to as the class of linear diversity indices, covers a wide range of diversity indices used in the literature. Second, a class of estimators for linear diversity indices is proposed and it is shown that these estimators have rapidly decaying biases and asymptotic normality.

  16. Visual indicator of absorbed radiation doses

    Energy Technology Data Exchange (ETDEWEB)

    Generalova, V V; Krasovitskii, B M; Vainshtok, B A; Gurskii, M N

    1968-10-15

    A visual indicator of the absorbed doses of ionizing radiation is proposed. The indicator has a polymer base with the addition of a dye. A distinctive feature of the indicator consists of the use of polystyrene as its polymer base with the addition of halogen-containing hydrocarbon and the light-proof dye. Such combination of the radiation-resistant polymer of polystyrene and the light-proof dyestuff makes the proposed indicator highly stable.

  17. Virus and indicator relationships in groundwater

    Science.gov (United States)

    This presentation examines indicator-virus relationships from 13 international studies of public groundwater systems. This presentation shows that the absence of classic indicators is a strong predictor of the absence of viral pathogens. However, indicators are often present in t...

  18. Facilities Performance Indicators Report, 2008-09

    Science.gov (United States)

    Hills, Christina, Ed.

    2010-01-01

    This paper features another expanded Web-based Facilities Performance Indicators Report (FPI). The purpose of APPA's Facilities Performance Indicators is to provide a representative set of statistics about facilities in educational institutions. The 2008-09 iteration of the Web-based Facilities Performance Indicators Survey was posted and…

  19. Computed Radiography Exposure Indices in Mammography | Koen ...

    African Journals Online (AJOL)

    Computed Radiography Exposure Indices in Mammography. L Koen, C Herbst, W Rae. Abstract. Background. Studies indicate that computed radiography (CR) can lead to increased radiation dose to patients. It is therefore important to relate the exposure indicators provided by CR manufacturers to the radiation dose ...

  20. Acute Aquatic Risk Indicator for Pesticides

    NARCIS (Netherlands)

    Luttik R; Kalf DF; CSR

    1998-01-01

    De acute aquatische risico-indicator voor bestrijdingsmiddelen kan beschouwd worden als een indicator voor de toxische druk van bestrijdingsmiddelen op het aquatische milieu. De indicator is gebaseerd op alle bestrijdingsmiddelen die in Nederland gebruikt worden of werden sinds 1984. Voor elk

  1. Early Reading Proficiency. Leading Indicator Spotlight

    Science.gov (United States)

    Musen, Lindsey

    2010-01-01

    In "Beyond Test Scores: Leading Indicators for Education," Foley and colleagues (2008) define leading indicators as those that "provide early signals of progress toward academic achievement" (p. 1) and stress that educators "need leading indicators to help them see the direction their efforts are going in and to take…

  2. Key Performance Indicators for Primary Schools.

    Science.gov (United States)

    Strand, Steve

    Focusing mostly on their application for primary schools, this document describes the educational key performance indicators (KPI) employed by the Wendsworth, England, Local Educational Authority (LEA). Indicators are divided into 3 areas, educational context, resource development, and outcomes. Contextual indicators include pupil mobility, home…

  3. Haematological and immunological indicators for radiation exposure

    International Nuclear Information System (INIS)

    Dehos, A.

    1990-01-01

    It is examined if haematological and immunological parameters can be used as biological indicators for radiation exposure. Additional criteria for biological indicators, apart from the dose dependence of the effect, are listed here. The state of the art concerning the development of haematological and immunological indicators is discussed. Several haematological indicators are currently used in diagnosis when excess radiation exposure has occurred (e.g., after the Chernobyl accident). However, further research work has to be done in the field of immunological indicators. (orig.) [de

  4. Financial Performance of Socially Responsible Indices

    Directory of Open Access Journals (Sweden)

    Śliwiński Paweł

    2017-03-01

    Full Text Available This article analyzes rate-of-return and risk related to investments in socially responsible and conventional country indices. The socially responsible indices are the DJSI Korea, DJSI US and Respect Index, and the corresponding conventional country indices are the Korea Stock Exchange Composite KOSPI, Dow Jones Industrial Average and WIG20TR. We conclude that investing in the analyzed SRI indices do not yield systematically better results than investing in the respective conventional indices, both in terms of neoclassical risk and return rate.

  5. [Family physicians attitude towards quality indicator program].

    Science.gov (United States)

    Shani, Michal; Nakar, Sasson; Azuri, Yossi

    2012-10-01

    Quality indicator programs for primary care are implanted throughout the world improving quality in health care. In this study, we have assessed family physicians attitudes towards the quality indicators program in Israel. Questionnaires were distributed to family physicians in various continuing educational programs. The questionnaire addressed demographics, whether the physician dealt with quality indicators, time devoted by the physician to quality indicators, pressure placed on the physician related to quality indicators, and the working environment. A total of 140 questionnaires were distributed and 91 (65%) were completed. The average physician age was 49 years (range 33-65 years]; the average working experience as a family physician was 17.8 years (range 0.5-42); 58 physicians were family medicine specialist (65.9%). Quality indicators were part of the routine work of 94% of the physicians; 72% of the physicians noted the importance of quality indicators; 84% of the physicians noted that quality indicators demand better team work; 76% of the physicians noted that quality indicators have reduced their professional independence. Pressure to deal with quality indicators was noted by 72% of the family physicians. Pressure to deal with quality indicators was related to reduced loyalty to their employer (P = 0.001), reducing their interest to practice family medicine (p programs, without creating a heavy burden on the work of family physicians.

  6. Examining pitch and numerical magnitude processing in congenital amusia: A quasi-experimental pilot study.

    Science.gov (United States)

    Nunes-Silva, Marilia; Moura, Ricardo; Lopes-Silva, Júlia Beatriz; Haase, Vitor Geraldi

    2016-08-01

    Congenital amusia is a developmental disorder associated with deficits in pitch height discrimination or in integrating pitch sequences into melodies. This quasi-experimental pilot study investigated whether there is an association between pitch and numerical processing deficits in congenital amusia. Since pitch height discrimination is considered a form of magnitude processing, we investigated whether individuals with amusia present an impairment in numerical magnitude processing, which would reflect damage to a generalized magnitude system. Alternatively, we investigated whether the numerical processing deficit would reflect a disconnection between nonsymbolic and symbolic number representations. This study was conducted with 11 adult individuals with congenital amusia and a control comparison group of 6 typically developing individuals. Participants performed nonsymbolic and symbolic magnitude comparisons and number line tasks. Results were available from previous testing using the Montreal Battery of Evaluation of Amusia (MBEA) and a pitch change detection task (PCD). Compared to the controls, individuals with amusia exhibited no significant differences in their performance on both the number line and the nonsymbolic magnitude tasks. Nevertheless, they showed significantly worse performance on the symbolic magnitude task. Moreover, individuals with congenital amusia, who presented worse performance in the Meter subtest, also presented less precise nonsymbolic numerical representation. The relationship between meter and nonsymbolic numerical discrimination could indicate a general ratio processing deficit. The finding of preserved nonsymbolic numerical magnitude discrimination and mental number line representations, with impaired symbolic number processing, in individuals with congenital amusia indicates that (a) pitch height and numerical magnitude processing may not share common neural representations, and (b) in addition to pitch processing, individuals with

  7. Dimensionality reduction of quality of life indicators

    Directory of Open Access Journals (Sweden)

    Andrea Jindrová

    2012-01-01

    Full Text Available Selecting indicators for assessing the quality of life at the regional level is not unambigous. Currently, there are no precisely defined indicators that would give comprehensive information about the quality of life on a local level. In this paper we focus on the determination (selection of groups of indicators that can be interpreted, on the basis of studied literature, as factors characterizing the quality of life. Furthermore, on the application of methods to reduce the dimensionality of these indicators, from the source of the database CULS KROK, which provides statistics on the regional and districts level. To reduce the number of indicators and the subsequent creation of derived variables that capture the relationships between selected indicators multivariate statistical analysis methods, especially method of principal components and factor analysis were used. This paper also indicates the methodology grant project “Methodological Approaches to assess Subjective Aspects of the life quality in regions of the Czech Republic”.

  8. Safety culture management and quantitative indicator evaluation

    International Nuclear Information System (INIS)

    Mandula, J.

    2002-01-01

    This report discuses a relationship between safety culture and evaluation of quantitative indicators. It shows how a systematic use of generally shared operational safety indicators may contribute to formation and reinforcement of safety culture characteristics in routine plant operation. The report also briefly describes the system of operational safety indicators used at the Dukovany plant. It is a PC database application enabling an effective work with the indicators and providing all users with an efficient tool for making synoptic overviews of indicator values in their links and hierarchical structure. Using color coding, the system allows quick indicator evaluation against predefined limits considering indicator value trends. The system, which has resulted from several-year development, was completely established at the plant during the years 2001 and 2002. (author)

  9. Three Cs in Measurement Models: Causal Indicators, Composite Indicators, and Covariates

    OpenAIRE

    Bollen, Kenneth A.; Bauldry, Shawn

    2011-01-01

    In the last two decades attention to causal (and formative) indicators has grown. Accompanying this growth has been the belief that we can classify indicators into two categories, effect (reflective) indicators and causal (formative) indicators. This paper argues that the dichotomous view is too simple. Instead, there are effect indicators and three types of variables on which a latent variable depends: causal indicators, composite (formative) indicators, and covariates (the “three Cs”). Caus...

  10. Indication for pharmacological treatment is often lacking

    DEFF Research Database (Denmark)

    Skoog, Jessica; Midlöv, Patrik; Beckman, Anders

    2015-01-01

    depending on gender, age, multimorbidity level and income were calculated. RESULTS: On average 45.1 % (range 12.9 % - 75.8 %) of the patients' prescribed drugs had indication. Proton pump inhibitors were associated with the lowest level of indication (12.9 %) and digoxin was associated with the highest......, if there are any differences in indication for treatment depending on gender, age, level of multimorbidity and income. METHOD: Data were collected on individuals aged 65 years or older in Östergötland County in Sweden. To estimate the individual level of multimorbidity the Johns Hopkins ACG Case-Mix System...... level of indication for treatment (75.8 %). Patients aged 80 years or older had the lowest odds ratios of having indication for treatment. CONCLUSION: On average, there was indication for treatment in less than half of the prescription drugs studied. The quality was highest in relation to multimorbidity...

  11. Development and integration of programmatic performance indicators

    International Nuclear Information System (INIS)

    Modarres, M.; Wrethall, J.; Appignani, P.L.

    1989-01-01

    This paper describes the results of an evaluation of maintenance-related programmatic performance indicators, and summarizes the direction being taken in a new project to integrate indirect performance indicators for nuclear power plants. Programmatic indicators allow NRC to monitor, at a distance, trends in functional activities before a significant impact appears on safety. Previously presented work described the selection of candidate performance indicators associated with maintenance for continued analysis. This evaluation focused on two aspects of the selected indicators: (1) an evaluation of the state of maintenance programs in the narrative text of SALP reports versus the frequencies of inadvertent ESF actuations from test and maintenance errors; and (2) an evaluation of alternative methods for analyzing the thermal performance of plants as an integral indicator of maintenance program effectiveness. 1 ref., 1 fig

  12. Energy conservation indicators. 1982 annual report

    Energy Technology Data Exchange (ETDEWEB)

    Belzer, D.B.

    1982-09-01

    A series of Energy Conservation Indicators were developed for the Department of Energy to assist in the evaluation of current and proposed conservation strategies. As descriptive statistics that signify current conditions and trends related to efficiency of energy use, indicators provide a way of measuring, monitoring, or inferring actual responses by consumers in markets for energy services. Related sets of indicators are presented in some 40 one-page indicator summaries. Indicators are shown graphically, followed by several paragraphs that explain their derivation and highlight key findings. Indicators are classified according to broad end-use sectors: Aggregate (economy), Residential, Commercial, Industrial, Transportation and Electric Utilities. In most cases annual time series information is presented covering the period 1960 through 1981.

  13. Condition Indicators for Gearbox Condition Monitoring Systems

    Directory of Open Access Journals (Sweden)

    P. Večeř

    2005-01-01

    Full Text Available Condition monitoring systems for manual transmissions based on vibration diagnostics are widely applied in industry. The systems deal with various condition indicators, most of which are focused on a specific type of gearbox fault. Frequently used condition indicators (CIs are described in this paper. The ability of a selected condition indicator to describe the degree of gearing wear was tested using vibration signals acquired during durability testing of manual transmission with helical gears. 

  14. A user's guide to functional diversity indices

    OpenAIRE

    Schleuter, D.; Daufresne, M.; Massol, F.; Argillier, C.

    2010-01-01

    Functional diversity is the diversity of species traits in ecosystems. This concept is increasingly used in ecological research, yet its formal definition and measurements are currently under discussion. As the overall behaviour and consistency of functional diversity indices have not been described so far, the novice user risks choosing an inaccurate index or a set of redundant indices to represent functional diversity. In our study we closely examine functional diversity indices to clari...

  15. A preliminary simulative assessment of disproportionality indices

    OpenAIRE

    Migheli, Matteo; Ortona, Guido; Ponzano, Ferruccio

    2009-01-01

    What do indices of disproportionality actually measure? They provide an aggregate estimation of the difference between votes cast and seats assignment, but the relation between the value of the indices and the will of the voters is highly questionable. The reason is that when casting the vote the voter is deeply affected by the electoral system itself, possibly more deeply than s/he understands. The aim of this paper is to assess the performance of the most used indices of disproportionality ...

  16. Establishing Key Performance Indicators : Case company X

    OpenAIRE

    Singh, Jatinder

    2015-01-01

    The key performance indicators serve as the navigational tools for a business organization to monitor its performance. They enable the management team to take real time decisions to keep organization’s resources aligned to its business strategy to accomplish its strategic objec-tives. This research was conducted to analyse the process of establishing successful key per-formance indicators for a business organization. The research was conducted to recommend key performance indicators developme...

  17. Competency Assessment Using Key Performance Indicators

    OpenAIRE

    Elena Alexandra Toader; Laura Brad

    2015-01-01

    The paper proposes a method for computing the scores of the key performance indicators resulted in the competency assessment process. The key performance indicators are estimated considering four performance levels that an IT professional can obtain at the end of the assessment process. We suggest as the best approach for estimating the performance key indicators an online questionnaire filled by 60 employees that work in IT Romanian companies. The results provide evidence that the difference...

  18. Safety indicators for the peat industry

    Energy Technology Data Exchange (ETDEWEB)

    Berezhnoy, S A; Sedov, Yu I; Yenoshevskiy, B A

    1981-01-01

    Members of the inter-institutional department of 'Labor Protection' of the KPI, in cooperation with members of the peat industry, have developed safety indicators for the peat industry in accordance with the requirements of GOST 12.4.026-76 SSBT, and established the range and order for their use. The safety indicators for the peat industry are divided into four groups (prohibiting, warning, regulating, and indicating), depending on the function.

  19. Forecasting Irish Inflation: A Composite Leading Indicator

    OpenAIRE

    Quinn, Terry; Mawdsley, Andrew

    1996-01-01

    This paper presents the results of research into the construction of a composite leading indicator of the Irish rate of inflation, as measured by the annual percentage change in the Consumer Price Index (CPI). It follows the work of Fagan and Fell (1994) who applied the business cycle leading indicator methodology, initially established by Mitchell and Burns (1938,1946), to construct a composite leading indicator of the Irish business cycle.

  20. EPA Monthly Key Performance Indicator Dashboards 2017

    Science.gov (United States)

    Each month, the Web Analytics Program posts updated Key Performance Indicator (KPI) dashboards that correspond to three Web performance goals: content consumption, content discovery, and audience engagement.

  1. Material management performance indicators for upper management

    International Nuclear Information System (INIS)

    O'Loughlin, R.C.

    1987-01-01

    The purpose of this paper is to develop a case for the use of performance indicators by upper management to monitor the effectiveness of material management operations at nuclear power plants. The paper establishes that the use of performance indicators is not a pro forma matter. There are specific standards and conditions to which the material management operation must conform for the performance measures to be meaningful. The paper concludes with discussion of the application and use of specific performance indicators. Proper use of selected performance indicators can remove the mystery and uncertainty for management about an aspect of nuclear plant operations that has significant budget implications

  2. Optical indicators based on environment sensitive fluorophors

    Energy Technology Data Exchange (ETDEWEB)

    Shakhsher, Z.M.; Seitz, W.R. (Univ. of New Hampshire, Durham, NC (USA))

    1990-01-01

    The authors are interested in the development of optical indicators based on environment sensitive fluorophors. The fluorophor is immobilized on a solid substrate. Interaction with analyte modifies the fluorophor environment, leading to a shift in the distribution of emission wavelengths. Because the indicator is based on spectral shift, it is possible to relate analyte concentration to a ratio of intensities at two different wavelengths. This parameter is insensitive to instrumental drift and slow loss of indicator. Two indicator systems have been investigated. Both involve dansyl derivation, i.e., derivatives of 5-dimethylamino-1-naphthalene sulfonic acid.

  3. An efficient compression scheme for bitmap indices

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kesheng; Otoo, Ekow J.; Shoshani, Arie

    2004-04-13

    When using an out-of-core indexing method to answer a query, it is generally assumed that the I/O cost dominates the overall query response time. Because of this, most research on indexing methods concentrate on reducing the sizes of indices. For bitmap indices, compression has been used for this purpose. However, in most cases, operations on these compressed bitmaps, mostly bitwise logical operations such as AND, OR, and NOT, spend more time in CPU than in I/O. To speedup these operations, a number of specialized bitmap compression schemes have been developed; the best known of which is the byte-aligned bitmap code (BBC). They are usually faster in performing logical operations than the general purpose compression schemes, but, the time spent in CPU still dominates the total query response time. To reduce the query response time, we designed a CPU-friendly scheme named the word-aligned hybrid (WAH) code. In this paper, we prove that the sizes of WAH compressed bitmap indices are about two words per row for large range of attributes. This size is smaller than typical sizes of commonly used indices, such as a B-tree. Therefore, WAH compressed indices are not only appropriate for low cardinality attributes but also for high cardinality attributes.In the worst case, the time to operate on compressed bitmaps is proportional to the total size of the bitmaps involved. The total size of the bitmaps required to answer a query on one attribute is proportional to the number of hits. These indicate that WAH compressed bitmap indices are optimal. To verify their effectiveness, we generated bitmap indices for four different datasets and measured the response time of many range queries. Tests confirm that sizes of compressed bitmap indices are indeed smaller than B-tree indices, and query processing with WAH compressed indices is much faster than with BBC compressed indices, projection indices and B-tree indices. In addition, we also verified that the average query response time

  4. Indicator taxa revisited: useful for conservation planning?

    DEFF Research Database (Denmark)

    Larsen, Frank Wugt; Bladt, Jesper; Rahbek, Carsten

    2009-01-01

    Aim:  Indicators for biodiversity are needed to facilitate the identification of complementary reserve networks for biodiversity conservation. One widely adopted approach is to use indicator taxa, i.e. a single taxon such as birds or butterflies, despite the ongoing debate regarding their usefuln......Aim:  Indicators for biodiversity are needed to facilitate the identification of complementary reserve networks for biodiversity conservation. One widely adopted approach is to use indicator taxa, i.e. a single taxon such as birds or butterflies, despite the ongoing debate regarding...

  5. Microorganisms as Indicators of Soil Health

    DEFF Research Database (Denmark)

    Nielsen, M. N.; Winding, A.; Binnerup, S.

    ecosystem parameters representing policy relevant end points. It is further recommended to identify a specific minimum data set for specific policy relevant end points, to carefully establish baseline values, to improve scientific knowledge on biodiversity and modelling of soil data, and to implement new......Microorganisms are an essential part of living soil and of outmost importance for soil health. As such they can be used as indicators of soil health. This report reviews the current and potential future use of microbial indicators of soil health and recommends specific microbial indicators for soil...... indicators into soil monitoring programmes as they become applicable....

  6. Bibliometric indicators of young authors in astrophysics

    DEFF Research Database (Denmark)

    Havemann, Frank; Larsen, Birger

    2015-01-01

    We test 16 bibliometric indicators with respect to their validity at the level of the individual researcher by estimating their power to predict later successful researchers. We compare the indicators of a sample of astrophysics researchers who later co-authored highly cited papers before...... their first landmark paper with the distributions of these indicators over a random control group of young authors in astronomy and astrophysics. We find that field and citation-window normalisation substantially improves the predicting power of citation indicators. The sum of citation numbers normalised...

  7. Development of Mental Health Indicators in Korea

    Science.gov (United States)

    Han, Hyeree; Ahn, Dong Hyun; Song, Jinhee; Hwang, Tae Yeon

    2012-01-01

    Objective Promoting mental health and preventing mental health problems are important tasks for international organizations and nations. Such goals entail the establishment of active information networks and effective systems and indicators to assess the mental health of populations. This being said, there is a need in Korea develop ways to measure the state of mental health in Korea. Methods This paper reviews the mental health indicator development policies and practices of seven organizations, countries, and regions: WHO, OECD, EU, United States, Australia, UK, and Scotland. Using Delphi method, we conducted two surveys of mental health indicators for experts in the field of mental health. The survey questionnaire included 5 domains: mental health status, mental health factor, mental health system, mental health service, and quality of mental health services. We considered 124 potential mental health indicators out of more than 600 from indicators of international organizations and foreign countries. Results We obtained the top 30 mental health indicators from the surveys. Among them, 10 indicators belong to the mental health system. The most important five mental health indicators are suicide rate, rate of increase in mental disorder treatment, burden caused by mental disorders, adequacy of identifying problems of mental health projects and deriving solutions, and annual prevalence of mental disorders. Conclusion Our study provides information about the process for indicator development and the use of survey results to measure the mental health status of the Korean population. The aim of mental health indicator development is to improve the mental health system by better grasping the current situation. We suggest these mental health indicators can monitor progress in efforts to implement reform policies, provide community services, and involve users, families and other stakeholders in mental health promotion, prevention, care and rehabilitation. PMID:23251193

  8. Circuit arrangement for indicating radiation dose rates

    International Nuclear Information System (INIS)

    Virag, Ernoe; Nyari, Istvan; Simon, Jozsef; Styevko, Mihaly; Krampe, Geza.

    1981-01-01

    The invention presents a dosemeter electronic circuit arrangement indicating hazardous dose rate threshold. If the treshold is reached or exceeded, well distinguished sound and light alarm is turned on immidiately. Moreover, certain critical levels can also be indicated by making the intermittent singalling continuous. (A.L.)

  9. Relationship between road pavement failures, engineering indices ...

    African Journals Online (AJOL)

    This article presents the results of a study carried out to relate the frequency of pavement failures, the engineering indices of the subgrade materials and the underlying geology. The results show a high variability in the indices such as the liquid limit, LL, the plasticity index, PI, the maximum dry density, MDD, the optimum ...

  10. Short Communication - Aquatic Oil Pollution Impact Indicators ...

    African Journals Online (AJOL)

    Aquatic oil pollution impact indicators such as oil-grease, low dissolved oxygen concentration, increased biochemical oxygen demand, increased water temperature and acidity of the water are associated with aquatic habitat degradation, reduced productivity and or loss of biodiversity. These impact indicators are ...

  11. A Recommended Set of Key Arctic Indicators

    Science.gov (United States)

    Stanitski, D.; Druckenmiller, M.; Fetterer, F. M.; Gerst, M.; Intrieri, J. M.; Kenney, M. A.; Meier, W.; Overland, J. E.; Stroeve, J.; Trainor, S.

    2017-12-01

    The Arctic is an interconnected and environmentally sensitive system of ice, ocean, land, atmosphere, ecosystems, and people. From local to pan-Arctic scales, the area has already undergone major changes in physical and societal systems and will continue at a pace that is greater than twice the global average. Key Arctic indicators can quantify these changes. Indicators serve as the bridge between complex information and policy makers, stakeholders, and the general public, revealing trends and information people need to make important socioeconomic decisions. This presentation evaluates and compiles more than 70 physical, biological, societal and economic indicators into an approachable summary that defines the changing Arctic. We divided indicators into "existing," "in development," "possible," and "aspirational". In preparing a paper on Arctic Indicators for a special issue of the journal Climatic Change, our group established a set of selection criteria to identify indicators to specifically guide decision-makers in their responses to climate change. A goal of the analysis is to select a manageable composite list of recommended indicators based on sustained, reliable data sources with known user communities. The selected list is also based on the development of a conceptual model that identifies components and processes critical to our understanding of the Arctic region. This list of key indicators is designed to inform the plans and priorities of multiple groups such as the U.S. Global Change Research Program (USGCRP), Interagency Arctic Research Policy Committee (IARPC), and the Arctic Council.

  12. Ordinal Welfare Comparisons with Multiple Discrete Indicators

    DEFF Research Database (Denmark)

    Arndt, Channing; Distante, Roberta; Hussain, M. Azhar

    We develop an ordinal method for making welfare comparisons between populations with multidimensional discrete well-being indicators observed at the micro level. The approach assumes that, for each well-being indicator, the levels can be ranked from worse to better; however, no assumptions are made...

  13. Indicators of cull in western Oregon conifers.

    Science.gov (United States)

    Paul E. Aho

    1982-01-01

    Descriptions and color photographs of important fungal sporophores (conks), other indicators of cull (wounds), and associated decays in western Oregon conifers are provided to aid timber markers, cruisers, and scalers in identifying them. Cull factors are given for the indicators by tree species.

  14. Lipoprotein metabolism indicators improve cardiovascular risk prediction.

    Directory of Open Access Journals (Sweden)

    Daniël B van Schalkwijk

    Full Text Available BACKGROUND: Cardiovascular disease risk increases when lipoprotein metabolism is dysfunctional. We have developed a computational model able to derive indicators of lipoprotein production, lipolysis, and uptake processes from a single lipoprotein profile measurement. This is the first study to investigate whether lipoprotein metabolism indicators can improve cardiovascular risk prediction and therapy management. METHODS AND RESULTS: We calculated lipoprotein metabolism indicators for 1981 subjects (145 cases, 1836 controls from the Framingham Heart Study offspring cohort in which NMR lipoprotein profiles were measured. We applied a statistical learning algorithm using a support vector machine to select conventional risk factors and lipoprotein metabolism indicators that contributed to predicting risk for general cardiovascular disease. Risk prediction was quantified by the change in the Area-Under-the-ROC-Curve (ΔAUC and by risk reclassification (Net Reclassification Improvement (NRI and Integrated Discrimination Improvement (IDI. Two VLDL lipoprotein metabolism indicators (VLDLE and VLDLH improved cardiovascular risk prediction. We added these indicators to a multivariate model with the best performing conventional risk markers. Our method significantly improved both CVD prediction and risk reclassification. CONCLUSIONS: Two calculated VLDL metabolism indicators significantly improved cardiovascular risk prediction. These indicators may help to reduce prescription of unnecessary cholesterol-lowering medication, reducing costs and possible side-effects. For clinical application, further validation is required.

  15. Presenting Software Metrics Indicators- A Case Study

    DEFF Research Database (Denmark)

    Pantazos, Kostas; Shollo, Arisa; Staron, Miroslaw

    2010-01-01

    Industrial measurement systems in software projects can generate a large number of indicators (main measurements). Having a large number of indicators might result in failing to present an overview of the status of measured entities. In consequence, managers might experience problems when making...

  16. Indicators of fetal and infant health outcomes

    NARCIS (Netherlands)

    Buitendijk, Simone; Zeitlin, Jennifer; Cuttini, Marina; Langhoff-Roos, Jens; Bottu, Jean

    2003-01-01

    OBJECTIVE: To assess the ability of the member states of the European Union to produce the indicators recommended by the PERISTAT project on perinatal health indicators and to provide an overview of fetal and infant health outcomes for these countries according to the information now available.

  17. Why Social Policy Needs Objective Indicators

    NARCIS (Netherlands)

    R. Veenhoven (Ruut)

    2002-01-01

    textabstractThere are many qualms about subjective indicators, and some believe that social policy would be better for not using them. This paper consists of a review of these objections. It is argued that policy makers need subjective indicators. The main reasons being: 1. Social policy is never

  18. Ranking national research systems by citation indicators

    DEFF Research Database (Denmark)

    Aksnes, Dag W.; Schneider, Jesper Wiborg; Gunnarsson, Magnus

    2012-01-01

    This paper presents an empirical analysis of two different methodologies for calculating national citation indicators: whole counts and fractionalised counts. The aim of our study is to investigate the effect on relative citation indicators when citations to documents are fractionalised among the...

  19. Multiple Indicator Stationary Time Series Models.

    Science.gov (United States)

    Sivo, Stephen A.

    2001-01-01

    Discusses the propriety and practical advantages of specifying multivariate time series models in the context of structural equation modeling for time series and longitudinal panel data. For time series data, the multiple indicator model specification improves on classical time series analysis. For panel data, the multiple indicator model…

  20. Causal Indicators Can Help to Interpret Factors

    Science.gov (United States)

    Bentler, Peter M.

    2016-01-01

    The latent factor in a causal indicator model is no more than the latent factor of the factor part of the model. However, if the causal indicator variables are well-understood and help to improve the prediction of individuals' factor scores, they can help to interpret the meaning of the latent factor. Aguirre-Urreta, Rönkkö, and Marakas (2016)…