177,248 research outputs found
Polymorphic CYP2C19 and N-acetylation: human variability in kinetics and pathway-related uncertainty factors
No full textCYP2C19-mediated oxidation and N-acetylation constitute major phase I and phase II polymorphic pathways of xenobiotic metabolism in humans. Analysis of human variability in kinetics for these pathways has been carried out for compounds metabolised extensively (>60%) by these routes. Data for minor substrates for CYP2C19 metabolism (10–60%) have also been analysed. Published pharmacokinetic studies (after oral and intravenous dosing) in CYP2C19 non-phenotyped healthy adults (NPs), and phenotyped extensive (EMs), slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration–time curve) and primarily to acute exposure (peak concentration). Similar analyses were performed for the N-acetylation pathway using data for fast acetylators (FA) and slow acetylators (SA). Interindividual variability in the kinetics of CYP2C19 substrates after oral dosage was greater in EMs than in NPs (60 vs 43% for clearances and 54 vs 45% for Cmax). Lower variability was found for N-acetylation for both phenotypes (32 and 22% for FA and SA, respectively). The internal dose of CYP2C19 substrates in PM subjects would be 31-fold higher than in EMs, while for N-acetylated substrates there was a three-fold difference between SA and FA subjects. Pathway-related uncertainty factors were above the default safety factor of 3.16 for most subgroups and values of 52 and 5.2 would be necessary to cover to the 99th centile of the poor metaboliser phenotype for CYP2C19 and N-acetylation, respectively. An exponential relationship (R²=0.86) was found between the extent of CYP2C19 metabolism and the difference in internal dose between EMs and PMs. The kinetic default factor (3.16) would cover PMs for substrates for which CYP2C19 was responsible for up to 20–30% of the metabolism in EMs
Human variability for metabolic pathways with limited data (CYP2A6, CYP2C9, CYP2E1, ADH, esterases, glycine and sulphate conjugation)
No full textHuman variability in the kinetics of a number of phase I (CYP2A6, CYP2C9, CYP2E1, alcohol dehydrogenase and hydrolysis) and phase II enzymes (glycine and sulphate conjugation) was analysed using probe substrates metabolised extensively (>60%) by these routes. Published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and available data on subgroups of the population (effects of ethnicity, age and disease) were abstracted using parameters relating primarily to chronic exposure [metabolic and total clearances, area under the plasma concentration time-curve (AUC)] and acute exposure (Cmax). Interindividual differences in kinetics for all these pathways were low in healthy adults ranging from 21 to 34%. Pathway-related uncertainty factors to cover the 95th, 97.5th and 99th centiles of healthy adults were derived for each metabolic route and were all below the 3.16 kinetic default uncertainty factor in healthy adults, with the possible exception of CYP2C9*3/*3 poor metabolisers (based on a very limited number of subjects). Previous analyses of other pathways have shown that neonates represent the most susceptible subgroup and this was true also for glycine conjugation for which an uncertainty factor of 29 would be required to cover 99% of this subgroup. Neonatal data were not available for any other pathway analysed.Abbreviations: CYP Cytochrome P450, AUC Area under the plasma-concentration-time-curve, Cmax Maximum plasma concentratio
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
"Closing the R&D Gap, Evaluating the Sources of R&D Spending"
No full textBoth spending and tax policies have been implemented in the United States with the goal of stimulating private sector research and development (R&D). Karier questions whether current R&D policy, especially the research and experimentation tax credit, can contribute to closing the gap between nondefense expenditures on R&D in the United States and such expenditures in other countries, such as Japan and Germany. He also explores possible changes to our current R&D policy to make it more effective.
Key to medically relevant Italian spider bites: A practical quick recognition tool for clinicians
No full textIntroduction. Spider bites are often overestimated because there are no specific clinical or histopathological aspects that characterize them, and skin lesions that resemble a spider bite are often wrongly considered to be a “true spider bite”. However, even in case of a true spider bite, it is almost impossible to confirm the biting species, since very often neither physicians nor patients are trained in spider identification. Objective. The aim of this report is to provide clinicians with a rapid and simple recognition of the few Italian medically relevant spiders, in order to take relative medical measures in case of spider bites. Materials and methods. We defined spiders of considerable medical relevance the ones that cause local symptoms with possible systemic involvement, while we defined spiders with mild medical relevance the ones whose bite is not a medical emergency but is particularly painful or can cause lasting symptoms. We focused on the identification of the four spider taxa of major clinical interest through a brief descriptive, photographic and graphic guide, in association to dermatological manifestations. Results. Spiders of considerable medical relevance are Loxosceles rufescens and Latrodectus tredecimguttatus, while spiders of less severe medical relevance are Steatoda paykulliana, S. nobilis, S. grossa, Cheiracanthium punctorium, Amblyocarenum spp. and Macrothele calpeiana (the presence of the latter in Italy is only accidental and very sporadic). The only species capable of causing necrosis is Loxosceles rufescens, while Latrodectus tredecimguttatus can cause more systemic symptoms. Discussion and Conclusion. With the aim of promoting a first and rapid recognition of the species, we performed a morphological usable aspect for an initial and quick recognition according to an identification key
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
TKPlate: R package prototype for TK models graphical interface
No full text<p>Included in this upload is an R package <code>httkgui</code>. It was a proof of concept for TKPlate, a graphical user interface (GUI) modification of a popular CRAN toxicokinetics R package <code>httk</code> (v1.4); <code>httkgui</code> modifies some of the TK models, allows rudimentary Monte Carlo simulations of said models and provides GUI (TKPlate) to run them and review the results. The <a href="https://cran.r-project.org/web/packages/httk/index.html">original 'httk' (v1.8 as of Jan 2019) package</a> is by John Wambaugh. </p>
<p>Source code (httkgui.zip) and Windows binary (httkgui1.0.zip) are included, together with a git repository of the project. This prototype doesn't include updated documentation, which may be added at a later time. All generic models in C are available in folder src/. The models modified by the authors are analogous to C models which are already included in httk.</p>
<p>To run the GUI prototype, type in pbtkUI() after installing the package.</p>
<p>The code modifications to 'httk' have been developed by Witold Wiecek with concept by Nadia Quignot and Billy Amzal at Analytica Laser (now Certara) and Jean-Lou Dorne (EFSA) as a part of an European Food Safety Authority project "Integrating toxicokinetics in chemical risk assessment: application to human, animal and environmental risk assessment" (OC/EFSA/SCER/2014/06)</p>UK; zip packages with source code (httkgui.zip) and Windows binary (httkgui1.0.zip); [email protected]
Letter from R. R. Zellick, Assistant Trust Officer, Anglo California National Bank of San Francisco, to Joseph R. Goodman, October 2, 1942
No full textLetter from R. R. Zellick, Assistant Trust Officer at The Anglo California National Bank of San Francisco, to Joseph R. Goodman, regarding property owned by Dave Tatsuno. Zellick mentions a dispute between current tenants and Tatsuno, and that Tatsuno has asked Goodman to help locate trustworthy tenants.Personal correspondence, organizational records, government documents, publications, and other papers created or collected by Joseph R. Goodman documenting the forced removal and incarceration of Japanese Americans during World War II, as well as organized resistance to incarceration. Included in the collection are records of the Japanese Young Men's Christian Association and the Japanese American Citizens' League in San Francisco, including papers of the Japanese YMCA's executive secretary Lincoln Kanai; Sakai family papers; Goodman's correspondence to and from Japanese American incarcerees, organizations opposing forced removal and incarceration of Japanese Americans, the War Relocation Authority, and others; publications, photographs, and ephemera from the Topaz Relocation Center, where Goodman taught high school; War Relocation Authority records and publications; and newspaper clippings, pamphlets, and reports about forced removal and incarceration created by various government, religious, and civic organizations, in California and nationwide
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Liftings for noncomplete probability spaces
No full textThe current state of knowledge concerning liftings for noncomplete probability spaces is discussed. This is a somewhat expanded version of the author's talk given at the 1991 Summer Conference on General Topology and Applications in Honor of Mary Ellen Rudin and Her Work.PT: S; CR: BURKE MR, IN PRESS P AM MATH S BURKE MR, 1991, ISRAEL J MATH, V73, P33 BURKE MR, 1992, ISRAEL J MATH, V79, P289 CARLSON T, THEOREM LIFTING CHRISTENSEN JPR, 1974, TOPOLOGY BOREL STRUC FREMLIN DH, 1989, HDB BOOLEAN ALGEBRAS, P877 INOESCUTULCEA A, 1966, 5TH P BERK S MATH ST, V2 IONESCUTULCEA A, 1967, CONTRIBUTIONS PROB 1, P63 IONESCUTULCEA A, 1969, TOPICS THEORY LIFTIN JECH TJ, 1978, SET THEORY JOHNSON RA, 1980, P AM MATH SOC, V80, P234 JUST W, IN PRESS T AM MATH S KUPKA J, 1983, INDIANA U MATH J, V32, P717 LOSERT V, 1983, LNM, V1080, P95 MAHARAM D, 1958, P AM MATH SOC, V9, P987 SHELAH S, 1983, ISRAEL J MATH, V45, P90 TALAGRAND M, 1982, P AM MATH SOC, V84, P379 VONNEUMANN J, 1931, CRELLES J MATH, V165, P109; NR: 18; TC: 0; J9: ANN N Y ACAD SCI; PG: 4; GA: BZ86BSource type: Electronic(1
- …
