1,721,072 research outputs found
Progetto Bayer Haemophilia Awards Program: Genetic components contributing to the pharmacokinetics of FVIII concentrates
No full textAlthough the heritability of plasma levels of several coagulation factors is high, the underlying molecular mechanisms are only partially known. For instance, the FVIII D1241E polymorphism is the only intragenic variation found to be associated with FVIII levels (Scanavini, 2005). Genes encoding for proteins involved in the multi-step biosynthesis, and/or processing and survival in plasma of FVIII might play a part in determining factor levels. Oligosaccharide structures, like determinants of ABO blood groups, are implicated in FVIII catabolism and evidence for a strong effect of ABO locus on FVIII levels has been detected. Other genetic loci on chromosomes 18, 5 and 11 have been suggested to be involved in modulation of FVIII levels. A multifunctional member of the LDL receptor super-family has been demonstrated, in cellular and animal models, to participate in the regulation of distribution phase of FVIII by binding and directing FVIII molecules to the intracellular degradation pathways. We have recently found that LRP genotypes, predicting differential LRP expression, are associated with significant differences in FVIII activity in patients (17%, P<0.009) and that combined ABO/LRP genotypes are associated with 50% variations.
These findings suggest that genes involved in the control of endogenous FVIII molecules could also modulate the decay of native/recombinant molecules infused for prophylactic or therapeutic purposes. Gene variation could produce significant individual differences in pharmacokinetics of infused FVIII concentrates.
We propose a systematic screening of 200 hemophilia A patients attending the Hemophilia Center of Florence for genetic polymorphisms found in genes which are (direct or indirect) candidate to participate in FVIII removal from plasma. We also propose to genotype patients for polymorphisms located in genomic regions that have been suggested to encode FVIII level “modifiers”, whose function is still unknown. Taken into account the very different biological role of these genes (receptors, ligand, ligand modifier and cofactors) different parameters of infused FVIII removal could be positively or negatively influenced by the hypothesized genetic control. This study has important biological and clinical consequences to individualize the dosage of these very expensive drugs and to tailor both on demand and prophylactic therapy. More than 20 markers have been already set up in our lab for the study of hemophilia A patients.
DNA extraction and identification of FVIII gene mutations will be performed in our local Genetic Service (Dr.sa F.Torricelli), the other genetic polymorphisms will be detected in Department of Biochemistry and Molecular Biology , University of Ferrara (Prof. F.Bernardi).
Each patient will undergo a single dose pharmacokinetic study, designed according to the FVIII/IX SSC of ISTH. The concentrate, rDNA- or plasma-derived, will be the same regularly used by the patient. The timing of blood sample collection will be partially modified in order to have a detailed and good fitting of FVIII decay during the first hours after infusion (distribution phase). The decay data will be analyzed both by Model independent and Two-compartment methods. The association of specific genotypes with pharmacokinetic parameters (In Vivo Recovery, AUC, Clearance, MRT, VdArea, Terminal half-life) will be tested by Multivariate analysis
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe 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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
CLINICAL FACTORS ASSOCIATED WITH PROGRESSION TO AIDS IN THE ITALIAN COHORT OF HIV-POSITIVE HEMOPHILIACS
No full textThis study updates estimates of the cumulative incidence of AIDS among Italian patients with congenital coagulation disorders (mostly hemophiliacs), and elucidates the role of age at seroconversion? type and amount of replacement therapy, and HBV co-infection in progression. Information was collected both retrospectively and prospectively on 767 HIV-I positive patients enrolled in the on-going national registry of patients with congenital coagulation disorders. The seroconversion date was estimated as the median point of each patient's seroconversion interval, under a Weibull distribution applied to the overall interval. The independence of factors associated to faster progression was assessed by multivariate analysis. The cumulative incidence of AIDS was estimated using the Kaplan-Meier survival analysis at 17.0% (95% CI = 14.1-19.9%) over an 8-year period for Italian hemophiliacs. Patients with age greater than or equal to 35 pears exhibited the highest cumulative incidence of AIDS over the same time period, 32.5% (95% CI = 22.2-42.8%). Factor IX recipients (i.e. severe B hemophiliacs) had higher cumulative incidence of AIDS (23.3% vs 14.2%, p = 0.01) than factor VIII recipients (i.e. severe A hemophiliacs)l as aid severe A hemophiliacs on less-than-20,000 IU/yearly of plasma-derived clotting factor concentrates, as opposed to A hemophiliacs using an average of more than 20,000 IU (18.8% vs 10.9%, p = 0.02). No statistically significant difference in progression was observed between HBsAg-positive vs HBsAg-negative hemophiliacs (10.5% vs 16.4%, p = 0.10). Virological, immunological or both reasons can account for such findings, and should be investigated from the laboratory standpoint
Solvent/detergent plasma for prevention of bleeding in recessively inherited coagulation disorders : dosing, pharmacokinetics and clinical efficacy
No full textBackground and Objectives. This open-label multicenter trial of solvent/detergent (SD) plasma involving 17 patients with recessively inherited coagulation disorders (one afibrinogenemia, four FV, six combined FV and FVIII, one FX and five FXI deficiencies) evaluated the pharmacokinetics of the deficient factors and hemostatic efficacy. Design and Methods. In vivo recovery (IVR) of the deficient coagulation factor was determined in a non-bleeding state in all patients and the mean values for FV, FVIII, FX, FXI and fibrinogen were 1.3, 1.2, 1.5, 1.3 and 1.5 dL/kg, respectively. The mean plasma half-life of FV, FVIII and FX was 18, 43 and 33 hours, respectively. All patients underwent replacement therapy for elective procedures at risk of bleeding (surgery in 14 cases and vaginal delivery in two patients), except one treated for a central nervous system surgical emergency. Results. Treatment courses with SD plasma were judged fully effective in 13/16 cases (81%). In the remaining three cases, mild bleeding occurred after major surgery in a FV deficient patient with a factor level of 43% and in a FXI deficient patient when factor levels were between 20% and 41%; and after minor surgery in a patient with FV and FVIII deficiency when factor levels were 41% and 18%, respectively. Bleeding was controlled by continuing or increasing treatment with SD plasma. Interpretation and Conclusions. These results suggest that, even though the current absolute risk of blood-borne infections associated with fresh-frozen plasma is relatively small, SD plasma should be preferred in patients with recessively inherited coagulation disorders who need replacement therapy when virus-inactivated single-factor concentrates are not available
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