1,721,356 research outputs found
The fate of levodopa in rats and man
No full textAlthough levodopa was introduced almost 30 years ago it still represents the first-choice treatment of Parkinson's disease. However, during long-term administration of the drug approximately 50% of patients suffer from unwanted side-effects such as end-of-dose deterioration or the `on-off' phenomenon. These side effects have been reported to be due to the pharmacokinetics and/or pharmacodynamics of the drug which are complex and at the present time not fully understood. Levodopa has been reported to be absorbed across the intestine by a saturable, active transport system used by other large neutral amino acids and known as the LNAA transport system. Evidence to support this was provided by experiments with inverted segments of rat intestine in-vitro. Uptake of levodopa by the segments was significantly reduced by rendering the tissues anoxic by gassing with N2, in the presence of the large neutral amino acids L-leucine, L-phenylalanine and by the metabolic inhibitor cyanide. The use of inverted gut sacs and isolated brush border membrane vesicles did not prove satisfactory for measuring the active transport system of levodopa absorption. Covalent binding of the drug occurred with the isolated brush border membrane vesicle preparations. Large individual and regional differences were observed in the L-aromatic amino acid decarboxylase (L-AAAD) activity of the rat stomach and intestine in-vitro. Furthermore, large individual differences in L-AAAD activity were observed in biopsy samples obtained from the human gastric and duodenal mucosae. These findings may explain the large individual differences in plasma concentrations often seen following oral administration of levodopa. In addition, the gut flora were found to be capable of extensive metabolism of levodopa. Age was found to be an important determinant of the pharmacokinetics of levodopa when given alone or in conjunction with the peripheral decarboxylase inhibitor carbidopa. Systemic clearance in the elderly was significantly lower than in the young, both in the absence and presence of carbidopa. In the absence of carbidopa the absolute oral bioavailability of levodopa, as assessed by an oral/IV comparison in young and elderly healthy volunteers, was found to be 63% in the elderly, significantly higher than that in the young (41%). In the presence of the decarboxylase inhibitor the age-related difference was abolished, the bioavailability in both groups increasing to 85% and 86% in elderly and young respectively. Levodopa inhibited gastric emptying in young healthy volunteers and resulted in the presence of multiple peaks following oral administration of the drug. Altered gastric emptying may be extremely important in patients suffering from the `on-off' phenomenon because such patients appear to be dependent on constant plasma levels of the drug. (DX88275)</p
The synergistic interaction between CD20 monoclonal antibodies and Histone Deacetylase inhibitors in B cell Non Hodgkin’s Lymphoma
No full textRecent improvements in molecular sub typing of Non Hodgkin’s lymphomashave resulted in targeted therapies becoming incorporated into treatmentparadigms. The anti-CD20 monoclonal antibody, Rituximab, has resulted indramatic improvements in survival for patients with B cell Non Hodgkin’slymphoma. Histone deacetylase inhibitors are a novel class of anti canceragents targeting epigenetic regulation.This thesis addresses the interaction between histone deacetylase inhibitorsand anti-CD20 monoclonal antibodies, including Rituximab, both in vitro andin vivo. The initial approach identified synergistic induction of apoptosis in anumber of B cell lines. In a Ramos xenograft model, combination treatmentwith suberoylanilide hydroxamic acid (SAHA) and Rituximab reduced tumourgrowth compared to either agent alone, without discernable toxicity. Thiseffect appears specific to CD20 since monoclonal antibodies directed to othersurface molecules (CD32b, CD22, CD37) did not exhibit cooperative effect.Analysis of apoptotic pathways demonstrated that PARP cleavage andcaspase processing is significantly higher in cells receiving both treatments.Co-treatment of Ramos cells with the pan caspase inhibitor QVD-OPHabolished the synergy observed with CD20 monoclonal antibodies,suggesting that caspase processing is necessary for synergy. Treatment ofRamos cells stably transfected to overexpress Bcl-2 resulted in loss ofsynergy with Rituximab, but not with the type II CD20 mAb B1 (Tositumomab).Gene expression array analysis of Ramos cells was performed. Genesetenrichment analysis identified significant regulation of NF?B target genes insome genesets (Rituximab Vs control, p<0.001) with a number associatedwith apoptosis and B cell activation (Bcl2A1, LTA, CD69) which wereconfirmed using RT-Q-PCR.This novel combination elicits the induction of apoptosis in vitro, potentiallythrough regulation of Bcl-2 family proteins and should be tested in a phaseI/II clinical trial
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
- …
