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The pathogenic role of T cells in severe adverse drug reactions: A molecular and functional analysis of T cell receptor repertoire in patients with Carbamazepine-induced Stevens-Johnson Syndrome
No full text藥物過敏仍然是個臨床上的重要問題。史帝文生強生症候群及其相關的毒性表皮溶解症都是嚴重的藥物過敏。這兩種症狀不但會針對特定藥物而產生劇烈的免疫反應還具有生命威脅的危險性。儘管HLA-B和特定的藥物所引起的嚴重過敏有密切關聯性，但負責釋放毒性物質的關鍵T細胞是如何被誘導的依照目前的研究仍無法解釋。現在的假說認為藥物反應的T細胞應有特別的族群，因此是否有特定的T細胞受器認識藥物和HLA-B所形成的複合體進而引發近一步的藥物過敏是一個重要的研究課題。藉由CBZ-SJS和HLA-B*1502的高度相關性, 我們欲以這個病例作為模組來研究藥物過敏的T細胞受器的變異性。在CBZ的體外刺激下，從CBZ-SJS的病人中所分離的CBZ專一性CD8 T細胞可以被放大並且活化進而產生干擾素-γ和毒性顆粒蛋白來毒殺標的細胞。在CDR3的圖譜分析的結果中，我們發現了藉由藥物所增生的CD8 T細胞具有共同並且受限的T細胞使用情形。在其T細胞受器使用中，beta鏈中的變異區第11號 (VB-11) 有明顯的集中表現的情況，這種情形在8個病人都有發生。同樣我們也利用定序分析來確認它的選植株表現情形，並鑑定VB-11-ISGSY為最優勢的選植株。這些選植株在19個人中有16個人有發病，17個人不會發病。為了瞭解VB-11-ISGSY的分布比例，我們也分析了這個基因在HLA-B*1502攜帶者的分佈情形，我們發現有相當低的比例的人帶有這樣的序列 (29個人中有4個人)。除此之外，這些帶有VB-11-ISGSY序列正常人的T細胞可以被CBZ所刺激而增生，這些T細胞也具有毒殺效果並且可以被anti-VB-11抗體所阻斷。更進一步的，我們也以TCR clone和T細胞轉殖株來表現這些特殊的T細胞受器證實其功能。因此這樣的研究建立了T細胞受器在SJS和TEN的致病機轉上的關鍵角色，並且解釋了為何有些帶有HLA-B*1502的人對於CBZ是有耐受性的，甚至提供了SJS和TEN的一個可能的治療標的。Drug hypersensitivity remains a major clinical problem. Stevens-Johnson syndrome (SJS) and the related disease toxic epidermal necrolysis (TEN) are life-threatening drug hypersensitivities with robust immune responses to drugs. Despite the strong genetic association between HLA-B*1502 and carbamazepine (CBZ)-induced SJS/TEN, it is not known whether particular T-cell receptor (TCR) repertoires participate in the recognition of small drug-peptide-HLA complexes in T cell-mediated drug hypersensitivity. Using the strong HLA predisposition in CBZ-SJS as a model, we studied the diversity of the TCR repertoire involved in drug hypersensitivity. Upon in vitro CBZ stimulation, CBZ-specific CD8+ T cells isolated from CBZ-SJS patients could be expanded, activated with release of interferon-γ and granulysin, and exhibited strong cytotoxicity. CDR3 spectratyping of drug-enriched CD8+ T cells revealed common, restricted TCR repertoire usages that were VB-11 skewed in all 8 CBZ-SJS patients examined. CDR3 sequence analysis confirmed this oligoclonality and identified VB-11-ISGSY as the most predominant clonotype. This clonotype was present in 16 of 19 (84%) SJS patients, absent in all 17 tolerant patients, and present at low frequency in normal individuals (4 of 29, 14.8%); all study subjects were HLA-B*1502 carriers. Moreover, CBZ-specific cytotoxicity could be primed in vitro in those normal individuals with disease-specific clonotypes; this cytotoxicity could be blocked by an anti-TCR VB-11 antibody. Thus, this study establishes the key role of the T cell receptor in the pathogenic mechanism of SJS/TEN, explains why some HLA-B*1502 positive individuals are tolerant to CBZ, and provides a potential therapeutic target for SJS/TEN
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
Genome-Wide Association Studies and the Selective T Cell Receptor (Tcr) Usage of Cd8+T Cells in Patients with Carbamazepine-Induced Stevens- Johnson Syndrome
No full textVariations 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
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