88 research outputs found
Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of mycophenolic acid in renal transplant recipients
No full textZ.I. Md Dom, I.S. Westley, J.K. Coller, A.A. Somogyi , B.C. Sallusti
T.T. Cloete as literary critic, theorist and literary historian (Part 2): T.T. Cloete as theorist of literary history
No full textIt had already been stated that Siegfried Schmidt (in Hjort 1992) discerned four ‘roles’ within the Literary System, that of literary production, dissemination, reception and literary processing. According to this definition, T.T. Cloete, the well-known author and critic, had played all of these roles. In this second part of a two-part article the focus is on Cloete as a literary historian and in particular on his theoretical (methodological) perceptions pertaining to literary history. It is abundantly clear that in all of his different roles a historical awareness was always present. For Cloete the literary work of art was inbedded in a historical timeframe which imposed hermeneutical imperatives on the critic; on the other hand the literary work of art is present in the here and now and accessible to any skilled reader. One of the objectives of this study is to argue that there was thus an implied dichotomy in Cloete’s thinking on literary history. On the one hand there had been a relativistic view that positioned literary texts in the past, and on the other hand a normative view that implied that certain texts (due to inherent qualities like integration and complexity) could gain a certain permanence. In the last part of this article-true to the narrative approach, an implied confrontation with Cloete’s (methodological) views of literary history lead to a personal standpoint as a confrontation with the self (cf. Sools 2009:27). This explication of a personal view on the writing of a literary history (as an implied homage to Cloete) concluded the article
A new simple diagnostic assay for the identification of the major CYP2D6 genotypes by DNA sequencing analysis
No full textAIM: To establish a method suitable for diagnostic genotyping of CYP2D6 alleles by DNA sequencing. METHODS: Initial PCR reactions were performed to specifically amplify exons 3, 4, 5 and 6 of the CYP2D6 gene using primers previously published. New primers were used to identify *2, *3, *4, *6, *7, *8, *9 and *41 in 2 sequencing reactions. Additional primers were designed for reverse sequencing in samples with 1 or 3 b.p. deletions. Previously published assays were used to detect *5, *10 and *16 alleles to complete genotype assignment. RESULTS: We reliably detected the nonfunctional alleles, *3, *4, *6, *7 and *8, which are associated with the poor metabolizer phenotype, and 2 important alleles associated with decreased enzyme activity, *9 and *41. Observed allele frequencies were comparable to those found previously in Caucasian populations. CONCLUSION: CYP2D6 genotype has been shown in previous clinical studies to be a good predictor of CYP2D6 phenotype and, therefore, related to therapeutic response and the risk of drug toxicity. This genotyping method is simple and reliable, and, therefore, can be routinely performed on an isolated patient sample, providing a relatively quick turnaround time needed for clinical practice. In addition, the simultaneous drawing of blood with the commencement of drug therapy will allow dosage adjustment on the basis of the CYP2D6 genotype to reduce the risk of adverse drug reactions.H.M. James, J.K. Coller, D. Gillis, J. Bahnisch, B.C. Sallustio and A.A. Somogy
Contextualiser pour didactiser : le copier-coller dans le champ des littératies universitaires
No full textInternational audienceThe practice of copy and paste among students is equated with plagiarism and the institutional response is devoted to “discipline and punish”. However this practice is an important issue within the framework of academic literacies, in relation to the necessary consideration of the digital literacy. The fact that it is conceived as a "misconduct" from an ethical point of view is to be understood with regard to a normative frame that calls for academic honesty and establishes the author and the sources as essential components of research writings, without much explaining the issues (why? how? etc.). How to think copy and paste and what to do? How to go from the state of unacceptable to a didactic view, and what to take into account? With the prospect of critical reflexivity in the field of academic literacies, we propose some elements of contextualization which make it possible to problematize copy and paste, as a gesture of writing, as an object of debates, and in order to better prepare students with academics expectations and in terms of literacy skills in general. We develop first the way copy and paste is received, then the fact of writing by copy and paste, and finally the tension and confusions around expectations related to students' writings. Context is understood here as an interpretative framework that serves a didactic approach as such.La pratique du copier-coller chez les étudiant.e.s est assimilée à du plagiat et la réponse apportée par l’institution se résume à « surveiller et punir ». Cette pratique mérite cependant d’être interrogée dans le cadre des littératies universitaires par rapport à la nécessaire prise en compte des littératies numériques. Le fait qu’elle soit conçue comme une « méconduite » d’un point de vue déontologique est à comprendre par rapport à un cadre normatif qui en appelle à l’honnêteté académique et institue l’auteur et les sources comme des composantes essentielles des écrits de savoirs, sans guère en expliciter les enjeux. Comment penser le copier-coller et qu’en faire ? En quoi peut-on passer de l’inacceptable au didactisable, et que prendre en compte ? Dans la perspective d’une réflexivité critique dans le champ des littératies universitaires, nous proposons des éléments de contextualisation qui permettent de problématiser le copier-coller, en tant que geste d’écriture, en tant qu’objet de débats, et de manière à mieux outiller les étudiant.e.s face aux attentes universitaires et en termes de compétences littéraciques en général. Nous nous intéressons à la réception du copier-coller, à l’énonciation par copier-coller et aux confusions qui entourent les attentes à l’égard des écrits des étudiant.e.s. Le contexte est compris comme un cadre interprétatif qui sert à construire un objet didactique en tant que tel
Toll-like receptor 4 (TLR4) antagonists as potential therapeutics for intestinal inflammation
No full textLink to a related website: https://link.springer.com/content/pdf/10.1007/s12664-020-01114-y.pdf, Open Access via UnpaywallGastrointestinal inflammation is a hallmark of highly prevalent disorders, including cancer treatment–induced mucositis and ulcerative colitis. These disorders cause debilitating symptoms, have a significant impact on quality of life, and are poorly managed. The activation of toll-like receptor 4 (TLR4) has been proposed to have a major influence on the inflammatory signalling pathways of the intestinal tract. Inhibition of TLR4 has been postulated as an effective way to treat intestinal inflammation. However, there are a limited number of studies looking into the potential of TLR4 antagonism as a therapeutic approach for intestinal inflammation. This review surveyed available literature and reported on the in vitro, ex vivo and in vivo effects of TLR4 antagonism on different models of intestinal inflammation. Of the studies reviewed, evidence suggests that there is indeed potential for TLR4 antagonists to treat inflammation, although only a limited number of studies have investigated treating intestinal inflammation with TLR4 antagonists directly. These results warrant further research into the effect of TLR4 antagonists in the intestinal tract.Janine S. Y. Tam, Janet K. Coller, Patrick A. Hughes, Clive A. Prestidge, Joanne M. Bowe
Structural insight and analysis of TLR4 interactions with IAXO-102, TAK-242 and SN-38: an in silico approach.
No full textIntroductionToll-like receptor 4 (TLR4) has attracted interest due to its role in chemotherapy-induced gastrointestinal inflammation. This structural study aimed to provide in silico rational of the recognition and potential binding of TLR4 ligands IAXO-102, TAK-242, and SN-38 (the toxic metabolite of the chemotherapeutic irinotecan hydrochloride), which could contribute to rationale development of therapeutic anti-inflammation drugs targeting TLR4 in the gastrointestinal tract.MethodsIn silico docking was performed between the human TLR4-MD-2 complex and ligands (IAXO-102, TAK-242, SN-38) using Autodock Vina, setting the docking grids to cover either the upper or the lower bound of TLR4. The conformation having the lowest binding energy value (kcal/mol) was processed for post-hoc analysis of the best-fit model. Hydrogen bonding was calculated by using ChimeraX.ResultsBinding energies of IAXO-102, TAK-242 and SN-38 at the upper bound of TLR4-MD-2 ranged between - 3.8 and - 3.1, - 6.9 and - 6.3, and - 9.0 and - 7.0, respectively. Binding energies of IAXO-102, TAK-242 and SN-38 at the lower bound ranged between - 3.9 and - 3.5, - 6.5 and - 5.8, and - 8.2 and - 6.8, respectively. Hydrogen bonding at the upper bound of TLR4/MD-2 with IAXO-102, TAK-242 and SN-38 was to aspartic acid 70, cysteine 133 and serine 120, respectively. Hydrogen bonding at the lower bound of TLR4-MD-2 with IAXO-102, TAK-242 and SN-38 was to serine 528, glycine 480 and glutamine 510, respectively.ConclusionThe in silico rational presented here supports further investigation of the binding activity of IAXO-102 and TAK-242 for their potential application in the prevention of gastrointestinal inflammation caused by SN-38.Janine S. Y. Tam, Jinxin V. Pei, Janet K. Coller, Clive A. Prestidge, Joanne M. Bowe
Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation
No full textBACKGROUND:CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression. However, the relationship between POR and NR1I2 genetics and acute rejection and kidney function has not been extensively investigated. OBJECTIVE:The aim of this study was to investigate the effect of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T, 3435C>T), CYP3A4*22, CYP3A5*3, NR1I2 (8055C>T, 63396C>T) and POR*28 genotypes/haplotypes on acute rejection and kidney function in the first 3 months after transplant. PARTICIPANTS AND METHODS:The study included 165 kidney transplant recipients, who received TAC, mycophenolate and prednisolone, and 129 donors. TAC dose was adjusted to target trough blood concentrations of 8-15 ng/ml by therapeutic drug monitoring. Recipient and donor genotype/haplotype differences in acute rejection incidence within the first 2 weeks after transplant were assessed by logistic regression, adjusting for induction therapy, human leucocyte antigen mismatches, kidney transplant number, peak panel-reactive antibodies and donor type. Recipient and donor genotype/haplotype differences in estimated glomerular filtration rate in the first 3 months after transplant were assessed by linear mixed effects analysis, adjusting for acute rejection, delayed graft function and donor type. RESULTS:No genetic factors significantly affected acute rejection or estimated glomerular filtration rate after correction for multiple comparisons (P>0.004). CONCLUSION:Recipient and donor dispositional genetics had no significant effect on short-term clinical outcomes in kidney transplant patients receiving TAC therapeutic drug monitoring.Ronga Hu, Daniel T. Barratt, Janet K. Coller, Benedetta C.Sallustio, Andrew A. Somogy
No major effect of innate immune genetics on acute kidney rejection in the first 2 weeks post-transplantation
No full textBackground: Innate immunity contributes to acute rejection after kidney transplantation. Genetic polymorphisms affecting innate immunity may therefore influence patients' risk of rejection. IL2 -330T > G, IL10 -1082G > A, -819C > T, and -592C > A, and TNF -308G > A are not associated with acute rejection incidence in Caucasian kidney transplant recipients receiving a calcineurin inhibitor, ciclosporin or tacrolimus (TAC). However, other important innate immune genetic polymorphisms have not yet been extensively studied in recipients and donors. In addition, innate immunogenetics have not been investigated in kidney transplant cohorts receiving only TAC as the calcineurin inhibitor. Objective: To investigate the effect of recipient and donor CASP1, CRP, IL1B, IL2, IL6, IL6R, IL10, MYD88, TGFB, TLR2, TLR4, and TNF genetics on acute kidney rejection in the first 2 weeks post-transplant in TAC-treated kidney transplant recipients. Methods: This study included 154 kidney transplant recipients and 81 donors successfully genotyped for 17 polymorphisms in these genes. All recipients were under triple immunosuppressant therapy of TAC, mycophenolate mofetil, and prednisolone. Recipient and donor genotype differences in acute rejection incidence within the first 2 weeks post-transplantation were assessed by logistic regression, adjusting for induction therapy, human leukocyte antigen mismatches, kidney transplant number, living donor, and peak panel-reactive antibody scores. Results: A trend (Cochran-Armitage P = 0.031) of increasing acute rejection incidence was observed from recipient IL6 -6331 T/T (18%) to T/C (25%) to C/C (46%) genotype [C/C versus T/T odds ratio (95% confidence interval) = 6.6 (1.7 to 25.8) (point-wise P = 0.017)]. However, no genotype differences were significant after Bonferroni correction for multiple comparisons. Conclusions: This study did not detect any statistically significant effects of recipient or donor innate immune genetics on acute rejection incidence in the first 2 weeks post-transplantation. However, the sample size was small, and future larger studies or meta-analyses are required to demonstrate conclusively if innate immune genetics such as IL6 influence the risk of acute rejection after kidney transplantation.Rong Hu, Daniel T. Barratt, Janet K. Coller, Benedetta C. Sallustio, and Andrew A. Somogy
Relationship between allograft cyclosporin concentrations and P-glycoprotein expression in the 1st month following renal transplantation
No full textThe immunosuppressant cyclosporin is a P-glycoprotein (P-gp) substrate whose impaired function has been associated with an increased risk of cyclosporin-induced nephrotoxicity following renal transplantation. This study investigated the relationship between blood and allograft cyclosporin concentration, and the effect of P-gp expression. Fifty biopsy samples were obtained from 39 renal transplant recipients who received cyclosporin as part of maintenance immunosuppression. Blood cyclosporin concentrations (2 hours postdose) were obtained from clinical records, matching allograft cyclosporin concentrations were measured in frozen biopsy tissue by liquid chromatography-tandem mass spectrometry, and allograft P-gp expression was assessed by immunohistochemistry. Blood and allograft cyclosporin concentrations in the 1st month post-transplantation ranged from 505-2005 μg/L and 0.01-16.7 ng/mg tissue, respectively. Dose was the only significant predictor of allograft cyclosporin concentrations (adjusted R2 = .24, F-statistic = 11.52, P = .0019), with no effect of P-gp expression or blood cyclosporin concentrations. P-gp expression is not the major determinant of allograft cyclosporin concentrations.Benedetta C. Sallustio, Benjamin D. Noll, Janet K. Coller, Jonathan Tuke
Graeme Russ, Andrew A. Somogy
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