Activation of T cells by carbamazepine and carbamazepine metabolites

BACKGROUND: T-cell-mediated hypersensitivity is a rare but serious manifestation of drug therapy. OBJECTIVES: To explore the mechanisms of drug presentation to T cells and the possibility that generation of metabolite-specific T cells may provoke cross-sensitization between drugs. METHODS: A lymphocyte transformation test was performed on 13 hypersensitive patients with carbamazepine, oxcarbazepine, and carbamazepine metabolites. Serial dilution experiments were performed to generate drug (metabolite)-specific T-cell clones to explore the structural basis of the T-cell response and mechanisms of antigen presentation. 3-Dimensional energy-minimized structures were generated by using computer modeling. The role of drug metabolism was analyzed with 1-aminobenzotriazole. RESULTS: Lymphocytes and T-cell clones proliferated with carbamazepine, oxcarbazepine, and some (carbamazepine 10,11 epoxide, 10-hydroxy carbamazepine) but not all stable carbamazepine metabolites. Structure activity studies using 29 carbamazepine (metabolite)-specific T-cell clones revealed 4 patterns of drug recognition, which could be explained by generation of preferred 3-dimensional structural conformations. T cells were stimulated by carbamazepine (metabolites) bound directly to MHC in the absence of processing. The activation threshold for T-cell proliferation varied between 5 minutes and 4 hours. 1-Aminobenzotriazole, which inhibits cytochrome P450 activity, did not prevent carbamazepine-related T-cell proliferation. Substitution of the terminal amine residue of carbamazepine with a methyl group diminished T-cell proliferation. CONCLUSION: These data show that carbamazepine and certain stable carbamazepine metabolites stimulate T cells rapidly via a direct interaction with MHC and specific T-cell receptors. CLINICAL IMPLICATIONS: Some patients with a history of carbamazepine hypersensitivity possess T cells that cross-react with oxcarbazepine, providing a rationale for cross-sensitivity between the 2 drugs.

America’s Newest Citizen - John Q. Corporation

A Montana Public Radio Commentary by Evan Barrett. Published newspaper columns written by Evan Barrett on this topic, which vary somewhat in content from this commentary, appeared in the following publications: Ravali Republic, July 19, 2014 Missoulian, July 11, 2014 Independent Record, July 16, 2014 Flathead Beacon, July 17, 2014

John Calvin's Impact on Church and Society, 1509-2009. Essays for the 500th birthday of Calvin

A tribute to the monumental influence of John Calvin in the 500 years since his birth. / What legacies, still enduring today, have John Calvin and Calvinism given to the church and society in Europe and North America? An international group of scholars tackles that question in this volume honoring Calvin's 500th birthday. These chapters together provide a comprehensive and accessible introduction to Calvin's life and thought, the history of the Reformation in Switzerland and worldwide, and his continuing relevance for ecclesial, social, and political questions today. / Contributors: Philip Benedict, James D. Bratt, Emidio Campi, Wulfert de Greef, Christopher Elwood, Eva-Maria Faber, Eric Fuchs, Ulrich H. J. Krtner, Christian Link, Christian Moser, Andrew Pettegree, Christoph Strohm, Mario Turchetti./ The essays in this book fit beautifully together to provide a solid, complete work that gives precise insight into the many different facets of Calvin and Calvinism. The high-level research found here clearly shows the great impact that Calvin has had on both church and society. It is a great pleasure to see Calvin here anew. Eberhard Busch / University of Gttingen / That John Calvin made a deep and lasting impact on many aspects of history is common knowledge but the character of the man and the nature of his influence are perhaps as controversial as any that can be named. It is thus a challenge to examine even a fraction of the many ways that Calvins life and thought have contributed to the shaping of later ages in both church and society. This volume offers essays on key points from an appropriately international group of authors appreciative but critical, drawing on a rich range of recent scholarship, presented in a pleasing and accessible form. It is a fine place for the new reader of Calvin to get a glimpse of his impact, while offering a fresh summary of some significant issues for more advanced students of the Reformer. Elsie Anne McKee / Princeton Theological Seminary / Hirzel and Sallmann have succeeded in gathering essays by an illustrious circle of experts both historians and theologians on important areas of Calvins thought and impact. Ranging from an insignificant city at the edge of the Swiss Confederation in the 1530s to the Accra Confession of 2004, these essays will serve to correct popular misconceptions. A fine introduction for a broader readership that wants more than mere armchair theology. Peter Opitz / University of Zurich