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      Assessment of the Stability of an Immunoadsorbent for the Extracorporeal Removal of Beta-2-Microglobulin from Blood

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          Abstract

          Background: Dialysis-related amyloidosis (DRA) is a devastating and costly condition that affects patients with end stage kidney disease. A key feature of DRA is the formation of amyloid fibrils, consisting primarily of β<sub>2</sub>-microglobulin. Except for kidney transplantation, conventional kidney replacement therapies, which are based on nonspecific mechanisms, do not adequately address β<sub>2</sub>-microglobulin removal. An antihuman β<sub>2</sub>-microglobulin single-chain variable region antibody fragment (scFv) was developed to confer specificity to β<sub>2</sub>-microglobulin removal during hemodialysis. Methods: The scFv was immobilized onto agarose and characterized for β<sub>2</sub>m binding capacity, thermal stability at 37°C, regeneration capacity, storage conditions, and sterility. Results: The β<sub>2</sub>-microglobulin binding capacity was 1.3 mg/ml scFv gel. The immunoadsorbent is thermally stable, can be regenerated, stored short-term in 20% ethanol, lyophilized for long-term storage, and withstand process conditions similar to that of a patient’s hemodialysis therapy. Conclusions: The results support further investigation of immobilized scFvs as a novel tool to remove β<sub>2</sub>-microglobulin from blood.

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          Most cited references 30

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          Stabilization of gelatin films by crosslinking with genipin.

          The possibility to stabilize gelatin films by crosslinking with genipin was investigated through a mechanical, chemical and thermal characterization of samples treated with genipin solutions at different concentrations. The extent of crosslinking, evaluated as difference between the number of free epsilon -amino groups before and after crosslinking, increases as a function of genipin concentration up to about 85%. Simultaneously, the deformability of the films decreases whereas the Young's modulus E, increases. Furthermore, crosslinking provokes a significant reduction of the swelling in physiological solution, and enhances the thermal stability of the samples, as indicated by the results of the d.s.c. investigation. The data obtained from the films treated with genipin at concentrations higher than 0.67% are quite similar, and indicative of a good stabilizing effect of genipin. In spite of the small gelatin release (2%) observed after 1 month of storage in buffer solution, the mechanical, thermal and swelling properties of the films are very close to those previously obtained for glutaraldehyde crosslinked gelatin, and suggest that genipin, which is by far less cytotoxic, can be considered a valid alternative for crosslinking gelatin biomaterials.
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            Crystal structure of monomeric human beta-2-microglobulin reveals clues to its amyloidogenic properties.

            Dissociation of human beta-2-microglobulin (beta(2)m) from the heavy chain of the class I HLA complex is a critical first step in the formation of amyloid fibrils from this protein. As a consequence of renal failure, the concentration of circulating monomeric beta(2)m increases, ultimately leading to deposition of the protein into amyloid fibrils and development of the disorder, dialysis-related amyloidosis. Here we present the crystal structure of a monomeric form of human beta(2)m determined at 1.8-A resolution that reveals remarkable structural changes relative to the HLA-bound protein. These involve the restructuring of a beta bulge that separates two short beta strands to form a new six-residue beta strand at one edge of this beta sandwich protein. These structural changes remove key features proposed to have evolved to protect beta sheet proteins from aggregation [Richardson, J. & Richardson, D. (2002) Proc. Natl. Acad. Sci. USA 99, 2754-2759] and replaces them with an aggregation-competent surface. In combination with solution studies using (1)H NMR, we show that the crystal structure presented here represents a rare species in solution that could provide important clues about the mechanism of amyloid formation from the normally highly soluble native protein.
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              A new form of amyloid protein associated with chronic hemodialysis was identified as β2-microglobulin

               F Gejyo,  T Yamada,  S Odani (1985)
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                Author and article information

                Journal
                BPU
                Blood Purif
                10.1159/issn.0253-5068
                Blood Purification
                S. Karger AG
                0253-5068
                1421-9735
                2005
                September 2005
                04 October 2005
                : 23
                : 4
                : 287-297
                Affiliations
                aBiomedical Engineering Department, Northwestern University, Evanston, Ill., bFeinberg School of Medicine, Northwestern University, Chicago, Ill., and cDivision of Nephrology, Evanston Northwestern Healthcare, Evanston, Ill., USA
                Article
                86207 Blood Purif 2005;23:287–297
                10.1159/000086207
                15942167
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 7, References: 64, Pages: 11
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/86207
                Categories
                Original Paper

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