Glutaraldehyde fixation of venous valve tissue: A benchmark for alternative fixation methods.

OBJECTIVE: Bioprosthetic venous valves have yet to achieve long-term patency due to issues with calcification following implantation that is influenced by current xenograft fixation methods, most notably glutaraldehyde. The goal of this study was to investigate the effects of glutaraldehyde fixation on the functional properties of venous tissue to establish a benchmark for the evaluation of alternative fixation methods. METHODS: The degree of crosslinking was evaluated by determining shrink temperature and the stability of tissue with pronase and collagenase digestion. RESULTS: Glutaraldehyde fixation of venous tissue was confirmed by a significant difference in the shrink temperature between fresh and glutaraldehyde treated samples. Significant differences in the amount of tissue remaining following digestion were observed for venous versus cardiac tissue. CONCLUSIONS: This study demonstrates the importance of tissue-specific evaluation in the development of alternative xenograft fixation methods to improve outcomes with bioprosthetic venous valves.

Performance changes of venous valves following tissue treatment with novel in vitro system.

OBJECTIVES: The purpose of this study is to test venous valve performance and identify differences between native tissue and replacement devices developed with traditional tissue treatment methods using a new in vitro model with synchronized hemodynamic parameters and high-speed valve image acquisition. METHODS: An in vitro model mimicking the venous circulation to test valve performance was developed using hydrostatic pressure driven flow. Fresh and glutaraldehyde-treated vein segments were placed in the setup and opening/closing of the valves was captured by a high-speed camera. Hemodynamic data were obtained using synchronized hardware and virtual instrumentation. RESULTS: Geometric orifice area and opening/closing time of the valves was evaluated at the same hemodynamic conditions. A reduction in geometric orifice area of 27.2 ± 14.8% (p < 0.05) was observed following glutaraldehyde fixation. No significant difference in opening/closing time following chemical fixation was observed. CONCLUSIONS: The developed in vitro model was shown to be an effective method for measuring the performance of venous valves. The observed decrease in geometric orifice area following glutaraldehyde treatment indicates a decrease in flow through the valve, demonstrating the consequences of traditional tissue treatment methods.

Identification of 4-substituted 1,2,3-triazoles as novel oxazolidinone antibacterial agents with reduced activity against monoamine oxidase A.

Oxazolidinones represent a new and promising class of antibacterial agents. Current research in this area is mainly concentrated on improving the safety profile and the antibacterial spectrum. Many oxazolidinones, including linezolid (marketed as Zyvox), are inhibitors of monoamine oxidase A (MAO-A), which presents an undesired side effect. Recently, it was found that the 1,2,3-triazole is a good replacement for the conventional acetamide functionality found in oxazolidinones. We now disclose the finding that 1,2,3-triazoles bearing a substituent like methyl, small substituted methyl, bromo, or a linear (sp-hybridized) group at the 4 position (compounds such as 5, 16, 19, and 21) are good antibacterials with reduced or no activity, within the detection limit of the assay, against MAO-A. The results are especially promising for the development of oxazolidinones with an improved safety profile. The MAO-A SAR can be rationalized on the basis of docking studies to a MAO-A/MAO-B homology model.

Design and synthesis of dipeptide nitriles as reversible and potent Cathepsin S inhibitors.

The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.