Mechanically-induced intercellular remodeling of cardiomyocytes by magnetic micromanipulation

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2006.Includes bibliographical references (leaves 68-72).Gap junctions are responsible for providing and maintaining a pathway for intercellular communication. This is critical in the heart where gap junctions are responsible for maintaining electrical impulse propagation. Connexin43 (Cx43) is the most abundant gap junction in the heart, and studies have shown that spatial heterogeneity of Cx43 may promote electrical instability and anisotropic conduction pathways that may cause cardiac arrhythmias. Structural and electrical remodeling of gap junctions have been linked to increases in stresses in conditions such as hypertrophy. Understanding how local mechanical forces influence the remodeling of gap junctions can provide insight into arrhythmias and reentry circuits. In this work, I describe a system for exerting local mechanical forces on cardiomyocytes to study gap junction remodeling and I show that cell-to-cell movement and subsequent remodeling of Cx43 can occur. The system consisted of patterned linear strands on polyacrylamide gels and mechanical stimulation using magnetic micromanipulation. Cardiomyocytes were patterned on polyacrylamide gel using 25pm and 50pm microchannels. Mechanical stimulation was induced in sections with high densities of magnetic beads.(cont.) With a maximal input current of 1.5A, the system generated 1.5nN at 100pm distance from the magnetic trap, and this was sufficient to induce cell-to-cell movement. Cell-to-cell movement was measured to be 0.032±0.03pm/min, three times faster than the average cell-to-cell movement under no applied force. Remodeling of Cx43 was also shown using Cx43-YFP transfected cells while a local force induced cell-to-cell movement. Changes in both the distribution and expression of the protein were seen throughout time as the linear strand was pulled by the magnetic force. We conclude that this system can induce remodeling of Cx43 by an applied local force. This work establishes a system to allow to quantification of applied mechanical loads and resultant Cx43 remodeling.by J.P. Michael Motion.M.Eng

Convection and Retro-Convection Enhanced Delivery: Some Theoretical Considerations Related to Drug Targeting

Delivery of drugs and macromolecules into the brain is a challenging problem, due in part to the blood–brain barrier. In this article, we focus on the possibilities and limitations of two infusion techniques devised to bypass the blood–brain barrier: convection enhanced delivery (CED) and retro-convection enhanced delivery (R-CED). CED infuses fluid directly into the interstitial space of brain or tumor, whereas R-CED removes fluid from the interstitial space, which results in the transfer of drugs from the vascular compartment into the brain or tumor. Both techniques have shown promising results for the delivery of drugs into large volumes of tissue. Theoretical approaches of varying complexity have been developed to better understand and predict brain interstitial pressures and drug distribution for these techniques. These theoretical models of flow and diffusion can only be solved explicitly in simple geometries, and spherical symmetry is usually assumed for CED, while axial symmetry has been assumed for R-CED. This perspective summarizes features of these models and provides physical arguments and numerical simulations to support the notion that spherical symmetry is a reasonable approximation for modeling CED and R-CED. We also explore the potential of multi-catheter arrays for delivering and compartmentalizing drugs using CED and R-CED

Policy as a struggle for meaning: disentangling knowledge translation across international health contexts

Over the last decade, research in medical science has focused on knowledge translation and diffusion of best practices to enable improved health outcomes. However, there has been less attention given to the role of policy in influencing the translation of best practice across different national contexts. This paper argues that the underlying set of public discourses of healthcare policy significantly influences its development with implications for the dissemination of best practices. Our research uses Critical Discourse Analysis to examine the policy discourses surrounding the treatment of stroke across Canada and the U.K. It focuses in specific on how concepts of knowledge translation, user empowerment, and service innovation construct different accounts of the ‘health service’ in the two countries. These findings provide an important yet overlooked starting point for understanding the role of policy development in knowledge transfer and the translation of science into health practice

Twentieth- and Twenty-First-Century Keats Criticism

This essay offers a survey of major twentieth- and twenty-first-century interpretations of Keats's life and work. Mapping lines of influence between distinctive formal, theoretical and historical approaches to Keats's oeuvre, I highlight significant critical trends and areas of recurrent formal and thematic interest in Keats studies. When appropriate, current confluences between these theoretical and historical methodologies are noted. Given the wide scope of material available, prominence has been given to those projects (where possible, emphasis is given to critical books) which both represent particular twentieth-century critical perspectives or thematic concerns and are important studies in themselves. This survey closes by indicating potential areas for future research and observes that many twentieth-century critical viewpoints and issues remain vital to Keats studies at the start of the twenty-first century