185 * RED BLOOD CELL DISTRIBUTION WIDTH PREDICTS MORBIDITY AND MORTALITY AFTER AORTIC VALVE REPLACEMENT

Objectives: Red blood cell distribution width (RDW) is a numerical measure of the variability in size of circulating erythrocytes and is emerging as a strong predictor of adverse advents for several categories of patients affected by cardiovascular disease. However, no data exist until now about the role of RDW in predicting mortality of aortic valve replacement (AVR) patients. Thus, in this pilot study we evaluated the value of RDW on early outcome following AVR. Methods: We enrolled 75 patients, who underwent AVR with or without concomitant procedure. A high value of RDW was defined as >43 fL for women and 47 fL for men. Multivariable and univariable analysis were used in determining the association between preoperative high RDW and postoperative outcome. Results: The prevalence of preoperative high RDW was 41% (31 patients). Univariable analysis showed that patients with high RDW were older (P < 0.02), with low weight (P = 0.12) and high level of platelets (P = 0.005). Patients with high RDW were more likely to require renal replacement therapy (P < 0.026) and prolonged ventilation (P < 0.01). Following multivariable adjustment, higher preoperative RDW was a combined predictor of mortality with higher creatinine level (P = 0.065). Conclusion: Increased RDW seems to be a good predictor of early outcome in patients who underwent AVR, in particular in patients with preoperative renal impairment and postoperative prolonged ventilatio

Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity

The highly effective anticancer agent doxorubicin (Dox) is a frontline drug used to treat a number of cancers. While Dox has a high level of activity against cancer cells, its clinical use is often complicated by dose-limiting cardiotoxicity. While this side effect has been linked to the drug’s direct activity in the mitochondria of cardiac cells, recent studies have shown that these result primarily from downstream effects of nuclear DNA damage. Our lab has developed a mitochondrially targeted derivative of Dox that enables the selective study of toxicity generated by the presence of Dox in the mitochondria of human cells. We demonstrate that mitochondria-targeted doxorubicin (mtDox) lacks any direct nuclear effects in H9c2 rat cardiomyocytes, and that these cells are able to undergo mitochondrial biogenesis. This recovery response compensates for the mitotoxic effects of Dox and prevents cell death in cardiomyocytes. Furthermore, cardiac toxicity was only observed in Dox but not mtDox treated mice. This study supports the hypothesis that mitochondrial damage is not the main source of the cardiotoxic effects of Dox

Solution Nuclear Magnetic Resonance Structure and Molecular Dynamics Simulations of a Murine 18.5 kDa Myelin Basic Protein Segment (S72-S107) in Association with Dodecylphosphocholine Micelles.

The 18.5 kDa myelin basic protein (MBP), the most abundant splice isoform in adult mammalian myelin, is a multifunctional, intrinsically disordered protein involved in the development and compaction of the myelin sheath in the central nervous system. A highly conserved central segment comprises a membrane-anchoring amphipathic alpha-helix followed by a proline-rich segment that represents a ligand for SH3 domain-containing proteins. Here, we have determined using solution nuclear magnetic resonance spectroscopy the structure of a 36-residue peptide fragment of MBP (murine 18.5 kDa residues S72-S107, denoted the alpha2-peptide) comprising these two structural motifs, in association with dodecylphosphocholine (DPC) micelles. The structure was calculated using CS-ROSETTA (version 1.01) because the nuclear Overhauser effect restraints were insufficient for this protein. The experimental studies were complemented by molecular dynamics simulations of a corresponding 24-residue peptide fragment (murine 18.5 kDa residues E80-G103, denoted the MD-peptide), also in association with a DPC micelle in silico. The experimental and theoretical results agreed well with one another, despite the independence of the starting structures and analyses, both showing membrane association via the amphipathic alpha-helix, and a sharp bend in the vicinity of the Pro93 residue (murine 18.5 kDa sequence numbering). Overall, the conformations elucidated here show how the SH3 ligand is presented to the cytoplasm for interaction with SH3 domain-containing proteins such as Fyn and contribute to our understanding of myelin architecture at the molecular level