923-3 Fluosol Reduces Myocardial Reperfusion Injury by Prolonged Suppression of Neutrophils by its Detergent Component (RheothRx) and not by Enhancing O2Delivery

Fluosol, a complex mixture of O2carrying perfluorocarbons (PFCs) emulsified by the detergent pluronic F-68 and a variety of lipids, significantly reduces myocardial reperfusion injury (RI) in animals and humans as shown in some initial clinical trials. Potential mechanisms for Fluosol include enhanced O2delivery to the reperfused tissue and modulation of various neutrophil (PMNs) functions. Recent studies in dogs and man demonstrate the same beneficial effect for treatment of Rl with the detergent component alone, RheothRx, which is currently undergoing clinical trials. We have shown that the effect of Fluosol on PMNs is related to this detergent. However, prolonged infusion (48 hrs) of detergent is required to reduce Rl to the same extent as Fluosol given over only 1 hr. Possible mechanisms for the beneficial effects of Fluosol (O2delivery vs effects on PMNs) were investigated in a model of regional ischemia utilizing rabbits undergoing 30mins of circumflex occlusion and 48 hrs of reperfusion. Infarct size (area of necrosis, AN) was determined histologically and expressed as percent of risk region (area at risk, AR). Animals received Fluosol (30cc/kg) with or without O2or saline over the first 60mins of reperfusion. AR was similar in all groups. (Mean±SEM of AN/AR (%), n=11 for all groups). The treatment with Fluosol with or without O2(44±3 and 40;±3, respectively) was significantly (p<0.05) reduced compared to control (63±4). Another group received F-I08, a larger size pluronic detergent found to be 2.5-fold more potent in suppressing PMN function in vitrocompared to F-68, during the first 3 hrs of reperfusion. This treatment did not alter the infarct size (63±5). RheothRx was found to form 4 nm micelles in solution whereas Fluosol formed particles approximately 100 times larger. Similar sized particles were formed by substituting the perfluorocarbons with mineral oil. The in vitroactivity of this pluronic/mineral oil micelle on PMN function was similar to Fluosol. Infusion of these larger oil micelles was tolerated by rabbits and used in further infarct studies.ConclusionsThese studies suggest that (1) reduction of RI by Fluosol is not due to enhanced O2delivery by the PFCs to reperfused myocardium and (2) since the Fluosol emulsion markedly reduces the clearance of the detergent F-68 (t½: Fluosol ≅ 8 hrs vs RheothRx ≅ 1.5 hrs). prolonged PMN suppression rather than potency of suppression is the mechanism whereby Fluosol ameliorates RI. Fluosol's clinical efficacy may be enhanced by prolonging its infusion to ensure an adequate blood level to suppress PMN function beyond the time of reperfusion injury. RheothRx's clinical usefulness may be facilitated by decreasing its renal clearance by delivering larger micelles of the detergent in order to produce prolonged PMN suppression with a shorter infusion time

Evidence for natural antisense transcript-mediated inhibition of microRNA function

MicroRNAs (miRNAs) have the potential to regulate diverse sets of mRNA targets. In addition, mammalian genomes contain numerous natural antisense transcripts, most of which appear to be non-protein-coding RNAs (ncRNAs). We have recently identified and characterized a highly conserved non-coding antisense transcript for beta-secretase-1 (BACE1), a critical enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript is markedly up-regulated in brain samples from Alzheimer's disease patients and promotes the stability of the (sense) BACE1 transcript. We report here that BACE1-antisense prevents miRNA-induced repression of BACE1 mRNA by masking the binding site for miR-485-5p. Indeed, miR-485-5p and BACE1-antisense compete for binding within the same region in the open reading frame of the BACE1 mRNA. We observed opposing effects of BACE1-antisense and miR-485-5p on BACE1 protein in vitro and showed that Locked Nucleic Acid-antimiR mediated knockdown of miR-485-5p as well as BACE1-antisense over-expression can prevent the miRNA-induced BACE1 suppression. We found that the expression of BACE1-antisense as well as miR-485-5p are dysregulated in RNA samples from Alzheimer's disease subjects compared to control individuals. Our data demonstrate an interface between two distinct groups of regulatory RNAs in the computation of BACE1 gene expression. Moreover, bioinformatics analyses revealed a theoretical basis for many other potential interactions between natural antisense transcripts and miRNAs at the binding sites of the latter

Muslim - Christian relations and the third crusade : medievalist imaginings

This article takes as its starting-point the responsiveness of children\u27s literature to socio-political events, considering how contemporary anxieties about relationships between Muslim and Christian individuals and&nbsp;cultures inform three historical novels set in the&nbsp;period of the Third Crusade (1189-92): Karleen Bradford\u27s Lionheart\u27s Scribe (1999), K. M. Grant\u27s Blood Red Horse (2004), and Elizabeth Laird\u27s Crusade (2008). In these novels, encounters between&nbsp;young Christian and Muslim protagonists are represented through language and representational modes which owe a good deal&nbsp;to the habits of&nbsp;thought and expression&nbsp;which typify orientalist discourses in Western fiction. In&nbsp;effect, the novels produce two&nbsp;versions of medievalism: a Muslim medieval&nbsp;world which is irretrievably pre-modern, locked into rigid pracices and beliefs against&nbsp;which&nbsp;individuals are powerless; and a Christian medieval world which offers individuals the possibility of progressing to an enhanced state of personal fulfilment. The article argues that the narratives of all three novels incorporate particularly telling moments&nbsp;when Christian protagonists return to England, regretfully leaving Muslim friends. The impossibility of&nbsp; enduring friendships between Muslims and Christians is based on the novels\u27 assumptions about the incommensurability of cultures and religions;&nbsp;specifically, that there existsan unbridgeable gulf between Islam and Christianity.<br /

Gene Expression in Uninvolved Oral Mucosa of OSCC Patients Facilitates Identification of Markers Predictive of OSCC Outcomes

<div><p>Oral and oropharyngeal squamous cell carcinomas (OSCC) are among the most common cancers worldwide, with approximately 60% 5-yr survival rate. To identify potential markers for disease progression, we used Affymetrix U133 plus 2.0 arrays to examine the gene expression profiles of 167 primary tumor samples from OSCC patients, 58 uninvolved oral mucosae from OSCC patients and 45 normal oral mucosae from patients without oral cancer, all enrolled at one of the three University of Washington-affiliated medical centers between 2003 to 2008. We found 2,596 probe sets differentially expressed between 167 tumor samples and 45 normal samples. Among 2,596 probe sets, 71 were significantly and consistently up- or down-regulated in the comparison between normal samples and uninvolved oral samples and between uninvolved oral samples and tumor samples. Cox regression analyses showed that 20 of the 71 probe sets were significantly associated with progression-free survival. The risk score for each patient was calculated from coefficients of a Cox model incorporating these 20 probe sets. The hazard ratio (HR) associated with each unit change in the risk score adjusting for age, gender, tumor stage, and high-risk HPV status was 2.7 (95% CI: 2.0–3.8, p = 8.8E-10). The risk scores in an independent dataset of 74 OSCC patients from the MD Anderson Cancer Center was also significantly associated with progression-free survival independent of age, gender, and tumor stage (HR 1.6, 95% CI: 1.1–2.2, p = 0.008). Gene Set Enrichment Analysis showed that the most prominent biological pathway represented by the 71 probe sets was the Integrin cell surface interactions pathway. In conclusion, we identified 71 probe sets in which dysregulation occurred in both uninvolved oral mucosal and cancer samples. Dysregulation of 20 of the 71 probe sets was associated with progression-free survival and was validated in an independent dataset.</p> </div

Kaplan-Meier survival curves.

<p>Kaplan-Meier curves comparing progression free survival of 69 OSCC patients in the MDACC dataset with low, medium, and high risk score.</p

Selected characteristics of OSCC patients by sample type and controls, University of Washington Affiliated Medical Centers, 2003–2010.

*<p>49 of 167 OSCC patients provided both tumor tissue and uninvolved oral tissue.</p