Hydrogen Sulfide Donor GYY4137 Acts Through Endothelial Nitric Oxide to Protect Intestine in Murine Models of Necrotizing Enterocolitis and Intestinal Ischemia

BACKGROUND: Necrotizing enterocolitis (NEC) in premature infants is often a devastating surgical condition with poor outcomes. GYY4137 is a long-acting donor of hydrogen sulfide, a gasotransmitter that is protective against intestinal injury in experimental NEC, likely through protection against injury secondary to ischemia. We hypothesized that administration of GYY4137 would improve mesenteric perfusion, reduce intestinal injury, and reduce inflammatory responses in experimental NEC and ischemia-reperfusion injury, and that these benefits would be mediated through endothelial nitric oxide synthase-dependent pathways. METHODS: NEC was induced in C57BL/6 wild-type (WT) and endothelial nitric oxide synthase (eNOS) knockout (eNOSKO) pups via maternal separation, formula feeding, enteral lipopolysaccharide, and intermittent hypoxic and hypothermic stress. Pups received daily intraperitoneal injections of 50 mg/kg GYY4137 or phosphate buffered saline vehicle. In separate groups, adult male WT and eNOSKO mice underwent superior mesenteric artery occlusion for 60 min. Before abdominal closure, 50 mg/kg GYY4137 or phosphate buffered saline vehicle was administered into the peritoneal cavity. Laser doppler imaging was used to assess mesenteric perfusion of pups at baseline and on postnatal day 9, and the adult mice at baseline and 24 h after ischemic insult. After euthanasia, the terminal ileum of each animal was fixed, paraffin embedded, sectioned, and stained with hematoxylin and eosin. Sections were blindly graded using published injury scores. Intestinal tissue was homogenized and cytokines measured by ELISA. Data were compared using Mann-Whitney U test, and P-values <0.05 were significant. RESULTS: After NEC and ischemia reperfusion (I/R) injury, GYY4137 improved perfusion in WT mice compared to vehicle, but this effect was lost in the eNOSKO animals. Histologic injury followed a similar pattern with reduced intestinal injury in WT mice treated with GYY4137, and no significant improvement in the eNOSKO group. Cytokine expression after GYY4137 administration was altered by the ablation of eNOS in both NEC and I/R injury groups, with significant differences noted in Interleukin 6 and vascular endothelial growth factor. CONCLUSIONS: GYY4137, a long-acting donor of hydrogen sulfide, has potential as a therapeutic compound for NEC. It improves mesenteric perfusion and intestinal injury in experimental NEC and intestinal I/R injury, and these benefits appear to be mediated through eNOS-dependent pathways

Social and Cultural Impact of a Proposed Reservoir on a Rural Kentucky School District

This study utilizes anthropological concepts and research methods to study the educational system of a Central Kentucky school district with the goal of predicting the impact on it of a proposed multi-purpose (flood control, recreation, etc.) reservoir, and proposing options for forestalling dysfunctional aspects of that impact. The impact will result from the fact that although the county is now rurally oriented, the proposed reservoir will attract (has already begun to attract) urbanite residents from nearby Louisville, Kentucky\u27s largest urban center, who can be expected to bring urban values concerning education, as well as other areas. To assess probable directions of change, a school in an upper middle class suburb of Louisville, the sort of milieu from which most new residents will come, was also studied. This research is another step in the program Anthropological analysis of sociocultural benefits and costs of stream-control devices

Ratcheting of granular materials

We investigate the quasi-static mechanical response of soils under cyclic loading using a discrete model of randomly generated convex polygons. This response exhibits a sequence of regimes, each one characterized by a linear accumulation of plastic deformation with the number of cycles. At the grain level, a quasi-periodic ratchet-like behavior is observed at the contacts, which excludes the existence of an elastic regime. The study of this slow dynamics allows to explore the role of friction in the permanent deformation of unbound granular materials supporting railroads and streets.Comment: Changed content Submitted to Physical Review Letter

Efficient Video Indexing on the Web: A System that Leverages User Interactions with a Video Player

In this paper, we propose a user-based video indexing method, that automatically generates thumbnails of the most important scenes of an online video stream, by analyzing users' interactions with a web video player. As a test bench to verify our idea we have extended the YouTube video player into the VideoSkip system. In addition, VideoSkip uses a web-database (Google Application Engine) to keep a record of some important parameters, such as the timing of basic user actions (play, pause, skip). Moreover, we implemented an algorithm that selects representative thumbnails. Finally, we populated the system with data from an experiment with nine users. We found that the VideoSkip system indexes video content by leveraging implicit users interactions, such as pause and thirty seconds skip. Our early findings point toward improvements of the web video player and its thumbnail generation technique. The VideSkip system could compliment content-based algorithms, in order to achieve efficient video-indexing in difficult videos, such as lectures or sports.Comment: 9 pages, 3 figures, UCMedia 2010: 2nd International ICST Conference on User Centric Medi

Universities, knowledge networks and regional policy

As knowledge becomes an increasingly important part of regional innovation and development processes, the role of universities has come to the fore of regional innovation and economic development policy The objective of this paper is to critically review and assess the structure and function of knowledge networks and modes of engagement between universities and the business community in regional settings and contexts. It is argued that while regional knowledge networks and modes of engagement between universities and the business community are becoming increasingly prevalent, it is often difficult to ascribe investments in knowledge-based infrastructure to improved regional competitiveness. It is concluded that in a globalised knowledge environment the engagement between universities and regional business communities must be based on a mutual understanding of the role of both network and market-based knowledge interactions

The route and timing of hydrogen sulfide therapy critically impacts intestinal recovery following ischemia and reperfusion injury

PURPOSE: Hydrogen sulfide (H2S) has many beneficial properties and may serve as a novel treatment in patients suffering from intestinal ischemia-reperfusion injury (I/R). The purpose of this study was to examine the method of delivery and timing of administration of H2S for intestinal therapy during ischemic injury. We hypothesized that 1) route of administration of hydrogen sulfide would impact intestinal recovery following acute mesenteric ischemia and 2) preischemic H2S conditioning using the optimal mode of administration as determined above would provide superior protection compared to postischemic application. METHODS: Male C57BL/6J mice underwent intestinal ischemia by temporary occlusion of the superior mesenteric artery. Following ischemia, animals were treated according to one of the following (N=6 per group): intraperitoneal or intravenous injection of GYY4137 (H2S-releasing donor, 50mg/kg in PBS), vehicle, inhalation of oxygen only, inhalation of 80ppm hydrogen sulfide gas. Following 24-h recovery, perfusion was assessed via laser Doppler imaging, and animals were euthanized. Perfusion and histology data were assessed, and terminal ileum samples were analyzed for cytokine production following ischemia. Once the optimal route of administration was determined, preischemic conditioning with H2S was undertaken using that route of administration. All data were analyzed using Mann-Whitney. P-values <0.05 were significant. RESULTS: Mesenteric perfusion following intestinal I/R was superior in mice treated with intraperitoneal (IP) GYY4137 (IP vehicle: 25.6±6.0 vs. IP GYY4137: 79.7±15.1; p=0.02) or intravenous (IV) GYY4137 (IV vehicle: 36.3±5.9 vs. IV GYY4137: 100.7±34.0; p=0.03). This benefit was not observed with inhaled H2S gas (O2 vehicle: 66.6±11.4 vs. H2S gas: 81.8±6.0; p=0.31). However, histological architecture was only preserved with intraperitoneal administration of GYY4127 (IP vehicle: 3.4±0.4 vs. IP GYY4137: 2±0.3; p=0.02). Additionally, IP GYY4137 allowed for significant attenuation of inflammatory chemokine production of IL-6, IP-10 and MIP-2. We then analyzed whether there was a difference between pre- and postischemic administration of IP GYY4137. We found that preconditioning of animals with intraperitoneal GYY4137 only added minor improvements in outcomes compared to postischemic application. CONCLUSION: Therapeutic benefits of H2S are superior with intraperitoneal application of an H2S donor compared to other administration routes. Additionally, while intraperitoneal treatment in both the pre- and postischemic period is beneficial, preischemic application of an H2S donor was found to be slightly better. Further studies are needed to examine long term outcomes and further mechanisms of action prior to widespread clinical application. TYPE OF STUDY: Basic science. LEVEL OF EVIDENCE: N/A

Impact of a Proposed Reservoir on Local Land Values

This project was designed to study the impact of private preconstruction land acquisition in a Central Kentucky area in which a flood-control dam and reservoir impoundment is planned. The research design was built around use of anthropological concepts and research techniques. By these means it was possible to analyze the perceived values of land to traditionalist residents, among which social and economic security concepts are paramount. Recent land purchases, locally believed to have been made chiefly by outsiders, (urbanites from nearby Louisville), at prices out of line in terms of local agricultural worth, has been extremely unsettling contributing to the anxiety pattern typical of persons facing dislocation and their sympathizers. The newly developing pattern of land purchase, with values related to residential convenience, and access to the urban center, rather than to traditional agricultural values, has been accepted by a certain segment of the local population who appear to be trying to take advantage of the urban economic opportunities while retaining at least part of the rural value system and continuing to participate in rural society and rurally esteemed activities

Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Evaluation of the Risks and Benefits

Limited evidence suggests that GLP-I may also preserve ventricular function and improve outcomes in human subjects with heart failure or myocardial infarction (11,12). [...] both exenatide and liraglutide reduce blood pressure, body weight, and plasma lipid profiles in subjects with type 2 diabetes (13), raising the hope that longterm treatment with these agents may reduce the incidence of cardiovascular events.\n However, two safety issues have been raised - pancreatitis and medullary carcinoma of the thyroid