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Parenteral nutrition (PN) is lifesaving for patients with short bowel syndrome and other gastrointestinal disorders, however long-term use may lead to complications including hepatosteatosis and sepsis. We have previously demonstrated the anti-steatotic, -fibrotic, and -inflammatory properties of SEFA-6179, an engineered medium-chain fatty acid analogue. We hypothesized that SEFA-6179 treatment would protect against endotoxin-induced liver injury in a murine model of PN-induced hepatosteatosis. C57Bl/6J mice were administered a high-carbohydrate liquid diet plus intravenous lipid emulsion (Intralipid, 4 g fat/kg/d) or intravenous saline for 19 days to induce hepatosteatosis. SEFA-6179 (100 mg/kg) or vehicle (MCT/medium-chain triglyceride) was administered via oral gavage for four days leading up to intraperitoneal challenge with lipopolysaccharide (15 mg/kg) or saline on day 19. Age-matched, chow-fed controls received the same treatments. The primary outcome was liver biomarkers: alanine aminotransferase and aspartate aminotransferase. Pro-inflammatory cytokines, IL-6, TNF-alpha, and monocyte chemoattractant protein (MCP1), were analyzed. Liver immunofluorescence staining was performed to evaluate macrophage phenotypes. In endotoxin-challenged mice, pre-treatment with SEFA-6179 lowered liver enzymes and pro-inflammatory cytokine levels compared to vehicle. On liver histology, SEFA-6179 pre-treatment led to greater polarization of M1/pro-inflammatory macrophages to an M2/anti-inflammatory phenotype compared to vehicle. SEFA-6179 is currently in Phase II clinical trials. These findings support the potential application of SEFA-6179 in high-risk, PN-dependent patients.

Parenteral (intravenous) nutrition is lifesaving for patients with intestinal failure, but long-term use of parenteral nutrition often leads to liver disease. SEFA-6179 is a synthetic medium-chain fatty acid analogue designed to target multiple fatty acid receptors regulating metabolic and inflammatory pathways. We hypothesized that SEFA-6179 would prevent hepatosteatosis and lipotoxicity in a murine model of parenteral nutrition-induced hepatosteatosis. Two in vivo experiments were conducted. In the first experiment, six-week-old male mice were provided an ad lib fat-free high carbohydrate diet (HCD) for 19 days with orogastric gavage of either fish oil, medium-chain triglycerides, or SEFA-6179 at a low (0.3mmol/kg) or high dose (0.6mmol/kg). In the second experiment, six-week-old mice were provided an ad lib fat-free high carbohydrate diet for 19 days with every other day tail vein injection of saline, soybean oil lipid emulsion, or fish oil lipid emulsion. Mice then received every other day orogastric gavage of medium-chain triglyceride vehicle or SEFA-6179 (0.6mmol/kg). Hepatosteatosis was assessed by a blinded pathologist using an established rodent steatosis score. Hepatic lipid metabolites were assessed using ultra-high-performance liquid chromatography-mass spectrometry. Effects of SEFA-6179 on fatty acid oxidation, lipogenesis, and fatty acid uptake in human liver cells were assessed in vitro. In the first experiment, mice receiving the HCD with either saline or medium-chain triglyceride treatment developed macrovesicular steatosis, while mice receiving fish oil or SEFA-6179 retained normal liver histology. In the second experiment, mice receiving a high carbohydrate diet with intravenous saline or soybean oil lipid emulsion, along with medium chain triglyceride vehicle treatment, developed macrovescular steatosis. Treatment with SEFA-6179 prevented steatosis. In each experiment, SEFA-6179 treatment decreased arachidonic acid metabolites as well as key molecules (diacylglycerol, ceramides) involved in lipotoxicity. SEFA-6179 increased both β- and complete fatty oxidation in human liver cells, while having no impact on lipogenesis or fatty acid uptake. SEFA-6179 treatment prevented hepatosteatosis and decreased toxic lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. An increase in both β- and complete hepatic fatty acid oxidation may underlie the reduction in steatosis.

Icosabutate is a structurally engineered eicosapentaenoic acid derivative under development for nonalcoholic steatohepatitis (NASH). In this study, we investigated the absorption and distribution properties of icosabutate in relation to liver targeting and used rodents to evaluate the effects of icosabutate on glucose metabolism, insulin resistance, as well as hepatic steatosis, inflammation, lipotoxicity, and fibrosis. The absorption, tissue distribution, and excretion of icosabutate was investigated in rats along with its effects in mouse models of insulin resistance (ob/ob) and metabolic inflammation/NASH (high‐fat/cholesterol‐fed APOE*3Leiden.CETP mice) and efficacy was compared with synthetic peroxisome proliferator‐activated receptor α (PPAR‐α) (fenofibrate) and/or PPAR‐γ/(α) (pioglitazone and rosiglitazone) agonists. Icosabutate was absorbed almost entirely through the portal vein, resulting in rapid hepatic accumulation. Icosabutate demonstrated potent insulin‐sensitizing effects in ob/ob mice, and unlike fenofibrate or pioglitazone, it significantly reduced plasma alanine aminotransferase. In high‐fat/cholesterol‐fed APOE*3Leiden.CETP mice, icosabutate, but not rosiglitazone, reduced microvesicular steatosis and hepatocellular hypertrophy. Although both rosiglitazone and icosabutate reduced hepatic inflammation, only icosabutate elicited antifibrotic effects in association with decreased hepatic concentrations of multiple lipotoxic lipid species and an oxidative stress marker. Hepatic gene‐expression analysis confirmed the changes in lipid metabolism, inflammatory and fibrogenic response, and energy metabolism, and revealed the involved upstream regulators. In conclusion, icosabutate selectively targets the liver through the portal vein and demonstrates broad beneficial effects following insulin sensitivity, hepatic microvesicular steatosis, inflammation, lipotoxicity, oxidative stress, and fibrosis. Icosabutate therefore offers a promising approach to the treatment of both dysregulated glucose/lipid metabolism and inflammatory disorders of the liver, including NASH. The aim of the present study was to evaluate the effects of icosabutate, a structurally engineered eicosapentaenoic acid (EPA) derivative, designed to overcome the inherent drawbacks of unmodified EPA for liver targeting. As a multi‐etiological disorder with limited success achieved to date with single target drugs, nonalcoholic steatohepatitis (NASH) is an attractive indication for drugs with pleiotropic targeting potential, such as ω‐3 fatty acids. However, a potentially important issue limiting their clinical efficacy is related to suboptimal liver targeting of ω‐3 fatty acids, which could be rectified through structural engineering. In this study, we investigated icosabutate in relation to liver targeting and used rodent models to evaluate the effects of icosabutate on glucose metabolism, insulin resistance, as well as NASH and fibrosis.

ObjectivesViolence is a major public health problem in the USA. In 2016, more than 1.6 million assault-related injuries were treated in US emergency departments (EDs). Unfortunately, information about the magnitude and patterns of violent incidents is often incomplete and underreported to law enforcement (LE). In an effort to identify more complete information on violence for the development of prevention programme, a cross-sectoral Cardiff Violence Prevention Programme (Cardiff Model) partnership was established at a large, urban ED with a level I trauma designation and local metropolitan LE agency in the Atlanta, Georgia metropolitan area. The Cardiff Model is a promising violence prevention approach that promotes combining injury data from hospitals and LE. The objective was to describe the Cardiff Model implementation and collaboration between hospital and LE partners.MethodsThe Cardiff Model was replicated in the USA. A process evaluation was conducted by reviewing project materials, nurse surveys and interviews and ED–LE records.ResultsCardiff Model replication centred around four activities: (1) collaboration between the hospital and LE to form a community safety partnership locally called the US Injury Prevention Partnership; (2) building hospital capacity for data collection; (3) data aggregation and analysis and (4) developing and implementing violence prevention interventions based on the data.ConclusionsThe Cardiff Model can be implemented in the USA for sustainable violent injury data surveillance and sharing. Key components include building a strong ED–LE partnership, communicating with each other and hospital staff, engaging in capacity building and sustainability planning.

OBJECTIVE: To study the effects of long-term oral benfotiamine supplementation on peripheral nerve function and soluble inflammatory markers in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: The study randomly assigned 67 patients with type 1 diabetes to receive 24-month benfotiamine (300 mg/day) or placebo supplementation. Peripheral nerve function and levels of soluble inflammatory variables were assessed at baseline and at 24 months. RESULTS: Fifty-nine patients completed the study. Marked increases in whole-blood concentrations of thiamine and thiamine diphosphate were found in the benfotiamine group (both P < 0.001 vs. placebo). However, no significant differences in changes in peripheral nerve function or soluble inflammatory biomarkers were observed between the groups. CONCLUSIONS: Our findings suggest that high-dose benfotiamine (300 mg/day) supplementation over 24 months has no significant effects upon peripheral nerve function or soluble markers of inflammation in patients with type 1 diabetes.

The transboundary Georgia Basin Puget Sound ecosystem is situated in the southwest corner of British Columbia and northwest comer of Washington State. While bountiful and beautiful, this international region is facing significant threats to its marine and freshwater resources, air quality, habitats and species. These environmental challenges are compounded by rapid population growth and attendant uiban sprawl. As ecosystem stresses amplified and partnerships formed around possible solutions, it became increasingly clear that the shared sustainability challenges in the Georgia Basin and Puget Sound required shared solutions. Federal, state and provincial institutional arrangements were made between jurisdictions, which formalized small scale interest in transboundary management of this ecosystem. Formal agreements, however, can only do so much to further management of an ecosystem that spans international boarders. A transboundary regional research meeting, the 2003 GB/PS Research Conference, opened the doors for large-scale informal cross-boarder cooperation and management. In addition to cooperation, continued efforts to stem toxic pollution, contain urban growth, and protect and restore ecosystems, require a commitment from scientists, educators and policy makers to better integrate research and science with decision-making.

BackgroundParenteral (intravenous) nutrition is lifesaving for patients with intestinal failure, but long-term use of parenteral nutrition often leads to liver disease. SEFA-6179 is a synthetic medium-chain fatty acid analogue designed to target multiple fatty acid receptors regulating metabolic and inflammatory pathways. We hypothesized that SEFA-6179 would prevent hepatosteatosis and lipotoxicity in a murine model of parenteral nutrition-induced hepatosteatosis.MethodsTwo in vivo experiments were conducted. In the first experiment, six-week-old male mice were provided an ad lib fat-free high carbohydrate diet (HCD) for 19 days with orogastric gavage of either fish oil, medium-chain triglycerides, or SEFA-6179 at a low (0.3mmol/kg) or high dose (0.6mmol/kg). In the second experiment, six-week-old mice were provided an ad lib fat-free high carbohydrate diet for 19 days with every other day tail vein injection of saline, soybean oil lipid emulsion, or fish oil lipid emulsion. Mice then received every other day orogastric gavage of medium-chain triglyceride vehicle or SEFA-6179 (0.6mmol/kg). Hepatosteatosis was assessed by a blinded pathologist using an established rodent steatosis score. Hepatic lipid metabolites were assessed using ultra-high-performance liquid chromatography-mass spectrometry. Effects of SEFA-6179 on fatty acid oxidation, lipogenesis, and fatty acid uptake in human liver cells were assessed in vitro.ResultsIn the first experiment, mice receiving the HCD with either saline or medium-chain triglyceride treatment developed macrovesicular steatosis, while mice receiving fish oil or SEFA-6179 retained normal liver histology. In the second experiment, mice receiving a high carbohydrate diet with intravenous saline or soybean oil lipid emulsion, along with medium chain triglyceride vehicle treatment, developed macrovescular steatosis. Treatment with SEFA-6179 prevented steatosis. In each experiment, SEFA-6179 treatment decreased arachidonic acid metabolites as well as key molecules (diacylglycerol, ceramides) involved in lipotoxicity. SEFA-6179 increased both β- and complete fatty oxidation in human liver cells, while having no impact on lipogenesis or fatty acid uptake.ConclusionsSEFA-6179 treatment prevented hepatosteatosis and decreased toxic lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. An increase in both β- and complete hepatic fatty acid oxidation may underlie the reduction in steatosis.