Dominant components of the Thoroughbred metabolome characterised by 1H‐NMR spectroscopy: a metabolite atlas of common biofluids

Summary Reasons for performing study: Metabonomics is emerging as a powerful tool for disease screening and investigating mammalian metabolism. This study aims to create a metabolic framework by producing a preliminary reference guide for the normal equine metabolic milieu. Objectives: To metabolically profile plasma, urine and faecal water from healthy racehorses using high resolution 1H-NMR spectroscopy and to provide a list of dominant metabolites present in each biofluid for the benefit of future research in this area. Study design: This study was performed using seven Thoroughbreds in race training at a single time-point. Urine and faecal samples were collected non-invasively and plasma was obtained from samples taken for routine clinical chemistry purposes. Methods: Biofluids were analysed using 1H-NMR spectroscopy. Metabolite assignment was achieved via a range of 1D and 2D experiments. Results: A total of 102 metabolites were assigned across the three biological matrices. A core metabonome of 14 metabolites was ubiquitous across all biofluids. All biological matrices provided a unique window on different aspects of systematic metabolism. Urine was the most populated metabolite matrix with 65 identified metabolites, 39 of which were unique to this biological compartment. A number of these were related to gut microbial host co-metabolism. Faecal samples were the most metabolically variable between animals; acetate was responsible for the majority (28%) of this variation. Short chain fatty acids were the predominant features identified within this biofluid by 1H-NMR spectroscopy. Conclusions: Metabonomics provides a platform for investigating complex and dynamic interactions between the host and its consortium of gut microbes and has the potential to uncover markers for health and disease in a variety of biofluids. Inherent variation in faecal extracts along with the relative abundance of microbial-mammalian metabolites in urine and invasive nature of plasma sampling, infers that urine is the most appropriate biofluid for the purposes of metabonomic analysis

Beyond blood sugar: the potential of NMR-based metabonomics for type 2 human diabetes, and the horse as a possible model.

Metabonomic analysis is a powerful tool for identifying and characterizing metabolic disorders, for example type 2 diabetes and the metabolic syndrome. Nuclear magnetic resonance (NMR) spectroscopy is an essential tool for such analysis, with special benefits. The review assesses the current status and potential of NMR-based metabonomics of type 2 diabetes. The horse is proposed as a possible model for studying this condition and disease. Some examples are shown of horse blood analyses by NMR

G Protein-coupled Receptor Biased Agonism.

G protein-coupled receptors are the largest family of targets for current therapeutics. The classic model of their activation was binary, where agonist binding induced an active conformation and subsequent downstream signaling. Subsequently, the revised concept of biased agonism emerged, where different ligands at the same G protein-coupled receptor selectively activate one downstream pathway versus another. Advances in understanding the mechanism of biased agonism have led to the development of novel ligands, which have the potential for improved therapeutic and safety profiles. In this review, we summarize the theory and most recent breakthroughs in understanding biased signaling, examine recent laboratory investigations concerning biased ligands across different organ systems, and discuss the promising clinical applications of biased agonism

Minimal Risk of Biliary Tract Complications, Including Hepatic Abscess, After Transarterial Embolization for Hepatocellular Carcinoma Using Concentrated Antibiotics Mixed with Particles.

PURPOSE: To assess the incidence of biliary complications, cholecystitis, and abscess formation in HCC patients following transarterial embolization (TAE) using particles mixed with concentrated antibiotics. MATERIALS AND METHODS: Retrospective review of HCC patients treated with embolization over a 10-year period revealed 499 procedures in 257 patients. TAE was performed with particles mixed with concentrated antibiotics in addition to IV antibiotics. All follow-up imaging after treatment was retrospectively reviewed for the development of bilomas, biliary strictures, acute cholecystitis, and hepatic abscess. Clinical notes and laboratory tests were also reviewed. RESULTS: Mean follow-up duration was 18.2 months. In total, there was one biliary complication consisting of biloma formation. This patient had subsegmental hepatic infarction identified on imaging 8 days post-embolization in the setting of subsegmental portal vein thrombus, with subsequent biloma development. There were no cases of new biliary strictures in the embolized portion of the liver at any point after treatment. One patient developed acute gangrenous cholecystitis 10 days post-procedure. No patients developed a hepatic abscess, although 10 patients had bilioenteric anastomoses or incompetent sphincters of Oddi. CONCLUSIONS: Biliary complications and cholecystitis occurred extremely rarely after TAE, at a markedly lower rate than historical data on TACE. Despite significant risk factors for abscess formation in 10 patients, TAE with particles mixed with concentrated antibiotics resulted in zero abscesses, in contrast to a very high rate after TACE in the literature

A model of sequential heart and composite tissue allotransplant in rats.

BACKGROUND: Some of the 600,000 patients with solid organ allotransplants need reconstruction with a composite tissue allotransplant, such as the hand, abdominal wall, or face. The aim of this study was to develop a rat model for assessing the effects of a secondary composite tissue allotransplant on a primary heart allotransplant. METHODS: Hearts of Wistar Kyoto rats were harvested and transplanted heterotopically to the neck of recipient Fisher 344 rats. The anastomoses were performed between the donor brachiocephalic artery and the recipient left common carotid artery, and between the donor pulmonary artery and the recipient external jugular vein. Recipients received cyclosporine A for 10 days only. Heart rate was assessed noninvasively. The sequential composite tissue allotransplant consisted of a 3 x 3-cm abdominal musculocutaneous flap harvested from Lewis rats and transplanted to the abdomen of the heart allotransplant recipients. The abdominal flap vessels were connected to the femoral vessels. No further immunosuppression was administered following the composite tissue allotransplant. Ten days after composite tissue allotransplantation, rejection of the heart and abdominal flap was assessed histologically. RESULTS: The rat survival rate of the two-stage transplant surgery was 80 percent. The transplanted heart rate decreased from 150 +/- 22 beats per minute immediately after transplant to 83 +/- 12 beats per minute on day 20 (10 days after stopping immunosuppression). CONCLUSIONS: This sequential allotransplant model is technically demanding. It will facilitate investigation of the effects of a secondary composite tissue allotransplant following primary solid organ transplantation and could be useful in developing future immunotherapeutic strategies

Effectiveness of Transarterial Embolization of Hepatocellular Carcinoma as a Bridge to Transplantation.

PURPOSE: To assess the effectiveness of bland transarterial embolization of hepatocellular carcinoma (HCC) as a bridge to transplantation. MATERIALS AND METHODS: In this retrospective study, 117 patients with HCC that met Milan criteria underwent bland embolization as their initial and sole therapy for treatment of HCC (88 men and 29 women; mean age, 60.4 y; range, 35-88 y). Subsequent postembolization contrast-enhanced computed tomography or magnetic resonance imaging studies were reviewed to determine whether Milan criteria were met in an intent-to-transplant analysis. Freedom from progression beyond Milan criteria and survival were calculated by Kaplan-Meier technique. Predictors of progression and survival were also assessed. RESULTS: After embolization, 87% and 78% of patients\u27 disease still met Milan criteria at 6 and 12 months, respectively. The median time until disease progression beyond Milan criteria was 22.6 months (95% confidence interval, 16.2-29 mo). α-Fetoprotein levels, number of lesions, United Network for Organ Sharing stage, Model for End-stage Liver Disease score, and cirrhosis etiology did not correlate significantly with stability within Milan criteria. A total of 34 patients (29%) underwent eventual liver transplantation at a median of 3.3 months (range, 0.5-20.9 mo). Liver transplantation was a significant independent predictor of longer survival (6.9 y vs 2.6 y; P \u3c .001). The major complication rate within 30 days of embolization was 2.6%, including one mortality. CONCLUSIONS: Bland transarterial embolization as a bridging strategy to maintain HCC within Milan criteria was successful in 78% of patients at 1 year, which compares favorably with other locoregional embolotherapies