Serum metabolic signatures of primary biliary cirrhosis and primary sclerosing cholangitis

BACKGROUND & AIMS: A greater understanding of cholestatic disease is necessary to advance diagnostic tools and therapeutic options for conditions such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The purpose of this study was to determine and compare the serum metabolomes of patients with PBC (n = 18) or PSC (n = 21) and healthy controls (n = 10) and to identify metabolites that may differentiate these two cholestatic diseases. METHODS AND RESULTS: Using a mass spectrometry-based, non-targeted biochemical profiling approach, we identified 420 serum metabolites, 101 that differed significantly (P ≤ 0.05) between PBC and control groups, 115 that differed significantly between PSC and control groups, and 56 that differed significantly between PSC and PBC groups. Random forest classification analysis was able to distinguish patients with PBC or PSC with 95% accuracy with selected biochemicals reflective of protein and amino acid metabolism identified as the major contributors. Metabolites related to bile acid metabolism, lipid metabolism, inflammation, and oxidative stress/lipid peroxidation were also identified as differing significantly when comparing the disease groups and controls, with some of these pathways differentially affected in the PBC and PSC groups. CONCLUSION: In this study, we identified novel metabolic changes associated with cholestatic disease that were both consistent and different between PBC and PSC. Validation studies in larger patient cohorts are required to determine the utility of these biochemical markers for diagnosis and therapeutic monitoring of patients with PBC and PSC

Hepatic lipid peroxidation and cytochrome P-450 2E1 in pediatric nonalcoholic fatty liver disease and its subtypes

GOAL: To compare hepatic lipid peroxidation and cytochrome P-450 2E1 (CYP2E1) protein content in liver biopsies from children with nonalcoholic fatty liver disease (NAFLD) and 2 control groups. BACKGROUND: Elevated hepatic lipid peroxidation resulting from increased hepatic CYP2E1 enzyme activity is involved in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) in adults, but studies in children are lacking. STUDY: Liver biopsies from 59 children with NAFLD (49 with NASH), 10 children with normal liver histology, and 9 children with mild chronic hepatitis C (HCV) infection were examined. Hepatic malondialdehyde (a measure of lipid peroxidation) levels and CYP2E1 protein content were quantitated, as a percentage of the total area, by immunohistochemical staining of liver biopsy material followed by digital image quantitation. RESULTS: Lipid peroxidation was significantly greater in NAFLD liver biopsies (46.7 ± 20.8%) compared with biopsies from children with normal liver histology (7.6 ± 9.4%; P<0.001) or HCV infection (7.7 ± 7.6%; P<0.001). However, hepatic CYP2E1 expression was not different across the NAFLD, normal liver histology, and HCV groups (60.7 ± 8.7%, 53.5 ± 10.7%, and 60.0 ± 11.9%, respectively; P=0.116). Among children with NAFLD, lipid peroxidation and CYP2E1 protein content did not differ between biopsies with and without NASH. Body mass index was independently associated with hepatic lipid peroxidation levels (r=0.549; P<0.001). CONCLUSIONS: Hepatic lipid peroxidation is increased in children with NAFLD but this is not related to hepatic CYP2E1 expression. No difference in lipid peroxidation in pediatric NAFLD versus NASH argues against a role in disease progression

Attitudes and Practice Patterns in the Use of OMM in Patients with Serious Illness

INTRODUCTION: In addition to evidence-based medicine, the osteopathic approach to person-centered care consists of the osteopathic philosophy of integrated structure and function and applying manual techniques to treat somatic dysfunction. Known collectively as Osteopathic Manipulative Medicine (OMM), this approach can be utilized when treating patients with both chronic and acute conditions; however, there is limited data on how often or to what extent OMM is used to treat pain and other symptoms in patients facing serious or life-limiting illnesses. METHODS: A voluntary, anonymous survey was created to capture the practice patterns and attitudes of osteopathic physicians, regardless of specialty, in the uses and benefits of OMM in treating patients with serious illness. The survey was approved by the IRB and designed using a Likert-scale, multiple choice format using Redcap software and permission to distribute the survey electronically was granted from various national and local professional organizations including the American Osteopathic Association (AOA), Pennsylvania Osteopathic Medical Association (POMA) and the PCOM alumni association. Among key data analyzed were the frequency of OMM use in serious or life-limiting illness (Cancer, CHF, and COPD), attitudes about OMM, beliefs about OMM, and use of OMM in older adults. RESULTS: Osteopathic Physicians that utilize OMM when treating patients with serious illness have found OMM to be beneficial when treating certain conditions such as chronic and musculoskeletal pain, shortness of breath, and nausea. The physicians who use OMM also felt comfortable and proficient when utilizing it to treat certain conditions. They also felt their foundation in osteopathic Medicine enabled them to approach and care for patients with empathy and compassion. DISCUSSION: OMM is used by many osteopathic physicians when treating pain and other symptoms of patients who have serious illness. OMM has been found to be beneficial when treating conditions related to CHF, COPD, and Cancer. Osteopathic Physicians who do utilize Osteopathic Manipulative Medicine believe that their training has allowed them to engage and treat patients with compassion and empathy

A new framework for assessing the contributions of professionals in the natural sciences

No abstract available

Metabolic Syndrome Abolishes Glucagon-Like Peptide 1 Receptor Agonist Stimulation of SERCA in Coronary Smooth Muscle

Metabolic syndrome (MetS) doubles the risk of adverse cardiovascular events. Glucagon-like peptide 1 (GLP-1) receptor agonists induce weight loss, increase insulin secretion, and improve glucose tolerance. Studies in healthy animals suggest cardioprotective properties of GLP-1 receptor agonists, perhaps partially mediated by improved sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) activity. We examined the acute effect of GLP-1 receptor agonists on coronary smooth muscle cells (CSM) enzymatically isolated from lean, healthy Ossabaw miniature swine. Intracellular Ca(2+) handling was interrogated with fura-2. The GLP-1 receptor agonist exenatide activated SERCA but did not alter other Ca(2+) transporters. Further, we tested the hypothesis that chronic, in vivo treatment with GLP-1 receptor agonist AC3174 would attenuate coronary artery disease (CAD) in swine with MetS. MetS was induced in 20 swine by 6 months' feeding of a hypercaloric, atherogenic diet. Swine were then randomized (n = 10/group) into placebo or AC3174 treatment groups and continued the diet for an additional 6 months. AC3174 treatment attenuated weight gain, increased insulin secretion, and improved glucose tolerance. Intravascular ultrasound and histology showed no effect of AC3174 on CAD. MetS abolished SERCA activation by GLP-1 receptor agonists. We conclude that MetS confers vascular resistance to GLP-1 receptor agonists, partially through impaired cellular signaling steps involving SERCA

Effect of different obesogenic diets on pancreatic histology in Ossabaw miniature swine

OBJECTIVE: Obesity is a factor in the outcome and severity of pancreatic conditions. We examined the effect of hypercaloric diets on the pancreata of Ossabaw swine, a large animal model of metabolic syndrome and obesity. METHODS: Swine were fed with 1 of 4 diets: high-fructose (n = 9), atherogenic (n = 10), modified atherogenic (n = 6), or eucaloric standard diet (n = 12) for 24 weeks. Serum chemistries were measured, and pancreata were examined for histological abnormalities including steatosis, inflammation or fibrosis, insulin content, and oxidative stress. RESULTS: The fructose, atherogenic, and modified atherogenic diet groups exhibited obesity, metabolic syndrome, islet enlargement, and significantly increased pancreatic steatosis (22.9% ± 7.5%, 19.7% ± 7.7%, and 38.7% ± 15.3% fat in total tissue area, respectively) compared with controls (9.3% ± 1.9%; P < 0.05). The modified atherogenic diet group showed significantly increased oxidative stress levels as evidenced by elevated serum malondialdehyde (3.0 ± 3.3 vs 1.5 ± 0.3 μmol/L in controls; P = 0.006) and pancreatic malondialdehyde (0.1 ± 0.12 vs 0.04 ± 0.01 nmol/mg protein in controls; P = 0.01). None of the swine exhibited pancreatitis or cellular injury. CONCLUSIONS: Ossabaw swine fed with a modified atherogenic diet developed significant pancreatic steatosis and increased oxidative stress, but no other histological abnormalities were observed

Phosphorus mobilizing consortium Mammoth P enhances plant growth

Global agricultural productivity may be constrained by the finite and limited supply of phosphorus (P), adding to the challenges in meeting the projected needs of a growing human population in the coming decades. In addition, when P fertilizers are added to soils, they can become bound to soils resulting in low fertilizer efficiency. However, P-mobilizing bacteria could potentially liberate soil-bound P, resulting in a higher plant P uptake and increased yield. Bacteria can mobilize P through several mechanisms, suggesting that consortia of P-bacteria may be more effective than single species. Species diversity can have a synergistic, or non-additive, effect on ecosystem functioning (&quot;the whole is more than the sum of its parts&quot;) but rarely is the microbial community structure intentionally managed to improve plant nutrient uptake. We investigated whether inoculation of soils with a four-species bacterial community developed to mobilize soil P could increase plant productivity. In wheat and turf trials, we found that Mammoth P was able to deliver yields equivalent to those achieved using conventional fertilizer applications. Herbs and fruits showed that the combination of fertilizer with Mammoth P significantly increased productivity -in some cases productivity doubled. Metabolites produced by the Mammoth P consortium led to increased yields in some cases, suggesting that microbial products (produced in the absence of plants) played a role in enhancing plant productivity. Results from these trials indicate substantial potential of Mammoth P to enhance P supply to plants, improving P fertilizer use-efficiency and increasing agricultural productivity. 19 Agricultural productivity may be constrained in the 21 st Century by the finite supply of global a 20 phosphorus (P), adding to the challenges in meeting the projected needs of a growing human population 21 in the coming decades. In addition, when P fertilizers are added to soils, they can become bound to soils 22 resulting in low fertilizer efficiency. However, bacteria have the ability to mobilize soil bound P through 23 several mechanisms potentially resulting in a higher plant P uptake and increased yield. Furthermore, 24 species diversity can have a synergistic effect on ecosystem functioning (&quot;the whole is more than the sum 25 of its parts&quot;) suggesting that bacterial communities, or consortia, may be more effective than single 26 species. However, in agriculture management practices, rarely is the soil microbial community structure 27 effectively manipulated to improve plant nutrient uptake. We investigated whether inoculation of soils 28 with a bacterial consortium developed to mobilize soil P named Mammoth P could increase plant 29 productivity. In turf, herbs and fruits, we showed that the combination of conventional inorganic fertilizer 30 combined with Mammoth P increased productivity up to twofold compared to the fertilizer treatments 31 without the Mammoth P inoculant. In wheat trials, we found that Mammoth P by itself was able to deliver 32 yields equivalent to those achieved with conventional inorganic fertilizer applications. The metabolites 33 produced by the consortium in Mammoth P likely played a role in enhancing plant productivity. Results 34 from this study indicate the substantial potential of Mammoth P to enhance P supply to plants, improving 35 P fertilizer use-efficiency and increasing agricultural productivity. 3

Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans

Rationale: Air pollution has been associated with increased prevalence of type 2 diabetes; however, the mechanisms remain unknown. We have shown that acute ozone exposure in rats induces release of stress hormones, hyperglycemia, leptinemia, and glucose intolerance that are associated with global changes in peripheral glucose, lipid, and amino acid metabolism

CANDELS: The progenitors of compact quiescent galaxies at z~2

We combine high-resolution HST/WFC3 images with multi-wavelength photometry to track the evolution of structure and activity of massive (log(M*) > 10) galaxies at redshifts z = 1.4 - 3 in two fields of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS). We detect compact, star-forming galaxies (cSFGs) whose number densities, masses, sizes, and star formation rates qualify them as likely progenitors of compact, quiescent, massive galaxies (cQGs) at z = 1.5 - 3. At z > 2 most cSFGs have specific star-formation rates (sSFR = 10^-9 yr^-1) half that of typical, massive SFGs at the same epoch, and host X-ray luminous AGN 30 times (~30%) more frequently. These properties suggest that cSFGs are formed by gas-rich processes (mergers or disk-instabilities) that induce a compact starburst and feed an AGN, which, in turn, quench the star formation on dynamical timescales (few 10^8 yr). The cSFGs are continuously being formed at z = 2 - 3 and fade to cQGs by z = 1.5. After this epoch, cSFGs are rare, thereby truncating the formation of new cQGs. Meanwhile, down to z = 1, existing cQGs continue to enlarge to match local QGs in size, while less-gas-rich mergers and other secular mechanisms shepherd (larger) SFGs as later arrivals to the red sequence. In summary, we propose two evolutionary scenarios of QG formation: an early (z > 2), fast-formation path of rapidly-quenched cSFGs that evolve into cQGs that later enlarge within the quiescent phase, and a slow, late-arrival (z < 2) path for SFGs to form QGs without passing through a compact state.Comment: Submitted to the Astrophysical Journal Letters, 6 pages, 4 figure