Catestatin induces glycogenesis by stimulating the phosphoinositide 3-kinase-AKT pathway

Aim: Defects in hepatic glycogen synthesis contribute to post-prandial hyperglycaemia in type 2 diabetic patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA 352-372) improves glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST induces hepatic glycogen synthesis. Methods: We determined liver glycogen, glucose-6-phosphate (G6P), uridine diphosphate glucose (UDPG) and glycogen synthase (GYS2) activities; plasma insulin, glucagon, noradrenaline and adrenaline levels in wild-type (WT) as well as in CST knockout (CST-KO) mice; glycogen synthesis and glycogenolysis in primary hepatocytes. We also analysed phosphorylation signals of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-dependent kinase-1 (PDK-1), GYS2, glycogen synthase kinase-3β (GSK-3β), AKT (a kinase in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mammalian/mechanistic target of rapamycin (mTOR) by immunoblotting. Results: CST stimulated glycogen accumulation in fed and fasted liver and in primary hepatocytes. CST reduced plasma noradrenaline and adrenaline levels. CST also directly stimulated glycogenesis and inhibited noradrenaline and adrenaline-induced glycogenolysis in hepatocytes. In addition, CST elevated the levels of UDPG and increased GYS2 activity. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST improved insulin signals downstream of IR and IRS-1 by enhancing phospho-AKT signals through the stimulation of PDK-1 and mTORC2 (mTOR Complex 2, rapamycin-insensitive complex) activities. Conclusions: CST directly promotes the glycogenic pathway by (a) reducing glucose production, (b) increasing glycogen synthesis from UDPG, (c) reducing glycogenolysis and (d) enhancing downstream insulin signalling

The Veterans Health Administration: Quality, Value, Accountability, and Information as Transforming Strategies for Patient-Centered Care

Abstract Countries around the world are in need of electronic medical record (EMR) systems that meet their specific needs. This paper describes briefly the benefits of EMRs in developing countries. It focuses on the basic EMR information, including types of EMRs, components of EMRs, and already existing EMRs, in order to establish which EMR systems would be feasible and effective for specific situations. Electronic Medical Record Systems for Developing Countries: Review Structure of Systems A. Data Model • Flat file structures (spread-sheet like) as compared with relational databases B. Networks • Stand-alone • Systems which are deployed on a single machine • Local area networks • Wide area network solutions • Deployed across a much larger area Discussion When choosing which electronic medical record system to implement, one should consider the following factors: population, location, and availability of resources. OpenMRS may be the best choice for today's EMR

Poisson-de Rham homology of hypertoric varieties and nilpotent cones

We prove a conjecture of Etingof and the second author for hypertoric varieties, that the Poisson-de Rham homology of a unimodular hypertoric cone is isomorphic to the de Rham cohomology of its hypertoric resolution. More generally, we prove that this conjecture holds for an arbitrary conical variety admitting a symplectic resolution if and only if it holds in degree zero for all normal slices to symplectic leaves. The Poisson-de Rham homology of a Poisson cone inherits a second grading. In the hypertoric case, we compute the resulting 2-variable Poisson-de Rham-Poincare polynomial, and prove that it is equal to a specialization of an enrichment of the Tutte polynomial of a matroid that was introduced by Denham. We also compute this polynomial for S3-varieties of type A in terms of Kostka polynomials, modulo a previous conjecture of the first author, and we give a conjectural answer for nilpotent cones in arbitrary type, which we prove in rank less than or equal to 2.Comment: 25 page

Muscle injury and impaired function, and insulin resistance in Chromogranin A knockout mice

Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and found that performance of CgA-deficient Chga-KO mice in treadmill exercise was impaired. Supplementation with CgA in Chga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal muscle function. Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokines Tnfα, Il6 and Ifnɣ, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise in Chga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. Since CgA sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular aggregates that is observed in Chga-KO mice. In conclusion, CgA deficiency renders the muscle energy deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue damage

Causes, patterns and severity of androgen excess in 487 consecutively recruited pre- and post-pubertal children

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (&gt;20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.</p

Improving the normalization of complex interventions: measure development based on normalization process theory (NoMAD): study protocol

&lt;b&gt;Background&lt;/b&gt; Understanding implementation processes is key to ensuring that complex interventions in healthcare are taken up in practice and thus maximize intended benefits for service provision and (ultimately) care to patients. Normalization Process Theory (NPT) provides a framework for understanding how a new intervention becomes part of normal practice. This study aims to develop and validate simple generic tools derived from NPT, to be used to improve the implementation of complex healthcare interventions.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Objectives&lt;/b&gt; The objectives of this study are to: develop a set of NPT-based measures and formatively evaluate their use for identifying implementation problems and monitoring progress; conduct preliminary evaluation of these measures across a range of interventions and contexts, and identify factors that affect this process; explore the utility of these measures for predicting outcomes; and develop an online users’ manual for the measures.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; A combination of qualitative (workshops, item development, user feedback, cognitive interviews) and quantitative (survey) methods will be used to develop NPT measures, and test the utility of the measures in six healthcare intervention settings.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Discussion&lt;/b&gt; The measures developed in the study will be available for use by those involved in planning, implementing, and evaluating complex interventions in healthcare and have the potential to enhance the chances of their implementation, leading to sustained changes in working practices

Extensive Mammalian Ancestry of Pandemic (H1N1) 2009 Virus

We demonstrate that the novel pandemic influenza (H1N1) viruses have human virus–like receptor specificity and can no longer replicate in aquatic waterfowl, their historic natural reservoir. The biological properties of these viruses are consistent with those of their phylogenetic progenitors, indicating longstanding adaptation to mammals

Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production Leading to Improved Insulin Sensitivity

The activation of Kupffer cells (KCs) and monocyte (Mc)-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Diet-induced obese (DIO) mice treated with Chromogranin A (CgA) peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of pro-inflammatory genes, increased expression of anti-inflammatory genes in McMΦs, and inhibition of the infiltration of McMΦs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very pro-inflammatory in CST-KO-NCD mice and produced glucose intolerance, we tested the effects of FACS-sorted F4/80+Ly6C- cells (representing KCs) and F4/80-Ly6C+ cells (representing McMΦs) on hepatic glucose production (HGP). Both basal and glucagon-induced HGP was markedly increased in hepatocytes co-cultured with KCs and McMΦs from NCD-fed CST-KO mice, and the effect was abrogated upon pre-treatment of CST-KO-MΦs with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function

Myeloid Differentiation Primary Response Gene 88 Is Required for the Resolution of Otitis Media

Signaling defects in the Toll-like receptor (TLR) pathway, such as interleukin-1 receptor–associated kinase 4 deficiency, highlight the prominence of TLR signaling in the defense against bacterial disease. Because myeloid differentiation primary response gene 88 (MyD88) can transduce signals from almost all TLRs, we studied its role in otitis media (OM), the most common upper respiratory tract bacterial infectious disease in young children

Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production Leading to Improved Insulin Sensitivity

The activation of Kupffer cells (KCs) and monocyte (Mc)-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Diet-induced obese (DIO) mice treated with Chromogranin A (CgA) peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of pro-inflammatory genes, increased expression of anti-inflammatory genes in McMΦs, and inhibition of the infiltration of McMΦs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very pro-inflammatory in CST-KO-NCD mice and produced glucose intolerance, we tested the effects of FACS-sorted F4/80+Ly6C- cells (representing KCs) and F4/80-Ly6C+ cells (representing McMΦs) on hepatic glucose production (HGP). Both basal and glucagon-induced HGP was markedly increased in hepatocytes co-cultured with KCs and McMΦs from NCD-fed CST-KO mice, and the effect was abrogated upon pre-treatment of CST-KO-MΦs with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function