Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

Objectives: The goal of the current study is to determine whether the ß-adrenoreceptor (ß-AR) plays a role in the anti-obesity and anti-diabetic effects of zinc-a2-glycoprotein (ZAG). Material and methods: This has been investigated in CHO-K1 cells transfected with the human ß1-, ß2-, ß3-AR and in ob/ob mice. Cyclic AMP assays were carried out along with binding studies. Ob/ob mice were treated with ZAG and glucose transportation and insulin were examined in the presence or absence of propranolol. Results: ZAG bound to the ß3-AR with higher affinity (Kd 46±1nM) than the ß2-AR (Kd 71±3nM) while there was no binding to the ß1-AR, and this correlated with the increases in cyclic AMP in CHO-K1 cells transfected with the various ß-AR and treated with ZAG. Treatment of ob/ob mice with ZAG increased protein expression of ß3-AR in gastrocnemius muscle, and in white and brown adipose tissues, but had no effect on expression of ß1- and ß2-AR. A reduction of body weight was seen and urinary glucose excretion, increase in body temperature, reduction in maximal plasma glucose and insulin levels in the oral glucose tolerance test, and stimulation of glucose transport into skeletal muscle and adipose tissue, were completely attenuated by the non-specific ß-AR antagonist propranolol. Conclusion: The results suggest that the effects of ZAG on body weight and insulin sensitivity in ob/ob mice are manifested through a ß-3AR, or possibly a ß2-AR.

Role of β-adrenergic receptors in the oral activity of zinc-α2-glycoprotein (ZAG)

Zinc-a2-glycoprotein (ZAG) is an adipokine with the potential as a therapeutic agent in the treatment of obesity and type 2 diabetes. In this study we show that human ZAG, which is a 41-kDa protein, when administered to ob/ob mice at 50 µg/d-1 orally in the drinking water produced a progressive loss of body weight (5 g after 8 d treatment), together with a 0.5 C increase in rectal temperature and a 40% reduction in urinary excretion of glucose. There was also a 33% reduction in the area under the curve during an oral glucose tolerance test and an increased sensitivity to insulin. These results were similar to those after iv administration of ZAG. However, tryptic digestion was shown to inactivate ZAG. There was no evidence of human ZAG in the serum but a 2-fold elevation of murine ZAG, which was also observed in target tissues such as white adipose tissue. To determine whether the effect was due to interaction of the human ZAG with the ß-adrenergic (ß-AR) in the gastrointestinal tract before digestion, ZAG was coadministered to ob/ob mice together with propanolol (40 mg/kg-1), a nonspecific ß-AR antagonist. The effect of ZAG on body weight, rectal temperature, urinary glucose excretion, improvement in glucose disposal, and increased insulin sensitivity were attenuated by propanolol, as was the increase in murine ZAG in the serum. These results suggest that oral administration of ZAG increases serum levels through interaction with a ß-AR in the upper gastrointestinal tract, and gene expression studies showed this to be in the esophagus.

Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

Aims - Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3 and 9 of GSK-3 respectively, required for inactivation by upstream kinases. Methods and results - Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts. Conclusion - Expression of inactivation-resistant GSK-3/does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3/, may enable a sustained cardiac response to chronic-agonist stimulation while preventing pathological remodelling. © 2010 The Author.

Evacuation responsiveness by government organisations (ERGO):the evacuation preparedness assessment workbook

This Evacuation Preparedness Assessment Workbook (EPAW) is a tool to assess the level of preparedness of Government Organisations (GOs) for the mass evacuation of their public. It has its origins in the results of a three-year, EU-funded research project called Evacuation Preparedness by Government Organisations (ERGO) which sought to research and strengthen the preparedness activities for the evacuation of cities, regions or even countries. This EPAW presents a list of tasks to be carried out at the different phases of evacuation preparedness. It also provides an assessment facility to evaluate how much progress GOs have made against each task, as well as indications of standard and best practices for each task. A brief background to the need for evacuation, the ERGO project and the development of the workbook is given next. After this, the application process of the workbook is explained and illustrated with an example.

Acute and long-term effects of peroxisome proliferator-activated receptor-γ activation on the function and insulin secretory responsiveness of clonal beta-cells

Thiazolidinediones (TZDs) are used as antidiabetic therapy. The purpose of the present study was to examine whether the TZD rosiglitazone has direct actions on pancreatic beta-cells that contribute to its overall effects. Effects of acute and prolonged (48 h) exposure to rosiglitazone, as a model glitazone compound, were assessed in clonal pancreatic BRIN-BD11 beta-cells maintained in standard, glucotoxic and lipotoxic cultures. In acute 20-min incubations, rosiglitazone (0.2-100 M) did not alter basal or glucose-stimulated insulin secretion. However, rosiglitazone (6.25 M) enhanced (p

Growth, uniformity, local responsiveness, and system-wide adaptation in multiunit franchising

Using the resource-based view framework, we investigate the link between multiunit franchising (MUF) and performance on four key challenges in franchise chain management: growth, uniformity, local responsiveness, and system-wide adaptation. Our findings support the assertion that system growth is positively related to MUF rate within a system, in particular in relation to geographic expansion. Interestingly, while uniformity does not seem to be related to MUF rate, we find marginal support for an inverted u-shaped relationship between system-wide adaptation and MUF rate. Furthermore, the data suggest that local responsiveness and MUF rate are related in a u-shaped function.

A hazai vállalatok elektronikus beszerzés iránti nyitottsága = E-procurement Responsiveness of the Hungarian Companies’

A Versenyképesség Kutató Központ 2004-ben a „Versenyben a világgal 1995-97.” kutatási program és az 1999-es vállalati versenyképességi kérdőíves felmérés hagyományait folytatva, valamint azok tapasztalataira építve egy hároméves kutatási programot kezdett el „Versenyben a világgal 2004-2006 − Gazdasági versenyképességünk vállalati nézőpontból” címmel. A kérdőíves felmérés nyomán létrejött adatbázist elemeztük hasonló témában 2005-ben. A korábbi eredményeken okulva, a kérdőív-elemzés kiterjesztésével azt kívántuk felmérni, hogy az elektronikus beszerzés iránti nyitottság növekedett-e hazánkban, illetve milyen egyéb összefüggések fedezhetők fel a beszerzési szervezet, a beszerzés vállalati kapcsolatai, valamint az elektronikus beszerzés értelmezésében az egyes válaszadóknál. A kutatás továbbra is eltér a hagyományos megoldásoktól, azaz nem kívánja vizsgálni a hazai vállalati honlapok elterjedtségét, azonban a korábbiaktól eltérően több információ-technológiával kapcsolatos információt kíván a válaszadóktól. A cél, tehát belső vállalati folyamatok, vevő-szállító kapcsolatok, az informatikai háttér elektronikus beszerzéssel való kapcsolatának feltárása és következtetéseink levonása volt annak érdekében, hogy megtudjuk milyen hatékonyságnövelési lehetőséget hordoz az elektronikus beszerzés és a hazai információs társadalmi fejlettség figyelembe vételével mennyire nyitottak erre a beszerzők és a pályázók egyaránt. Az elektronikus beszerzés és versenyképesség kapcsolata különösen a 2000-es éves eleje óta foglalkoztatja a kutatókat. Vita az elektronikus beszerzés beszerzési költségre gyakorolt hatásában, valamint a kormányzati politika által gyakorolt hatás jellegében van, melyet a közbeszerzés mint speciálisan szabályozott beszerzési tevékenység és az e-beszerzés kapcsolatára fejt ki. A vállalatok versenyképességének és az elektronikus beszerzés folyamatosan bővülő és fejlődő eszközrendszerének kapcsolata azonban nem kérdéses, ezt kutatási eredményeink is megerősítik. _________ The Competitiveness Research Center based on the experience of the „ In Global Competition 1995-1997” research programme and continuing the company competitiveness survey (1999) has begun a three-year research programme with the following title: „In Global Competition 2004-2006” Our economic competitiveness, company point of view”. We had analyzed a database generated on the basis of a questionnaire survey with a similar theme in 2005. Drawing the lessons from earlier researches and expanding the questionnaire examination, we now seek to find out how far receptiveness to electronic procurement has increased in Hungary and what other relations can be observed in responses concerning the interpretation of procurement organizations, the corporate aspects of procurement and electronic procurement. The new research project continues to differ from traditional solutions insofar as it does not intend to examine the currency of corporate web pages, but, in contrast to earlier practice, it does want responders to provide information on IT technology. The objectives are thus to understand how electronic procurement relates to corporate processes, purchaser-supplier relations and IT base, and to see what opportunities of increasing efficiency there are in electronic procurement and how far procurers and bidders are open to this at the level of information society development in Hungary. Researchers have focused on the relation between electronic procurement and competitiveness since the early 2000s. What is debated is how electronic procurement influences procurement costs, and how government policies influence the relation between public procurement as a specially regulated procurement activity and electronic procurement. The relation between corporate competitiveness and the continually increasing means of electronic procurement is beyond doubt, evidenced by our research findings.

Parent emotional functioning, parent responsiveness, and child adjustment

Over the past two decades, interest in the psychological development of children has steadily increased (Beg, Casey, & Saunders, 2007), presumably because statistics describing childhood psychological illness are alarming. Certain parent interaction styles or behaviors are known to influence child adjustment. According to attachment theory, the reason for these findings is that interaction with a caregiver informs an individual’s construction of an internal working model (IWM) of the self in relation to others in the environment. The purpose of this study was to gain a greater understanding of the factors contributing to child adjustment by examining the influence of parents’ emotional functioning and parent responsiveness to children’s bids for interaction. This dissertation tested a multivariate model of attachment-related processes and outcomes with an ethnically diverse sample. Results partially supported the model, in that parent emotional intelligence predicted some aspects of child adjustment. Overall, the study adds to knowledge about how parent characteristics influence child adjustment and provides support for conceptualizing emotional intelligence as a concrete and observable manifestation of the nonconscious attachment IWM.

Responsiveness of voltage-gated calcium channels in SH-SY5Y human neuroblastoma cells on quasi-three-dimensional micropatterns formed with poly (l-lactic acid)

Introduction: In this study, quasi-three-dimensional (3D) microwell patterns were fabricated with poly (l-lactic acid) for the development of cell-based assays, targeting voltage-gated calcium channels (VGCCs). Methods and materials: SH-SY5Y human neuroblastoma cells were interfaced with the microwell patterns and found to grow as two dimensional (2D), 3D, and near two dimensional (N2D), categorized on the basis of the cells’ location in the pattern. The capability of the microwell patterns to support 3D cell growth was evaluated in terms of the percentage of the cells in each growth category. Cell spreading was analyzed in terms of projection areas under light microscopy. SH-SY5Y cells’ VGCC responsiveness was evaluated with confocal microscopy and a calcium fluorescent indicator, Calcium GreenTM-1. The expression of L-type calcium channels was evaluated using immunofluorescence staining with DM-BODIPY. Results: It was found that cells within the microwells, either N2D or 3D, showed more rounded shapes and less projection areas than 2D cells on flat poly (l-lactic acid) substrates. Also, cells in microwells showed a significantly lower VGCC responsiveness than cells on flat substrates, in terms of both response magnitudes and percentages of responsive cells, upon depolarization with 50 mM K+. This lower VGCC responsiveness could not be explained by the difference in L-type calcium channel expression. For the two patterns addressed in this study, N2D cells consistently exhibited an intermediate value of either projection areas or VGCC responsiveness between those for 2D and 3D cells, suggesting a correlative relation between cell morphology and VGCC responsiveness. Conclusion: These results suggest that the pattern structure and therefore the cell growth characteristics were critical factors in determining cell VGCC responsiveness and thus provide an approach for engineering cell functionality in cell-based assay systems and tissue engineering scaffolds.

Responsiveness and clinical utility of the geriatric self-efficacy index for urinary incontinence

OBJECTIVES: To report on the responsiveness testing and clinical utility of the 12-item Geriatric Self-Efficacy Index for Urinary Incontinence (GSE-UI). DESIGN: Prospective cohort study. SETTING: Six urinary incontinence (UI) outpatient clinics in Quebec, Canada. PARTICIPANTS: Community-dwelling incontinent adults aged 65 and older. MEASUREMENTS: The abridged 12-item GSE-UI, measuring older adults' level of confidence for preventing urine loss, was administered to all new consecutive incontinent patients 1 week before their initial clinic visit, at baseline, and 3 months posttreatment. At follow-up, a positive rating of improvement in UI was ascertained from patients and their physicians using the Patient's and Clinician's Global Impression of Improvement scales, respectively. Responsiveness of the GSE-UI was calculated using Guyatt's change index. Its clinical utility was determined using receiver operating curves. RESULTS: Eighty-nine of 228 eligible patients (39.0%) participated (mean age 72.6+5.8, range 65–90). At 3-month follow-up, 22.5% of patients were very much better, and 41.6% were a little or much better. Guyatt's change index was 2.6 for patients who changed by a clinically meaningful amount and 1.5 for patients having experienced any level of improvement. An improvement of 14 points on the 12-item GSE-UI had a sensitivity of 75.1% and a specificity of 78.2% for detecting clinically meaningful changes in UI status. Mean GSE-UI scores varied according to improvement status (P<.001) and correlated with changes in quality-of-life scores (r=0.7, P<.001) and reductions in UI episodes (r=0.4, P=.004). CONCLUSION: The GSE-UI is responsive and clinically useful.

Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes.

The goal of this study was to determine whether beta(1)-adrenergic receptor (AR) and beta(2)-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac beta(2)-AR can activate both G(s) and G(i) proteins, whereas cardiac beta(1)-AR couples only to G(s). To avoid complicated crosstalk between beta-AR subtypes, we expressed beta(1)-AR or beta(2)-AR individually in adult beta(1)/beta(2)-AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of beta(1)-AR, but not beta(2)-AR, markedly induced myocyte apoptosis, as indicated by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling or Hoechst staining positive cells and DNA fragmentation. In contrast, beta(2)-AR (but not beta(1)-AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G(i), G(beta gamma), or phosphoinositide 3 kinase (PI3K) with pertussis toxin, beta ARK-ct (a peptide inhibitor of G(beta gamma)), or LY294002, respectively. This indicates that beta(2)-AR activates Akt via a G(i)-G(beta gamma)-PI3K pathway. More importantly, inhibition of the G(i)-G(beta gamma)-PI3K-Akt pathway converts beta(2)-AR signaling from survival to apoptotic. Thus, stimulation of a single class of receptors, beta(2)-ARs, elicits concurrent apoptotic and survival signals in cardiac myocytes. The survival effect appears to predominate and is mediated by the G(i)-G(beta gamma)-PI3K-Akt signaling pathway.

Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial infarction.

When the heart fails, there is often a constellation of biochemical alterations of the beta-adrenergic receptor (betaAR) signaling system, leading to the loss of cardiac inotropic reserve. betaAR down-regulation and functional uncoupling are mediated through enhanced activity of the betaAR kinase (betaARK1), the expression of which is increased in ischemic and failing myocardium. These changes are widely viewed as representing an adaptive mechanism, which protects the heart against chronic activation. In this study, we demonstrate, using in vivo intracoronary adenoviral-mediated gene delivery of a peptide inhibitor of betaARK1 (betaARKct), that the desensitization and down-regulation of betaARs seen in the failing heart may actually be maladaptive. In a rabbit model of heart failure induced by myocardial infarction, which recapitulates the biochemical betaAR abnormalities seen in human heart failure, delivery of the betaARKct transgene at the time of myocardial infarction prevents the rise in betaARK1 activity and expression and thereby maintains betaAR density and signaling at normal levels. Rather than leading to deleterious effects, cardiac function is improved, and the development of heart failure is delayed. These results appear to challenge the notion that dampening of betaAR signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of betaARK1 and preservation of myocardial betaAR function.