Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Managing the Transition to a Sustainable Enterprise

In combining practice and theory, this textbook provides a management perspective on the ‘business case’ for sustainability. Drawing on examples from 20 frontrunner companies located in the Netherlands, it builds upon a unique research project in which CEOs and middle-managers gave access not only to their decision-making process, but also revealed how their perceptions shaped the transition process.This book identifies four different archetypes of business cases and related business models that business students and managers can use to identify phases and related attitudes towards sustainability. The book provides in-depth analysis and insight into:• theoretical concepts and an overview of the relevant literature• the different business cases for sustainability• behavioural characteristics of each phase and the typical barriers between them• more than 70 tipping points• approaches to shaping stakeholder dialogue• effective engagement of stakeholders in each phase of transition• how companies move through the phases towards higher levels of sustainability• insights of employees of the 20 companies whether the business case was really achieved• summary of the interventions which have proved successful in these companies.This book offers students as well as managers of vocational and academic institutions at undergraduate and postgraduate level insight into real-life transition processes towards sustainability

Duurzaam ondernemen waarmaken

Op 28 september 2012 presenteerde Stichting Management Studies tijdens een druk bezocht middagsymposium in Amersfoort het nieuwe boek “Duurzaam ondernemen waarmaken, het bedrijfskundig perspectief”. Het boek is gebaseerd op een onderzoek dat Royal HaskoningDHV (Ir. Rob van Tilburg van DHV, drs. Mara Francken) en de Erasmus Universiteit Rotterdam (prof.dr. Rob van Tulder van RSM/EUR en Andrea da Rosa MSc ) uitvoerden naar de implementatie van duurzaam ondernemen bij 20 vooraanstaande Nederlandse bedrijven. In het boek en op het symposium wordt een uniek fasen model gepresenteerd dat bedrijven in staat stelt implementatieroutes naar duurzaam ondernemen te ontwikkelen. Duurzaam ondernemen biedt grote kansen. En het wordt steeds meer een randvoorwaarde voor overleven. Grote uitdagingen als grondstoffen schaarste, minder biodiversiteit, armoede en vergrijzing hebben steeds meer invloed op het succes en de continuïteit van ondernemingen. Zij moeten duurzaamheid daarom daadwerkelijk inbedden in hun organisatie. Duurzaam ondernemen waarmaken analyseert en illustreert hoe twintig vooraanstaande Nederlandse bedrijven omgaan met deze strategische uitdaging. Het schetst de verschillende fasen van duurzaam ondernemen die ze hebben doorlopen. Soms gestaag en planmatig, soms snel en schoksgewijs. Soms alleen, steeds meer in samenspraak met stakeholders. Daarmee biedt het vanuit bedrijfskundig perspectief inzicht in welke interventies blijken te werken om duurzaamheid meer waard te laten zijn voor de organisatie. De auteurs identificeren kantelpunten en bieden inzichten en handvatten die elke onderneming helpen om duurzaam ondernemen waar te maken

Admixture as a source for HLA variation in Neolithic European farming communities

Abstract Background The northern European Neolithic is characterized by two major demographic events: immigration of early farmers from Anatolia at 7500 years before present, and their admixture with local western hunter-gatherers forming late farmers, from around 6200 years before present. The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is understudied. Results We analyzed genome-wide data of 125 individuals from seven archeological early farmer and late farmer sites located in present-day Germany. The late farmer group studied here is associated with the Wartberg culture, from around 5500–4800 years before present. We note that late farmers resulted from sex-biased admixture from male western hunter-gatherers. In addition, we observe Y-chromosome haplogroup I as the dominant lineage in late farmers, with site-specific sub-lineages. We analyze true HLA genotypes from 135 Neolithic individuals, the majority of which were produced in this study. We observe significant shifts in HLA allele frequencies from early farmers to late farmers, likely due to admixture with western hunter-gatherers. Especially for the haplotype DQB1*04:01-DRB1*08:01, there is evidence for a western hunter-gatherer origin. The HLA diversity increased from early farmers to late farmers. However, it is considerably lower than in modern populations. Conclusions Both early farmers and late farmers exhibit a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time