G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2
Andrew C. Pearce
Jennifer C. Spalton
Johannes Andreas Eble
Michael G. Tomlinson
Yotis A. Senis
Steve P. Watson
- Platelets play an essential role in wound healing by forming thrombi that plug holes in the walls of damaged blood vessels. To achieve this, platelets express a diverse array of cell surface receptors and signaling proteins that induce rapid platelet activation. In this study we show that two platelet glycoprotein receptors that signal via an immunoreceptor tyrosine-based activation motif (ITAM) or an ITAM-like domain, namely the collagen receptor complex glycoprotein VI (GPVI)-FcR γ-chain and the C-type lectin-like receptor 2 (CLEC-2), respectively, support constitutive (i.e. agonist-independent) signaling in a cell line model using a nuclear factor of activated T-cells (NFAT) transcriptional reporter assay that can detect low level activation of phospholipase Cγ (PLCγ). Constitutive and agonist signaling by both receptors is dependent on Src and Syk family kinases, and is inhibited by G6b-B, a platelet immunoglobulin receptor that has two immunoreceptor tyrosine-based inhibitory motifs in its cytosolic tail. Mutation of the conserved tyrosines in the two immunoreceptor tyrosine-based inhibitory motifs prevents the inhibitory action of G6b-B. Interestingly, the inhibitory activity of G6b-B is independent of the Src homology 2 (SH2)-domain containing tyrosine phosphatases, SHP1 and SHP2, and the inositol 5′-phosphatase, SHIP. Constitutive signaling via Src and Syk tyrosine kinases is observed in platelets and is associated with tyrosine phosphorylation of GPVI-FcR γ-chain and CLEC-2. We speculate that inhibition of constitutive signaling through Src and Syk tyrosine kinases by G6b-B may help to prevent unwanted platelet activation.
Editorial: Experimental models of asthma
Jan David Alexander Groneberg
- Since 2002, a workshop entitled “Asthma in animal models” has been held once a year in Hannover, Germany. It is organized by the Fraunhofer Institute of Toxicology and Experimental Medicine in collaboration with the collaborative research centre “Sonderforschungsbereich” 587, “Immune reactions of the lung in infection and allergy” (Hannover Medical School). The aim of these meetings is an intense scientific exchange between researchers and clinicians coming from academic or industrial background. Over the years the topics within the extensive field of asthma and COPD have ranged from methodological aspects to the influence of infections and environmental factors up to perspectives in the development of new therapeutic strategies.
Effect of montelukast on platelet activating factor- and tachykinin induced mucus secretion in the rat
Jan David Alexander Groneberg
- Background: Platelet activating factor and tachykinins (substance P, neurokinin A, neurokinin B) are important mediators contributing to increased airway secretion in the context of different types of respiratory diseases including acute and chronic asthma. Leukotriene receptor antagonists are recommended as add-on therapy for this disease. The cys-leukotriene-1 receptor antagonist montelukast has been used in clinical asthma therapy during the last years. Besides its inhibitory action on bronchoconstriction, only little is known about its effects on airway secretions. Therefore, the aim of this study was to evaluate the effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity.
Methods: The effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity in the rat were assessed by quantification of secreted 35SO4 labelled mucus macromolecules using the modified Ussing chamber technique.
Results: Platelet activating factor potently stimulated airway secretion, which was completely inhibited by the platelet activating factor receptor antagonist WEB 2086 and montelukast. In contrast, montelukast had no effect on tachykinin induced tracheal secretory activity.
Conclusion: Cys-leukotriene-1 receptor antagonism by montelukast reverses the secretagogue properties of platelet activating factor to the same degree as the specific platelet activating factor antagonist WEB 2086 but has no influence on treacheal secretion elicited by tachykinins. These results suggest a role of montelukast in the signal transduction pathway of platelet activating factor induced secretory activity of the airways and may further explain the beneficial properties of cys-leukotriene-1 receptor antagonists.
Development and evaluation of a computer-based medical work assessment programme
Torsten T. Bauer
Burghard F. Klapp
Jan David Alexander Groneberg
- Background: There are several ways to conduct a job task analysis in medical work environments including pencil-paper observations, interviews and questionnaires. However these methods implicate bias problems such as high inter-individual deviations and risks of misjudgement. Computer-based observation helps to reduce these problems. The aim of this paper is to give an overview of the development process of a computer-based job task analysis instrument for real-time observations to quantify the job tasks performed by physicians working in different medical settings. In addition reliability and validity data of this instrument will be demonstrated.
Methods: This instrument was developed in consequential steps. First, lists comprising tasks performed by physicians in different care settings were classified. Afterwards content validity of task lists was proved. After establishing the final task categories, computer software was programmed and implemented in a mobile personal computer. At least inter-observer reliability was evaluated. Two trained observers recorded simultaneously tasks of the same physician.
Results: Content validity of the task lists was confirmed by observations and experienced specialists of each medical area. Development process of the job task analysis instrument was completed successfully. Simultaneous records showed adequate interrater reliability.
Conclusion: Initial results of this analysis supported the validity and reliability of this developed method for assessing physicians' working routines as well as organizational context factors. Based on results using this method, possible improvements for health professionals' work organisation can be identified.
kurz und kn@pp news : Nr. 11
- * Preis für exzellente Lehre
* Verordnungssicherheit bei niereninsuffizienten Patienten
* Prof. Gerlach im Gesundheits-forschungsrat des BMBF
* Gesundheit im Alter
* DEGAM gegen IGeLn
* Expertentreffen chronische Herzinsuffizienz
kurz und kn@pp news : Nr. 12
- * 1. Tag der Allgemeinmedizin in Frankfurt
* Dosisanpassung bei Patienten mit chronischer Niereninsuffizienz
* KoMed: Kommunikation im Medizinstudium
* Prof. Dr. med. Jochen Gensichen an die Universität Jena berufen
* Prof. Gerlach zum geschäftsführenden Direktor ZGW gewählt
* Studie zur Sicherheitskultur:noch Praxen gesucht
kurz und kn@pp news : Nr. 13
- * Professionalisierung der Allgemeinmedizin
* 42. Kongress der Deutschen Gesellschaft für Allgemeinmedizin und Familienmedizin (DEGAM)
* Online-Eintragung für Studierende jetzt möglich
* Opernkarten für Teilnehmer der PRoMPT-Studie
* MultiCare: Multimorbiditätsmuster in der hausärztlichen Versorgung
* Berliner Gesundheitspreis 2008: Gesagt ist nicht getan
kurz und kn@pp news : Nr. 14
- * Lothar Beyer-Preis für Frankfurt
* Gut angekommen: 1. Frankfurter Tag der Allgemeinmedizin
* Mitarbeiter/innen gesucht
* EbM Frankfurt erhält Preis für junge Lehrende 2008
* Frankfurter Wissenschaftlerin goes Oxford
* EGPRN – Europäisches Netzwerk allgemeinmedizinischer Forschung
kurz und kn@pp news : Nr. 11 [engl. Fassung]
- * Prize for excellent teaching
* Drug prescription safety and renal failure
* Prof. Gerlach on the Health Research Council of the German Ministry for Education and Research
* Health in Old Age
* DEGAM against IGeLn
* A Meeting of Experts on Chronic Heart Failure
kurz und kn@pp news : Nr. 13 [engl. Fassung]
- * The Professionalization of General Practice
* 42nd Congress of the DEGAM German Society of General Practice and Family Medicine
* Online Registration for students now possible
* Opera tickets for participants in the PRoMPT study
* MultiCare: Multimorbidity patterns in General Practice
* Berlin Health Prize 2008: Words are not enough