Thrombozytenhemmung und -aktivierung: Mechanismen und klinische Implikationen

Zusammenfassung : Die Empfindlichkeit der Aktivierung von Thrombozyten ist Teil des delikaten Gleichgewichts, welches Hämostase von Thrombose unterscheidet. Unter physiologischen Bedingungen wird es durch die Hemmung der Thrombozytenaktivität und Entfernung von Agonisten erhalten. Unter pathologischen prothrombotischen Bedingungen versucht der Mediziner, das Gleichgewicht mit Hilfe von Arzneimitteln wiederherzustellen. Die Resultate dieser Behandlungen verbessern sich stetig, aber dennoch sind ein besseres Verständnis der Mechanismen und die Suche nach alternativen Inhibitoren nach wie vor wichti

Transcriptional and epigenetic control of cell fate decisions in early embryos

Mammalian embryo development is characterized by regulative mechanisms of lineage segregation and cell specification. A combination of carefully orchestrated gene expression networks, signalling pathways and epigenetic marks define specific developmental stages that can now be resolved at the single-cell level. These new ways to depict developmental processes have the potential to provide answers to unresolved questions on how lineage allocation and cell fate decisions are made during embryogenesis. Over the past few years, a flurry of studies reporting detailed single-cell transcription profiles in early embryos has complemented observations acquired using live-cell imaging following gene editing techniques to manipulate specific genes. The adoption of this newly available toolkit is reshaping how researchers are designing experiments and how they view animal development. This review presents an overview of the current knowledge on lineage segregation and cell specification in mammals, and discusses some of the outstanding questions that current technological advances can help scientists address, like never before

Ruxolitinib in the treatment of polycythemia vera: patient selection and special considerations.

The discovery of JAK2 V617F mutation in the mid-2000s started to fill the gap between clinical presentation of polycythemia vera (PV), first described by Vaquez at the end of the 19th century, and spontaneous erythroid colony formation, reported by Prchal and Axelrad in the mid-1970s. The knowledge on this mutation brought an important insight to our understanding of PV pathogenesis and led to a revision of the World Health Organization diagnostic criteria in 2008. JAK-STAT is a major signaling pathway implicated in survival and proliferation of hematopoietic precursors. High prevalence of JAK2 V617F mutation among myeloproliferative neoplasms (>95% in PV and ~50% in primary myelofibrosis and essential thrombocythemia) together with its role in constitutively activating JAK-STAT made JAK2 a privileged therapeutic target. Ruxolitinib, a JAK 1 and 2 inhibitor, has already proven to be efficient in relieving symptoms in primary myelofibrosis and PV. In the latter, it also appears to improve microvascular involvement. However, evidence regarding its potential role in altering the natural course of PV and its use as an adjunct to current standard therapies is sparse. Therapeutic advances are needed in PV as phlebotomy, low-dose aspirin, cytoreductive agents, and interferon alpha are the only therapeutic tools available at the moment to influence outcome. Even though several questions are still unanswered, this review aims to serve as an overview article of the potential role of ruxolitinib in PV according to current literature and expert opinion. It should help hematologists to visualize the place of this tyrosine kinase inhibitor in the field of current practice and offer criteria for a careful patient selection

Protein C Replacement in Severe Meningococcemia: Rationale and Clinical Experience

Severe meningococcemia, which is associated with hemodynamic instability, purpura fulminans and disseminated intravascular coagulation, still has a high mortality rate, and patients who survive are often left invalids because of amputations and organ failure. Clinical studies have shown that levels of protein C are markedly decreased in patients with severe meningococcemia and that the extent of the decrease correlates with a negative clinical outcome. There is a growing body of data demonstrating that activated protein C, in addition to being an anticoagulant, is also a physiologically relevant modulator of the inflammatory response. The dual function of protein C may be relevant to the treatment of individuals with severe meningococcal sepsis. In the present review we give a basic overview of the protein C pathway and its anticoagulant activity, and we summarize experimental data showing that activated protein C replacement therapy clearly reduces the mortality rate for fulminant meningococcemi

Recombinant human factor VIIa prevents hysterectomy in severe postpartum hemorrhage: single center study

Objective: To evaluate the effectiveness of human recombinant activated factor VII (rhFVIIa, NovoSeven) in avoiding hysterectomy postpartum in the management of severe postpartum hemorrhage (PPH). Methods: We performed a prospective cohort study at our university tertiary care center. Patients with severe post partum hemorrhage (blood loss >2000 mL) and failed medical and uterus-preserving surgical management, were treated with intravenous bolus administration of rhVIIa. Main outcome measures were cessation of bleeding, postpartum hysterectomy and thromboembolic events. Results: In 20/22 patients included, PPH was caused primarily by uterine atony, including 7 (32%) with additional lower genital tract lesion; in two women, it was due to pathologic placentation (placenta increta, 9%). One case of amniotic fluid embolism and one woman with uterine inversion were included. Recombinant hFVIIa was successful in stopping the PPH and in preventing a hysterectomy in 20/22 women (91%). The remaining two patients with persistent bleeding despite rhFVIIa treatment, who underwent postpartum hysterectomy, had placenta increta. No thromboembolic event was noticed. Conclusions: This study describes the largest single center series of rhFVIIa treatment for fertility preservation in severe postpartum hemorrhage published to date. Our data suggest that administration of rhFVIIa is effective in avoiding postpartum hysterectomy after conservative medical and surgical measures have failed. Although randomized studies are lacking, rhFVIIa should be considered as a second-line therapeutic option of life-threatening postpartal bleeding, in particular if preservation of fertility is warranted and hysterectomy is to be avoide

Prediction of Post-Weaning Fibrinogen Status during Cardiopulmonary Bypass: An Observational Study in 110 Patients.

BACKGROUND: After cardiac surgery with cardiopulmonary bypass (CPB), acquired coagulopathy often leads to post-CPB bleeding. Though multifactorial in origin, this coagulopathy is often aggravated by deficient fibrinogen levels. OBJECTIVE: To assess whether laboratory and thrombelastometric testing on CPB can predict plasma fibrinogen immediately after CPB weaning. PATIENTS / METHODS: This prospective study in 110 patients undergoing major cardiovascular surgery at risk of post-CPB bleeding compares fibrinogen level (Clauss method) and function (fibrin-specific thrombelastometry) in order to study the predictability of their course early after termination of CPB. Linear regression analysis and receiver operating characteristics were used to determine correlations and predictive accuracy. RESULTS: Quantitative estimation of post-CPB Clauss fibrinogen from on-CPB fibrinogen was feasible with small bias (+0.19 g/l), but with poor precision and a percentage of error >30%. A clinically useful alternative approach was developed by using on-CPB A10 to predict a Clauss fibrinogen range of interest instead of a discrete level. An on-CPB A10 ≤10 mm identified patients with a post-CPB Clauss fibrinogen of ≤1.5 g/l with a sensitivity of 0.99 and a positive predictive value of 0.60; it also identified those without a post-CPB Clauss fibrinogen <2.0 g/l with a specificity of 0.83. CONCLUSIONS: When measured on CPB prior to weaning, a FIBTEM A10 ≤10 mm is an early alert for post-CPB fibrinogen levels below or within the substitution range (1.5-2.0 g/l) recommended in case of post-CPB coagulopathic bleeding. This helps to minimize the delay to data-based hemostatic management after weaning from CPB

Parkinson's disease plasma biomarkers: An automated literature analysis followed by experimental validation

Diagnosis of Parkinson's disease (PD) is currently assessed by the clinical evaluation of extrapyramidal signs. The identification of specific biomarkers would be advisable, however most studies stop at the discovery phase, with no biomarkers reaching clinical exploitation. To this purpose, we developed an automated literature analysis procedure to retrieve all the background knowledge available in public databases. The bioinformatic platform allowed us to analyze more than 51,000 scientific papers dealing with PD, containing information on 4121 proteins. Out of these, we could track back 35 PD-related proteins as present in at least two published 2-DE maps of human plasma. Then, 9 different proteins (haptoglobin, transthyretin, apolipoprotein A-1, serum amyloid P component, apolipoprotein E, complement factor H, fibrinogen γ, thrombin, complement C3) split into 32 spots were identified as a potential diagnostic pattern. Eventually, we compared the collected literature data to experimental gels from 90 subjects (45 PD patients, 45 non-neurodegenerative control subjects) to experimentally verify their potential as plasma biomarkers of PD

La recherche partenariale à l'UQAR : les formes en action : compte rendu de la journée d'étude organisée par le GRIDEQ et le CRDT-UQAR le 13 avril 2016

La recherche partenariale prend une place de plus en plus importante dans le paysage scientifique. Se présentant sous une grande variété d’appellations (recherche-action, recherche collaborative, participative, recherche-intervention, etc.) (Dumais, 2011), elle regroupe un ensemble de pratiques de recherche variées, mais fondées sur le grand principe de « coconstruction de sens » (Bussières et Fontan, 2011). Sous cette définition large, il s’agit plus précisément de recherches ou d’interventions effectuées dans le cadre universitaire avec un ou plusieurs partenaires (entreprises privées, administrations publiques, associations, syndicats, etc.). Ainsi, la recherche partenariale exige une mobilisation tant des chercheurs que des partenaires, qui combinent leurs savoirs respectifs, leurs méthodes et leurs ressources (Sutton, 2007). Les partenaires sont donc conjointement impliqués dans le processus de recherche, à des niveaux variables, de l’identification du problème et de l’objet d’étude à la réalisation du projet et la valorisation des connaissances, soit leur diffusion et leur transfert dans les milieux de pratique (Sutton, 2007). Les organismes subventionnaires reconnaissent désormais cette pratique, mais l’inscrivent surtout dans des programmes prévus à cet effet. Les administrateurs y voient un mode de financement possible d’activités pour des universités en mal de ressources. Mais qu’en pensent les chercheurs ? En particulier ceux qui l’expérimentent, comment la définissent-elles ? Y voient-ils des défis particuliers ? Telles sont les grandes questions qui ont motivé la tenue d’une journée d’étude à l’UQAR, organisée par le GRIDEQ et le pôle UQAR du CRDT le 13 avril 2016. Pour aller au-delà des expériences individuelles, il nous semblait important de réunir des chercheurs provenant d’horizons différents, pour réfléchir et amorcer une discussion collective qui, nous l’espérons, se poursuivra. Trois objectifs étaient visés : • Prendre connaissance des pratiques touchant la recherche collaborative ou partenariale menées à l’UQAR, pour mieux en saisir et distinguer les formes variées ; • Dégager les enjeux et défis associés à ces pratiques, tant sur les plans individuel que collectif ; • Cerner les conditions et les besoins particuliers – pouvant varier d’une discipline à l’autre - requis pour ce type de pratiques scientifiques. Une dizaine de chercheurs de l’UQAR ont répondu à l’invitation lancée par le GRIDEQ et le CRDT. Les professeurs-chercheurs proviennent d’horizons disciplinaires variés et de différents départements de l’UQAR : Bruno Jean et Nathalie Lewis (développement territorial), Emmanuel Guy (gestion), Emmanuelle Jean (sciences infirmières), Ariane Plourde (sciences de la mer) et Lucie Gélineau (psychosociologie et travail social). S’ajoutent deux intervenants pour lesquels la recherche partenariale représente une part centrale de leur pratique, Guillaume Werstink, professionnel au Décanat à la recherche, et David Bourdages, directeur du CIRADD, un centre collégial de transfert de technologie en pratiques sociales novatrices (CCTT-PSN) situé en Gaspésie et qui a un lien particulier de collaboration et partenariat avec l’UQAR. Le programme a été bâti sur un principe simple : donner la parole aux chercheurs

Ovine induced pluripotent stem cells are resistant to reprogramming after nuclear transfer

Induced pluripotent stem cells (iPSCs) share similar characteristics of indefinite in vitro growth with embryonic stem cells (ESCs) and may therefore serve as a useful tool for the targeted genetic modification of farm animals via nuclear transfer (NT). Derivation of stable ESC lines from farm animals has not been possible, therefore, it is important to determine whether iPSCs can be used as substitutes for ESCs in generating genetically modified cloned farm animals. We generated ovine iPSCs by conventional retroviral transduction using the four Yamanaka factors. These cells were basic fibroblast growth factor (bFGF)- and activin A-dependent, showed persistent expression of the transgenes, acquired chromosomal abnormalities, and failed to activate endogenous NANOG. Nonetheless, iPSCs could differentiate into the three somatic germ layers in vitro. Because cloning of farm animals is best achieved with diploid cells (G1/G0), we synchronized the iPSCs in G1 prior to NT. Despite the cell cycle synchronization, preimplantation development of iPSC-NT embryos was lower than with somatic cells (2% vs. 10% blastocysts, p<0.01). Furthermore, analysis of the blastocysts produced demonstrated persistent expression of the transgenes, aberrant expression of endogenous SOX2, and a failure to activate NANOG consistently. In contrast, gene expression in blastocysts produced with the parental fetal fibroblasts was similar to those generated by in vitro fertilization. Taken together, our data suggest that the persistent expression of the exogenous factors and the acquisition of chromosomal abnormalities are incompatible with normal development of NT embryos produced with iPSCs

Transverse momentum fluctuations and percolation of strings

The behaviour of the transverse momentum fluctuations with the centrality of the collision shown by the Relativistic Heavy Ion Collider data is naturally explained by the clustering of color sources. In this framework, elementary color sources --strings-- overlap forming clusters, so the number of effective sources is modified. These clusters decay into particles with mean transverse momentum that depends on the number of elementary sources that conform each cluster, and the area occupied by the cluster. The transverse momentum fluctuations in this approach correspond to the fluctuations of the transverse momentum of these clusters, and they behave essentially as the number of effective sources.Comment: 16 pages, RevTex, 4 postscript figures. Enhanced version. New figure