[Atherosclerosis, an inflammatory disease]. / L'athérosclérose, une maladie inflammatoire.

Chronic inflammation is recognized as a contributing factor to the development, progression and complications of atherosclerosis. The inflammatory nature of atherosclerosis has been proven by the presence of inflammatory cells, cytokines and chemokines at all stages of the disease. There is a widely accepted association between cardiovascular events and serum inflammatory markers, such as CRP, IL-6 and IL-1? produced via the inflammasome pathway. The involvement of inflammatory processes in atherosclerosis and progress in the therapeutic strategy are detailed in the article.

: L'inflammation chronique est reconnue comme un facteur contribuant au développement, à la progression et aux complications de l'athérosclérose. La nature inflammatoire de l'athérosclérose a été prouvée par la présence de cellules inflammatoires, de cytokines et chimiokines à tous les stades de celle-ci. Il existe une association largement acceptée entre les événements cardiovasculaires et les marqueurs inflammatoires sériques tels que la CRP, l'IL-6 et l'IL-1? produite via la voie de l'inflammasome. L'implication des processus inflammatoires dans l'athérosclérose et les progrès dans la stratégie thérapeutique sont détaillés dans l'article.

[Coagulopathies, thrombotic risk and anticoagulation in COVID-19]. / Coagulopathies, risque thrombotique et anticoagulation dans la COVID-19.

Clinical observations indicate that COVID-19 often provokes coagulopathies, which have been associated with high morbidity and mortality rates. These coagulopathies likely result from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection-elicited systemic inflammation and endothelial damage. Patients with severe COVID-19 are at high risk of venous and arterial thromboembolic diseases; they can also develop disseminated intravascular coagulation in the most advanced stages of the disease. Medical Organisations on Thrombosis and Hemostasis, among which the Belgian Society on Thrombosis and Haemostasis (BSTH), have formulated recommendations for the prophylaxis and treatment of COVID-19-related venous thromboembolism in ambulatory and hospitalised patients, as well as for the anticoagulation of COVID-19 patients in need of long-term anticoagulation for unrelated cause.These recommendations provide every hospital and primary care physicians with an easy-to-use clinical guidance; they mainly rely on limited level of evidence and are likely to evolve with knowledge of COVID-19 pathophysiology and availability of data from ongoing clinical trials.

Les observations cliniques indiquent qu'une grande proportion des patients atteints de la COVID-19 développent des coagulopathies plus ou moins sévères et associées à un taux élevé de morbidité et de mortalité. Ces troubles de la coagulation seraient liés à l'inflammation systémique et aux lésions endothéliales causées par l'infection par le SARS-CoV-2 («Severe Acute Respiratory Syndrome Coronavirus 2¼). Leur incidence augmente avec la sévérité de la COVID-19. Ils se traduisent par un risque accru de maladies thromboemboliques veineuses (MTEV) ou artérielles ou par le développement d'une coagulation intravasculaire disséminée (CIVD) aux stades cliniques les plus avancés. Les Organisations médicales de Thrombose et Hémostase, parmi lesquelles la Société Belge de Thrombose et Hémostase (BSTH), ont formulé des recommandations pour la prophylaxie et le traitement des MTEV associées à la COVID-19 chez le patient hospitalisé, ambulatoire, et le patient sous traitement anti-thrombotique au moment du développement de la maladie. Ces recommandations ont été rédigées afin de répondre à un besoin médical urgent, de manière adaptée aux soins de santé propres à chaque système local; elles reposent, essentiellement, sur un niveau de preuve limité et sont, dès lors, susceptibles d'évoluer avec une meilleure connaissance de la COVID-19 et la disponibilité des données des essais cliniques en cours.

[Lung lesions in severe COVID-19 : anatomoclinical confrontation]. / Lésions pulmonaires dans la COVID-19 sévère : confrontation anatomoclinique.

We report the fatal outcome of two patients infected by SARS-CoV-2 and exhibiting severe lung lesions at the thoracic imaging and autopsic examination. We also describe the biosecurity measures to adopt when performing autopsies during the Covid-19 pandemia.

Nous rapportons l'évolution fatale de deux patients infectés par le SARS-CoV-2 et porteurs de lésions pulmonaires sévères à l'imagerie thoracique et à l'examen autopsique. Nous décrivons également les mesures de biosécurité à adopter pour la réalisation des autopsies au cours de la pandémie de la Covid-19.

[Natriuretic peptides in heart failure]. / Peptides natriurétiques dans l'insuffisance cardiaque.

The diagnosis of heart failure can sometimes be challenging for the clinician because presentation circumstances and heart failure phenotypes are varied. The identification and validation of sensitive and specific biomarkers for this condition are still a subject of intensive research. Among them, natriuretic peptides (ANP, BNP, NTproBNP) are widely used and validated as markers of heart failure. Their appropriate use and correct interpretation, however, require knowledge of their indications, specificities and limitations. The European Society of Cardiology has recently issued recommendations in this regard. This article summarizes them in order to facilitate the understanding and the use of natriuretic peptides in clinical practice. It also discusses their use in the etiological diagnosis of pleural effusions caused by heart failure.

Le diagnostic d'insuffisance cardiaque peut parfois mettre en difficulté le clinicien tant les circonstances de présentation et les phénotypes de cette pathologie sont variés. L'identification et la validation de biomarqueurs sensibles et spécifiques à cette condition particulière font toujours l'objet d'une recherche intensive. Parmi eux, les peptides natriurétiques (ANP, BNP, NTproBNP) sont largement utilisés et validés comme marqueurs de l'insuffisance cardiaque. Leur usage approprié et leur interprétation correcte requièrent, toutefois, la connaissance de leurs indications, spécificités et limitations. La Société Européenne de Cardiologie a récemment publié des recommandations à cet égard. Cet article propose d'en résumer les lignes principales afin de faciliter l'utilisation des peptides natriurétiques en pratique clinique. Il aborde, aussi, leur utilisation dans le diagnostic étiologique des épanchements pleuraux.

[COVID-19 andcardiovascular diseases]. / COVID-19 et maladies cardiovasculaires.

COVID-2019 disease mainly affects the respiratory tract and can progress in severe cases to pneumonia, acute respiratory distress syndrome and multi-organ failure. Patients with prior cardiovascular disease are at higher risk of developing an infection and progressing to a severe form of the disease. Also, due to the growing number of infected cases, it is clear that, in addition to the typical respiratory symptoms caused by the infection, some patients suffer from cardiovascular damage. This condition can, in fact, cause significant myocardial damage, which worsens the disease and affects the prognosis. Based on the results of currently published research, it seems important to discuss the manifestations and characteristics of myocardial damage induced by COVID-19 and its impact on patient prognosis.

Le COVID-19 affecte principalement les voies respiratoires et peut évoluer, dans les cas graves, vers une pneumonie, un syndrome de détresse respiratoire aiguë et une défaillance multi-systémique. Les patients souffrant d'une atteinte cardiovasculaire préalable sont plus à risque de développer une infection et d'évoluer vers une forme grave de la maladie. Aussi, de par le nombre croissant de cas infectés, force est de constater, qu'en plus des symptômes respiratoires typiques causés par l'infection, certains patients souffrent d'atteintes cardiovasculaires. Cette affection peut, en effet, entraîner des dommages myocardiques importants, qui aggravent la maladie et affectent le pronostic. Sur base des résultats des recherches actuellement publiées, il nous semble important de discuter des manifestations et des caractéristiques des atteintes myocardiques induites par le COVID-19 et de son impact sur le pronostic.

[Why and how to treat iron deficiency in heart failure ?] / Pourquoi et comment traiter la carence martiale du patient insuffisant cardiaque ?

Anemia and iron deficiency are two common comorbidities in heart failure with reduced ejection fraction (HFrEF) and are associated with a poor prognosis. In contrast to iron oral supplementation, administration of intravenous ferric carboxymaltose (Injectafer®) improves quality of life, exercise capacity, and seems to reduce hospitalizations for heart failure. Unfortunately, although anaphylactic reactions are extremely rare, it is recommended to administer Injectafer® in a suitable medical environment. This limitation hinders Injectafer® administration and may cause reluctance from both physician and patient. The aim of this article is to optimize and harmonize management of iron deficiency in heart failure, by proposing a simple solution for the patient and the practitioner.

L'anémie et la carence martiale sont deux comorbidités fréquentes dans l'insuffisance cardiaque à fraction d'éjection réduite (HFrEF) et sont associées à un moins bon pronostic. Contrairement à la supplémentation martiale per os, l'administration de carboxymaltose ferrique intraveineux (Injectafer®) améliore la qualité de vie, la capacité à l'effort et semble réduire les hospitalisations pour insuffisance cardiaque. Bien que les réactions anaphylactiques soient extrêmement rares, il est recommandé d'administrer l'Injectafer® dans un environnement médical adapté. Ceci entraîne des contraintes d'administration qui peuvent susciter une réticence de la part du médecin et du patient. Cet article a pour objectif d'optimaliser et d'harmoniser la prise en charge de la carence martiale dans l'insuffisance cardiaque, en proposant une solution simple pour le patient et le soignant.

[Infective endocarditis:an emergency well too minimized]. / Une urgence bien souvent méconnue.

Infective endocarditis is a rare disease that can lead to some diagnostic wandering because of its often nonspecific and polymorphic clinical manifestations. This latency is at the origin of severe cardiac and extra-cardiac complications, yet highly fatal. The clinician should always bear in mind the differential diagnosis of a patient with fever of undetermined origin, with risk factors for valve infection such as foreign material, and history recent invasive procedures (including dental procedures) or recent hospitalization. The current medical tools make it possible to highlight the infection and its complications in a fast and complete manner, so as not to delay the patient's management, particularly with the introduction of urgent empirical antibiotherapy.

L'endocardite infectieuse est une maladie rare pouvant entraîner une certaine errance diagnostique au vu de ses manifestations cliniques souvent aspécifiques et polymorphes. Cette latence est à l'origine de complications cardiaques et extra-cardiaques potentiellement mortelles. Le clinicien doit toujours avoir à l'esprit ce diagnostic différentiel face à un patient avec une fièvre d'origine indéterminée, et qui présente des facteurs de risque d'infection valvulaire tels qu'un matériel étranger, des antécédents récents de gestes invasifs (entre autres dentaires) ou d'hospitalisation récente. Les outils médicaux actuels permettent de mettre en évidence l'infection et ses complications de façon rapide et complète, afin de ne pas retarder la prise en charge du patient avec, notamment, l'instauration urgente d'une antibiothérapie empirique.

Platelets contribute to the initiation of colitis-associated cancer by promoting immunosuppression.

Essentials Inflammation plays a key role in the development of colorectal cancer. Understanding mechanisms of cancer initiation might reveal new anticancer preventive strategy. Hyperactive platelets promote tumor formation by fostering immune evasion of cancer. Platelet inhibition by clopidogrel prevents carcinogenesis by restoring antitumor immunity. SUMMARY: Background Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, although the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors in inflammation; they have also been shown to be involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and platelet reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at the pretumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results At the pretumoral stage, hyperactive platelets constituted a major source of circulating protumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of the plasma SAA protein level, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells, as well as their infiltration into tumors, but increased the number of tissue CD8+ T cells. Platelets and releasates of platelets from mice with cancer were both able to polarize myeloid cells towards an immunosuppressive phenotype. Conclusions Thus, platelets promote the initiation of colitis-associated cancer by enhancing myeloid cell-dependent immunosuppression. Antiplatelet agents may help to prevent inflammation-elicited carcinogenesis by restoring antitumor immunity.

Targeting of C-type lectin-like receptor 2 or P2Y12 for the prevention of platelet activation by immunotherapeutic CpG oligodeoxynucleotides.

Essentials CpG oligodeoxynucleotide (ODN) immuotherapeutics cause undesired platelet activating effects. It is crucial to understand the mechanisms of these effects to identify protective strategies. CpG ODN-induced platelet activation depends on C-type lectin-like receptor 2 (CLEC-2) and P2Y12. Targeting CLEC-2 or P2Y12 fully prevents CpG ODN-induced platelet activation and thrombosis. SUMMARY: Background Synthetic phosphorothioate-modified CpG oligodeoxynucleotides (ODNs) show potent immunostimulatory properties that are widely exploited in clinical trials of anticancer treatment. Unexpectedly, a recent study indicated that CpG ODNs activate human platelets via the immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptor glycoprotein VI. Objective To further analyze the mechanisms of CpG ODN-induced platelet activation and identify potential inhibitory strategies. Methods In vitro analyses were performed on human and mouse platelets, and on cell lines expressing platelet ITAM receptors. CpG ODN platelet-activating effects were evaluated in a mouse model of thrombosis. Results We demonstrated platelet uptake of CpG ODNs, resulting in platelet activation and aggregation. C-type lectin-like receptor 2 (CLEC-2) expressed in DT40 cells bound CpG ODNs. CpG ODN uptake did not occur in CLEC-2-deficient mouse platelets. Inhibition of human CLEC-2 with a blocking antibody inhibited CpG ODN-induced platelet aggregation. CpG ODNs caused CLEC-2 dimerization, and provoked its internalization. They induced dense granule release before the onset of aggregation. Accordingly, pretreating platelets with apyrase, or inhibiting P2Y12 with cangrelor or clopidogrel, prevented CpG ODN platelet-activating effect. In vivo, intravenously injected CpG ODN interacted with platelets adhered to mouse injured endothelium, and promoted thrombus growth, which was inhibited by CLEC-2 deficiency or by clopidogrel. Conclusions CLEC-2 and P2Y12 are required for CpG ODN-induced platelet activation and thrombosis, and might be targeted to prevent adverse events in patients at risk.

[Cancer therapy-induced cardiotoxicity]. / La cardiotoxicité des traitements anti-cancéreux.

The incidence of cancer is raising and the treatments are increasingly aggressive. Consequently, physicians are regularly facing side effects of cytotoxic therapies. Cancer- therapy-induced cardiotoxicity is a serious complication because it can be fatal and causes a temporary or permanent cessation of the treatment. In this article, we summarize the mechanisms, the monitoring and the multidisciplinary management of patients with cancer-therapy induced cardiotoxicity.

Les cancers sont de plus en plus fréquents et leurs traitements de plus en plus agressifs. En conséquence, les médecins se trouvent régulièrement confrontés aux effets secondaires des traitements cytotoxiques. La cardiotoxicité induite par les traitements anti-cancéreux est une complication gravissime, car elle peut être mortelle et provoque un arrêt temporaire, voire définitif, des traitements. Dans cet article, nous décrivons les mécanismes, le dépistage et la prise en charge multidisciplinaire de la cardiotoxicité des agents anti-cancéreux.

[European society of cardiology guidelines for the management of infective endocarditis (partim 1)]. / Recommandations européennes sur la prise en charge de l'endocardite infectieuse (partim 1).

Until recently, the recommendations of infective endocarditis were based on expert opinions, due to its low incidence and the absence of controlled trials. The update in 2015 of the new guidelines of the European Society of Cardiology (compared with 2009) relates to the publication of a randomised study on the surgical treatment, the innovations in imaging procedures (especially functional imaging in nuclear medicine) and the new concept of «Team Endocarditis¼ (multidisciplinary approach). Their aim is to remind the limitations of antibiotic prophylaxis and to insist on hospital hygiene measures. Future challenges will be to obtain a better understanding of the mechanisms associated with the contamination of the valve and to optimize the adaptation of the current epidemiological prophylaxis. In this first part, we will describe the preventive and diagnostic approaches of infective endocarditis.

Jusqu'à ce jour, les recommandations concernant le traitement de l'endocardite infectieuse étaient essentiellement basées sur l'opinion d'experts, à cause de sa faible incidence et de l'absence d'essais contrôlés. La mise à jour, en 2015, des recommandations de la Société Européenne de Cardiologie de 2009, est justifiée par la publication d'une première étude randomisée sur le traitement chirurgical, par les innovations concernant les procédures d'imagerie (particulièrement l'imagerie fonctionnelle en médecine nucléaire) et par le nouveau concept d'«Endocarditis Team¼ (approche multidisciplinaire). Ces directives européennes ont le mérite de rappeler les limitations de l'antibioprophylaxie et d'insister sur les mesures préventives à prodiguer. Les défis futurs seront de mieux comprendre les mécanismes associés à la contamination de l'endocarde valvulaire et de mieux adapter la prophylaxie à l'évolution épidémiologique. Dans cette première partie, nous décrivons la prophylaxie et les moyens diagnostiques de l'endocardite infectieuse.

Left ventricular regional function and maximal exercise capacity in aortic stenosis.

AIMS: The objective assessment of maximal exercise capacity (MEC) using peak oxygen consumption (VO2) measurement may be helpful in the management of asymptomatic aortic stenosis (AS) patients. However, the relationship between left ventricular (LV) function and MEC has been relatively unexplored. We aimed to identify which echocardiographic parameters of LV systolic function can predict MEC in asymptomatic AS. METHODS AND RESULTS: Asymptomatic patients with moderate to severe AS (n = 44, aortic valve area <1.5 cm(2), 66 ± 13 years, 75% of men) and preserved LV ejection fraction (LVEF > 50%) were prospectively referred for resting echocardiography and cardiopulmonary exercise test. LV longitudinal strain (LS) of each myocardial segment was measured by speckle tracking echocardiography (STE) from the apical (aLS) 4-, 2-, and 3-chamber views. An average value of the LS of the analysable segments was provided for each myocardial region: basal (bLS), mid (mLS), and aLS. LV circumferential and radial strains were measured from short-axis views. Peak VO2 was 20.1 ± 5.8 mL/kg/min (median 20.7 mL/kg/min; range 7.2-32.3 mL/kg/min). According to the median of peak VO2, patients with reduced MEC were significantly older (P < 0.001) and more frequently females (P = 0.05). There were significant correlations between peak VO2 and age (r = -0.44), LV end-diastolic volume (r = 0.35), LV stroke volume (r = 0.37), indexed stroke volume (r = 0.32), and E/e' ratio (r = -0.37, all P < 0.04). Parameters of AS severity and LVEF did not correlate with peak VO2 (P = NS for all). Among LV deformation parameters, bLS and mLS were significantly associated with peakVO2 (r = 0.43, P = 0.005, and r = 0.32, P = 0.04, respectively). With multivariable analysis, female gender (ß = 4.9; P = 0.008) and bLS (ß = 0.50; P = 0.03) were the only independent determinants (r(2) = 0.423) of peak VO2. CONCLUSION: In asymptomatic AS, impaired LV myocardial longitudinal function determines reduced MEC. Basal LS was the only parameter of LV regional function independently associated with MEC.

The Ca(2+) /calmodulin-dependent kinase kinase ß-AMP-activated protein kinase-α1 pathway regulates phosphorylation of cytoskeletal targets in thrombin-stimulated human platelets.

BACKGROUND: Platelet activation requires sweeping morphologic changes, supported by contraction and remodeling of the platelet actin cytoskeleton. In various other cell types, AMP-activated protein kinase (AMPK) controls the phosphorylation state of cytoskeletal targets. OBJECTIVE: To determine whether AMPK is activated during platelet aggregation and contributes to the control of cytoskeletal targets. RESULTS: We found that AMPK-α1 was mainly activated by thrombin, and not by other platelet agonists, in purified human platelets. Thrombin activated AMPK-α1 ex vivo via a Ca(2+) /calmodulin-dependent kinase kinase ß (CaMKKß)-dependent pathway. Pharmacologic inhibition of CaMKKß blocked thrombin-induced platelet aggregation and counteracted thrombin-induced phosphorylation of several cytoskeletal proteins, namely, regulatory myosin light chains (MLCs), cofilin, and vasodilator-stimulated phosphoprotein (VASP), three key elements involved in actin cytoskeletal contraction and polymerization. Platelets isolated from mice lacking AMPK-α1 showed reduced aggregation in response to thrombin, and this was associated with defects in MLC, cofilin and VASP phosphorylation and actin polymerization. More importantly, we show, for the first time, that the AMPK pathway is activated in platelets of patients undergoing major cardiac surgery, in a heparin-sensitive manner. CONCLUSION: AMPK-α1 is activated by thrombin in human platelets. It controls the phosphorylation of key cytoskeletal targets and actin cytoskeletal remodeling during platelet aggregation.

ATP-gated P2X1 ion channels protect against endotoxemia by dampening neutrophil activation.

BACKGROUND: In sepsis, extracellular ATP, secreted by activated platelets and leukocytes, may contribute to the crosstalk between hemostasis and inflammation. Previously, we showed that, in addition to their role in platelet activation, ATP-gated P2X(1) ion channels are involved in promoting neutrophil chemotaxis. OBJECTIVES: To elucidate the contribution of P2X(1) ion channels to sepsis and the associated disturbance of hemostasis. METHODS: We used P2X(1) (-/-) mice in a model of lipopolysaccharide (LPS)-induced sepsis. Hemostasis and inflammation parameters were analyzed together with outcome. Mechanisms were further studied ex vivo with mouse and human blood or isolated neutrophils and monocytes. RESULTS: P2X(1) (-/-) mice were more susceptible to LPS-induced shock than wild-type mice, despite normal cytokine production. Plasma levels of thrombin-antithrombin complexes were higher, thrombocytopenia was worsened, and whole blood coagulation time was markedly reduced, pointing to aggravated hemostasis disturbance in the absence of P2X(1). However, whole blood platelet aggregation occurred normally, and P2X(1) (-/-) macrophages displayed normal levels of total tissue factor activity. We found that P2X(1) (-/-) neutrophils produced higher amounts of reactive oxygen species. Increased amounts of myeloperoxidase were released in the blood of LPS-treated P2X(1) (-/-) mice, and circulating neutrophils and monocytes expressed higher levels of CD11b. Neutrophil accumulation in the lungs was also significantly augmented, as was lipid peroxidation in the liver. Desensitization of P2X(1) ion channels led to increased activation of human neutrophils and enhanced formation of platelet-leukocyte aggregates. CONCLUSIONS: P2X(1) ion channels play a protective role in endotoxemia by negatively regulating systemic neutrophil activation, thereby limiting the oxidative response, coagulation, and organ damage.

The platelet ATP and ADP receptors.

Adenine nucleotides, ADP and ATP, are coreleased from dense granules during platelet activation, as well as from endothelial cells and damaged red blood cells following vascular injury. Through autocrine and paracrine mechanisms, these extracellular signaling molecules interact with the platelet P2 receptors to amplify ongoing platelet activation. Two receptors for ADP, the G(q)-protein-coupled P2Y1 and G(i)-protein-coupled P2Y12 and one receptor for ATP, the P2X1 ion channel, have been identified on platelets. Due to distinct pharmacological properties and differential regulation, the P2Y and P2X receptors essentially operate on different scales of time and distance and trigger selective intracellular signaling cascades. Recent advances in the understanding of the P2Y receptor physiology have reinforced the concept of these receptors as useful targets for antithrombotic therapy. The function of P2X1 in platelet activation only recently started to be unraveled. This review focuses on recent findings on the physiology of these platelet ADP and ATP receptors, their distinct downstream intracellular signaling pathways as well as on the available agonists, antagonists and inhibitors that allow their pharmacological discrimination.

ERK2 activation in arteriolar and venular murine thrombosis: platelet receptor GPIb vs. P2X.

The functional significance of extracellular signal-regulated kinase 2 (ERK2) activation was investigated during shear induced human platelet aggregation (SIPA) in vitro and during shear controlled thrombosis in vivo in intestinal arterioles and venules of wild type (WT) and transgenic (TG) mice with platelet-specific overexpression of human P2X(1) (TG). In SIPA, ERK2 was rapidly phosphorylated during GPIb stimulation, its activation contributing to SIPA for 50%, independently of P2X(1) regulation. Thrombotic occlusion of injured arterioles occurred considerably faster in TG (4.3 +/- 2.3 min) than in WT (38 +/- 8 min) arterioles, but occlusion times in TG (19 +/- 12) and WT (48 +/- 4.5 min) venules differed less. Both the alphabeta-meATP triggered desensitization of platelet P2X(1), as well as P2X(1) antagonism by NF279 or NF449 prolonged mean occlusion to about 75 min in WT and 65 min in TG arterioles, but venular occlusion times were less affected. Preventing ERK2 activation by U0126 prolonged occlusion times in TG (41 +/- 10 min) and WT (51 +/- 17) arterioles more than in TG (46 +/- 5 min) and WT (56 +/- 6 min) venules, uncovering a role for ERK2 in shear controlled thrombosis. Antagonism of GPIb by a recombinant murine von Willebrand factor (VWF)-A1 fragment prolonged occlusion times to comparable values, ranging from 55 to 58 min, both in TG and WT arterioles and venules. Further inhibition strategies, combining VWF-A1, U0126 and NF449 in WT and TG mice and resulting in occlusion in various time windows, identified that inhibition by VWF-A1 largely abrogated the ERK2 contribution to thrombosis. In conclusion, P2X(1) and ERK2 both participate in shear stress controlled thrombosis, but ERK2 activation is initiated predominantly via GPIb-VWF interactions.

Implementation of guidelines for seasonal allergic rhinitis: a randomized controlled trial.

BACKGROUND: Allergic rhinitis is a common disease altering quality of life. Its treatment is well established and guidelines have been proposed. However, their efficacy has never been tested. The aim of the study was to validate the guidelines of the International Consensus on Rhinitis in the treatment of seasonal allergic rhinitis. METHODS: A multicenter, multinational, open label, parallel, randomized study compared two therapeutic strategies in seasonal allergic rhinitis during a 3-week treatment. General practitioners were randomized into two groups. In the first group of 224 patients, doctors followed guidelines from the International Consensus on Rhinitis. Depending on the severity of nasal and ocular symptoms defined using visual analogue scales, patients received ebastine (an oral antihistamine), triamcinolone acetonide (a topical corticosteroid) and/or ophthalmic nedocromil sodium (a topical ocular cromone). In the second group of 241 patients, general practitioners had a free choice of treatment. The primary efficacy end points were quality of life measured using the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ) and the symptom-medication scores assessed daily with an electronic dairy system. RESULTS: Adjusted mean total symptom scores over 21 days were 4.93 in the guidelines strategy group compared with 7.48 in the free-choice treatment group (P = 0.0001). Mean total scores in the RQLQ decreased by 2.19 in the guidelines group compared with a decrease of 1.79 in the free-choice treatment group (P = 0.0001). At 21 days, the least square mean difference in improvement in overall scores for RQLQ in the guidelines group compared with the free-choice treatment group was 0.53, which was greater than the minimal important difference. CONCLUSIONS: Patients with seasonal allergic rhinitis often present severe symptoms which are not well recognized or controlled by physicians using their own criteria of severity and treatment. Using a simple method for the evaluation of the severity and a simple therapeutic scheme based on International Guidelines, patients with seasonal allergic rhinitis presented a significant improvement by comparison with those receiving a non-standardized treatment.