Peut-on évaluer te risque hémorragique tors d'anticoagutation orale [Oral anticoagulation and the risk of major bleeding]

Oral anticoagulants are frequently used in clinical practice. The most important complication of oral anticoagulation is major bleeding. The incidence of major bleeding is about 2-3%/year in randomized controlled trials but may be considerably higher under real life conditions. Major bleeding risk in patients receiving oral anticoagulants depends on factors related to anticoagulation itself (intensity and quality), patient-related factors (demographic characteristics and comorbid diseases), and concomitant treatments with antiplatelet or non-steroidal anti-inflammatory drugs. The role of clinical prediction rules for major bleeding is discussed.

NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?

The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that activates caspase 1, leading to the processing and secretion of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and IL-18. The NLRP3 inflammasome is activated by a wide range of danger signals that derive not only from microorganisms but also from metabolic dysregulation. It is unclear how these highly varied stress signals can be detected by a single inflammasome. In this Opinion article, we review the different signalling pathways that have been proposed to engage the NLRP3 inflammasome and suggest a model in which one of the crucial elements for NLRP3 activation is the generation of reactive oxygen species (ROS).

Suppression of tumor angiogenesis through the inhibition of integrin function and signaling in endothelial cells: which side to target?

Tumor angiogenesis is an essential step in tumor progression and metastasis formation. Suppression of tumor angiogenesis results in the inhibition of tumor growth. Recent evidence indicates that vascular integrins, in particular alpha V beta 3, are important regulators of angiogenesis, including tumor angiogenesis. Integrin alpha V beta 3 antagonists, such as blocking antibodies or peptides, suppress tumor angiogenesis and tumor progression in many preclinical tumor models. The potential therapeutic efficacy of extracellular integrin antagonists in human cancer is currently being tested in clinical trials. Selective disruption of the tumor vasculature by high doses of tumor necrosis factor (TNF) and interferon gamma (IFN-gamma), and the antiangiogenic activity of nonsteroidal anti-inflammatory drugs are associated with the suppression of integrin alpha V beta 3 function and signaling in endothelial cells. Furthermore, expression of isolated integrin cytoplasmic domains disrupts integrin-dependent adhesion, resulting in endothelial cell detachment and apoptosis. These results confirm the critical role of vascular integrins in promoting endothelial cell survival and angiogenesis and suggest that intracellular targeting of integrin function and signaling may be an alternative strategy to extracellular integrin antagonists for the therapeutic inhibition of tumor angiogenesis.

Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation.

Omega-3 fatty acids (ω-3 FAs) have potential anti-inflammatory activity in a variety of inflammatory human diseases, but the mechanisms remain poorly understood. Here we show that stimulation of macrophages with ω-3 FAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and other family members, abolished NLRP3 inflammasome activation and inhibited subsequent caspase-1 activation and IL-1β secretion. In addition, G protein-coupled receptor 120 (GPR120) and GPR40 and their downstream scaffold protein β-arrestin-2 were shown to be involved in inflammasome inhibition induced by ω-3 FAs. Importantly, ω-3 FAs also prevented NLRP3 inflammasome-dependent inflammation and metabolic disorder in a high-fat-diet-induced type 2 diabetes model. Our results reveal a mechanism through which ω-3 FAs repress inflammation and prevent inflammation-driven diseases and suggest the potential clinical use of ω-3 FAs in gout, autoinflammatory syndromes, or other NLRP3 inflammasome-driven inflammatory diseases.

Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study.

INTRODUCTION: We report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis. METHODS: In this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to--or had contraindications for--non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version). RESULTS: At baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P < 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose. CONCLUSIONS: Canakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg. TRIAL REGISTRATION: clinicaltrials.gov: NCT00798369.

A comparative study of reactive hyperemia in human forearm skin and muscle

Résumé en français: L'hyperémie réactive dans la microcirculation musculature et cutanée de l'avant-bras permet d'évaluer l'atteinte vasculaire dans les maladie cardiovasculaires. Cette méthode permet d'obtenir un reflet de la progression de l'atteinte vasculaire, de traquer la progression de la maladie ainsi que le risque cardio-vasculaires. Elle est en étude également pour tester l'efficacité d'une intervention thérapeutique. L'hyperémie réactive est dépendante d'une dilatation post ischémique par diminution des résistances artériolaires. Au niveau des membres, l'ischémie peut-être débutée et interrompue très facilement par une manchette à pression gonflée au-dessus de la pression systolique suivie quelques minutes plus tard de son dégonflement. Les mesures de flux sanguin musculaire et cutané au niveau d'un membre sont facile à réaliser chez l'homme, tout particulièrement au niveau de l'avant-bras. Pour l'instant aucune étude utilisant cette approche ne spécifiait quel avant-bras était utilisé. Il est cependant concevable que la réponse varie selon que l'on teste le bras dominant ou non-dominant. Il parait donc important de clarifier ce point. Le premier but de l'étude consiste donc à investiguer une éventuelle différence entre le bras dominant et le bras non-dominant d'un sujet lors de tests de l'hyperémie réactive dans le muscle et la peau. Il est connu que l'hyperémie réactive au niveau musculaire peut-être diminuée par les médicaments antiinflammatoires non stéro~idiens (AINS), indiquant une implication partielle des métabolites de la cyclo-oxygénase. L'influence des AINS sur la réponse cutanée est moins clairement établie. Ainsi, le second but de cette étude est de comparer l'effet de l'inhibition de la cyclo-oxygénase sur l'hyperémie réactive musculaire et cutanée chez des sujets sains. Le collectif de patients consiste en 23 sujets masculins volontaires, en bonne santé, non fumeurs, de 18 à 30 ans. Aucuns antécédents médicaux ne sont connus et aucune médication n'est prise durant la période de l'étude. Tous . les sujets ont donné leur consentement par écrit. Le flux sanguin musculaire de l'avant-bras est mesuré au moyen d'une pléthysmographie par occlusion veineuse, et le flux cutané l'est par imagerie laser Doppler. Les expériences ont lieu entre 16 et 18 h dans une chambre calme à température constante (23-24°C) chez un sujet couché. Les participants n'ont pas consommé d'AINS durant la semaine précédente ni bu de café dans les 12 h précédant l'expérience. Les mesures sont effectuées en triplicat au niveau musculaire puis cutané ou inversement selon un ordre aléatoire. Suite à une occlusion artérielle l'étude du flux se fait sur 3 min et 5 min de récupération sont prises entre 2 mesures. L'expérience 1 consiste à tester un possible effet systématique de la latéralisation du bras dominant ou non sur la réponse à l'hyperémie réactive dans la peau et le muscle de l'avant-bras. 16 sujets sont étudiés à 2 reprises, espacées de 1 à 3 jours. A la première visite, l'hyperémie musculaire est étudiée dans un avant-bras, la réaction cutanée dans l'autre et inversement lors de la deuxième visite. Une précaution est observée afin de mesurer le flux sanguin cutané à la même distance du poignet dans les 2 avant-bras. L'expérience 2 est développée pour évaluer l'impact d'une inhibition des cyclo-oxygénases. Sept sujet sont considérés à 2 occasions espacées de 7 à 10 j. L'étude s'effectue uniquement au niveau de l'avant-bras dominant. Le site cutané au niveau du poignet est marqué lors de la première visite afin d'utiliser le même site de mesure lors de la seconde visite. Le sujet ingère 1,8 g d'Aspegic (équivalant à 1 g d'acide acétylsalilcylique) dissout dans 125 ml de jus d'orange ou le jus d'orange seul lors de l'autre visite selon un ordre randomisé. Les mesures sont débutées 2 h après la prise. Summary Reactive hyperemia (RH) in forearm muscle or skin microcirculation has been considered as a surrogate endpoint in clinical studies of cardiovascular disease. We evaluated two potential confounders that might limit such use of RH, namely laterality of measurement and intake of non-steroidal anti-inflammatory drugs (NSAIDS). Twenty-three young non-smoking healthy adults were enrolled. In Experiment 1 (n=16), the RH elicited by 3 min of ischemia was recorded in the muscle (strain gauge plethysmography, hand excluded) and skin (laser Doppler imaging) of both forearms. In Experiment 2 (n=7), RH was determined in the dominant forearm only, one hour following oral acetylsalicylic acid (1 g) or placebo. In Experiment 1, peak RH was identical in both forearms, and so were the corresponding durations of responses. RH lasted significantly less in muscle than in skin (p=0.003), a hitherto unrecognized fact. In the skin, acetylsalicylate reduced duration (43 vs 57.4 s for placebo, p=0.03), without affecting the peak response. In muscle, duration tended to decrease with acetylsalicylate (21.4 vs 26.0 s with placebo, p=0.06) and the peak increase in blood flow was blunted (27.2 vs 32.4 ml/min/100 ml tissue with placebo, p=0.003). We conclude that, when using RH as a surrogate endpoint in studies of cardiovascular disease, a confounding by laterality of measurement need not be feared, but NSAIDS may have an influence, although perhaps not on the peak response in the skin.

Haben selektive COX-2-Hemmer unerwünschte renale und kardiovaskuläre Wirkungen [Do selective COX-2 inhibitors have adverse renal and cardiovascular effects?].

Selective cyclooxygenase-2-inhibitors (COX-2) were developed as an alternative to the non-steroidal anti-inflammatory drugs (NSAID) in order to reduce their known gastrointestinal and renal toxicity. Several recent studies have shown the complex mechanism of the cyclooxygenase-2. The inhibition of the COX-2 has effects on renal hemodynamics, renal salt and water retention and may increase the thromboembolic and therefore the cardiovascular risk. The renal toxicity of the COX-2 inhibitors is similar to that of traditional NSAID. Regarding these data, COX-2 inhibitors should be prescribed with much caution to high risk patients, that is, patients with renal failure and/or cardiovascular diseases.

PPARs in diseases: control mechanisms of inflammation.

The three isotypes of peroxisome proliferator-activated receptors (PPARs), PPARalpha, beta/delta and gamma, are ligand-inducible transcription factors that belong to the nuclear hormone receptor family. PPARs are implicated in the control of inflammatory responses and in energy homeostasis and thus, can be defined as metabolic and anti-inflammatory transcription factors. They exert their anti-inflammatory effects by inhibiting the induction of pro-inflammatory cytokines, adhesion molecules and extracellular matrix proteins or by stimulating the production of anti-inflammatory molecules. Furthermore, PPARs modulate the proliferation, differentiation and survival of immune cells including macrophages, B cells and T cells. This review discusses the molecular mechanisms by which PPARs and their ligands modulate the inflammatory response. In addition, it presents recent developments implicating PPAR specific ligands in potential treatments of inflammation-related diseases, such as atherosclerosis, inflammatory bowel diseases, Parkinson's and Alzheimer's diseases.

Neutrophils and TNF: two key players in the immune response induced by "Leishmania major" infection

Summary Resolution of the inflammation is as important as its induction. In this thesis, we investigated the contributions of two prominent factors involved in inflammation, Tumour Necrosis Factor (TNF) and neutrophils. We studied their role in the resolution óf the inflammatory lesion induced by the infection with the protozoan parasite Leishmania major. In mice susceptible to infection with L. major, unhealing lesions are characterized by an elevated number and sustained presence of inflammatory neutrophils in the infected tissue, illustrating an acute inflammatory process. In contrast, mice from resistant strains, which resolve their lesions, can control the presence of neutrophils at the site of infection. Neutrophil persistence in the infected tissue may result from several events including an increased survival of neutrophils mediated by factors produced by the pathogen or the microenvironment. Following infection with L. major, the cellular composition of the inflammatory lesion differs significantly between susceptible and resistant mice and a higher proportion of macrophages is present in the lesions of resistant strains. In an attempt to clarify the factors involved in neutrophil persistence, we investigated the mechanisms modulating neutrophil cell death. We demonstrated that macrophages could induce neutrophil apoptosis in a process involving TNF. TNF is an essential cytokine with pro- and anti-inflammatory properties, which is expressed as a transmembrane protein that can be cleaved releasing the secreted form. Our data show the essential role of the transmembrane form of TNF (mTNF) in the induction of neutrophil apoptosis by macrophages, revealing macrophages and mTNF as important regulators of neutrophil apoptosis. TNF is critical in the resolution of the inflammatory lesion induced by L. major infection, and in L. major resistant strains its absence results in increased swelling of the lesions. We investigated the contribution of mTNF in the outcome of L. major infection. Our data demonstrate that following infection with L. major, mTNF is sufficient to support the resolution of the inflammatory lesion and optimal parasite killing. In addition, we show that the presence of mTNF is essential to induce neutrophil clearance in the infected tissue. While the persistence of neutrophils is deleterious for the host, we could demonstrate an early anti-inflammatory role of neutrophils. Altogether, this study demonstrates the importance of mTNF in the induction of neutrophil apoptosis, a process involved in the resolution of the inflammatory lesion induced by L. major infection. Résumé La résolution de l'inflammation est toute aussi importante que son initiation. Durant ce travail de thèse, nous avons étudié les contributions de deux facteurs importants impliqués dans l'inflammation, le TNF (Facteur Nécrosant des Tumeurs) et les neutrophiles, dans la résolution de la lésion inflammatoire induite par l'infection avec le parasite protozoaire Leishmania major. Chez les souris sensibles à l'infection avec L. major, des lésions importantes qui ne guérissent pas se développent ; celles-ci sont caractérisées par un nombre élevé et une présence soutenue de neutrophiles dans les tissus infectés, ce qui illustre un processus inflammatoire aigu. Au contraire, les souris résistantes à l'infection qui guérissent leurs lésions, sont capables de contrôler la présence des neutrophiles au site d'infection. La persistance des neutrophiles dans la lésion inflammatoire peut être la conséquence de plusieurs événements, dont une augmentation de la survie des neutrophiles induite par des facteurs produits par le pathogène ou le micro-environnement. Suite à l'infection avec L. major, la composition cellulaire de la lésion inflammatoire est significativement différente entre les souris sensibles et résistantes à l'infection, et une plus grande proportion de macrophages est présente dans les lésions des souris résistantes. Dans l'objectif de clarifier les facteurs impliqués dans la persistance des neutrophiles dans les tissus infectés par L. major, nous avons étudié les mécanismes de régulation de la mort des neutrophiles. Nous avons démontré que les macrophages pouvaient induire l'apoptose des neutrophiles dans un procédé impliquant le TNF. Le TNF est une cytokine aux propriétés pro- et anti-inflammatoires, exprimée sous une forme transmembranaire qui peut être clivée pour relâcher la forme sécrétée. Nos expériences illustrent le rôle essentiel de la forme transmembranaire du TNF (mTNF) dans l'induction de l'apoptose des neutrophiles par les macrophages. Lé TNF est une cytokine importante dans la résolution de la réaction inflammatoire induite par L. major, et chez les souris résistantes l'absence de TNF provoque des lésions inflammatoires plus importantes. Nous avons étudié la contribution du mTNF dans la résolution de l'infection avec L. major. Nos résultats démontrent que suite à une infection avec le parasite, la présence du mTNF est suffisante pour guérir la lésion inflammatoire et contrôler efficacement la réplication du parasite. De plus, le mTNF joue un rôle essentiel dans l'élimination des neutrophiles du tissu infecté. Alors que la persistance des neutrophiles est nocive pour l'hôte, nous avons montré que les neutrophiles avaient un rôle précoce anti-inflammatoire. En résumé, cette étude révèle l'importance du mTNF dans l'induction de l'apoptose des neutrophiles par les macrophages, un procédé impliqué dans la résolution de la lésion inflammatoire induite par l'infection avec L. major.

La dysménorrhée: un problème pour le pédiatre [Dysmenorrhea: a problem for the pediatrician?].

Dysmenorrhea is common in adolescent years, especially after the onset of ovulatory cycles, usually 2 to 3 years after menarche. Pain and symptoms are responsible for school absenteeism and interruption of sports and social activities. OBJECTIVES: This study aims to measure the prevalence of severe dysmenorrhea and its consequences on adolescent girls in Switzerland. Treatment of dysmenorrhea is discussed and recommendations for clinical practice are given. STUDY DESIGN: Cross sectional survey (SMASH 02) on a nationally representative sample of adolescents (n=7548; 3340 females), aged 16 to 20 years who attended post-mandatory education. A self-administered questionnaire was used to assess the severity of dysmenorrhea and its consequences on daily life pursuit of medical help and medications used. RESULTS: Among 3340 girls, 86.6% suffered from dysmenorrhea-related symptoms: 12.4% described having severe dysmenorrhea and 74.2% moderate dysmenorrhea. Girls with severe dysmenorrhea described heavier consequences on daily activities compared with girls without dysmenorrhea: 47.8% of girls with severe dysmenorrhea reported staying at home and 66.5% declared reducing their sportive activities. Yet, fewer than half have consulted a physician for this complaint and even fewer were treated properly. RECOMMENDATION: The pediatrician has a pivotal role in screening young patients for dysmenorrhea, as well as, educating and effectively treating adolescent girls with menstruation-associated symptoms. Non-steroidal anti-inflammatory drugs are considered the first-line of treatment for dysmenorrhea, and adolescents with symptoms that do not respond to this treatment for 3 menstrual periods should be offered combined oestroprogestative contraception and must be followed up, as non-responders may have an underlying organic pathology. CONCLUSION: Dysmenorrhea is a frequent health problem in adolescent years and adolescent care providers should be able to care for these patients in an efficient way.

Rejet de greffe et iontophorèse de corticoïdes: à propos de 3 cas [Corneal graft rejection and corticoid iontophoresis: 3 case reports].

This is the first report of three cases of severe acute corneal graft rejection, treated by transscleral methylprednisolone (Solumédrol) iontophoresis. The efficacy of the treatment was evaluated by corneal transparency, visual acuity and corneal inflammation parameters. The patient was treated with Solumédrol iontophoresis once a day for 3 days with a topical corticotherapy reduced to three drops of dexamethasone per day. Iontophoresis was performed, under topical anesthesia, and lasted 3 minutes with a 1.5-mA current. The subjective and objective tolerance of iontophoresis was good. No side-effect was observed. Corneal transparency and visual acuity improved rapidly after the second iontophoresis procedure. These observations show that Solumédrol iontophoresis might be an alternative to pulse therapy in the treatment of corneal graft rejection. Further comparative studies are necessary to confirm these preliminary observations.

A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis.

PURPOSE: To evaluate the effect of XG-102 (formerly D-JNKI1), a TAT-coupled dextrogyre peptide that selectively inhibits the c-Jun N-terminal kinase, in the treatment of endotoxin-induced uveitis (EIU). METHODS: EIU was induced in Lewis rats by LPS injection. XG-102 was administered at the time of LPS challenge. The ocular biodistribution of XG-102 was evaluated using immunodetection at 24 hours after either 20 microg/kg IV (IV) or 0.2 microg/injection intravitreous (IVT) administrations in healthy or uveitic eyes. The effect of XG-102 on EIU was evaluated using clinical scoring, infiltration cell quantification, inducible nitric oxide synthase (iNOS) expression and immunohistochemistry, and cytokines and chemokines kinetics at 6, 24, and 48 hours using multiplex analysis on ocular media. Control EIU eyes received vehicle injection IV or IVT. The effect of XG-102 on c-Jun phosphorylation in EIU was evaluated by Western blot in eye tissues. RESULTS: After IVT injection, XG-102 was internalized in epithelial cells from iris/ciliary body and retina and in glial and microglial cells in both healthy and uveitic eyes. After IV injection, XG-102 was concentrated primarily in inflammatory cells of uveitic eyes. Using both routes of administration, XG-102 significantly inhibited clinical signs of EIU, intraocular cell infiltration, and iNOS expression together with reduced phosphorylation of c-Jun. The anti-inflammatory effect of XG-102 was mediated by iNOS, IFN-gamma, IL-2, and IL-13. CONCLUSIONS: This is the first evidence that interfering with the JNK pathway can reduce intraocular inflammation. Local administration of XG-102, a clinically evaluated peptide, may have potential for treating uveitis.

Eosinophilic aseptic arachnoiditis. A neurological complication in HIV-negative drug-addicts.

The finding of an eosinophilic aseptic meningitis in IV drug abuse is usually suggestive of an opportunistic infection or an allergic reaction. However, HIV-negative patients are at lower risk for developing these complications. Two young HIV-negative patients, with previous intravenous polytoxicomany, developed cystic arachnoiditis over the spinal cord associated with eosinophilic meningitis. Histology of the meningeal spinal cord lesions revealed a vasculocentric mixed inflammatory reaction. In one patient prednisone led to marked clinical improvement. Since infection, vasculitis, sarcoidosis and previous myelography were ruled out, we believe that the syndrome of eosinophilic aseptic arachnoiditis may be related to an hyperergic reaction in the meniges toward drug-adulterants inoculated through the intravenous route.