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International audience; IntroductionCerebral venous sinus thrombosis (CVST) is a rare disease with highly variable clinical presentation and outcomes. Clinical studies suggest a role of inflammation and coagulation in CVST outcomes. The aim of this study was to investigate the association of inflammation and hypercoagulability biomarkers with CVST clinical manifestations and prognosis.MethodsThis prospective multicenter study was conducted from July 2011 to September 2016. Consecutive patients referred to 21 French stroke units and who had a diagnosis of symptomatic CVST were included. High-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), D-dimer, and thrombin generation using calibrated automated thrombogram system were measured at different time points until 1 month after anticoagulant therapy discontinuation.ResultsTwo hundred thirty-one patients were included. Eight patients died, of whom 5 during hospitalization. The day 0 hs-CRP levels, NLR, and D-dimer were higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; NLR: 3.51 [2.15-5.88] vs 4.78 [3.10-9.59], respectively; D-dimer: 950 μg/L [520-2075] vs 1220 μg/L [950-2445], respectively). Patients with ischemic parenchymal lesions (n = 31) had a higher endogenous thrombin potential5pM than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min (1646-2441) vs 1629 nM min (1371-2090), respectively (P = .0082). Using unadjusted logistic regression with values >75th percentile, day 0 hs-CRP levels of >29.7 mg/L (odds ratio, 10.76 [1.55-140.4]; P = .037) and day 5 D-dimer levels of >1060 mg/L (odds ratio, 14.63 [2.28-179.9]; P = .010) were associated with death occurrence.ConclusionTwo widely available biomarkers measured upon admission, especially hs-CRP, could help predict bad prognosis in CVST in addition to patient characteristics. These results need to be validated in other cohorts.

Introduction: Cerebral venous thrombosis (CVT) is a rare disease with highly variable clinical presentation and outcome. Etiological assessment may be negative. The clinical and radiological presentation and evolution can be highly variable. The mechanisms involved in this variability remain unknown.Objective: The aim of this multicenter French study registered on ClinicalTrials.gov (NCT02013635) was therefore to prospectively recruit a cohort of patients with cerebral venous thrombosis (FPCCVT) in order to study thrombin generation and clot degradation, and to evaluate their influence on clinical radiological characteristics. The first part of the study was to compare our cohort with a reference cohort.Methods: This prospective, multicenter, French study was conducted from July 2011 to September 2016. Consecutive patients (aged >15 years) referred to the stroke units of 21 French centers and who had a diagnosis of symptomatic CVT were included. All patients gave their written informed consent. The diagnosis of CVT had to be confirmed by imaging. Clinical, radiological, biological, and etiological characteristics were recorded at baseline, at acute phase, at 3 months and at last follow-up visit. Thrombophilia screening and the choice of treatment were performed by the attending physician. All data were compared with data from the International Study on CVT published by Ferro et al.Results: Two hundred thirty-one patients were included: 117 (50.6%) had isolated intracranial hypertension, 96 (41.5%) had focal syndrome. During hospitalization, 229 (99.1%) patients received anticoagulant treatment. Median length of hospital stay was 10 days. Five patients died during hospitalization (2.2%). At 3 months, 216 patients (97.0%) had follow-up with neurological data based on an outpatient visit. The mean duration of antithrombotic treatment was 9 months, and the mean time to last follow-up was 10.5 months. At the end of follow-up, eight patients had died, and 26 patients were lost to follow-up. At least one risk factor was identified in 200 patients.Conclusions: We demonstrated that the FPCCVT cohort had radiological, biological, and etiological characteristics similar to the historical ISCVT cohort. Nevertheless, the initial clinical presentation was less severe in our study probably due to an improvement in diagnostic methods between the two studies.

Detection of high on-treatment platelet reactivity (HPR) by point-of-care tests has not been validated after successful fibrinolysis for ST-elevation myocardial infarction. We assessed the validity of the point-of-care VerifyNow P2Y12 (VN) and INNOVANCE PFA P2Y (PFA) tests on HPR compared to light transmittance aggregometry (LTA) in these patients. The HPR was identified in 10 (34.5%) patients, 15 (51.7%) patients, and 14 (50%) patients using LTA, VN, and PFA, respectively. Discrepancies were observed between the tests despite significant correlations between platelet reactivity measures by LTA and VN ( r = 0.74; P < .0001) and LTA and PFA ( r = .75; P < .0001). Compared to LTA, VN and PFA were associated with a 92% and 53% and 92% and 64% positive predictive value (PPV) and negative predictive value (NPV), respectively, in detecting HPR. When combined, VN and PFA results yielded 90% and 100% PPV and NPV values if discrepancies between the 2 tests were considered as non-HPR. The VN or PFA identify patients without HPR correctly but overestimate the proportion of HPR patients. The association of the 2 tests, in case of HPR, improves the accuracy of the detection of HPR.

To analyse the association between patients’ socioeconomic position (SEP) and the use of emergency departments (EDs). This population-based study included all visits to ED in 2012 by inhabitants of the French Midi-Pyrenees region, recorded by the Regional Emergency Departments Observatory. We compared ED visit rates and the proportion of non-severe visits according to the patients’ SEP as assessed by the European Deprivation Index. We analysed 496,388 visits. The annual ED visit rate increased with deprivation level: 165.9 [95% CI (164.8–166.9)] visits per 1000 inhabitants among the most advantaged group, compared to 321.9 [95% CI (320.3–323.5)] per 1000 among the most disadvantaged. However, the proportion of non-severe visits was about 14% of the visits, and this proportion did not differ according to SEP. Although the study shows a difference of ED visit rates, the probability of a visit being non-severe is not meaningfully different according to SEP. This supports the assumption that ED visit rate variations according to SEP are mainly explained by SEP-related differences in health states rather than SEP-related differences in health behaviours.

Point of care testing (POCT) must comply with regulatory requirements according to standard EN ISO 22870, which identify biologists as responsible for POCT. INR for vitamin K antagonists (VKAs) monitoring is a test frequently performed in haemostasis laboratories. Bedside INR is useful in emergency room, in particular in case of VKAs overdosage but also for specific populations of patients like paediatrics or geriatrics. INR POCT devices are widely used at home by the patients for self-testing, but their use in the hospital by the clinical staff for bedside measurement is growing, with devices which now comply with standard for POCT accreditation for hospital use. The majority of point of care devices for INR monitoring has shown a good precision and accuracy with results similar to those obtained in laboratory. With the aim to help the multidisciplinary groups for POCT supervision, the medical departments and the biologists to be in accordance with the standard, we present the guidelines of the GFHT (Groupe francais d'etude sur l'hemostase et la thrombose, subcommittee "CEC et biologie delocalisee") for the certification of POCT INR. These guidelines are based on the SFBC guidelines for the certification of POCT and on the analysis of the literature to ascertain the justification of clinical need and assess the analytical performance of main analysers used in France, as well as on a survey conducted with biologists.

Objectives The objectives of this study are to describe an emergency department (ED) adult population with the chief complaint of mental and behavioral disorders due to psychoactive substance use and to investigate sex- and age-related differences. Methods We analyzed data (2009-2011) from the Regional Observatory of Emergency Medicine ORU-MiP (700000 patients per year) for all patients with a primary diagnosis of mental and behavioral disorders due to psychoactive substance use. Day data were weighted by the number of days in the year and expressed for 100000 inhabitants of the area. Pearson χ 2 test and Fisher tests were used. The Brown-Mood test was used to compare medians. Results Of the 1411597 ED visits analyzed, 20838 consults (1.3%) were for primary diagnosis of mental and behavioral disorders due to psychoactive substance use. The median age (interquartile range) was 41 (28-51) years; 69.5% were men. More women consulted the ED for sedative or hypnotic use (4.9% vs 1.5%, P −4 ) than men, and more men consulted for alcohol consumption (93.5% vs 90%, P −4 ) and cannabinoids (1.4% vs 1.0%, P −3 ) than women. Young consumer visits dramatically increased during weekends (average of 88 visits a day per 100000 inhabitants vs 34 on Mondays to Thursdays). Another difference was found between young adults and middle-aged adults, with a peak in visits at 2 am and 9 pm respectively. Conclusions Mental and behavioral disorders due to psychoactive substance use account for 1.3% of ED visits. Older people should be screened for chronic alcohol consumption. Our findings underscore the opportunity provided by the ED for screening and brief intervention in drug- and alcohol-related problems.

La Presse Medicale - In Press.Proof corrected by the author Available online since vendredi 1 novembre 2013

Point of care testing (POCT) must comply with regulatory requirements according to standard EN ISO 22870, which identify biologists as responsible for POCT. Activated clotting time (ACT) is mandatory to monitor on whole blood, anticoagulation achieved by unfractionated heparin during cardiopulmonary bypass (CPB) or cardiac catheterization. This test has no equivalent in the laboratory. With the aim to help the multidisciplinary groups for POCT supervision when they have to analyse the wish of medical departments to use ACT and to help the biologists to be in accordance with the standard, we present the guidelines of the GEHT (Groupe d'etude d'hemostase et thrombose) subcommittee "CEC et Biologie delocalisee" for the certification of ACT. These guidelines are based on the SFBC guidelines for the certification of POCT and on the analysis of the literature to ascertain the justification of clinical need and assess the analytical performance of main analyzers used in France, as well as on a survey conducted with French and Belgian biologists.

As regulation on dioxin and furan contamination of foodstuffs was lacking in France, French Sanitary Authorities managed the crisis triggered by such environmental or food pollutions by turning to the statements and recommendations issued by CSHPF (Conseil Supérieur d’Hygiène Publique de France) and later by AFSSA (Agence Française de Sécurité Sanitaire des Aliments). The maximum levels set by EU regulations for various products intended for human or animal consumption are applicable since July 1st 2002., En l’absence de réglementation relative à la contamination des denrées alimentaires par les dioxines et furannes en France, les autorités sanitaires françaises ont géré les différentes crises déclenchées lors de pollutions environnementales ou alimentaires par ces contaminants en se fondant sur les avis et recommandations du Conseil Supérieur d’Hygiène Publique de France (CSHPF) puis de l’Agence Française de sécurité Sanitaire des Aliments (AFSSA). Depuis le 1er juillet 2002, la réglementation communautaire fixant des teneurs maximales dans un certain nombre de produits destinés à l’alimentation humaine et animale est applicable., Le Querrec Frédérique. Réglementation relative aux dioxines et furannes dans les denrées alimentaires. In: Bulletin de l'Académie Vétérinaire de France tome 156 n°3, 2003. pp. 17-21.

SummaryQuantification of lupus anticoagulant (LA) in clinical samples is hampered by the lack of a suitable standard of activity. We evaluated the use of mAbs displaying LA activity for this purpose. As most patient samples contain both β2Glycoprotein I (β2GP1) and prothrombin dependent LA, a combination of two mAbs, one of each specificity, was added to normal plasma in a concentration from 0 to 60 g/ml. Eight assay systems using different reagents and instruments were used. The calibration curves were linear for all but one, with marked differences between the responsiveness to each mAb. A panel of plasmas from 69 patients with persistent LA diagnosed using the SSCISTH criteria was tested. An antiphospholipid syndrome (APS) was present in 40, whereas 29 were asymptomatic. LA activities of individual plasmas varied between assays (p

The authors report the case of a 30-year-old man who died from pulmonary embolism and multiorgan failure caused by mesenteric and inferior vena cava thrombosis. The patient was found heterozygous for the prothrombin gene variant (G 20210 A). The family study showed the same asymptomatic anomaly in his brother. This recently described mutation is associated with an increased risk for venous thrombosis. The investigations and treatment of mesenteric venous thrombosis are discussed.

Etude de la repercussion sur l'economie marchande, de l'implantation de cooperatives de peche au Quebec. (1930-1945).

SummaryThe recommended therapeutic range of International Normalized Ratio (INR) for oral anticoagulant treatment in patients with the antiphospholipid syndrome remains controversial. As a part of this controversy, it has been suggested that lupus anticoagulants (LA) could interfere with the determination of prothrombin time, thus questioning the validity of monitoring the treatment of these patients using INR. To clarify this point, we compared the values of INR obtained in the plasmas of two groups of patients, one without LA (n = 47), and the other with LA (n = 43). INR were determined using 8 different thromboplastin reagents on the same automated coagulation instrument. Chromogenic factor X, which is supposed to be insensitive to the presence of LA, was also measured. The results are the following: provided INR was calculated using calibrated reference plasmas, there was no significant difference between INR values obtained with the 8 reagents, both in the non-LA and in the LA groups (CV: 5.9 and 6.7%, respectively). Closer examination revealed that INR results obtained with one reagent (the recombinant thromboplastin Innovin) diverged from those of the 7 others, leading to an overestimation of INR, to a very large extent in some instances. However this effect was restricted to a subset of the patient population with LA (6 out of 43). Finally, the relationship between INR (average value obtained using the 8 reagents) and factor X was identical in non-LA and in LA patient groups. We conclude that, provided the reagents which display the LA interference are identified and excluded for this purpose, the INR system is valid for monitoring oral anticoagulant treatment in patients with LA.

SummaryWe analyzed the clinical features of 36 patients homozygous for the Arg 506 to Gin factor V mutation and found a circumstantial event at risk for thrombosis in 29 of the 31 patients with thrombosis. The most frequent predisposing factors were the post-partum period and the use of oral contraceptives in women, and surgery in both sexes. Venous thrombosis recurred in 48% of the patients. One patient had a myocardial infarction at age 33 years, and also had an antiphospholipid syndrome. Homozygous Gin 506 mutation leads to far less severe thrombotic complications than homozygous protein C and protein S deficiencies and does not seem to predispose patients to arterial thrombosis.

Monitoring of the anticoagulant effect with the International normalized ratio (INR) is essential for patients receiving vitamin K antagonists (VKAs). The majority of point of care (POC) devices for INR monitoring has shown a good precision and accuracy with results similar to those obtained in a laboratory. In many countries, INR POC devices are widely used at home by the patients for self-testing. Their use in the hospital by the clinical staff (doctor or nurses) for bedside measurement is also growing. The INR POC testing is performed using fully automated devices. Capillary blood samples are easy to obtain. In the emergency room, POC INR devices are commonly used. This improves the quality of care for patient with suspicion of VKAs overdosage. INR measurement using bedside monitors is also of great interest in care units for specific populations of patients like paediatrics or geriatrics. Moreover, bedside INR monitoring may be useful in anticoagulant clinics or when the care unit is far from a laboratory. Although the bedside INR monitors are easy to use, their implementation requires adequate training and intermittent re-evaluation of any person performing the tests to ensure reliability of results. Such equipment must comply with EN ISO 22870 standard for POC testing accreditation, under the supervision of a biologist. In order to achieve these targets, connect the instrument to the laboratory's data management system is essential.

The U1 small nuclear ribonucleoprotein (snRNP)-specific U1C protein participates in 5′ splice site recognition and regulation of pre-mRNA splicing. Based on an RNA-Seq analysis in HeLa cells after U1C knockdown, we found a conserved, intra-U1 snRNP cross-regulation that links U1C and U1-70K expression through alternative splicing and U1 snRNP assembly. To investigate the underlying regulatory mechanism, we combined mutational minigene analysis, in vivo splice-site blocking by antisense morpholinos, and in vitro binding experiments. Alternative splicing of U1-70K pre-mRNA creates the normal (exons 7–8) and a non-productive mRNA isoform, whose balance is determined by U1C protein levels. The non-productive isoform is generated through a U1C-dependent alternative 3′ splice site, which requires an adjacent cluster of regulatory 5′ splice sites and binding of intact U1 snRNPs. As a result of nonsense-mediated decay (NMD) of the non-productive isoform, U1-70K mRNA and protein levels are down-regulated, and U1C incorporation into the U1 snRNP is impaired. U1-70K/U1C-deficient particles are assembled, shifting the alternative splicing balance back towards productive U1-70K splicing, and restoring assembly of intact U1 snRNPs. Taken together, we established a novel feedback regulation that controls U1-70K/U1C homeostasis and ensures correct U1 snRNP assembly and function., Author Summary The accurate removal of intervening sequences (introns) from precursor messenger RNAs (pre-mRNAs) represents an essential step in the expression of most eukaryotic protein-coding genes. Alternative splicing can create from a single primary transcript various mature mRNAs with diverse, sometimes even antagonistic, biological functions. Many human diseases are based on alternative-splicing defects, and most interestingly, certain defects are caused by mutations in general splicing factors that participate in each splicing event. To address the question of how a general splicing factor can regulate alternative splicing events, here we investigated the regulatory role of the U1C protein, a specific component of the U1 small nuclear ribonucleoprotein (snRNP) and important in initial 5′ splice site recognition. Our RNA-Seq analysis demonstrated that U1C affects more than 300 cases of alternative splicing in the human system. One U1C target, U1-70K, appeared to be particularly interesting, because both protein products are components of the U1 snRNP and functionally depend on each other. Analyzing the mechanistic basis of this intra-U1 snRNP cross-regulation, we discovered a U1C-dependent alternative splicing switch in the U1-70K pre-mRNA that regulates U1-70K expression. In sum, this feedback loop controls and links U1C and U1-70K homeostasis to guarantee correct U1 snRNP assembly and function.

Eighteen patients with an acute thrombosis of the splanchnic veins were reviewed. Most of apparently idiopathic cases of splanchnic vein thrombosis are related to an increased coagulation related to a congenital or acquired defect of haemostasis. The aim of this study was to assess the effects of a new and effective treatment. Nine male and 9 female patients (range of age : 19 to 81 years) experienced a mesenteric venous thrombosis. There were 14 mesenteric vein thromboses with infarction, two transient mesenteric venous ischaemias without bowel infarction and two acute thromboses of the splanchinc veins without bowel ischaemia. A coagulopathy was detected in seven patients : oral contraception, protein C (PC) or antithrombin III (AT III) congenital deficiencies, acquired deficiency of AT III, PC and protein S (PS), polycythaemia in the post-partum period and primary myeloproliferative disorder. No coagulopathy was associated with thrombosis in eight cases : mesenteric haematoma, splenomegaly, cirrhosis, appendicectomy, cholescytectomy, chronic heart failure, treatment with beta-adrenergic receptor antagonist and digitalis, stenosis of the portal anastomosis after liver transplantation. Twelve patients required surgery : eight intestinal bowel resections with immediate anastomosis, four resections without immediate anatomosis. Only one patient underwent a second look for a repeat bowel resection. No death occurred in the early postoperative period and 17 out of 18 patients were alive after 12 years. An oral anticoagulant therapy was undertaken from two months to seven years. However, three patients suffered a recurrent thrombosis. Two of them required a long-term anticoagulation. Six patients experienced a portal hypertension and oral anticoagulants were discontinued in three of them because of bleeding oesophageal varices. Six patients were treated only by unfractionated heparin (UFH) or low molecular weight heparin (LMWH) followed by oral anticoagulants. After laparotomy, two were only treated with UFH without any bowel resection, as mesenteric venous ischaemia was too extensive. These observations suggest that the choice between an appropriate medical or surgical treatment is important and must be discussed. Since 1989, the therapeutic choice has been modified by ultrasonography and contrast enhanced computed tomographic scan which confirmes diagnosis, allows to follow up and check the effects of anticoagulation and to choose the time for surgery. When the diagnosis is established and the patient's risk is low, the anticoagulant therapy is decided. UFH is administered by continuous infusion at the average dose of 500 IU · kg−1 · d−1 to obtain an antifactor Xa activity between 0.3 and 0.6 antiXa IU mL−1. When the diagnosis is uncertain and the patient's risk is high, a laparotomy is required. During surgery, UFH must be delivered at a low dose of 100–150 IU · kg−1 · d−1 and progressively increased to obtain the same antifactor Xa activity in two three days. Congenital or acquired AT III or PC deficiencies should be treated by appropriate concentrates. Duration of treatment with oral anticoagulants is not determined and has to be discussed. A 6-month therapy with an INR of 2.0 to 3.0 seems to be reasonable when no coagulopathy is associated with splanchnic venous thrombosis. A long term anticoagulation must be discussed when a coagulopathy is associated with a splanchnic venous thrombosis.

Summary The progressive emergence of a close relationship between the formation of blood vessels in the vicinity of tumour cells and the development and spreading of tumours, strongly suggests that angiogenesis might be a pre-requisite for tumour development. Angiogenesis starts and develops in response to two sets of extracellular signals: soluble angiogenic factors and extracellular matrix. Different experimental models have been used to study angiogenesis in vivo, but they have numerous limitations. Three-dimensional culture systems reconstitute normal interactions between endothelial cells and the surrounding extracellular matrix. Numerous parameters including angiogenic growth factors and cytokines, cell-to-cell interactions and cell-to-extracellular matrix adhesion influence the growth and differentiation of endothelial cells in vitro as well as in vivo. Angiogenesis plays a major role not only in tumour growth but also in metastasis development. Mechanisms of switching to angiogenic phenotype have been recently described and onset of angiogenic activity is now recognized as another discrete step in tumorigenesis. Tumour cells can induce b-FGF expression and exportation, VEGF and VEGF receptor expression and inactivation of the cancer suppressor gene encoding for a fragment of thrombospondin. A controlled net proteolytic balance produced by tumour cells or endothelial cells is required to favour migration and invasion of endothelial cells and angiogenesis. The hypothesis that assessment of tumour angiogenesis might predict tumour aggressiveness in human cancer has recently gained support from several clinical studies. This has been shown for cutaneous melanoma, breast carcinoma, and non-small-cell lung cancer by quantitation of microvessels in human biopsies using von Willebrand factor or CD 3 antigen labelling with specific antibodies. However, more specific and sensitive markers are needed to improve this approach for predicting tumour aggressiveness. Folkman proposed twenty years ago that inhibition of angiogenesis might represent a suitable complementary strategy for the treatment of various forms of cancer. Since then numerous angiostatic compounds have been identified but very few of them fit the required criteria of a potential drug. Fumagillin and particularly its synthetic analogue AGM 1470 might be developed for use in humans in the near future.