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Geriatric caregivers are subjected to physically and psychologically demanding situations. A geriatric short-stay service has implemented measures with a unique, creative and dynamic approach. These include participatory management, benevolence and the enhancement of the quality of work.

Geriatric caregivers are subjected to physically and psychologically demanding situations. A geriatric short-stay service has implemented measures with a unique, creative and dynamic approach. These include participatory management, benevolence and the enhancement of the quality of work.

BACKGROUND: Noninvasive ventilation (NIV) is the recommended ventilatory support for acute cardiogenic pulmonary edema (CPE) associated with acute respiratory failure or hypercapnia. High-flow nasal cannula (HFNC) has emerged as an alternative to NIV in acute hypoxemic respiratory failure. We aimed to assess the efficacy of HFNC on early changes in PaCO2 and respiratory parameters in patients in the emergency department with acute hypercapnic CPE and to compare it to NIV. METHODS: We conducted a prospective observational study in consecutive emergency department patients with acute hypercapnic CPE. Subjects received either HFNC or NIV, according to the attending emergency physician’s expertise in HFNC. The primary outcome was change in PaCO2 after treatment for 1 h. Secondary outcomes were change in pH, breathing frequency, signs of work of breathing, and comparisons to NIV. RESULTS: Twenty-seven subjects with a discharge diagnosis of hypercapnic CPE were analyzed. Subjects had a median age of 87 y (interquartile range [IQR] 78–93); 37% were male. Twelve (44%) received HFNC, and 15 (56%) received NIV. Median of changes in PaCO2 from baseline to after 1 h of treatment were 7 mm Hg (IQR 4–11, P = .002) for HFNC and 3 mm Hg (IQR 1–8, P = .02) for NIV, with no between-group difference. pH, breathing frequency and signs of work of breathing also improved after both HFNC and NIV. CONCLUSION: This preliminary study suggests that HFNC treatment for 1 h improves PaCO2 and respiratory parameters in subjects with hypercapnic acute CPE in a manner that is comparable to NIV. Further studies are needed to assess HFNC as a possible alternative to NIV in early management of acute hypercapnic respiratory failure of cardiogenic origin. (ClinicalTrials.gov registration NCT03883555.)

Background Centrifugation is a consuming time step which participates to increase the turnaround time (TAT) in laboratories, likewise hemolysis sample that needs a re-sampling could delay management of patients. Recently, it has been postulated that BD Barricor™ tube could allow to decrease the centrifugation time and prevent hemolysis, two key feature to ensure high-quality results. Aim of the study was to evaluate the impact of replacing 4 mL BD vacutainer heparin lithium tube by low vacuum 3.5 mL BD vacutainer Barricor™ tube in an emergency department (ED) on hemolysis rate and TAT. Methods Data of hemolysis index (HI) and TAT were compared between the first period of 15 days using 4 mL BD vacutainer heparin lithium tubes with 15 min at 2000xg as centrifugation setting and a second period of 15 days using BD vacutainer Barricor™ tube centrifuged 3 min at 4000xg. Results A significantly reduced time duration between reception of sample and available results in informatics lab system was observed with the reduction time of centrifugation allowed by use of Barricor™ tube compared to regular heparin lithium tubes (p, Highlights • Improving turnaround time and quality samples is a challenge for all laboratories. • Hemolyzed samples occurrence is higher in the emergency department. • Low vacuum tube can reduce the hemolysis rate of blood sampling. • Higher speed centrifugation could reduce centrifugation time and turnaround time. • Low vacuum Barricor tube in emergency unit improve hemolysis rate and turnaround time.

International audience; INTRODUCTION:Obese patients with acute dyspnea may be prone to misorientation from the emergency department (ED), due to impaired gas exchange evaluation and altered basal respiratory profiles. This study aims to evaluate the prognostic value of arterial blood pH in obese ED patients with acute dyspnea in comparison to non-obese counterparts.METHODS:Single-center observational study of a cohort of 400 consecutive ED patients with acute dyspnea. The primary endpoint was a composite of Intensive Care Unit admission (with critical care needs) or in ED mortality. Predictors of the primary endpoint were assessed using multivariable logistic regression and ROC curve analysis, in obese (BMI ≥ 30 kg·m-2) and non-obese patients.RESULTS:252 patients who had arterial blood gas testing were analyzed including 76 (30%) obese comparable to non-obese in terms of clinical history. 51 patients were admitted to ICU and 2 deceased before admission (20 obese (26%) vs 33 non-obese (19%); p = 0.17). Factors associated with ICU admission were arterial blood pH (pH

BACKGROUND: Postural changes are known to affect normal lung volumes. A reduction in sitting to supine functional residual capacity (FRC) is well-described in non-obese subjects adopting a supine position. However, postural changes in lung volumes in the obese require further exploration. We aimed to longitudinally address the effects of weight loss on postural changes in lung volumes and pulmonary function in obese subjects. We tested the hypothesis that supine reduction in FRC would be absent in morbid obesity and recovered upon weight loss. METHODS: This was a prospective, observational, longitudinal study. Consecutive morbidly obese adults (N = 12, age: 44 ± 14 y, body mass index: 45 ± 5 kg/m2) enrolled in a bariatric surgery program were included. Standard pulmonary function tests and blood gas analysis were performed both before and 1 y after surgery. Pulmonary function was assessed in both the sitting and supine position using spirometry and multi-breath helium dilution. Parameters recorded before and after weight loss were compared. The main outcome measure was FRC. RESULTS: Ten subjects were retested 1 y after surgery (body mass index: 31 ± 5 kg/m2). FRC was not affected by change in posture before surgery. Supine reduction in FRC was observed after weight loss (ΔFRC: −0.6 ± 0.4 L, sitting vs supine, P = .002). Pulmonary gas exchange improved (alveolar-to-arterial oxygen partial pressure difference: −8 ± 11 mm Hg, P = .035). CONCLUSIONS: Although postural change in FRC is absent when the morbidly obese adopt a supine position, supine reduction in FRC can be recovered following gastroplasty-induced weight loss, despite residual mild to moderate obesity. This also shows that mild to moderate obesity may affect supine FRC more than morbid obesity. (ClinicalTrials.gov registration NCT02207192.)

This paper presents four blue-sky ideas for lowering the cost of the Government of Canada’s debt without increasing the debt’s risk profile. We argue that each idea would improve the secondary-market liquidity of government debt, thereby increasing the demand for government bonds and thus lowering their cost at issuance. The first two ideas would improve liquidity by enhancing the active management of the government’s debt through market operations used to support the liquidity of outstanding bonds. The second two ideas would simplify the set of securities issued by the government, concentrating issuance in a smaller set of bonds that would each be more highly traded. We discuss the ideas and give an account of the political, legal and operational impediments., Cette étude présente quatre idées imaginatives visant à réduire le coût de la dette du gouvernement du Canada sans accroître le profil de risque de la dette. Nous soutenons que chacune d’entre elles permettrait d’améliorer la liquidité des titres d’emprunt du gouvernement sur le marché secondaire, et par le fait même de hausser la demande d’obligations d’État et de diminuer leur coût à l’émission. Les deux premières idées amélioreraient la liquidité en favorisant la gestion active de la dette publique au moyen des opérations de marché servant à assurer la liquidité des obligations en cours. Les deux autres idées simplifieraient l’ensemble de titres émis par le gouvernement en concentrant l’émission d’obligations dans un groupe restreint de titres qui seraient négociés en plus grands volumes. Nous analysons ces solutions et donnons un aperçu des contraintes présentes sur le plan politique, juridique et opérationnel.

TNF-Receptor Associated Factor (TRAF)-3 is a master regulator of B cell homeostasis and function. TRAF3 has been shown to bind and regulate various proteins involved in the control of innate and adaptive immune responses. Previous studies showed that TRAF3 overexpression renders B cells hyper-reactive to antigens and Toll-like receptor (TLR) agonists, while TRAF3 deficiency has been implicated in the development of a variety of B cell neoplasms. In this report, we show that transgenic mice overexpressing TRAF3 and BCL2 in B cells develop with high incidence severe lymphadenopathy, splenomegaly and lymphoid infiltrations into tissues and organs, which is the result of the growth of monoclonal and oligoclonal B cell neoplasms, as demonstrated by analysis of VHDJH gene rearrangement. FACS and immunohistochemical analyses show that different types of mature B cell neoplasms arise in TRAF3/BCL2 double-transgenic (tg) mice, all of which are characterized by the loss of surface IgM and IgD expression. However, two types of lymphomas are predominant: (1) mature B cell neoplasms consistent with diffuse large B cell lymphoma and (2) plasma cell neoplasms. The Ig isotypes expressed by the expanded B-cell clones included IgA, IgG, and IgM, with most having undergone somatic hypermutation. In contrast, mouse littermates representing all the other genotypes (TRAF3-/BCL2-; TRAF3+/BCL2-, and TRAF3-/BCL2+) did not develop significant lymphadenopathy or clonal B cell expansions within the observation period of 20 months. Interestingly, a large representation of the HCDR3 sequences expressed in the TRAF3-tg and TRAF3/BCL2-double-tg B cells are highly similar to those recognizing pathogen-associated molecular patterns and damage-associated molecular patterns, strongly suggesting a role for TRAF3 in promoting B cell differentiation in response to these antigens. Finally, allotransplantation of either splenocytes or cell-containing ascites from lymphoma-bearing TRAF3/BCL2 mice into SCID/NOD immunodeficient mice showed efficient transfer of the parental expanded B-cell clones. Altogether, these results indicate that TRAF3, perhaps by promoting exacerbated B cell responses to certain antigens, and BCL2, presumably by supporting survival of these clones, cooperate to induce mature B cell neoplasms in transgenic mice., Funding was from Instituto de Salud Carlos III (ISCIII) PI080170, PI12/01135, and PI16/00895 to JZ and from the National Institutes of Health (AI070859 to JZ and CA163743 to JR)., The cost of this publication was paid in part by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI) and by funds from the European Fund for Economic and Regional Development (FEDER).

International audience; Dans les années 1990, les travaux de révision du cadre chronologique des occupations corrélées préalablement au SIM 5 de la chronologie marine ou même à un stade antérieur en Europe centrale et moyenne permirent définitivement d’asseoir la présence de Néandertaliens durant l’Eemien à l’Est du Rhin. Pour la partie Ouest du Rhin, il fallut attendre la (re)découverte du gisement de Caours dans la Somme au début des années 2000 pour pouvoir affirmer que l’homme de Néandertal parcourait les plaines septentrionales de la France à cette période. En 2013, le fond de vallée de la Scarpe, un affluent de l’Escault (Scheldt) livra un gisement inédit et exceptionnel corrélable à l’Eemien. La séquence stratigraphique mise au jour lors d’un diagnostic d’archéologie préventive livra une série de dépôts d’alluvions organiques limoneux puis tourbeux surmontés de dépôts lœssiques. L’attribution à l’Eemien de la base de la séquence (limons et tourbes) fut rapidement confirmée par la présence d’espèces de mammifères et de mollusques uniquement connues durant le Pléistocène en période interglaciaire, d’une date U/Th (TIMS) sur oogones de characées donnant un âge minimum de 103 +3.5/-3.4 ka, et de lœss de couverture weichséliens surmontant la séquence fluviatile. Malgré la rareté de tels dépôts il fut impossible de monter une opération d'archéologie préventive sur la zone et l'étude du site a été réalisée dans le cadre d'un projet de recherche programmée lancé en 2014. Cette communication proposera de présenter les principaux résultats obtenus et mettra en évidence la richesse et le potentiel archéologique de ce gisement. Il exposera l'importance des apports que laissent entrevoir les premiers résultats d’analyses obtenus sur le gisement de Waziers à nos connaissances du paysage Eemien et des dynamiques de peuplement des groupes Néandertaliens des plaines et des vallées du Nord-Ouest de l’Europe.

We sought to evaluate the added value of ultrasensitive copeptin (us-copeptin) for early rule out of acute myocardial infarction in a prospective cohort of emergency department (ED) patients with acute chest pain.This was a prospective study including consecutive patients with acute chest pain presenting to the ED within 12 hours of symptom onset. High-sensitivity cardiac troponin T (hs-cTnT, Roche Diagnostics, Meylan, France) and us-copeptin (ThermoFisher Scientific, Clichy, France) were blindly assayed from venous blood samples obtained at admission. Diagnosis was made by 2 ED physicians using all available data and serial cardiac troponin I as the biochemical standard. Diagnostic performances of us-copeptin combined with hs-cTnT were assessed using logistic regression. Analysis was conducted in all patients and in patients without ST-elevation myocardial infarction.A total of 194 patients were included (age, 61 [48-75] years; male sex, 63%). Acute myocardial infarction occurred in 52 (27%) patients, including non-ST-elevation myocardial infarction (NSTEMI) in 25 (13%). Patients with acute myocardial infarction had higher levels of hs-cTnT (50 [95% confidence interval, 19-173] ng/L) and us-copeptin (30 [13-113] pmol/L) at admission compared with those without (P.05). Combination of markers significantly improved receiver operating characteristic area under the curve (from 0.89 [0.85-0.92] for hs-cTnT alone to 0.93 [0.89-0.97], P = .018). Sensitivity and negative predictive value were increased, particularly for NSTEMI diagnosis (sensitivity, 76% [54.9-90.6] to 96% [79.6-99.9]; negative predictive value, 95% [90.4-98.3] to 98.9% [94.2 to 100]).Assessment of us-copeptin combined with hs-cTnT on ED admission could allow safe and early rule out of NSTEMI for patients with negative results on both markers and help identify patients who may be suitable for discharge.

BACKGROUND: The RAD-57 pulse CO-oximeter is a lightweight device allowing noninvasive measurement of blood carboxyhemoglobin (SpCO). We assessed the diagnostic value of pulse CO-oximetry, comparing SpCO values from the RAD-57 to standard laboratory blood carboxyhemoglobin (COHb) measurement in emergency department patients with suspected carbon monoxide (CO) poisoning. METHODS: This was a prospective, diagnostic accuracy study according to the Standards for the Reporting of Diagnostic Accuracy Studies criteria in consecutive adult emergency department patients with suspected CO poisoning. SpCO was measured with the RAD-57 simultaneously with blood sampling for laboratory blood gas analysis. We made no changes to our standard management of CO poisoning. Blood COHb > 5% for non-smokers, and > 10% for smokers were applied as the reference standard. RESULTS: We included 93 subjects: 37 smokers and 56 non-smokers. CO poisoning was diagnosed in 26 subjects (28%). The SpCO values ranged from 1% to 30%, with a median of 4% (IQR 2.7–7.3%). The COHb values ranged from 0% to 34%, with a median of 5% (IQR 2–9%). The mean differences between the COHb and SpCO values were −0.2% ± 3.3% (95% limits of agreement of −6.7% and 6.3%) for the whole cohort, −0.7% (limits of agreement −7.7% and 6.2%) for the non-smokers, and 0.6% (limits of agreement −5.0% and 6.2%) for the smokers. The optimal thresholds for detecting CO poisoning were SpCO of 9% and 6% for smokers and non-smokers, respectively. CONCLUSIONS: SpCO measured with the RAD-57 was not a substitute for standard blood COHb measurement. However, noninvasive pulse CO-oximetry could be useful as a first-line screening test, enabling rapid detection and management of CO-poisoned patients in the emergency department.

Peripheral venous (PV) cannulation, one of the most common technical procedures in Emergency Medicine, may prove challenging, even to experienced Emergency Department (ED) staff. Morbid obesity (body mass index [BMI] ≥ 40) has been reported as a risk factor for PV access failure in the operating room.We investigated PV access difficulty in the ED, across BMI categories, focusing on patient-related predicting factors.Prospective, observational study including adult patients requiring PV lines. Operators were skilled nurses and physicians. PV accessibility was clinically evaluated before all cannulation attempts, using vein visibility and palpability. Patient and PV placement characteristics were recorded. Primary outcome was failure at first attempt. Outcome frequency and comparisons between groups were examined. Predictors of difficult cannulation were explored using logistic regression. A p-value0.05 was considered significant.PV lines were placed in 563 consecutive patients (53 ± 23 years, BMI: 26 ± 7 kg/m(2)), with a success rate of 98.6%, and a mean attempt of 1.3 ± 0.7 (range 1-7). Failure at the first attempt was recorded in 21% of patients (95% confidence interval [CI] 17.6-24.4). Independent risk factors were: a BMI ≥ 30 (odds ratio [OR] 1.98, 95% CI 1.09-3.60), a BMI18.5 (OR 2.24; 95% CI 1.07-4.66), an unfavorable (OR 1.66, 95% CI 1.02-2.69), and very unfavorable clinical assessment of PV accessibility (OR 2.38, 95% CI 1.15-4.93).Obesity, underweight, an unfavorable, and a very unfavorable clinical evaluation of PV accessibility are independent risk factors for difficult PV access. Early recognition of patients at risk could help in planning alternative approaches for achieving rapid PV access.

El pdf es la versión post-print., Tumor necrosis factor (TNF) receptor–associated factor 3 (TRAF3) regulates both innate and adaptive immunity by modulating signaling by Toll-like receptors (TLR) and TNF receptors. TRAF3 was recently identified as a tumor suppressor in human multiple myeloma, suggesting a prominent role in plasma cell homeostasis. We have generated transgenic mice expressing human TRAF3 in lymphocytes. These mice are normal at birth, but they develop over time plasmacytosis and hypergammaglobulinemia, as well as systemic inflammation and tertiary lymphoid organ formation. The analysis of the humoral responses of the TRAF3 mice demonstrated increased responses to T-dependent and T-independent antigens with increased production of antigen-specific immunoglobulin Gs (IgGs) compared with wild-type mice. Furthermore, TLR-mediated IgG production is also increased in TRAF3 B cells. In addition, TRAF3 mice develop autoimmunity and are predisposed to cancer, particularly squamous cell carcinomas of the tongue (≈ 50% incidence) and salivary gland tumors. In summary, TRAF3 renders B cells hyperreactive to antigens and TLR agonists, promoting autoimmunity, inflammation, and cancer, hereby providing a new model for studying de novo carcinogenesis promoted by B cell–initiated chronic inflammation., This work was supported by National Institutes of Health grants AI-069356 and CA-69381, Programa Ramón y Cajal, SAF2004-7675, and a fellowship from the Spanish Ministerio de Sanidad y Consumo (FI05/00 191).

El pdf es la versión pre-print., Ubc13 is a ubiquitin-conjugating enzyme responsible for noncanonical ubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in Toll-like receptor and TNF-family cytokine receptor signaling, which are regulators of innate immunity. Gene ablation was used to study the function of Ubc13 in mice. Whereas homozygous ubc13 gene disruption resulted in embryonic lethality, heterozygous ubc13 +/− mice appeared normal, without alterations in immune cell populations. Haploinsufficient ubc13 +/− mice were resistant to lipopolysaccharide-induced lethality, and demonstrated reduced in vivo ubiquitination of TRAF6. Macrophages and splenocytes isolated from ubc13 +/− mice exhibited reduced lipopolysaccharide-inducible cytokine secretion and impaired activation of TRAF-dependent signal transduction pathways (NF-κB, JNK, and p38 MAPK). These findings document a critical role for Ubc13 in inflammatory responses and suggest that agents reducing Ubc13 activity could have therapeutic utility., We thank the National Institutes of Health for generous funding through Grants CA69381, AI070859, and CA078419.

International audience; At the end of the 1980’s, C. Gamble launched a debate on the ability of Early hominids to colonize northern latitudes of Europeduring Middle and Late Pleistocene Interglacial periods. At that time, the Eemian (MIS 5e) was characterised by a total absence ofhuman occupation in Northern France, Belgium, Netherlands, Germany and Great Britain. Since the 1990’s, a few sites with humanoccupation attributed to the Eemian have been discovered and excavated in north-west Europe, particularly in Germany. Afterthese discoveries some authors like Roebroeks et al. [2, 3] rejected Gamble’s model. In northern France, several Middle Palaeolithiclevels were discovered at the base of the Eemian tufa of Caours (Somme basin) in 2006. They represent the first record of Humanoccupation during the Last Interglacial in the area.Recently, in 2012 an archaeological diagnostic conducted at Waziers (North, France) before the building of a Do-it-Yourselfshop, led to the discovery of a peat layer at 3,2 metres deep in some test pits, overlying fluvial silts and sands. Complementaryobservations made in 2013 allowed to propose an Eemian age for the fluvial sequence. This interpretation relies on geomorphologicaland palaeontological observations: (1) the presence of loess covering the fluvial deposits and the peat, and (2) the occurrenceof both Interglacial Pleistocene mammals (aurochs and red deer) and Pleistocene aquatic mollusc species (Belgrandia marginata,Anisus septemgyratus) that no longer exist in this area, in the fluvial deposits and in the peat. Moreover, a minimum age of 103+3.5/-3.4 ka was obtained by U/Th dating of small CacO3 nodules (oogons of characeae) extracted from a fine grained tufa layerdirectly underlying the peat (GEOTOP Montreal). This result reinforces the allocation of the the Waziers interglacial sequence tothe Eemian (a radiocarbon measurement undertaken earlier on the peat logically gave an age prior to 43 500 BP). The presence oflithic artefacts and aurochs bones with anthropic fractures lead to design an extended archaeological excavation in order to confirmthe existence of a second site with Eemian human occupation in Northern France.In 2013, a complete overview of the geomorphology of the valley has been carried out by geophysical research using two differentmethods. An EM31 connected to a GPS was used to record the mean electrical conductivity of soils (continuous, 4-6 m deep)and to obtain a map with the location of the Eemian channel. Two electric panels were made perpendicularly to the palaeochannelin order to observe the morphology of the valley and the fluvial deposits. Based on this information, a series of core drillings allowedto build five transects.In 2014, during a first campaign, 41 m2 were excavated. The geomorphology of the site was investigated and continuous samplingcolumns of the stratigraphical sequence were undertaken for paleontological studies on mollusc, pollen and mammal assemblages(presently in progress). The palaeoenvironmental reconstruction will be completed by the study of the rich corpus of woodand other organic remains such as hazelnuts or insects preserved in the peat. Thanks to the discovery of some lithic artefacts andhuman activity traces on faunal remains (cut maks on beaver tibia, burnt bones, aurochs bones typical breakage patterns) found insitu in fluvial deposit, the presence of human occupation during the Eemian at Waziers has been definitively demonstrated. Datings(OSL) are in progress and a second field campaign will take place this summer.References: [1] Gamble, C., 1986. The Palaeolithic Settlement of Europe. Cambridge University Press.[2] Roebroeks, W.,Conard, N. J., Van Kolfschoten, T., 1992. Dense forests, cold steppes, and the palaeolithic settlement of northern europe [andcomments and replies]. Current Anthropology, 33, 551-586.[3] Roebroeks, J.W.M., Tuffreau, A., 1999. Palaeoenvironment andsettlement patterns of the Northwest European Middle Palaeolithic. In: Roebroeks, W., Gamble, C. (red.), The MiddlePalaeolithic Occupation of Europe, pp. 121-138.[4] Antoine, P., Limondin-Lozouet, N., Auguste, P., Locht, J.-L., Galheb, Reyss,J.-L., Escude, É., Carbonel, P., Mercier, N., Bahain, J.-J., Falguères, C., Voinchet, P., 2006. Le tuf de Caours (Somme, France miseen évidence d’une séquence eemienne et d’un site paléolithique associé. Quaternaire, 17,4, 281-320.

Objective We sought to evaluate the added value of heart fatty acid protein assay (HFABP) for rapid diagnosis of acute myocardial infarction in a prospective cohort of emergency department (ED) patients with acute chest pain. Methods High-sensitivity cardiac troponin T (hs-cTnT; Roche Diagnostics, Meylan, France) and HFABP (Randox, Mauguio, France) were blindly assayed from venous blood samples obtained at admission. Diagnosis was made by 2 ED physicians using all available data and serial cardiac troponin I as the biochemical standard. Diagnostic performances of HFABP combined with hs-cTnT were assessed using logistic regression. Analysis was conducted in all patients and in patients without ST-elevation myocardial infarction. Results A total of 181 patients were included (age, 61 ±17 years; male sex, 66%). Acute myocardial infarction occurred in 47 (25.9%) patients, including non–ST-elevation myocardial infarction in 31 (17.1%). The receiver operating characteristic area under the curve was 0.893 for hs-cTnT levels at presentation (95% confidence interval, 0.812-0.974) and 0.908 (95% confidence interval, 0.839-0.977) for the combination of hs-cTnT and HFABP, with no significant ( P =.07). Adding HFABP to hs-cTnT increased both sensitivity and negative predictive value (NPV) for non–ST-elevation myocardial infarction diagnosis, with about 13% and 3% increase, respectively, leading to a sensitivity of 97% and an NPV of 99%. Conclusion The assessment of HFABP at ED admission adds incremental value to initial hs-cTnT. The increase of sensitivity and NPV without sacrificing the specificity and positive predictive value in patients with chest pain with noncontributive electrocardiogram could potentially allow safe and early rule out of acute myocardial infarction without the need for further serial troponin testing.

The nonclassical HLA-G primary transcript is alternatively spliced to generate several mRNAs that have the capacity to encode four membrane bound isoforms, namely HLA-G1, -G2, -G3, and -G4 and two soluble isoforms HLA-G5 and -G6. We aimed at defining the capacity of full length and truncated soluble HLA-G transcripts to be translated in human cell lines. Our study of HLA-G alternative transcripts in various human tissues led us to identify a new splice variant of the HLA-G mRNA, named G7, in which open reading frame continues in intron 2. Due to the presence of a stop codon within intron 2, HLA-G7 transcripts retain the capacity to be translated as soluble truncated HLA-G proteins bearing the alpha1 domain linked to two specific aminoacids encoded by intron 2. Expression vectors containing cDNAs encoding HLA-G5, -G6, and -G7 isoforms were transfected into human cell lines. The presence of translated HLA-G5, -G6, and -G7 proteins was detected in protein extracts of transfected cells by Western blot and immunoprecipitation, but only the full length HLA-G5 soluble isoform could be clearly detected as a secreted protein in both transfected cells supernatants and body fluids.

The expression pattern of MHC class I genes in trophoblast cells at the feto-maternal interface is thought to be the basis of the maintenance of pregnancy by protecting the fetus from maternal immune rejection. Transcription of classical HLA class I genes is low or undetectable in most trophoblast cells as well as in JEG-3 and BeWo trophoblast-derived choriocarcinoma cells. The aim of this study was to characterize the regulatory mechanisms that repress HLA-A transcription in these cell types. We show that the -335 to ATG region of the HLA-A11 gene promoter is inactive in JEG-3 and BeWo cells while able to control efficient reporter gene transcription in other cell types, indicating that this region is the target for downregulation of HLA-A expression in choriocarcinoma cell lines. The regulatory sequence involved in HLA-A gene repression was further mapped to a proximal regulatory element within the -107 to +2 ATG region of the promoter. We show that the HLA-A promoter activity cannot be induced by interferon-gamma (IFN-gamma) and that exogenous MHC class II transactivator CIITA is able to induce HLA class I promoter activity in these cells. Stringent transcriptional regulatory mechanisms, implicating the lack of basal and IFN-gamma-inducible class I promoter activity, are thus involved in the downregulation of HLA-A expression in JEG-3 and BeWo trophoblast-derived choriocarcinoma cells.

‘Human Immunoglobulin Heavy Variable Genes’, the fourth report of the ‘IMGT Locus on Focus’ section, comprises five tables entitled: (1) ‘Number of human germline IGHV genes at 14q32.33 and potential repertoire’; (2) ‘Human germline IGHV genes at 14q32.33’; (3) ‘Human IGHV orphons on chromosome 15 (15q11.2)’; (4) ‘Human IGHV orphons on chromosome 16 (16p11.2)’, and (5) ‘Human IGHV allele table’. These tables are available at the IMGT Marie-Paule page from IMGT, the international ImMunoGeneTics database (http://imgt.cnusc.fr:8104) created by Marie-Paule Lefranc, Université Montpellier II, CNRS, France.

Many stochastic models and analysis techniques have been proposed in the literature during the last two decades for the performance evaluation of parallel and distributed systems. However, few of them are directly applicable to practical systems which are generally too complex. In this paper, we analyze performances of the master–slave computational model, one of the most commonly used models in parallel and distributed computations. We propose a hybrid analytical approach by using techniques from the theories of both stochastic task graphs and queueing networks. We apply this method to the analysis of a computational chemistry application running on a Transputer based system. The proposed method turns out to be not only very efficient in time for large systems but also very accurate compared to measuring.

Multiple studies have evaluated copeptin, a surrogate for arginine vasopressin, in the diagnosis of acute myocardial infarction (AMI) with mixed results. A systematic review and collaborative meta-analysis were performed for diagnosis of AMI and assessment of prognosis in patients presenting to the emergency department with chest pain. MEDLINE/PubMed, Cochrane CENTRAL, and EMBASE were searched for studies assessing copeptin in such patients. Study investigators were contacted, and many provided previously unpublished data. Random-effects methods were used to compare the data for copeptin, troponin, and their combination. There were a total of 9,244 patients from the 14 included studies. Mean age was 62 years; 64% were men; and 18.4% were ultimately diagnosed with AMI. Patients with AMI had a higher presentation copeptin level than those without AMI (22.8 vs 8.3 pmol/L, respectively, p0.001). Although troponin had better diagnostic accuracy than copeptin for AMI, the combination of copeptin and troponin significantly improved the sensitivity (0.905 [0.888 to 0.921] vs 0.686 [0.661 to 0.710], respectively, p 0.001) and negative predictive value (0.97 [0.964 to 0.975] vs 0.93 [0.924 to 0.936], respectively, p0.001) compared with troponin alone. Elevation in copeptin carried a similar risk of all-cause mortality to an elevation in troponin (odds ratio 5.84 vs 6.74, respectively, p = 0.67). In conclusion, copeptin not only identifies patients at risk of all-cause mortality, but its addition to troponin improved the sensitivity and negative likelihood ratio for diagnosis of AMI compared with troponin alone. Thus, copeptin may help identify patients who may be safely discharged early from the emergency department.

BACKGROUND We evaluated the essential assay characteristics of the newly developed, fully automated Kryptor Copeptin assay including the assay performances and the clinical implications in parallel with the dosage of the cardiac Troponin I (cTnI) in patients presenting to the Emergency Department with chest pain with or without ECG abnormalities. METHODS Analytical performance of the B-R-A-H-M-S Copeptin Kryptor was carried out according to the CLSI protocol EP17-A, volume 24, number 34 [3] including linearity imprecision, determination of quantification, and detection limits. An evaluation of the clinical concordance between cTnI and copeptin results was performed on consecutive patients, with chest pain suggestive of acute coronary syndromes (ACS), admitted to the Emergency Department of our hospital. RESULTS At a total imprecision of 20% (which corresponds to the limit of the quantification) and the level giving a CV of 10%, the functional sensitivity was approximately 10.4 and 23 pmol/L, respectively. The mean detection limit for the B-R-A-H-M-S Copeptin Kryptor assay was 8 pmol/L (range 5.57-10.37 pmol/L) in our study. Clearly, the combination of the cTnI and copeptin markers at the decision limit of 0.04 microg/L and 10.4 pmol/L, respectively, improves the diagnosis of exclusion of ACS. CONCLUSIONS The combination of negative troponin and negative copeptin (< quantification limit) could improve rapid sorting of ACS patients in an emergency. The Copeptin Kryptor assay is a useful diagnosis tool to rule out ACS and might be further enhanced by the recent development of sensitive troponins.

Enterococcus faecalis (E. faecalis) has become a major leading cause of nosocomial endocarditis. Treatment of such infections remains problematic and new therapeutic options are needed. Nine E. faecalis strains were tested: six obtained from patients presenting endocarditis, one with isolated bacteremia, and two reference strains. Antibiotics included daptomycin, alone or in combination, linezolid, tigecycline, rifampicin, gentamicin, teicoplanin, ceftriaxone and amoxicillin. Time-kill studies included colony counts at 1, 4 and 24 h of incubation. Significant bactericidal activity was defined as a decrease of ≥3log10CFU/ml after 24 h of incubation. Antibiotics were tested at a low (10(6) CFU/ml) and high (10(9) CFU/ml) inoculum, against exponential- and stationary-phase bacteria. We also performed time kill studies of chemically growth arrested E. faecalis. Various pH conditions were used during the tests. In exponential growth phase and with a low inoculum, daptomycin alone at 60 µg/ml and the combination amoxicillin-gentamicin both achieved a 4-log10 reduction in one hour on all strains. In exponential growth phase with a high inoculum, daptomycin alone was bactericidal at a concentration of 120 µg/ml. All the combinations tested with this drug were indifferent. In stationary phase with a high inoculum daptomycin remained bactericidal but exhibited a pH dependent activity and slower kill rates. All combinations that did not include daptomycin were not bactericidal in conditions of high inoculum, whatever the growth phase. The results indicate that daptomycin is the only antibiotic that may be able of overcoming the effects of growth phase and high inoculum.

A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure–activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing–remitting multiple sclerosis.

We evaluated the essential assay characteristics of the newly developed, fully automated Kryptor Copeptin assay including the assay performances and the clinical implications in parallel with the dosage of the cardiac Troponin I (cTnI) in patients presenting to the Emergency Department with chest pain with or without ECG abnormalities.Analytical performance of the B-R-A-H-M-S Copeptin Kryptor was carried out according to the CLSI protocol EP17-A, volume 24, number 34 [3] including linearity imprecision, determination of quantification, and detection limits. An evaluation of the clinical concordance between cTnI and copeptin results was performed on consecutive patients, with chest pain suggestive of acute coronary syndromes (ACS), admitted to the Emergency Department of our hospital.At a total imprecision of 20% (which corresponds to the limit of the quantification) and the level giving a CV of 10%, the functional sensitivity was approximately 10.4 and 23 pmol/L, respectively. The mean detection limit for the B-R-A-H-M-S Copeptin Kryptor assay was 8 pmol/L (range 5.57-10.37 pmol/L) in our study. Clearly, the combination of the cTnI and copeptin markers at the decision limit of 0.04 microg/L and 10.4 pmol/L, respectively, improves the diagnosis of exclusion of ACS.The combination of negative troponin and negative copeptin (quantification limit) could improve rapid sorting of ACS patients in an emergency. The Copeptin Kryptor assay is a useful diagnosis tool to rule out ACS and might be further enhanced by the recent development of sensitive troponins.

The aim of the present study was, first, to evaluate the prognostic value of mid-regional proadrenomedullin (proADM) in emergency department (ED) patients with a diagnosis of community acquired pneumonia (CAP) and, second, to analyze the added value of proADM as a risk stratification tool in comparison with other biomarkers and clinical severity scores. We evaluated proADM, C-reactive protein and procalcitonin, along with the Pneumonia Severity Index (PSI) score in consecutive CAP patients. Ability to predict 30-day mortality was assessed using receiver operating characteristic curve analysis, logistic regression, and reclassification metrics for all patients and for patients with high PSI scores. Primary outcome was death within 30 days after ED admission. One hundred nine patients were included (median age [interquartile range] 71 [27] years). Nine patients died within 30 days. A significant correlation between proADM and PSI was found (ρ = 0.584, P.001). PSI and proADM levels were significantly predictive of risk of death. In patients with PSI class IV and V (score90), proADM levels significantly predicted risk of death (OR [95% CI], 4.681 (1.661-20.221), P = .012) whereas PSI score did not (P = .122). ROC(AUC) (area under the receiver operating characteristic curve) was higher for proADM than for PSI score (ROC(AUC) [95% CI], 0.810 [0.654-0.965] and 0.669 [0.445-0.893] respectively). Reclassification analysis revealed that combination of PSI and proADM allows a better risk assessment than PSI alone (P = .001). MR-proADM may be helpful in individual risk stratification of CAP patients with a high PSI score in the ED, allowing to a better identification of patients at risk of death.

Multiple factors may contribute to the observed survival variability following in-hospital cardiopulmonary resuscitation (CPR). While in-hospital CPR is most often performed on patients lying on a bed or stretcher, CPR training uses primarily manikins placed on the floor. We analyzed the quality of external chest compressions (ECC) in simulated cardiac arrest scenarios occurring both on a stretcher and on the floor.Prospective cross-over simulation study enrolling ED nurses and nurse's aides as part of an annual evaluation. Simulated CPR was performed in the 2 rescuer-mode for 2 min, both kneeling on the floor, and standing beside a knee high stretcher. The order of position was randomized. ECC parameters were compared.ED nurses (n=48) and nurse's aides (n=26) performed 128 scenarios. Mean ECC depth was 32 ± 13 mm on the floor and 27 ± 11 mm on a stretcher (∆: 5 mm, 95%CI [3-7], P.001). Participants last trained within a year (n=17) developed deeper ECCs than their colleagues (n=47) in both positions (floor: 39 ± 12 mm vs stretcher: 34 ± 11 mm (p=0.016) for those trained within the year, and floor: 29 ± 12 mm vs stretcher: 24 ± 10 mm (P.001) for those trained over a year ago).The quality of chest compressions performed by ED staff was below 2005 guideline standards, with decreased ECC depth during CPR on a stretcher. Annual refresher courses should be implemented in the ED, with a focus on obtaining required ECC depth while standing next to a stretcher.

Background Acute alcohol intoxication is a frequent cause of emergency department (ED) visits. Evaluating a patient's alcohol intoxication is commonly based on both a physical examination and determination of blood alcohol concentration (BAC). Objective To demonstrate the feasibility and usefulness of using a last-generation infrared breath analyzer as a non-invasive and rapid screening tool for alcohol intoxication in the ED. Methods Adult patients suspected of acute alcohol intoxication were prospectively enrolled over 10 days. Breath alcohol concentrations (BrAC) were measured using a handheld infrared breath analyzer. BAC was determined simultaneously by automated enzymatic analysis of a venous blood sample. The relationship between BAC and BrAC values was examined by both linear regression and Bland-Altman analysis. Results The study included 54 patients (mean age 40±14 years, sex ratio M/F of 3/1). Breath and blood alcohol concentrations ranged from 0 to 1.44mg/L and from 0 to 4.40g/L (0–440mg/dL), respectively. The mean individual BAC/BrAC ratio was 2615±387, 95% confidence interval 2509–2714, which is 30% higher than the legal ratio in France (2000). The correlation between both measurements was excellent: r =0.95 (0.92–0.97). Linear regression revealed BAC=0.026+1.29 (BrAC×2000) and BAC=0.026+0.99 (BrAC×2615). Mean BAC-BrAC differences and limits of agreement were 0.49 g/L [−0.35, 1.34] (or 49 mg/dL [−35, 134] and 0.01 g/L [−0.68, 0.71] (or 1 mg/dL [−68, 71]), for the 2000 and 2615 ratios, respectively. Conclusion The calculated conversion coefficient provided a satisfactory determination of blood alcohol concentration. Breath alcohol testing, using appropriate BAC/BrAC conversion, different from the legal BAC/BrAC, could be a reliable alternative for routine screening and management of alcohol intoxication in the ED.

We designed and synthesized conjugates between pyrrole-imidazole polyamides and seco-CBI that alkylate within the coding regions of the histone H4 genes. DNA alkylating activity on the histone H4 fragment and cellular effects against K562 chronic myelogenous leukemia cells were investigated. One of the conjugates, 5-CBI, showed strong DNA alkylation activity and good sequence specificity on a histone H4 gene fragment. K562 cells treated with 5-CBI down-regulated the histone H4 gene and induced apoptosis efficiently. Global gene expression data revealed that a number of histone H4 genes were down-regulated by 5-CBI treatment. These results suggest that sequence-specific DNA alkylating agents may have the potential of targeting specific genes for cancer chemotherapy.

TNF-receptor associated factors (TRAFs) are the molecules that upon engagement of the TNF-receptor (TNFR) by a TNF-family ligand come first in contact with the activated TNFR, initially acting as docking molecules for kinases and other effector proteins that are recruited to the activated receptor. TRAFs later regulate the subcellular relocalization of the receptor-ligand complex and finally they modulate the extent of the response by controlling the degradation of key proteins in the pathway. In this chapter, we review the involvement of different TRAF family members in the etiology of a variety of pathologies and address the question of whether the use of TNFR-mimic-peptides or small molecule modulators targeting TRAFs might be suitable for therapeutic intervention, discussing the advantages and disadvantages of this strategy.

The TNF-receptor associated factor (TRAF) domain (TD), also known as the meprin and TRAF-C homology (MATH) domain is a fold of seven anti-parallel p-helices that participates in protein-protein interactions. This fold is broadly represented among eukaryotes, where it is found associated with a discrete set of protein-domains. Virtually all protein families encompassing a TRAF/MATH domain seem to be involved in the regulation of protein processing and ubiquitination, strongly suggesting a parallel evolution of the TRAF/MATH domain and certain proteolysis pathways in eukaryotes. The restricted number of living organisms for which we have information of their genetic and protein make-up limits the scope and analysis of the MATH domain in evolution. However, the available information allows us to get a glimpse on the origins, distribution and evolution of the TRAF/MATH domain, which will be overviewed in this chapter.

El pdf es la versión post-print., The TNF-receptor associated factor (TRAF) domain (TD), also known as the meprin and TRAF-C homology (MATH) domain is a fold of seven anti-parallel ß-helices that participates in protein-protein interactions. This fold is broadly represented among eukaryotes, where it is found associated with a discrete set of protein-domains. Virtually all protein families encompassing a TRAF/MATH domain seem to be involved in the regulation of protein processing and ubiquitination, strongly suggesting a parallel evolution of the TRAF/MATH domain and certain proteolysis pathways in eukaryotes. The restricted number of living organisms for which we have information of their genetic and protein make-up limits the scope and analysis of the MATH domain in evolution. However, the available information allows us to get a glimpse on the origins, distribution and evolution of the TRAF/MATH domain, which will be overviewed in this chapter., We are indebted to the Ministerio de Educación y Ciencia (BES2005-8383), Programa Ramón y Cajal, SAF2004-7675 and NIH grants DK67515, HD044803 and AI070859.

FTY720 is an immunomodulator with demonstrated efficacy in a phase II trial of relapsing multiple sclerosis. FTY720-phosphate, the active metabolite generated upon phosphorylation in vivo, acts as a potent agonist on four of the five known sphingosine-1-phosphate (S1P(1)) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P(1) receptor. Due to its selectivity and pharmacokinetic profile, AUY954 is an excellent pharmacological probe of S1P(1)-dependent phenomena. Oral administration of AUY954 induces a profound and reversible reduction of circulating lymphocytes and, in combination with RAD001 (Certican/Everolimus, an mTOR inhibitor), is capable of prolonging the survival of cardiac allografts in a stringent rat transplantation model. This demonstrates that a selective agonist of the S1P(1) receptor is sufficient to achieve efficacy in an animal model of transplantation.

The HLA-G molecule is a non-classical HLA class I antigen selectively expressed by trophoblastic cells that invade the maternal decidua during human pregnancy. HLA-G is believed to contribute to tolerance of the semi-allogeneic fetus by inhibiting maternal immune responses. Similarly, HLA-G expression in tumour cells may favour their escape from host immune surveillance. This study investigated HLA-G expression in human mammary tumours. Immunohistochemical analysis of cryo-preserved and paraffin-embedded breast tissue biopsies, using two HLA-G-specific antibodies, revealed that unlike non-cancerous breast tissue in the vicinity of the tumour, 14 out of 36 breast cancer lesions selectively expressed HLA-G. HLA-G expression was significantly more frequent in lesions that were highly infiltrated by host immune cells, thus correlating HLA-G activation with inflammation. Further histological and double-staining immunofluorescence analysis attributed HLA-G expression mainly to tumour epithelial cells and to subsets of infiltrating CD68+ and CD8+ cells. RT-PCR analysis suggested that HLA-G was activated at the transcriptional level in breast tumours. The presence of ILT2 (Ig-like transcript 2) killing inhibitory receptors known to interact with HLA-G was also demonstrated in host immune cells that infiltrate breast cancer lesions. These results indicate that HLA-G is up-regulated at high frequencies in human breast cancer, where it may impair efficient anti-tumour immunity.

Expression of the nonclassical HLA class I antigen, HLA-G, is tightly regulated. HLA-G physiologic expression is mostly restricted to some placental and thymic cell types. Only few established cell lines express HLA-G in vitro. Cytokine-induced expression of HLA-G is hardly observed and also depends on the cell lineage. We assessed expression and cytokine regulation of HLA-G in primary cultures derived from human thymus and amnion epithelial cells, which also express HLA-G in vivo. We show that HLA-G cell surface expression is maintained, but decreases gradually, in primary cultures derived from human thymus and amnion epithelial cells. We also show that IFN-gamma re-induces HLA-G cell surface expression and upregulates classical class I gene expression in both primary cultures and in a thymus derived cell line. We further show that IFN-gamma also upregulates levels of HLA-G transcripts in TEC primary cultures. This study provides evidence that IFN-gamma induction of HLA-G expression occurs in the human amnion and the thymus, and is mediated at the transcriptional level in these tissues. These results also suggest a role for the microenvironment in regulating HLA-G in vivo gene expression in the thymus and amnion membrane.

Type I interferons display a broad range of immunomodulatory functions. Interferon beta increases gene expression at the transcriptional level through binding of factors to the interferon-stimulated response element (ISRE) within the promoters of interferon-inducible genes, such as HLA class I. Despite mutation of the class I ISRE sequence within the nonclassical HLA-G class I gene promoter, we show that interferon beta enhances both transcription and cell surface expression of HLA-G in trophoblasts and amniotic and thymic epithelial cells that selectively express it in vivo. Deletion and mutagenesis analysis of a putative interferon-regulatory factor (IRF)-1 binding site within the HLA-G promoter show that HLA-G transactivation is mediated through an ISRE sequence 746 base pairs upstream from ATG, which is distinct from the interferon-responsive element described within proximal classical class I gene promoters. Electrophoretic mobility shift analysis and supershift analysis further demonstrate that interferon-responsive transcription factors, including IRF-1, specifically bind to the HLA-G ISRE. Our results provide evidence that IRF-1 binding to a functional ISRE within the HLA-G promoter mediates interferon beta-induced expression of the HLA-G gene. These observations are of general interest considering the implication of HLA-G in mechanisms of immune escape involved in fetal-maternal tolerance and other immune privilege situations.

The discrimination between Staphylococcus epidermidis strains that contaminate and infect blood cultures is a daily challenge for clinical laboratories. The results of PCR detection of putative virulence genes were compared for contaminating strains, sepsis-related strains, catheter strains, and saprophytic strains. Multiplex PCR was used to explore the atlE gene, which is involved in initial adherence, the intercellular adhesion gene cluster ( ica ), which mediates the formation of the biofilm, and the agrA , sarA , and mecA genes, which might contribute to the pathogenicity of S. epidermidis . Whereas the atlE , agrA , and sarA genes were almost ubiquitously amplified, the ica and mecA genes were detected significantly more in infecting strains than in contaminating strains ( P ≤ 0.02) and thus appeared to be related to the potential virulence of S. epidermidis .

HLA-G molecule is thought to play a major role in down-regulating the maternal immune response by inhibiting NK and T cell cytolytic activities. We examined the molecular regulatory mechanisms that may control the restricted expression pattern of the HLA-G gene. We first analyzed protein interactions between nuclear extracts from the HLA-G-positive JEG-3 choriocarcinoma and the HLA-G-negative NK-like YT2C2 cell lines to a 244 bp regulatory element located 1.2 kb from the HLA-G gene, previously shown to direct HLA-G expression in transgenic mouse placenta. This allowed characterization of cell-specific DNA-protein interactions that could account for differential cell-specific expression of the HLA-G gene. In particular two DNA-protein complexes were exclusively observed in YT2C2, suggesting that this HLA-G regulatory element is a target for putative cell-specific repressor factors. We further mapped nuclear factor binding sites to a 70 bp fragment in the upstream region of the regulatory element. We then investigated the effect of IFN-gamma on HLA-G gene expression. HLA-G cell surface expression was enhanced by IFN-gamma treatment in JEG-3 and U937 cell lines and peripheral blood monocytes while no effect was observed in tera-2 teratocarcinoma cell line. HLA-G transcriptional activity was increased only in JEG-3 and U937 cell lines. Activity of the 1.4-kb HLA-G promoter region was unchanged after IFN-gamma treatment in JEG-3 and Tera-2. These results suggest that both post-transcriptional and transcriptional mechanisms implicating IFN-responsive regulatory sequences outside the 1.4 kb-region are involved in IFN-gamma gene activation of the HLA-G gene.