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IL-9 is involved in various T cell-dependent inflammatory models including colitis, encepahlitis, and asthma. However, the regulation and specificity of IL-9 responsiveness by T cells during immune responses remains poorly understood. Here, we addressed this question using two different models: experimental colitis induced by transfer of naive CD4+ CD45RBhigh T cells into immunodeficient mice, and OVA-specific T cell activation. In the colitis model, constitutive IL-9 expression exacerbated inflammation upon transfer of CD4+ CD45RBhigh T cells from WT but not from Il9r-/- mice, indicating that IL-9 acts directly on T cells. Suprisingly, such naive CD4+ CD45RBhigh T cells failed to express the Il9r or respond to IL-9 in vitro, in contrast with CD4+ CD45RBlow T cells. By using OVA-specific T cells, we observed that T cells acquired the capacity to respond to IL-9 along with CD44 upregulation, after long-lasting (5 to 12 days) in vivo antigenic stimulation. Il9r expression was associated with Th2 and Th17 phenotypes. Interestingly, in contrast to the IL-2 response, antigen restimulation downregulated IL-9 responsiveness. Taken together, our results demonstrate that IL-9 does not act on naive T cells but that IL-9 responsiveness is acquired by CD4+ T cells after in vivo activation and acquisition of memory markers such as CD44.

The stochastic finite element procedure presented in this paper consists in representing in a probabilistic form the response of a system whose material properties and loading are random. Each random variable is expanded into Hermite polynomial series. The response is expanded onto the so-called polynomial chaos. The coefficients of the expansion of the response (e.g. the nodal displacement vector) are obtained by a Galerkin-type method in the space of probability. This stochastic finite element procedure is applied to the parametric study of the reliability of a foundation on a two-layer elastic soil mass. The method reveals accurate and more efficient than a direct coupling between a finite element code and a probabilistic code.

Gas hydrate quantification using acoustic data requires proper knowledge of the mineralogy of their host sediment. In this paper, a petrophysical model allowing GH quantification at sites where mineralogy profiles are absent is proposed. This approach is applied to a high gas flux pockmark system in the Gulf of Guinea where in-situ acoustic and geotechnical measurements together with core measurements could have been correlated and tied to seismic data. Projections of the in-situ measurements on seismic profiles have shown that the study area not only accommodates zones of shallow and dense GH; but also zones where solid hydrate and free gas coexist as well as pockets of free gas. Further analysis of several seismic profiles has allowed illustrating the detailed GH occurrence zone within the study area, estimate its volume and its occupancy ratio of the pockmark. Correlations between GH content and 3D bathymetry sections have allowed to draw a link between different GH contents and the morphology of the pockmark, which also shares similarities with the morphology of the GH occurrence zone it accommodates.

Background In workers exposed mostly to laboratory animals (LA), symptoms may be due to irritants or allergens. Correct aetiological diagnosis is important for health surveillance. Objectives This study aims to test whether work-related (WR) allergen-induced symptoms are associated with a cytokine profile distinct from that due to irritants. Methods In a cross-sectional study (n=114), WR respiratory and/or skin symptoms were assessed through a standardised clinical examination and sensitisation to rat and/or mouse allergen determined by serum immunoglobulin E. Serum cytokine concentrations were measured by multiplex assays. The predefined cytokine profiles ‘sensitiser’ (interleukin (IL)-4, IL-5, IL-13, eotaxin-1) and ‘irritation’ (IL-8, IL-17A, IL-17F, IL-22) were considered positive, when ≥3 concentrations exceeded the 95th percentile of the asymptomatic non-sensitised group. Results were examined by hierarchical clustering analyses (HCA) and multiple linear regression. Explorative analyses were carried out for nine additional cytokines. Exposure to allergens and endotoxin was assessed in a subpopulation. Results The prevalence of the profile ‘irritation’ was comparable in 28 symptomatic non-sensitised workers and 71 asymptomatic non-sensitised workers. HCA showed that nearly all symptomatic non-sensitised workers were gathered in two subclusters, characterised by high IL-17A levels, but different IL-8 levels. Multiple linear regression identified drug consumption and current complaints as confounders. Sensitised subjects were too few (n=14) for testing the profile ‘sensitiser’. Conclusions In this unselected population of LA workers, the profile ‘irritation’ did not prove to be a valuable health surveillance tool. Low power precluded assessment of the profile ‘sensitiser’. The increased IL-17A concentration may originate from irritative constituents of organic dust.

Persistent oxidative stress plays an important role in a variety of pathologies, and the search for an effective and well tolerated antioxidant agent continues. Molecular hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. The non-specific mechanism of hydrogen as a therapeutic antioxidant gives it broad therapeutic potential across a wide range of medical applications, as has been shown by a substantial volume of preclinical data, as well as a growing body of clinical evidence. This review provides an overview of the therapeutic potential of hydrogen, in ageing and wellness applications as well as medical applications, including acute ischemia/reperfusion injury, inflammation and ulceration, metabolic disorders, neurodegenerative disorders, and cancer (anti-cancer effects, radiation toxicities, and side effects of cisplatin) with an emphasis on clinical data. Overall, this review shows that hydrogen is an effective antioxidant, anti-inflammatory and cytoprotective agent.

Immunotherapy brings new hope to the fight against lung cancer. General immunostimulatory agents represent an immunotherapy strategy that has demonstrated efficacy with limited toxicity when delivered intratumorally. The goal of this study was to enhance the antitumor efficacy of unmethylated oligodeoxynucleotides containing CpG motifs (CpG) and polyinosinic-polycytidylic acid (poly I:C) double-stranded RNA following their local delivery in lung cancer by encapsulating them in liposomes. Liposomes encapsulation of nucleic acids could increase their uptake by lung phagocytes and thereby the activation of toll-like receptors within endosomes. Liposomes were prepared using a cationic lipid, dioleoyltrimethylammoniumpropane (DOTAP), and dipalmitoylphosphatidylcholine (DPPC), the main phospholipid in lung surfactant. The liposomes permanently entrapped CpG but could not efficiently withhold poly I:C. Both poly I:C and CpG delayed tumor growth in the murine B16F10 model of metastatic lung cancer. However, only CpG increased IFN-γ levels in the lungs. Pulmonary administration of CpG was superior to its intraperitoneal injection to slow the growth of lung metastases and to induce the production of granzyme B, a pro-apoptotic protein, and IFNγ, MIG and RANTES, T helper type 1 cytokines and chemokines, in the lungs. These antitumor activities of CpG were strongly enhanced by CpG encapsulation in DOTAP/DPPC liposomes. Delivery of low CpG doses to the lungs induced increased inflammation markers in the airspaces but the inflammation did not reach the systemic compartment in a significant manner. These data support the use of a delivery carrier to strengthen CpG antitumor activity following its pulmonary delivery in lung cancer.

IL-22 has a detrimental role in skin inflammatory processes, for example in psoriasis. As transcription factor, AhR controls the IL-22 production by several cell types (i.e. Th17 cells). Here, we analyzed the role of Ahr in IL-22 production by immune cells in the inflamed skin, using an imiquimod-induced psoriasis mouse model. Our results indicate that IL-22 is expressed in the ear of imiquimod-treated Ahr(-/-) mice but less than in wild-type mice. We then studied the role of AhR on three cell populations known to produce IL-22 in the skin: γδ T cells, Th17 cells, and ILC3, and a novel IL-22-producing cell type identified in this setting: CD4(-) CD8(-) TCRβ(+) T cells. We showed that AhR is required for IL-22 production by Th17, but not by the three other cell types, in the imiquimod-treated ears. Moreover, AhR has a role in the recruitment of γδ T cells, ILC3, and CD4(-) CD8(-) TCRβ(+) T cells into the inflamed skin or in their local proliferation. Taken together, AhR has a direct role in IL-22 production by Th17 cells in the mouse ear skin, but not by γδ T cells, CD4(-) CD8(-) TCRβ(+) T cells and ILCs.

Introduction Coll2-1 est un peptide de 9 acides amines situe dans la triple helice du collagene de type II. Il s’agit d’un marqueur biologique de la degradation du cartilage. Coll2-1NO2 est la forme nitree de Coll2-1. Il est considere comme un marqueur de la degradation du cartilage associe a l’inflammation. Cette etude prospective non-interventionnelle et multicentrique avait comme objectif d’etudier les relations entre les marqueurs biologiques s-Coll2-1 et s-Coll2-1NO2 et la severite et la progression de la gonarthrose evaluee par la douleur, la fonction mais aussi les changements structurels a l’imagerie par resonance magnetique (IRM). Patients et methodes 116 sujets souffrant d’arthrose du genou ont ete suivis pendant 1 an. Les parametres suivants ont ete evalues a l’inclusion, apres 3, 6 et 12 mois : l’intensite de la douleur (Echelle Visuelle Analogique - EVA), l’activite globale de la maladie (EVA) et l’indice algo-fonctionnel KOOS (Knee injury and Osteoarthritis Outcome Score). Les changements structurels ont ete evalues en utilisant le score WORMS (Whole-Organ Magnetic Resonance Imaging Score) total et les sous-scores “cartilage”, “effusion” et “œdeme osseux”. Les patients ont ete classes en progresseurs cliniques selon les criteres OARSI-OMERACT et en progresseurs structurels s’ils presentaient une aggravation de plus de 1 point dans au moins 1 des sous-scores du WORMS et 2 points au WORMS total. Coll2-1 et Coll2-1NO2 ont ete mesures directement dans le serum par un dosage immunologique (Artialis SA, Liege, Belgique). Resultats A l’inclusion, S-Coll2-1 etait significativement correle avec les items « bursite » (r = 0,29, p Conclusion Les biomarqueurs du cartilage S-Coll2-1 et S-Coll2-1NO2 sont associes a plusieurs caracteristiques de l’arthrose du genou a l’IRM. Les valeurs seriques de S-Coll2-1NO2 sont egalement associees a une aggravation de la douleur au genou cible sur un an. Coll2-1 et Coll2-1NO2, en association avec d’autres caracteristiques structurelles ou cliniques pourraient aider a definir les phenotypes d’arthrose et les patients a risque de progression rapide.

Background:Coll2-1 is a peptide of 9 amino acid located in the triple helix of type II collagen molecule reflecting cartilage degradation (1). Coll2-1NO2 is the nitrated form of Coll2-1 and considered as a biomarker of the inflammatory-related cartilage degradation (2). This peptide is involved in osteoarthritis physiopathology since it was demonstrated that Coll2-1 induced synovitis in rat.Objectives:To identify if biochemical markers s-Coll2-1 and s-Coll2-1NO2 are associated to knee osteoarthritis (OA), focusing on pain, function as well as structural features assessed by MRI in various knee compartments and to assess their ability at predicting knee OA worsening.Methods:116 subjects with knee OA were followed during one year with pain, function and MRI evaluation (PRODIGE study,NCT02070224). Type II collagen-specific biomarker Coll2-1 and its nitrated form Coll2-1NO2 were directly measured in serum using immunoassays at baseline and after three, six and twelve months follow-up.Results:sColl2-1 and sColl2-1NO2 were associated to several baseline knee features quantified with Whole-Organ Magnetic Resonance Imaging Score (WORMS). S-Coll2-1 was significantly correlated with bursitis (r=0.29, PConclusion:Cartilage biomarkers s-Coll2-1 and s-Coll2-1NO2 are associated to several knee OA features quantified with WORMS scoring system on MRI. Serum values of Coll2-1NO2 are also associated to a worsening of target knee pain over one year. Coll2-1 and Coll2-1NO2, in association with other structural features, pain and function, could help at identifying OA phenotypes and patients at risk of OA worsening.References:[1]Mobasheri A, Lambert C, Henrotin Y. Coll2-1 and Coll2-1NO2 as exemplars of collagen extracellular matrix turnover - biomarkers to facilitate the treatment of osteoarthritis? Expert Rev Mol Diagn. 2019 Sep;19(9):803-812. doi: 10.1080/14737159.2019.1646641. Epub 2019 Sep 4.[2]Lambert C, Borderie D, Dubuc JE, Rannou F, Henrotin Y. Type II collagen peptide Coll2-1 is an actor of synovitis. Osteoarthritis Cartilage. 2019 Nov;27(11):1680-1691. doi: 10.1016/j.joca.2019.07.009. Epub 2019 Jul 17.Acknowledgments:PRODIGE study (NCT02070224) was performed in the framework of a convention between the Walloon region and ARTIALIS SA. (convention n°6905).Disclosure of Interests:Yves Henrotin Grant/research support from: HEEL, TILMAN, Berenice Costes Employee of: Artialis SA, Michel Malaise: None declared, Damien Loeuille: None declared, Thierry Conrozier Consultant of: LABRHA, SANOFI, MEDAC, Yves Maugars: None declared, Franz Pelousse Shareholder of: Sodiray, Jean-Marc Lemaire Shareholder of: Sodiray, Thibault Helleputte Shareholder of: DNAlytics, Cedric Tits Employee of: DNAlytics, Elisabeth Cobraiville Employee of: Artialis SA, Sebastien Pirson Employee of: Artialis, Laetitia Garcia Employee of: Artialis, Alain Labasse Employee of: Artialis SA, Anne-Christine Hick Employee of: Artialis SA

Introduction et but de l’etude Apres agression, l’acquisition d’une faiblesse musculaire est frequente et peut etre a l’origine de consequences fonctionnelles severes et durables, partiellement prevenues par la combinaison d’apports nutritionnels et d’activite physique adaptes. La securite de la mobilisation active n’est pas connue chez les patients dont les reserves physiologiques et la capacite a l’effort sont limitees. La mesure de la depense energetique (DE) peut constituer une information utile pour selectionner le mode de mobilisation le mieux adapte. L’objectif de cette etude est d’evaluer l’evolution de la DE des patients de soins intensifs au cours d’une mobilisation passive et d’une mobilisation active sur cycloergometre. Materiel et methodes Nous avons inclus les patients adultes hospitalises en soins intensifs pour plus de 24 heures ne presentant pas de contre-indication a la mobilisation. Le score de gravite SAPS III et le score fonctionnel musculaire MRC (faiblesse musculaire si Resultats et analyse statistique Douze patients (âge median 59 [53–73], 7 hommes, IMC median 24 [22–28], SAPS III median 64 [47–74], MRC median 49 [43–52]) ont participe a l’etude. Les variables cardiorespiratoires n’ont pas ete influencees par l’exercice. La dyspnee etait plus marquee apres mobilisation active que passive (EVN 5,0 [5,0–6,0] versus 3,5 [2,5–5,0], p Conclusion La mobilisation sur cycloergometre, qu’elle soit realisee activement ou passivement, n’est pas associee a un accroissement significatif de la DE chez le patient de soins intensifs agresse et stabilise sur le plan cardiovasculaire. Le rapport risque/benefice est donc clairement en faveur de l’utilisation du cycloergometre apres la phase initiale d’instabilite chez le patient agresse.

Initial management of comatose patients aims at maintaining vital functions to assess the etiology of coma and administer any specific treatments if required. Management is multidisciplinary. Caregivers play an important role to prevent and treat intensive care unit (ICU)-acquired complications including skin, bone and joint, muscle, lung, thromboembolic and vascular complications. Prolonged immobilization-related complications may rapidly occur in the comatose patients, requiring a rehabilitation program in the first days of ICU stay. The physiotherapist should be aware of the different etiologies of coma as well as their specific features during the acute phase, especially in case of intracranial hypertension since education of caregivers regarding patient’s specific positioning is mandatory. Additionally, the physiotherapist should adapt treatments to each comatose patient’s specificities, be able to assess consciousness level and develop all the different techniques contributing to the patient’s awakening. Early rehabilitation is mandatory to improve the physical and functional outcome of ICU patients as well as their final quality of life.

Management of early mobilisation (including electrostimulation) in adult and pediatric patients in the intensive care unit

Phosphorylation of the aquaporin-2 (AQP2) water channel at four COOH-terminal serines plays a central role in the regulation of water permeability of the renal collecting duct. The level of phosphorylation at these sites is determined by a balance between phosphorylation by protein kinases and dephosphorylation by phosphatases. The phosphatases that dephosphorylate AQP2 have not been identified. Here, we use large-scale data integration techniques to identify serine-threonine phosphatases likely to interact with AQP2 in renal collecting duct principal cells. As a first step, we have created a comprehensive list of 38 S/T phosphatase catalytic subunits present in the mammalian genome. Then we used Bayes’ theorem to integrate available information from large-scale data sets from proteomic and transcriptomic studies to rank the known S/T phosphatases with regard to the likelihood that they interact with AQP2 in renal collecting duct cells. To broaden the analysis, we have generated new proteomic data (LC-MS/MS) identifying 4538 distinct proteins including 22 S/T phosphatases in cytoplasmic fractions from native inner medullary collecting duct cells from rats. The official gene symbols corresponding to the top-ranked phosphatases (common names in parentheses) were: Ppp1cb (PP1-β), Ppm1g (PP2C), Ppp1ca (PP1-α), Ppp3ca (PP2-B or calcineurin), Ppp2ca (PP2A-α), Ppp1cc (PP1-γ), Ppp2cb (PP2A-β), Ppp6c (PP6C), and Ppp5c (PP5). This ranking correlates well with results of prior reductionist studies of ion and water channels in renal collecting duct cells.

Background The infectious risks of parenteral nutrition (PN) in critical illness are well described, although most literature predates tight glucose control (TGC) practice. The authors hypothesized that PN-related complications are ameliorated by TGC and are equivalent to those in enteral nutrition (EN) patients. Methods A prospective cohort study of patients admitted to the surgical intensive care unit was conducted, comparing PN and EN patients. TGC target was 80 to 110 mg/dL. Univariate and multivariate logistic regression was used to explore the association between infectious outcomes and PN use. Results One hundred fifty-five patients were studied. Mean daily glucose values were lower for the PN group than for the EN patients (118.2 vs 125.6 mg/dL, P = .002). Nonetheless, the incidence of bloodstream infection and catheter-related bloodstream infection was significantly associated with the administration of PN. In a multivariate logistic regression model, PN was associated with a >4-fold increase in the odds of having a catheter-related bloodstream infection (odds ratio, 4.48; 95% confidence interval, 1.14–17.49; P = .03). Conclusions Despite the successful implementation of TGC, PN is still a significant risk factor for infectious complications among surgical intensive care unit patients.

Structural calculation, and more especially design, is widely based on mechanical computations from characteristic values of design variables and from the so-called partial (safety) factors listed in the design rules. These design rules are the results of both designer know-how and epistemic knowledge. Their deterministic use hides the existence of the structural probability of failure due to several structural imperfections and uncertainties. Lots of structural failures are due to fatigue problems. This work aims at describing a probabilistic methodology for the calibration of partial factors for the design of structures subjected to potential fatigue failure. The general calibration procedure is based on the resolution of an optimisation problem. This solution can easily be found using optimisation algorithms when the mechanical model is explicit but it is very computer time expensive when the mechanical model is based on finite elements. This paper presents an original economical method to solve this o...

IL-9 contributes to lung inflammatory processes such as asthma, by promoting mast cell differentiation, B cell activation, eosinophilia, and mucus production by lung epithelial cells. The observation that IL-9 overexpressing mice show increased mast cell numbers in the intestinal mucosa suggests that this cytokine might also play a role in intestinal inflammation. In colons from IL-9 transgenic mice, the expression of Muc2, a major intestinal mucin gene, was up-regulated, together with that of CLCA3 chloride channel and resistin like α, which are goblet cell-associated genes. Additional IL-9 up-regulated genes were identified and included innate immunity genes such as angiogenin 4 and the PLA2g2a phospholipase A2, which are typical Paneth cell markers. Histochemical staining of Paneth cells by phloxine/tartrazine showed that IL-9 induces Paneth cell hyperplasia in Lieberkühn glands of the small intestine, and in the colonic mucosa, where this cell type is normally absent. Expression of Paneth cell markers, including angiogenin 4, PLA2g2a, and cryptdins, was induced in the colon of wild-type mice after two to four daily administrations of IL-9. By crossing IL-9 transgenic mice with IL-13−/− mice, or by injecting IL-9 into IL-4R−/− mice, we showed that IL-13 was required for the up-regulation of these Paneth cell-specific genes by IL-9. Taken together, our data indicate that Paneth cell hyperplasia and expression of their various antimicrobial products contribute to the immune response driven by TH2 cytokines, such as IL-9 and IL-13 in the intestinal mucosa.

The chloroplastic nicotinamide adenine dinucleotide phosphate-malate dehydrogenase (NADP-MDH) (EC 1.1.1.82), a key enzyme of photosynthetic carbon assimilation of the C4 NADP-malic enzyme type plants, is strictly regulated by light through the ferredoxin-thioredoxin system. It is inactive in the dark, in the oxidized form, and activated in the light by the reduction of specific regulatory disulfides. A site-directed mutagenesis approach allowed localization of the regulatory disulfides in the N- and C-terminal sequence extensions conserved in all the light-regulated chloroplastic malate dehydrogenases. These extensions do not exist in the permanently active NAD-dependent MDHs (EC 1.1.1.37). Biochemical characterization of the mutants and elimination of negative charges at the C-terminus provided evidence for auto-inhibition of the oxidized enzyme by its C-terminal end through interaction with the active site and showed that the more compact structure of the oxidized dimer was linked to the presence of the N-terminal disulfide. The recently published 3-dimensional structures of the oxidized enzyme confirmed the location of the regulatory disulfides and fully support the auto-inhibition hypothesis. Indeed, the C-terminus is trapped inside the active site, interacting with active-site residues, and the N-termini are inserted at the dimer contact area where they are bound by hydrophobic interactions with both subunits. The physiological function of such complex regulation is discussed.

Replication of statistically significant associations between single nucleotide polymorphisms (SNPs) and disease phenotypes has been problematic. One reason for conflicting observations may be failure to consider confounding factors, including gene-gene (epistatic) interactions. Our experience with the insertion/deletion polymorphism at -688 in the promoter region of plasminogen activator inhibitor (PAI-1) seems to support this contention and may foreshadow problems for genome-wide association scans, which tend to use unadjusted analytical methodologies. One hundred forty-nine patients withor =15% total body surface area (TBSA) burns, without significant nonburn-related trauma (injury severity scoreor =16), traumatic or anoxic brain injury or spinal cord injury who survived48 hours postadmission were enrolled under a protocol approved by the UT Southwestern and Parkland Hospital IRBs. Clinical data were collected prospectively and candidate polymorphisms in PAI-1 (-688), toll-like receptor 4 (+896), CD14 (-159), tumor necrosis factor-alpha (-308), and interleukin-6 (-174) were genotyped. The PAI-1 SNP was significantly associated (P-value for trend = 0.036) with risk for death when evaluated in isolation by unadjusted analysis. However, after adjustment for potential confounders using multiple logistic regression, only age, full-thickness burn size, and CD14 genotype (as previously reported) were associated with increased mortality. Genetic association analyses should be adjusted for interactions between multiple SNPs, injury or disease characteristics, and demographic variables. Increasingly sophisticated analytical methods will be required as gene-mapping studies transition from a candidate-gene based approach to genome-wide association scans.

We studied the effectiveness of lansoprazole and ranitidine in promoting gastric ulcer healing in a multicentre double-blind trial, by comparing the proportion of healed ulcers after 4 and 8 weeks of treatment. One hundred and fifty-eight patients were randomly given either ranitidine (150 mg each morning and at bedtime) or lansoprazole (30 mg each morning and placebo at bedtime). One hundred and twenty-eight patients completed the trial (62 taking lansoprazole, 66 taking ranitidine). Fifty-one (80%) of those treated with lansoprazole and forty-two (62%) of those treated with ranitidine had healed ulcers at 4 weeks (P < 0.05). Sixty-one (98%) patients who received lansoprazole and 57 (86%) who received ranitidine had healed ulcers at 8 weeks (P < 0.05). The observed differences were not significant in the intention-to-treat analysis. No serious adverse event was reported with lansoprazole.

SUMMARY Background: Lansoprazole and omeprazole are proton pump inhibitors which both strongly inhibit acid secretion, resulting in a significant increase in serum gastrin levels. However, no direct comparison of recommended doses (20 mg for omeprazole and 30 mg for lansoprazole) has been reported so far. Our aims were to compare the effects of omeprazole 20 mg/day and lansoprazole 30 mg/day on intragastric acidity and serum gastrin concentration in 12 healthy volunteers. Methods: The study was double-blind, randomized and placebo-controlled with a cross-over design. On the seventh day of each period, 24-hour intragastric pH was measured using a combined glass electrode placed in the proximal stomach. The last morning dose of each regimen was taken at the end of 24-hour pH monitoring; acid output and serum gastrin concentrations were then studied in the fasting state and after stimulation with pentagastrin (maximal acid output) and a meal (post-prandial gastrin response). Results: Compared to placebo, both drug regimens induced a sustained increase of 24-hour intragastric pH and significantly decreased basal and pentagastrin-stimulated acid secretion. Lansoprazole 30 mg was slightly more effective than omeprazole 20 mg in terms of time spent above pH 3 (P < 0.05). Accordingly post-prandial gastrin concentrations rose slightly more after lansoprazole than after omeprazole. All other differences were insignificant. Conclusions: Both lansoprazole 30 mg and omeprazole 20 mg induce potent and long-lasting acid inhibition, with few minor differences when the two proton pump inhibitors are used at standard doses.

Classically, drug penetration through the blood-brain barrier depends on the lipid solubility of the substance, except for some highly lipophilic drugs, like colchicine and vinblastine, both substrates of P-glycoprotein, a drug efflux pump present at the luminal surface of the brain capillary endothelial cells. Colchicine and vinblastine uptake into the brain was studied in the rat using the in situ brain perfusion technique and two inhibitors of P-glycoprotein, verapamil and SDZ PSC-833. When rats were pretreated with PSC-833 (10 mg/kg, intravenous bolus), colchicine and vinblastine uptake was enhanced 8.42- and 9.08-fold, respectively, in all the gray areas of the rat brain studied. The mean colchicine distribution volume was increased from 0.67 +/- 0.41 to 5.64 +/- 0.70 microliters/g and vinblastine distribution volume from 2.74 +/- 1.15 to 24.88 +/- 4.03 microliters/g. When rats were pretreated with verapamil (1 mg/kg, intravenous bolus), colchicine distribution volume was increased 3.70-fold. The increase in colchicine and vinblastine did not differ between the eight brain gray areas. PSC-833 and verapamil pretreatment had no influence on the distribution volume of either drug in the choroid plexus. Nevertheless, distribution volumes remained small, considering the highly lipophilic nature of the substances. We suggest that P-glycoprotein is either only partially inhibited (difficulty of fully saturating P-glycoprotein, especially under in vivo conditions) or not the only barrier to these two drugs.

Nous avons realise du 4 au 31 octobre 1999 une enquete sur le theme «Approche de la souffrance du soignant dans l'accompagnement de fin de vie. Etat des lieux a l'hopital de Seclin». Deux cent soixante douze soignants ont ete inclus dans l'etude.

While deep hydrodesulfurization of gas oil is more and more important, elimination of sulfur compounds such as 4,6-dialkyldibenzothio-phenes still attracts considerable attention. A new process based on the association of a separation process by charge-transfer complex (CTC) formation and classical catalytic hydrotreating (HDT) was evaluated. The results indicated that a CTC pretreatment allows the rate of hydrodesulfurization (HDS) to increase and the final sulfur level to decrease. This process is even more efficient for feeds difficult to desulfurize.

Purpose This study aimed to evaluate the uptake of fertility preservation, rate of pregnancy, pregnancy outcome and breast cancer outcome after diagnosis of early breast cancer in young women who were referred to Maastricht University Medical Center, from the regional hospitals in the Southeast part of the Netherlands. Patients and methods We prospectively registered the demographics of patients, who visited our university hospital for counseling on fertility preservation at diagnosis of stage I-III invasive breast cancer in the years 2008-2015. At baseline, tumor and treatment characteristics were registered. During follow-up information on fullfilled childwish and disease status was collected. To compare the fertility preservation group and the non-fertility preservation group independent samples Student t-tests and Chi-square tests were conducted. Results In total 128 women with a median age of 32 years (19 – 43) were referred for fertility preservation counseling before start of chemotherapy, with an increase in referral in the more recent years. Thirty-nine (30.5%) women chose for fertility preservation: in 26 patients embryos were frozen, in seven oocytes, and in one both embryos and oocytes. In four patients the procedure was not succesfull. Patients who had chosen for fertility preservation more often had a male partner (87.2% vs 70.8%, P = 0.05) and had a smaller tumor size (median 19 versus 23 mm, P = 0.04) at the time of diagnosis compared to those who did not chose for fertility preservation. During a median follow-up of 30.3 months (range 0 – 96.9), 27 (21.1%) patients had tried to conceive: 14 (35.9%) women in the fertility versus 13 (14.6%) in the non-fertility preservation group. All of these had recovery of ovarian function after chemotherapy-induced ovarian failure. Only two women used the cryopreserved embryos, both succesfully and combined with preimplantation genetic diagnosis of the embryos because of germline mutations in BRCA1-gene. Eight patients in the fertility preservation group and seven patients in the non-fertility preservation group became at least once pregnant. In the fertility preservation group, eight healthy babies were born, one baby had Morbus Hirschsprung, one women is pregnant at this moment and one woman had a miscarriage. Of the eleven pregnancies in the non-fertility preservation group, nine healthy babies were born and one woman had two miscarriages. Of the referred 128 women, nine (7.0%) had breast cancer recurrence, three in the fertility preservation group versus six in the non-fertility preservation group. Conclusion One third of referred patients choose for fertility preservation before start of chemotherapy. In all of these patients, the ovarian function recovered. However, two couples used their cryopreserved embryos for preimplantation genetic diagnosis and both became pregnant. Since the follow-up time is relatively short, more data are mandatory to make a statement on the effectiveness of fertility preservation techniques in young breast cancers patients. Citation Format: Vriens IJ, Butalid EM, Schepers-van der Sterren EE, van der Poel MH, Jansen-Engelen SL, van Riel A-MM, van de Wouw YJ, Vriens BE, van Haaren ER, Lemaire BM, Dercksen WW, Luiten EJ, de Boer M, de Die-Smulders CE, Derhaag JG, van Golde RJ, Tjan-Heijnen VC. Preserving fertility in young women undergoing chemotherapy for early breast cancer; the Maastricht experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD6-03.

Recent studies have questioned the importance of the entorhinal cortex (ERC) for normal hippocampal function. For example, fibre-sparing ERC lesions have been found to have no effect on spatial learning in the watermaze. There is also doubt as to the importance of the ERC for contextual fear conditioning, with previous studies having yielded conflicting results. In an attempt to resolve this issue, the present study compared aspiration and cytotoxic ERC lesioned rats, along with fimbria-fornix (FFX) lesioned animals and sham operated controls, on an unsignalled contextual fear conditioning paradigm. The results of the present study show that whereas lesions of the FFX disrupted contextual freezing, neither aspiration nor cytotoxic ERC lesions had any effect on this behaviour. Aspiration ERC lesioned rats, however, like FFX lesioned animals, did display hyperactivity prior to the delivery of footshock. These results suggest that whereas projections between the hippocampus and subcortical structures are important for normal levels of contextual freezing, projections from the entorhinal cortex are not essential.

A number of studies have implicated the hippocampal formation in social-recognition memory in the rat. The present study addressed this issue directly by assessing the effects of cytotoxic lesions confined to the hippocampus proper, encompassing the four CA subfields and the dentate gyrus, on this behavioural task. Ibotenate-induced hippocampal lesions led to locomotor hyperactivity and a marked spatial working-memory impairment on the elevated T-maze. In addition, they also led to increased social investigation. However, despite these clear effects, there was no effect of the lesions on social-recognition memory. These results suggest that the hippocampus proper does not subserve social-recognition memory; but does not, however, preclude the possibility that other areas of the hippocampal formation (e.g. entorhinal cortex or subiculum) may support this memory process.

Following the 1995 national reorganization of the transfusion system, the Nord Pas de Calais blood transfusion center has modified its blood collection organization, with the creation of four districts divided into three or four subdivisions. This change was part of Quality Assurance implementation in the center. This article provides the job description for a physician in charge of such a subdivision as well as the method chosen to design this description (inspired by the diagram of Hijman). This job was conceived as an association of human skills knowledge with the strategy of the blood center. In addition to his medical activity, the district subdivision physician becomes a manager and an organizer. The method used highlights the participation of all disciplines involved in blood donation.

Head and neck paraganglioma is a rare tumour, especially in its familial form. We report a case of a multifocal head and neck paraganglioma in a young man with a family history of cervical tumours. At the age of 24, exploration of a left cervical swelling disclosed jugulotympanic and carotid body paragangliomas. Surgical removal of both tumours was performed. Two years later, a right carotid body as well as vagal paragangliomas were discovered. Follow-up at age 30 demonstrated relapse of the bilateral cervical paragangliomas, but also aortopulmonary and mesogastric paragangliomas. Cervical paragangliomas were also detected in the patient's sister and daughter, but not in his father. Furthermore, the proband's paternal grandmother and a maternal great-uncle had a history of 'neck scar'. This family history is suggestive of an autosomal dominant pattern of inheritance with maternal genomic imprinting. Genetic analysis of paraganglioma kindreds showed linkage with two different loci: 11q13.1 and 11q22.3-q23. Further knowledge of the genes involved could provide early diagnosis and accurate genetic counselling in affected families. Thorough familial investigation is consequently mandatory in all head and neck paragangliomas, especially in younger patients with multiple localizations, as surgical removal is safer at an early stage.

The pharmacokinetic profile of SDZ EAA 494, a new NMDA receptor antagonist, was investigated following i.v. administration of 4 mg kg −1 to freely moving rats. Microdialysis probes were implanted in the right frontal cortex, the left lateral ventricle and the right jugular vein. In vivo recovery was quantified by retrodialysis and amounted to 15.2±2.3% and 5.9±0.7% (mean±S.E.M., n =4) in blood and brain, respectively. As it was not possible to determine the exact recovery for the ventricle probes, polyethylene tubes were implanted into the cisterna magna of a parallel group of rats allowing direct and repeated sampling of cerebrospinal fluid (CSF) from conscious animals. After correction for recovery, the AUCs of free SDZ EAA 494 in blood and brain cortex extracellular fluid (ECF) were 7632±675 and 860±72 ng ml −1 h −1 (mean±S.E.M., n =4), respectively. The AUC of free SDZ EAA 494 in CSF was 1261±449 ng ml −1 h −1 (mean±S.E.M., n =5) and was not significantly different from that observed with microdialysis in brain cortex ECF. Terminal t 1/2 was 0.5 h in blood, 1.0 h in brain cortex and 1.0 h in CSF. Thus, this study demonstrated, that SDZ EAA 494 penetrates the brain and that the AUC of free SDZ EAA 494 in the ECF of the brain cortex represents approximately 1/10 of that in blood. Moreover, free SDZ EAA 494 is equally distributed into the brain cortex ECF and the CSF, whereas the elimination of free drug from these compartments is about twice as long than that observed in the blood compartment.

Calc-alkaline volcanic deposits from the south-west of the Turan plate, near the city of Turkmenbasi (40°00'N, 52°58&E) in Turkmenistan, were studied paleomagnetically. These rocks have been affected by a greenschist-facies metamorphism, possibly of regional extent, that has been K/Ar-dated as 200 to 227 Ma old. A low-blocking-temperature component (D = 349°, I = 64°), close to the present field direction and probably of viscous or recent chemical origin, was isolated by a negative fold test at three sites. The mean direction of a high-blocking-temperature component isolated at 15 sites, mainly carried by magnetite, is scattered before and after tectonic correction and is therefore difficult to interpret. A group of seven sites with low inclinations before and after tectonic correction was isolated. The mean inclination of these sites (31 ± 8°), syn-folding or post-folding, corresponds to a paleolatitude of 17 ± 8° which is lower than the conventional Eurasian paleolatitudes for post-Permian times. The paleomagnetic data from the Turan and Iran plates constrain this low paleolatitude to the Late Triassic and Jurassic period. This requires a shortening of at least 7° between the Turan plate and Eurasia during this time.

Pulmonary vaccination is a promising route for immunization against tuberculosis because the lung is the natural site of infection with Mycobacterium tuberculosis. Yet, adjuvants with a suitable safety profile need to be found to enhance mucosal immunity to recombinant antigens. The aim of this study was to evaluate the immunogenicity, the safety and the protective efficacy of a subunit vaccine composed of the immunodominant mycolyl-transferase antigen 85A (Ag85A) and one of three powerful mucosal adjuvants: the oligodeoxynucleotide containing unmethylated cytosine-phosphate-guanine motifs (CpG), the monophosphoryl lipid A of Salmonella minnesota (MPLA) or the B subunit of heat-labile enterotoxin of Escherichia coli (LTB). BALB/c mice were vaccinated in the deep lungs. Our results showed that lung administration of these adjuvants could specifically induce different types of T cell immunity. Both CpG and MPLA induced a Th-1 type immune response with significant antigen-specific IFN-γ production by spleen mononuclear cells in vitro and a tendency of increased IFN-γ in the lungs. Moreover, MPLA triggered a Th-17 response reflected by high IL-17A levels in the spleen and lungs. By contrast, LTB promoted a Th-2 biased immune response, with a production of IL-5 but not IFN-γ by spleen mononuclear cells in vitro. CpG did not induce inflammation in the lungs while LTB and MPLA showed a transient inflammation including a neutrophil influx one day after pulmonary administration. Pulmonary vaccination with Ag85A without or with MPLA or LTB tended to decrease bacterial counts in the spleen and lungs following a virulent challenge with M. tuberculosis H37Rv. In conclusion, CpG and MPLA were found to be potential adjuvants for pulmonary vaccination against tuberculosis, providing Th-1 and Th-17 immune responses and a good safety profile.

OBJECTIVE: In the present study, the diagnostic value of somatostatin receptor scintigraphy (SRS) was evaluated in the preoperative workup in patients with pancreatic duct cancers and islet cell tumors, as well as in the follow-up of these patients. METHODS: Twenty-six patients with suspected primary pancreatic duct cancers and 48 patients with islet cell tumors were studied. The SRS was performed using the radionuclide-labeled somatostatin analogue 111In-octreotide. Another group of 12 patients who were still alive more than 3 years after pancreaticoduodenectomy for pancreatic duct adenocarcinomas also underwent SRS. RESULTS: In 31 (65%) of 48 patients, the primary pancreatic islet cell tumor as well as its often previously not yet recognized metastases could be visualized. In contrast, none of the 26 pancreatic adenocarcinomas or their metastases could be seen. In 5 of 12 patients who were alive more than 3 years after pancreaticoduodenectomy for pancreatic duct adenocarcinomas, metastatic lesions were visualized at SRS. In retrospect, these patients were not operated on for adenocarcinomas but for "nonfunctioning" islet cell tumors. CONCLUSIONS: The present study supports the concept that SRS has a place in the preoperative differential diagnosis of islet cell tumors and pancreatic duct cancers as well as in the follow-up, especially in those cases in which no tumor histologic analysis was obtained, or the pathologic examination of the tumor tissue had not included special staining procedures for neuroendocrine characteristics. Our results also indicate that the evaluation of the results of investigations on the role of surgery or radiation therapy and chemotherapy or both in pancreatic duct cancer have to be interpreted with caution, if no histologic analysis and staining for neuroendocrine characteristics was performed.

The aim of the present studies was to compare the transport of drugs using two in vitro models routinely used in our laboratories: a primary culture of brain microvessel endothelial cells and a coculture of brain capillary endothelial cells and astrocytes. For this purpose we selected a set of compounds corresponding to a wide range of lipid solubility. Additionally the in vitro results were compared to in vivo results obtained with the single carotid injection, and a good correlation between in vivo extraction ratios (Et) and in vitro permeability coefficients (Pe) was shown as indicated by the Spearman's correlation coefficient (r = 0.90 andr = 0.96 for primary culture and coculture, respectively). The studies show that the use of brain capillary endothelial cells together with astrocytes is slightly more predictive and significantly easier than the use of primary cultured brain microvessels.

In this paper, an efficient reliability method is proposed for space framed structures. It is based on linearization of the mechanical behaviour. The elastic-plastic behaviour of material is piecewise linearized by a plastic criterion taking into account the interaction of internal forces. The buckling effect is represented by using an equivalent negative strain-hardening, introduced to the material model. In order to identify the negative strain-hardening parameters, a powerful method is given. The proposed model also takes into account the unloading of members and the behaviour at criterion singular points. The structural reliability is estimated by the safety margin concepts. Numerical examples show the high performance of the model, verified by a good precision and a very low computational time.

Introduction et but de l’etude Les patients severement agresses presentent une insulinoresistance qui participe a la reponse adaptative a l’agression. Cependant, une reduction prolongee de l’insulinosensibilite (IS) contribue a un catabolisme excessif a l’origine des defaillances d’organes et des dysfonctions musculaires [1] , [2] . Parmi les modalites therapeutiques, l’activite physique active ou passive limite l’IS chez le sujet sain, mais ses effets ne sont pas connus chez le patient agresse. Le but de cette etude a ete de rechercher les effets de la mobilisation sur l’IS de patients en reanimation. Materiel et methodes Des patients adultes hospitalises en soins intensifs depuis 2 a 7 jours, et qui avaient une hyperglycemie de stress necessitant un traitement par insuline intraveineuse ont ete etudies. L’IS a ete calculee [3] deux jours d’affilee a partir des valeurs de glycemie, des apports nutritionnels en glucides et des debits d’insuline, au repos et avant, pendant et apres seances de mobilisation par cycloergometrie (30 minutes, 20 rpm) active (0,1–3 W) ou passive (0 W) (Motomed, Letto2), selon la capacite du patient. L’ordre des seances de mobilisation et de repos a ete attribue par tirage au sort. Une analyse de variance a ete utilisee pour la comparaison des donnees. Les mesures repetees ont ete comparees a l’aide de la procedure « modeles mixtes ». Resultats et analyse statistique Douze patients ont ete inclus (âge median : 65 ans [59–73 ans] ; indice de masse corporelle [IMC] median : 28 kg/m2 [24–30 kg/m2], neuf hommes, sept admissions pour raison chirurgicale). Les 24 seances de mobilisation ont ete realisees sans necessite d’interruption (16 passives, huit actives). L’IS n’a pas ete modifiee durant et jusqu’a 4 h apres la fin des seances de cycloergometrie ( Tableau 1 ). L’IS n’a pas ete modifiee durant les periodes de repos (de 0,62 ± 0,32 a 0,55 ± 0,31 L/mU.min). Conclusion Dans les conditions de cette etude, l’activite physique n’a pas modifie l’IS chez le patient agresse de reanimation qui presente une hyperglycemie de stress. Cependant, les effets de seances prolongees et/ou plus intenses sur l’IS devraient etre evalues sur des cohortes plus importantes de patients.