Oral Abstracts

<span title="2013-04-25">2013</span> <i title="Wiley"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/g2gsla6isbdvxcsbzkh7hx4iym" style="color: black;">Fundamental &amp; Clinical Pharmacology</a> </i> &nbsp;
Bone is the only tissue of the vertebrate body that contains a cell type, the osteoclast, whose only function is to destroy the host tissue. This does not occur at random but rather in the context of a well ordered physiological process called bone modeling during childhood and remodeling during adulthood. We hypothesized that this process requires a daily delivery of a large amount of energy to bone cells; a large body of clinical observations supports this hypothesis. Testing this hypothesis
more &raquo; ... ed us to reveal the bone endocrine nature of bone and to identify osteocalcin as an osteoblast-derived hormone affecting multiple aspects of energy metabolism. We will review during this lecture the functions and mode of action of osteocalcin and address its overall importance in the control of whole body glucose homeostasis. Futur developments in personalized human obesity management: is systemic medicine usefull? K Clement a a Institut Cardiom etabolisme et Nutrition (ICAN), INSERM/UPMC, Hôpital de la Piti e-Salpêtri ere, Paris Abstract not available: SESSION 1: GS MIXTE RESPIRATION Bitter taste receptors in the lung: a new pharmacological target? S Grassin-Delyle a a UPRES EA220, Hôpital Foch, Universit e Versailles Saint Quentin en Yvelines, Saint Quentin en Yvelines Bitter taste receptors (TAS2Rs) are known for long for their role in taste as sensors of the presence of toxic compounds in foods, but their unexpected expression in airways epithelium and smooth muscle cells or in peripheral blood leucocytes has been recently documented. This family of GPCRs includes about 25 members in humans and each subtype has a variable selectivity towards bitter compounds, some of them being restrictedly selective to a unique molecule and others responding to a wider range. More than a hundred molecules such as chloroquine, caffeine, strychnine, colchicine or erythromycin have thus been described as TAS2R agonists while TAS2R19, 41, 42, 45 and 60 are considered as orphans since no agonist has been identified. In the airways, the initial observation by Desphandes et al. (2010) described the relaxation of pre-contracted mouse trachea following exposure to chloroquine, denatonium, quinine or saccharine, which was suggested to be even more pronounced that the relaxation obtained with the reference relaxing agents b2adrenoreceptor agonists. Interestingly, an original intracellular signaling pathway in the response of airway smooth muscle cells to bitter-taste receptor agonists was proposed, involving the G-protein bc subunit and leading to a localized increase in intracellular calcium, which in turn causes membrane hyperpolarisation through an activation of large conductance potassium channels (BK Ca). In addition to these results in cell cultures or airways preparations, inhaled bitter tastants were shown effective in decreasing airway resistance in ovalbumin-sensitized mice, but very little is known in humans to date. However, transcriptome analysis revealed upregulation of TAS2R signaling in peripheral blood leucocytes from patients with severe asthma, as well as a correlation between clinical markers of asthma severity and TAS2R expression. Overall, these works suggest that bitter taste receptors may constitute a new pharmacological target for obstructive lung diseases such as asthma and COPD. We will address the role of bitter taste receptors in respiratory pharmacology, with a special focus on results obtained in human tissues. Objectives: Biological systems exhibit nonlinear deterministic dynamics that can be chaotic, either at a cellular, organ or system levels. Human ventilation exhibits chaotic behavior, as well*. Direct evidences that ventilatory complexity is linked to the activity of the respiratory neural centers are still lacking in humans. Methods: In 25 healthy subjects and 25 patients with chronic obstructive pulmonary disease (COPD), we evaluate airway flow chaos (noise titration, largest Lyapunov exponent and correlation dimension). Brainstem respiratory centers are located with cerebral functional magnetic resonance imaging (fMRI) in the ventro-lateral (VL) medulla (PreB€ otzinger complex) and the VL pons (parafacial group). Neural activity of the centers is studied through the low frequency of amplitude oscillations (LFAO) of fMRI signal of the selected brainstem regions of interest. It is a validated index of fMRI neural activation. Results: COPD patients display a higher level of airway flow complexity as compared with healthy subjects. In controls and COPD patients ventilatory complexity correlates with the activity of the respiratory neural centers. During spontaneous breathing in controls, inspiratory chaos is tightly linked with the LFAO of the ventro-lateral (VL) medulla (R 2 = 0.75, P = 0.01) while in COPD patients, expiratory chaos correlates with LFAO of the VL pons (R 2 = 0.4, P = 0.03). External inspiratory resistive overload inhibits brainstem fMRI signal while significantly decreasing the resulting airway flow complexity in parallel in both populations. Conclusions: We present the first study showing that airway flow complexity is strongly depending on the activity of the respiratory central pattern generators assess with fMRI. COPD patients have a high neural ventilatory drive due to chronically enhance respiratory load. We show in patients, at rest and during an increase load, a high level of airway flow complexity that translates the altered high activity of the brainstem respiratory centers. These findings may be involved in the onset of respiratory failure when the neural network becomes inefficient to sustain respiratory overload. Pharmacology were also administered as a curative treatment at D15-19-22-26 for both MCT and CH. Pulmonary arterial pressure was assessed at D28. Pulmonary arterial luminal occlusion, intimal or medial thickness were evaluated on lung sections after hematoxylin and eosin stainings, or after immunohistochemical stainings with anti-von Willebrand factor or anti-a-smooth muscle actin antibodies. NGFinduced proliferation of PASMC and PAEC in primary culture was assessed by the BrdU technique. Results: In both MCT and CH rats, anti-NGF blocking antibodies displayed preventive as well as curative effects on medial and intimal remodelling of pulmonary arteries. In vitro, NGF induced PASMC proliferation at low concentrations through activation of the TrkA receptor and PI3-kinase dependent pathways. NGF also induced PAEC proliferation, but only at higher concentrations through activation of both TrkA and p75 NTR receptors and PI3-kinase independent signalling pathways. Conclusion: We show here that anti-NGF blocking antibodies administered in vivo both prevent and reverse medial and intimal remodelling of pulmonary arteries in PH rat models. NGF may contribute to pulmonary arterial remodelling by stimulating proliferation of both PASMC and PAEC, but through activation of distinct receptors and signalling pathways. These results suggest that blocking both NGF receptors may be of therapeutical interest in pulmonary arterial remodelling, and therefore confirms the interest of targeting NGF in pulmonary hypertension. Keywords: nerve growth factor NGF, pulmonary hypertension, pulmonary arterial remodelling. 01-04 Effect of oro-phayngeal povidone-iodine preventive oral care on ventilator-associated pneumonia in severe brain injury or cerebral haemorrhage patients: a multicentre randomized controlled trial for the SPIRIT-ICU study and AtlanR ea groups Objectives: Oral use of povidone-iodine to prevent ventilator-associated pneumonia remains unclear especially in high-risk patients [1, 2] . We assessed the efficacy and safety of oral care with povidone-iodine on the incidence of ventilatorassociated pneumonia in a high-risk population. Methods: This was a multicentre, placebo-controlled, randomised, double-blind, two-parallel-group trial performed in patients with severe (Glasgow coma scale 8) brain injury or cerebral haemorrhage requiring mechanical ventilation. Participants were assigned to receive oropharyngeal care with povidoneiodine (n = 91) or placebo (n = 88) six times daily until extubation. Primary enpoint was the rate of ventilator-associated pneumonia. Secondary end point included the rates of ventilator-associated tracheobronchitis and acute respiratory distress syndrome. Results: The number of patients evaluable for the primary endpoint (preplanned modified intention-to-treat population) was 150 (78 in the povidone iodine group, and 72 in the placebo group). Ventilator-associated pneumonia occurred in 24 (31%) in the povidone-iodine group and 20 (28%) in the placebo group (RR 1.11, 95% CI 0.67-1.82, P = 0.69). There was no significant difference between the two groups for ventilator-associated tracheobronchitis: eight patients (10%) in the povidone-iodine group and 5 (7%) in the placebo group (RR 1.48, 95% CI 0.51-4.31, P = 0.47). Acute respiratory distress syndrome occurred in five patients in the povidone-iodine group and zero patient in the placebo group (P = 0.06). Conclusion: There is no evidence to recommend oral care with povidone-iodine to prevent ventilator-associated pneumonia in high-risk patients. Moreover, this strategy seems to increase the rate of acute respiratory distress syndrome. References: 1. Seguin P.,Tanguy M., Laviolle B., et al. Effect of oropharyngeal decontamination by povidone-iodine on ventilator-associated pneumonia in patients with head trauma. Crit. Care Med. (2006) 34 1514-1519. 2. Labeau S.O., Van de Vyver K., Brusselaers N., et al. Prevention of ventilatorassociated pneumonia with oral antiseptics: a systematic review and meta-analysis. Lancet Infect. Dis. (2011) 11 845-854. Aim: At maximal exercise, the arterial oxygen flow to active muscles becomes insufficient to meet the oxygen demand. A competition between respiratory and peripheral muscles perfusions favouring the former might occur with a redistribution of blood flow in favour of respiratory muscles. The purpose of the study was to investigate the relative adaptation of intercostals and thigh muscles during exercise in the hypoxic condition of altitude in lowlanders as well as in highlanders. Due to adaptation to hypoxia, differences between the groups of subjects were expected. Method: Eighteen recently acclimatized lowlanders and 27 highlanders (13 healthy subjects, and 14 with Chronic Mountain Sickness, (CMS)) were investigated in Cerro de Pasco (4350 m, Perou). The subjects underwent an incremental cardio-pulmonary exercise test on cycle ergometer. The exercise test was performed three times in lowlanders (sea-level, arriving at altitude and a week later). During exercise, regional tissue oxygenation (rSO 2 ) and tissue haemoglobin concentration (Hbt) of intercostal muscles and vastus medialis were monitored by near-infrared spectroscopy (NIRS, Nonin Regional Oximetry Technology, Plymouth, MN, USA). Results: Intercostal and vastus medialis-rSO 2 were lower at altitude than at sea level (À8% to À12%) and decreased similarly during incremental exercise (P < 0.05 from rest, above 60% VO2max). The time patterns of vastus medialis and intercostal-rSO 2 were similar in highlanders. At maximal exercise and during recovery, intercostal-rSO 2 was lower than vastus medialis-rSO 2 in lowlanders. Conversely in highlanders, intercostal-rSO 2 was greater than vastus medialis-rSO 2, from rest to 80% VO2max. Changes in intercostal-rSO 2 in highlanders were smaller than those in lowlanders at exercise. Intercostal and vastus medialis-Hbt increased from sea level to altitude in lowlanders. [Hb] in lowlanders was increased after a week in altitude but was lower than in CMS. Conclusion: Compared to sea level, maximal exercise in hypoxia did not alter the kinetic of rSO 2 and Hbt in peripheral muscle. At maximal exercise, even in acute hypoxia, the increase in ventilation did not alter lowlander's peripheral 2 Oral Abstracts 2013 muscle oxygenation. Lower changes in intercostal-rSO 2 were observed at maximal exercise in highlanders likely due to lower ventilation. Overall these findings do not favor the hypothesis of a blood shift to respiratory muscles. Aim: The aim was to select among the several published equations relating the conductance of Hb for CO (hCO) to PO2 the one(s) which would gave the same DmCO/Vc ratios in the conditions of slight hypoxia (Pcap O2: 82 mmHg) and normoxia (118 mmHg ). The assumption made was that the slight change in PO2 would not change Vc and DmCO, as it would change TLCO. Method: Eight subjects were included. They performed duplicated measurements of CO and NO lung transfer using the single breath method (Hypercompact, Medisoft Dinant B) with either a slightly hypoxic mixture (15% O2) or the standard mixture (19%) Standard concentrations of inspired NO (40 ppm) and CO (2000 ppm) were used. All calibrations were made before and after a session with a given subject. DmCO and Vc were calculated using the Roughton Forster (1957) equation and a conductance of Hb for NO of 4.5 mL/(min mmHg) according to Borland et al (2010). Results: Dm/Vc ratios were calculated in slightly hypoxic and normoxic conditions. Seven published equations cited by Hughes and Bates were tested. Only three equations gave Dm/Vc ratios different from <10% [Holland 2.47 (hypoxic) vs. 2.58 (normoxic), Forster 2.46 vs. 2.70, Roughton Forster (k = 1.5) 3.43 vs. 3.23]. This last equation was however not kept as deriving from in vitro experiments at pH 8. The two remaining equations gave similar results for Vc and DmCO. The differences for Vc were+2.4 and À1.7 mL for Holland and Forster respectively as those for DmCO were +12 and +9 mL/(min mmHg). These differences were <10% of the raw values. Both equations are acceptable for practical use of diffusion tests as all others would give inaccurate values. A compromise between the the selected equations would be 1/hCO = 1.19 + 0.0053 PO2 (mmHg). Conclusion: The present results could mark the end of decades of uncertainty on Vc and DmCO values due to the scatter of the hCO values used. It is worthy to note that the hNO value used here leads to high DmCO values, close to morphometric data at least during exercise. Introduction: Microparticles are membrane vesicles from damaged or activated cells that are associated with atherosclerosis, cancer and inflammatory diseases. Long-term exposure to microparticles induces vascular hyporeactivity in aortae via the Fas/FasL pathway and endothelial dysfunction in pulmonary arteries (PA). We hypothesized that microparticles have acute effects on pulmonary vascular contractility and Kv channel function. Methods: Resistance PA (300-500 lm internal diameter) were isolated from male Wistar rats and PA myocytes were isolated by enzymatic digestion. Vascular reactivity was assessed using isometric wire myographs. The responses induced by microparticles from apoptotic T lymphocytic cells (10 mg protein/mL) or the FasLigand (10 mg/mL) were measured after 30 min. Some experiments were performed in the presence of nifedipine (1 mM), tiron (1 mM), an anticeramide antibody (200 ng/mL) or inhibitors of the acid (D-609, 100 mM) or neutral sphingomyelinases (GW4869, 10 mM). Potassium currents and membrane potential were recorded using the patch clamp technique in freshly isolated PASMC. Reactive oxygen species (ROS) were measured in human PASMC in culture incubated with dichlorofluorescein. Results: Microparticles reduced Kv current amplitude (37 AE 6% inhibition at +30 mV; P < 0.01) and produced membrane depolarization in PASMC (from À32 AE 2 to À20 AE 4 mV; P < 0.05). Moreover, microparticle-induced a slow developing contraction in PA (8 AE 2% of KCl contraction after 30 min) that was blunted by the L-type Ca 2+ channel blocker nifedipine (0.8 AE 2% KCl; P < 0.01). Microparticle-induced contraction was attenuated by the anticeramide antibody (2.4 AE 2.1%) and by D-609 (1.5 AE 1.7 %), but not by GW4869 (7.8 AE 1.7%) as compared to parallel controls (12 AE 2% KCl). Similar to microparticles, FasLinduced contraction (14.5 AE 3.9%) was attenuated by the anticeramide antibody (1.6 AE 1.6%) and by D-609 (3.8 AE 2.2%), but not by GW4869 (7.2 AE 1.9%). Microparticles also increased ROS in human PASMC in culture and the contractile effect in PA was abolished by the ROS scavenger tiron (3 AE 1% vs. 15 AE 3% in parallel control). Microparticles expressed FasL and PA expressed Fas. Conclusion: Microparticles from apoptotic T lymphocytes produce pulmonary vasoconstriction involving the activation of Fas, acid sphingomyelinase, increase in ROS and inhibition of Kv channels. Background: Antithrombotic therapy (mainly with vitamin-K antagonisms: VKA) is currently recommended in idiopathic and familial Pulmonary Arterial Hypertension (PAH) and in PAH associated with anorexigens. As VKA are currently deeply challenged by new oral anticoagulants (NOA) in the setting of venous thrombo-embolism and atrial fibrillation, we searched for potential pharmacological interactions between NOA and oral PAH therapies. Methods: We reviewed the potential pharmacokinetic and pharmacodynamics drug-drug interactions (DDI), in particularly regarding metabolism and drug transport, with two endothelin-receptor antagonisms (ERA): bosentan (B) and ambrisentan (A), two phosphodiesterase-5 inhibitors (PDE5i): sildenafil (S) and tadalafil (T), and NOA (rivaroxaban, apixaban, dabigatran). Results: Within ERA, B is mainly metabolized by hepatic cytochrome P450 (CYP) 3A4, A by uridine 5' diphosphate glucuronyltransferase and to a lesser extent, by CYP3A4 and CYP2C19. The organic anion transport proteins for B and P-glycoprotein for both are probably involved in the transports of these drugs. B, but not A, induces CYP3A4, which is involved in the metabolism of anti-Xa NOA rivaroxaban (30%) and apixaban (50%). Concomitant use of B may diminish their biological efficacy. Regarding PDE5i, S and T are also mainly metabolized by CYP3A4, but act as slight CYP3A4 inhibitors. The risk for clinically significant DDI seems small between anti-Xa NOA and S or T. The effect of PAH-combination therapy is unknown but it may decrease deeper the concentration of anti-Xa NOA. Conversely, dabigatran (an anti-IIa drug not metabolised by CYP) should be avoided in PAH because of its potential increased risk of myocardial infarction. Conclusion: Concomitant use of PAH therapies (mainly bosentan) and NOA may expose patients to DDI. In the absence of robust clinical and pharmacological data, NOA are not recommended in PAH. Objective: Fluoroquinolones and 3rd-generation cephalosporins (3GC) have become the antibiotics of choice in many hospitals in recent years for the treatment of infections such as a Lower Respiratory Tract Infection (LRTI). Because fluoroquinolones and 3GC select multiple bacterial resistances, usage of both classes should be restricted. Our objectives were to assess the frequency of prescription of 3GC and fluoroquinolones in LRTI and to evaluate the avoidable part of these prescriptions. Methods: Retrospective serie of 88 adult cases of community-acquired pneumonia and acute exacerbation of COPD admitted to the emergency department. Compliance with French national guidelines was assessed. Furthermore, prescriptions that complied with guidelines were deemed justified if at least one criterion was present: allergy or intolerance to penicillin, failure of penicillin, penicillin therapy in the previous month, admission in ICU, and only for quinolones, suspected legionellosis. Avoidable prescriptions included prescriptions that did not comply with national guidelines and prescriptions that complied with guidelines but were not justified. Avoidable prescriptions of 3GC and fluoroquinolones may be replaced by amoxicillin/clavulanate. Results: We included 72 pneumonia, 16 acute exacerbation of COPD. Median age was 79 (32-94). Thirty-two [36.4% (27.1-46.8)] and 10 [11.3% (5.2-20.1)] patients received respectively 3GC and fluoroquinolone. The majority of prescriptions of fluoroquinolone [85.7% (46.7-99.5)] and 3GC [93.1% (77.0-99.1)] complied with national guidelines. However, 51.7% (34.4-68.6) of 3GC prescriptions and 57.1% (25.0-84.2) of quinolone prescriptions were avoidable. Discussion: 3GC and fluoroquinolones are frequently prescribed for lower respiratory tract infections in the ED. Half of these prescriptions may be avoided. Antibiotic restriction policy should be implemented in our hospital in order to promote prudent use of 3GC. . diomyocytes by aldosterone via MR activation; (ii) the increase of cardiac endothelial cells proliferation. We are now studying, with HUVEC cells, the mechanisms underlying the proliferation of endothelial cells. Context and objective: Obesity and the metabolic syndrome are accompanied by increased visceral adipose tissue as well as liver steatosis, both leading to increased cardiovascular risk. High plasma osteoprotegerin has been more
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