Impact of the C2/C6 ratio of high-molecular-weight hydroxyethyl starch on pharmacokinetics and blood coagulation in pigs

Rapport de synthèse : Contexte: l'hydroxyéthylamidon (HEA) est largement utilisé comme expanseur volémique en anesthésiologie et réanimation. Cependant, cette classe de produits perturbe le system de la coagulation. Des améliorations restent possibles dans le choix de la combinaison optimale de poids moléculaire, de degré de substitution en radicaux éthyle et de localisation de ces radicaux sur le squelette glucidique des polymères, afin d'optimiser leur efficacité et leur tolérance. L'HEA de poids moléculaire élevé et faiblement substitué n'affecte pas plus la coagulation sanguine que de l'HEA de bas poids moléculaire faiblement substitué. Nous examinons in vivo l'effet d'un abaissement du rapport C2/C6 sur les caractéristiques pharmacocinétiques et l'impact sur la coagulation sanguine d'un HEA de haut poids moléculaire faiblement substitué. Matériels et méthode: nous comparons dans une étude prospective, randomisée et parallèle l'HEA 650/0.42/2.8 avec l'HEA 650/0.42/5.6 auprès de 30 cochons. Avant, pendant et jusqu'à 630 minutes après une perfusion de 30 ml/kg d'HEA, des échantillons sanguins ont été collectés pour mesurer les concentrations d'HEA, les tests de coagulation plasmatique classiques et la coagulation sanguine par thrombélastographie (TEG®, Haemoscope Corporation, Niles, II, U.S.). Les paramètres pharmacocinétiques ont été estimés en adaptant un modèle à deux compartiments. Résultats: la constante d'élimination est de 0.009 ± 0.001 (min-1) pour l'HEA 650/0.42/2.8 et 0.007 ± 0.001 (min-1) pour l'HEA 650/0.42/5.6 (p<0.001); la surface sous la courbe de concentration est de 1374 ± 340 min*g/L pour l'HEA 650/0.42/2.8 et 1697 ± 411 min*g/L pour l'HEA 650/0.42/5.6 (p=0.026). Les concentrations mesurées d'HEA ne montrent pas de différence entre l'HEA 650/0.42/2.8 et l'HEA 650/0.42/5.6. Les deux solutions d'HEA affectent de façon identique la coagulation sanguine: l'index de coagulation thrombélastographique diminue pareillement à ta fin de la perfusion d'HEA 650/0.42/2.8 et d'HEA 650/0.42/5.6 (p=0.29). De même, le temps de thromboplastine partielle activée et le temps de prothrombine augmentent de manière similaire pour l'HEA 650/0.42/2.8 et l'HEA 650/0.42/5.6 (p=0.83). Conclusion: la réduction du rapport C2/C6 de l'HEA de poids moléculaire élevé et faiblement substitué aboutit à une élimination légèrement accélérée d'HEA. Cependant, elle ne modifie pas l'effet perturbateur sur la coagulation.

Maximal Physiological Parameters during Partial Body-Weight Support Treadmill Testing.

PURPOSE: This study investigated maximal cardiometabolic response while running in a lower body positive pressure treadmill (antigravity treadmill (AG)), which reduces body weight (BW) and impact. The AG is used in rehabilitation of injuries but could have potential for high-speed running, if workload is maximally elevated. METHODS: Fourteen trained (nine male) runners (age 27 ± 5 yr; 10-km personal best, 38.1 ± 1.1 min) completed a treadmill incremental test (CON) to measure aerobic capacity and heart rate (V˙O2max and HRmax). They completed four identical tests (48 h apart, randomized order) on the AG at BW of 100%, 95%, 90%, and 85% (AG100 to AG85). Stride length and rate were measured at peak velocities (Vpeak). RESULTS: V˙O2max (mL·kg·min) was similar across all conditions (men: CON = 66.6 (3.0), AG100 = 65.6 (3.8), AG95 = 65.0 (5.4), AG90 = 65.6 (4.5), and AG85 = 65.0 (4.8); women: CON = 63.0 (4.6), AG100 = 61.4 (4.3), AG95 = 60.7 (4.8), AG90 = 61.4 (3.3), and AG85 = 62.8 (3.9)). Similar results were found for HRmax, except for AG85 in men and AG100 and AG90 in women, which were lower than CON. Vpeak (km·h) in men was 19.7 (0.9) in CON, which was lower than every other condition: AG100 = 21.0 (1.9) (P < 0.05), AG95 = 21.4 (1.8) (P < 0.01), AG90 = 22.3 (2.1) (P < 0.01), and AG85 = 22.6 (1.6) (P < 0.001). In women, Vpeak (km·h) was similar between CON (17.8 (1.1) ) and AG100 (19.3 (1.0)) but higher at AG95 = 19.5 (0.4) (P < 0.05), AG90 = 19.5 (0.8) (P < 0.05), and AG85 = 21.2 (0.9) (P < 0.01). CONCLUSIONS: The AG can be used at maximal exercise intensities at BW of 85% to 95%, reaching faster running speeds than normally feasible. The AG could be used for overspeed running programs at the highest metabolic response levels.

Impaired glucose homeostasis in mice lacking the alpha1b-adrenergic receptor subtype.

To assess the role of the alpha1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (alpha1b-AR-/-). Mutant mice had normal blood glucose and insulin levels, but elevated leptin concentrations in the fed state. During the transition to fasting, glucose and insulin blood concentrations remained markedly elevated for at least 6 h and returned to control levels after 24 h whereas leptin levels remained high at all times. Hyperinsulinemia in the post-absorptive phase was normalized by atropine or methylatropine indicating an elevated parasympathetic activity on the pancreatic beta cells, which was associated with increased levels of hypothalamic NPY mRNA. Euglycemic clamps at both low and high insulin infusion rates revealed whole body insulin resistance with reduced muscle glycogen synthesis and impaired suppression of endogenous glucose production at the low insulin infusion rate. The liver glycogen stores were 2-fold higher in the fed state in the alpha1b-AR-/- compared with control mice, but were mobilized at the same rate during the fed to fast transition or following glucagon injections. Finally, high fat feeding for one month increased glucose intolerance and body weight in the alpha1b-AR-/-, but not in control mice. Altogether, our results indicate that in the absence of the alpha1b-AR the expression of hypotalamic NPY and the parasympathetic nervous activity are both increased resulting in hyperinsulinemia and insulin resistance as well as favoring obesity and glucose intolerance development during high fat feeding.

Patients' prediction of extubation success.

The spontaneous breathing trial (SBT)-relying on objective criteria assessed by the clinician-is the major diagnostic tool to determine if patients can be successfully extubated. However, little is known regarding the patient's subjective perception of autonomous breathing. We performed a prospective observational study in 211 mechanically ventilated adult patients successfully completing a SBT. Patients were randomly assigned to be interviewed during this trial regarding their prediction of extubation success. We compared post-extubation outcomes in three patient groups: patients confident (confidents; n = 115) or not (non-confidents; n = 38) of their extubation success and patients not subjected to interview (control group; n = 58). Extubation success was more frequent in confidents than in non-confidents (90 vs. 45%; p < 0.001/positive likelihood ratio = 2.00) or in the control group (90 vs. 78%; p = 0.04). On the contrary, extubation failure was more common in non-confidents than in confidents (55 vs. 10%; p < 0.001/negative likelihood ratio = 0.19). Logistic regression analysis showed that extubation success was associated with patient's prediction [OR (95% CI): 9.2 (3.74-22.42) for confidents vs.non-confidents] as well as to age [0.72 (0.66-0.78) for age 75 vs. 65 and 1.31 (1.28-1.51) for age 55 vs. 65]. Our data suggest that at the end of a sustained SBT, extubation success might be correlated to the patients' subjective perception of autonomous breathing. The results of this study should be confirmed by a large multicenter trial.

Emissions distribution in post-Kyoto international negotiations: a policy

An abundant scientific literature about climate change economics points out that the future participation of developing countries in international environmental policies will depend on their amount of pay offs inside and outside specific agreements. These studies are aimed at analyzing coalitions stability typically through a game theoretical approach. Though these contributions represent a corner stone in the research field investigating future plausible international coalitions and the reasons behind the difficulties incurred over time to implement emissions stabilizing actions, they cannot disentangle satisfactorily the role that equality play in inducing poor regions to tackle global warming. If we focus on the Stern Review findings stressing that climate change will generate heavy damages and policy actions will be costly in a finite time horizon, we understand why there is a great incentive to free ride in order to exploit benefits from emissions reduction efforts of others. The reluctance of poor countries in joining international agreements is mainly supported by historical responsibility of rich regions in generating atmospheric carbon concentration, whereas rich countries claim that emissions stabilizing policies will be effective only when developing countries will join them.Scholars recently outline that a perceived fairness in the distribution of emissions would facilitate a wide spread participation in international agreements. In this paper we overview the literature about distributional aspects of emissions by focusing on those contributions investigating past trends of emissions distribution through empirical data and future trajectories through simulations obtained by integrated assessment models. We will explain methodologies used to elaborate data and the link between real data and those coming from simulations. Results from this strand of research will be interpreted in order to discuss future negotiations for post Kyoto agreements that will be the focus of the next. Conference of the Parties in Copenhagen at the end of 2009. A particular attention will be devoted to the role that technological change will play in affecting the distribution of emissions over time and to how spillovers and experience diffusion could influence equality issues and future outcomes of policy negotiations.

Predictors of weight change in sedentary smokers receiving a standard smoking cessation intervention

L'arrêt de la cigarette est généralement associé à une prise de poids. Celle-ci peut menacer la motivation des fumeurs à s'engager dans un processus d'arrêt du tabac et constitue un motif de rechute. L'ordre de grandeur et la cinétique de la prise de poids liée à une tentative d'arrêt chez les fumeurs pris en charge selon les recommandations cliniques actuelles est peu décrite dans la littérature médicale. Le but de cette étude était de quantifier cette prise de poids, d'en déterminer la cinétique ainsi que les facteurs qui l'influencent, chez des fumeurs sédentaires bénéficiant d'une intervention d'aide à l'arrêt du tabac individualisée, composée de conseils individuels et d'une substitution nicotinique associant plusieurs modes d'administration. Nous avons analysé des données récoltées durant un essai clinique randomisé contrôlé au cours duquel était étudié l'impact d'une activité physique modérée sur les taux d'arrêt du tabac après un an chez des fumeurs sédentaires. Nous avons modélisé l'évolution du poids de l'ensemble des participants au cours du temps, selon la technique statistique des « modèles mixtes longitudinaux ». En séparant les périodes d'abstinence de la cigarette de celles de rechute et de l'utilisation reportée de substituts nicotiniques. Cette approche nous a permis de prendre en compte chaque participant à l'étude, par opposition à un modèle plus simple qui séparerait les sujets abstinents de ceux qui rechutent à n'importe quel moment de la période de suivi. Nous avons également ajusté ces modèles pour l'âge, le sexe, le niveau de dépendance à la nicotine et le niveau de formation des participants. Parmi l'ensemble des participants, nous avons noté une augmentation du poids durant les trois premiers mois de l'intervention, suivie d'une stabilisation. Au total, la prise de poids moyenne s'est élevée à 3.3 kg pour les femmes et 3.9 kg pour les hommes. Durant les périodes d'abstinence, les caractéristiques suivantes étaient associées à la prise de poids : sexe masculin et forte dépendance nicotinique. Un âge supérieur à 43 ans était associé à une prise de poids également durant les périodes de rechute. Nous avons observé une tendance, non statistiquement significative, vers une réduction de la prise des poids avec l'utilisation de substituts nicotiniques. Notre étude apporte de nouvelles données sur l'évolution du poids chez les fumeurs sédentaires qui bénéficient d'une intervention d'aide à l'arrêt du tabac. Ils prennent donc du poids, de manière modérée et limitée aux premiers mois. Parmi eux, les hommes, les individus les plus dépendants à la nicotine et les plus âgés doivent s'attendre à une prise de poids supérieure à la moyenne.

A characterization of two weight norm inequalities for maximal singular integrals

"Vegeu el resum a l'inici del document del fitxer adjunt."

First Report of a Newborn Rat Ventilation Model for Bronchopulmonary Dysplasia Permitting Evaluation of Long-Term Outcome

Background: Bronchopulmonary dysplasia (BPD) remains the leading cause of chronic pulmonary morbidity among preterm neonates. However, the exact pathophysiology is still unknown. Here we present the first results from a new model inteAbstracts, 25th International Workshop on Surfactant Replacement 400 Neonatology 2010;97:395-400 grating the most common risk factors for BPD (lung immaturity, inflammation, mechanical ventilation (MV), oxygen), which allows long-term outcome evaluation due to a non-traumatic intubation procedure. Objectives: To test the feasibility of a new rat model by investigating effects of MV, inflammation and oxygen applied to immature lungs after a ventilation-free interval. Methods: On day 4, 5, or 6 newborn rats were given an intraperitoneal injection of lipopolysaccharides to induce a systemic inflammation. 24 h later they were anesthetized, endotracheally intubated and ventilated for 8 h with 60% oxygen. After weaning of anesthesia and MV the newborn rats were extubated and returned to their mothers. Two days later they were killed and outcome measurements were performed (histology, quantitative RT-PCR) and compared to animals investigated directly after MV. Results: Directly after MV, histological signs of ventilator-induced lung injury were found. After 48 h, the first signs of early BPD were seen with delayed alveolar formation. Expression of inflammatory genes was only transiently increased. After 48 h genes involved in alveolarization, such as matrix metalloproteinase-9 and tropoelastin, showed a significant change of their expression. Conclusion: For the first time we can evaluate in a newborn rat model the effects of MV after a ventilation-free interval. This allows discrimination between immediate response genes and delayed changes of expression of more structural genes involved in alveolarization.

Post-translational modifications regulate distinct functions of CARMA1 and BCL10.

Activation of the transcription factor nuclear factor (NF)-kappaB is essential for the normal functioning of the immune system. Deregulated NF-kappaB signalling in lymphocytes can lead to immunodeficiency, but also to autoimmunity or lymphomas. Many of the signalling components controlling NF-kappaB activation in lymphocytes are now known, but it is less clear how distinct molecular components of this pathway are regulated. Here, we summarize recent findings on post-translational modifications of intracellular components of this pathway. Phosphorylation of the CARMA1 and BCL10 proteins and ubiquitylation of BCL10 affect the formation and stability of the CARMA1-BCL10-MALT1 (CBM) complex, and also control negative feedback regulation of the NF-kappaB signalling pathway. Moreover, the study of BCL10 phosphorylation isoforms has revealed a new mechanism controlling BCL10 nuclear translocation and an unexpected role for BCL10 in the regulation of the actin cytoskeleton.

Changing the awareness of low vitamin D status in a rheumatology population: a pre/post-study.

INTRODUCTION: In 2009 hypovitaminosis D was highly prevalent in a population of Swiss rheumatology patients (86%). We aimed to evaluate the evolution of vitamin D status in the same population two years later, after the results of the first study were disseminated to local physicians and patients, in order to determine the evolution of the problem and the impact of physician information. METHOD: Patients in our rheumatology clinic were screened for 25-OH vitamin D. Results were categorised as: deficient (<10 ng/ml or <25 nmol/l), insufficient (10 to 30 ng/ml or 25 to 75 nmol/l) or normal (>30 ng/ml or >75 nmol/l). We also used another cut-off of 20 ng/ml (50 nmol/l). We evaluated the evolution of 25-OH vitamin D dosages and vitamin D3 prescriptions between 2008 and 2011 in our institution and the number of publications on vitamin D in three important medical journals of the French speaking part of Switzerland. RESULTS: Compared with 2009, significantly more patients had normal results in 2011. Fifty-two percent of patients had levels >20 ng/ml in 2009 and 66% in 2011, difference statistically significant (p = 0.001). During the years separating the two study periods the number of 25-OH vitamin D dosages and the prescription of high doses of vitamin D3 increased in our hospital. In addition the number of publications on vitamin D increased between 2008 and 2011. CONCLUSION: We concluded that lower prevalence in hypovitaminosis D is certainly related to better adherence to daily supplements, and to better information and awareness of the physicians about hypovitaminosis D.

Cytomegalovirus infection and new-onset post-transplant diabetes mellitus.

We analyzed data from all consecutive kidney transplant patients at our institution between April 2003 and October 2006. We found 15 cases of late-onset cytomegalovirus (CMV) infection, two of which developed concurrent post-transplant diabetes mellitus (PTDM). In these two cases, PTDM was transient and normal glucose tolerance was achieved after an eight-wk therapeutic course of oral valganciclovir. These findings suggest that CMV infection after organ transplantation may be associated with concurrent PTDM. The distinct causative relationship is yet to be determined.

Pre- and post-treatment immunodiagnostic evaluation in human schistosomiasis mansoni

Schistosomiasis control seems to be different in countries were low parasitic burden and asymptomatic clinical patients are the features of majority of cases. Immunological methods must substitute the traditional coprologic techniques used for some decades in the Control Program. Circumoval Precipitin Test (COPT), intradermal test and ELISA with soluble egg antigen (SEA) are evaluated for using as tools for seroepidemiologic studies. COPT and ELISA were performed after treatment to known their utility when impact of chemotherapy must be assessed. One hundred sixty five persons were followed up 3, 6, 9 and 12 months after treatment. The mean sensitivity of CPT studied by age groups was 95.6% which is very important considering that 88.4% of the studied population excreted less than 100 egg/gr of feces, while sensitivity of intradermal test was 58.2%. Children showed the highest ractivity to COPT. When treatment is effective, COPT reactivity progressively disminish until become negative one year later. In the non cure group, the COPT reactivity disminished but never below 20%. ELISA-SEA did not modify one year after treatment. Effort should be made to isolate fractions of eggs Schistosoma mansoni whose antibodies disappear after treatment.

Post-traumatic mutism in children: clinical characteristics, pattern of recovery and clinicopathological correlations.

Among the numerous clinical syndromes observed after severe traumatic head injury, post-traumatic mutism is a disorder rarely reported in adults and not studied in any detail in children. We report seven children between the ages of 3 1/2 and 14 years who sustained severe head injury and developed post-traumatic mutism. We aim to give a precise clinical characterization of this disorder, discuss differential diagnosis and correlations with brain imaging and suggest its probable neurological substrate. After a coma lasting from 5 to 25 days, the seven patients who suffered from post-traumatic mutism went through a period of total absence of verbal production lasting from 5 to 94 days, associated with the recovery of non-verbal communication skills and emotional vocalization. During the first days after the recovery of speech, all patients were able to produce correct small sentences with a hypophonic and monotonous voice, moderate dysarthria, word finding difficulties but no signs of aphasia, and preserved oral comprehension. The neurological signs in the acute phase (III nerve paresis in three of seven patients, signs of autonomic dysfunctions in five of seven patients), the results of the brain imaging and the experimental animal data all suggest the involvement of mesencephalic structures as playing a key role in the aetiology of post-traumatic mutism.