Effects of single-dose injectable paracetamolversus propacetamol in pain management after minor gynecologic surgery: A multicenter, randomized, double-blind, active-controlled, two-parallel-group study

AbstractBackground:Intravenous administration is the route of choice for drug therapy in the immediate postoperative period. Propacetamol (ProAPAP), an injectable prodrug of paracetamol requiring reconstitution, has demonstrated efficacy in managing acute pain and fever. However, it has been associated with pain at the injection site. A stable, ready-to-use formulation of paracetamol solution infused intravenously (IV-APAP) has been developed and might be associated with less pain at the injection site compared with ProAPARObjective:The objective of this study was to assess the tolerability and efficacy of a single dose of IV APAP 1 g compared with those of a single dose of ProAPAP 2 g in patients with moderate to severe pain after minor gynecologic surgery.Methods:This single-dose, randomized, double-blind, active-controlled,2-parallel-group study was conducted at 23 hospitals and outpatient clinics in France. After minor gynecologic surgery, patients reporting moderate to severe pain were randomized to receive a single 15-minute infusion of IV-APAP 1 g or ProAPAP 2 g (bioeyuivalent doses). Tolerability was monitored using local and systemic adverse event (AE) reporting, clinical examination including vital sign measurement, and patients' ratings of acceptability of the infusion. Efficacy end points included pain intensity at 0, 1, 2, 4, and 6 hours; median time to rescue medication (defined as the time at which 50% of patients requested rescue medication); and percentage of patients requesting rescue medication. Patients' satisfaction with the study drugs was assessed using patient's global evaluation (PGE) and the percentage of patients willing to receive the treatment again.Results:Of the 163 women who were randomized, 161 received the studymedication. The IV-APAP group comprised 80 patients (mean [SD] age, 38.3 [12.8] years [range, 18.0-69.0 years]; mean [SD] weight, 61.1 [11.0] kg [range, 49.0–90.0 kg]), and the ProAPAP group comprised 81 patients (mean [SD] age, 33.9 [12.0] years [range, 18.0–67.0 years]; mean [SD] weight, 61.6 [10.2] kg [range, 42.0–95.5 kg]); the difference in mean age between the 2 groups was statistically significant (P < 0.05). The incidence of local treatment-emergent AEs (TEAEs) was significantly lower in the IV-APAP group compared with that in the ProAPAP group (7.5% vs 38.3%; P < 0.001). No between-group differences in the incidence of systemic TEAEs was found. All patients in the IV-APAP group found the infusion tolerable, compared with 95% of patients in the ProAPAP group. The median time to rescue medication was not evaluated because <50% of the patients in each group requested it. No significant differences in mean pain intensity score or percentage of patients requesting rescue medication were found between the 2 groups at any time point. The percentages of patients in the IV-APAP and ProAPAP groups who rated the study medication as good or excellent on the PGE (83.6% vs 75.6%; P < 0.05) and who were willing to receive the same treatment again (96.0% vs 81.0%; P = 0.005) were significantly higher with IV-APAP compared with ProAPAPConclusion:In these patients with moderate to severe pain after minor gynecologic surgery, a single dose of IV-APAP was associated with better local tolerability, similar analgesic efficacy, and greater patient satisfaction compared with a single bioequivalent dose of ProAPAP

L-Type Bovine Spongiform Encephalopathy in Genetically Susceptible and Resistant Sheep: Changes in Prion Strain or Phenotypic Plasticity of the Disease-Associated Prion Protein?

Background. Sheep with prion protein (PrP) gene polymorphisms QQ171 and RQ171 were shown to be susceptible to the prion causing L-type bovine spongiform encephalopathy (L-BSE), although RQ171 sheep specifically propagated a distinctive prion molecular phenotype in their brains, characterized by a high molecular mass proteaseresistant PrP fragment (HMM PrPres), distinct from L-BSE in QQ171 sheep. Methods. The resulting infectious and biological properties of QQ171 and RQ171 ovine L-BSE prions were investigated in transgenic mice expressing either bovine or ovine PrP. Results. In both mouse lines, ovine L-BSE transmitted similarly to cattle-derived L-BSE, with respect to survival periods, histopathology, and biochemical features of PrPres in the brain, as well as splenotropism, clearly differing from ovine classic BSE or from scrapie strain CH1641. Nevertheless and unexpectedly, HMM PrPres was found in the spleen of ovine PrP transgenic mice infected with L-BSE from RQ171 sheep at first passage, reminiscent, in lymphoid tissues only, of the distinct PrPres features found in RQ171 sheep brains. Conclusions. The L-BSE agent differs from both ovine classic BSE or CH1641 scrapie maintaining its specific strain properties after passage in sheep, although striking PrPres molecular changes could be found in RQ171 sheep and in the spleen of ovine PrP transgenic mice

Examen del plan presentado a las Córtes, para el reconocimiento de la independencia de la América española

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 200

A C-Terminal Protease-Resistant Prion Fragment Distinguishes Ovine “CH1641-Like” Scrapie from Bovine Classical and L-Type BSE in Ovine Transgenic Mice

The protease-resistant prion protein (PrPres) of a few natural scrapie isolates identified in sheep, reminiscent of the experimental isolate CH1641 derived from a British natural scrapie case, showed partial molecular similarities to ovine bovine spongiform encephalopathy (BSE). Recent discovery of an atypical form of BSE in cattle, L-type BSE or BASE, suggests that also this form of BSE might have been transmitted to sheep. We studied by Western blot the molecular features of PrPres in four “CH1641-like” natural scrapie isolates after transmission in an ovine transgenic model (TgOvPrP4), to see if “CH1641-like” isolates might be linked to L-type BSE. We found less diglycosylated PrPres than in classical BSE, but similar glycoform proportions and apparent molecular masses of the usual PrPres form (PrPres #1) to L-type BSE. However, the “CH1641-like” isolates differed from both L-type and classical BSE by an abundant, C-terminally cleaved PrPres product (PrPres #2) specifically recognised by a C-terminal antibody (SAF84). Differential immunoprecipitation of PrPres #1 and PrPres #2 resulted in enrichment in PrPres #2, and demonstrated the presence of mono- and diglycosylated PrPres products. PrPres #2 could not be obtained from several experimental scrapie sources (SSBP1, 79A, Chandler, C506M3) in TgOvPrP4 mice, but was identified in the 87V scrapie strain and, in lower and variable proportions, in 5 of 5 natural scrapie isolates with different molecular features to CH1641. PrPres #2 identification provides an additional method for the molecular discrimination of prion strains, and demonstrates differences between “CH1641-like” ovine scrapie and bovine L-type BSE transmitted in an ovine transgenic mouse model

Comment concilier développement économique et environnement ?

Rapport du Conseil économique pour le développement durable (France), consultable ici : http://www.developpement-durable.gouv.fr/IMG/pdf/Comment_concilier_developpement_economique_et_environnement.pd

An integrated hypothesis on the domestication of Bactris gasipaes

Peach palm (Bactris gasipaes Kunth) has had a central place in the livelihoods of people in the Americas since pre-Columbian times, notably for its edible fruits and multi-purpose wood. The botanical taxon includes both domesticated and wild varieties. Domesticated var gasipaes is believed to derive from one or more of the three wild types of var. chichagui identified today, although the exact dynamics and location of the domestication are still uncertain. Drawing on a combination of molecular and phenotypic diversity data, modeling of past climate suitability and existing literature, we present an integrated hypothesis about peach palm's domestication. We support a single initial domestication event in south western Amazonia, giving rise to var. chichagui type 3, the putative incipient domesticate. We argue that subsequent dispersal by humans across western Amazonia, and possibly into Central America allowed for secondary domestication events through hybridization with resident wild populations, and differential human selection pressures, resulting in the diversity of present-day landraces. The high phenotypic diversity in the Ecuadorian and northern Peruvian Amazon suggest that human selection of different traits was particularly intense there. While acknowledging the need for further data collection, we believe that our results contribute new insights and tools to understand domestication and dispersal patterns of this important native staple, as well as to plan for its conservation. (Résumé d'auteur

Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists

Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-α treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4(+ )T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-γ. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-α treatment had no effect on the proliferation of CD4(+ )T lymphocytes. In contrast, the number of IFN-γ-releasing CD4(+ )T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-γ release to a similar extent. In vitro addition of TNF antagonists to CD4(+ )T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF(+ )CD4(+ )T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4(+ )T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4(+ )T lymphocytes rapidly releasing IFN-γ upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4(+ )T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation

Search for an Association between V249I and T280M CX3CR1 Genetic Polymorphisms, Endothelial Injury and Preeclampsia: The ECLAXIR Study

BACKGROUND: Preeclampsia and coronary-artery disease share risk factors, suggesting common pathophysiological mechanisms. CX3CR1/CX3CL1 mediates leukocyte migration and adhesion and has been implicated in the pathophysiology of several inflammatory diseases. M280/I249 variants of CX3CR1 are associated with an atheroprotective effect and reduced endothelial dysfunction. The aim of this study was to search for an association between V249I and T280M polymorphisms of CX3CR1, preeclampsia and endothelial dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: We explored these polymorphisms with real-time polymerase chain reaction in a case-control study (184 white women with preeclampsia and 184 matched normotensive pregnant women). Endothelial dysfunction biomarkers including von Willebrand factor, VCAM-1 and thrombomodulin, as well as the soluble form of CX3CL1 were measured by enzyme-linked immunosorbent assays (ELISA). The I249 and M280 alleles were associated neither with preeclampsia, nor with its more severe form or with endothelial injury. In contrast, we found a trend toward increased CX3CL1 levels in preeclampsia patients, especially in early-onset- preeclampsia as compared to its level in later-onset- preeclampsia. CONCLUSIONS/SIGNIFICANCE: This is the first study to characterize the CX3CR1 gene polymorphisms in patients with preeclampsia. We found no differences in genotype or haplotype frequencies between patients with PE and normal pregnancies, suggesting that maternal CX3CR1 V249I and T280M polymorphisms do not increase susceptibility to preeclampsia. Further studies should be performed to directly evaluate the pathophysiological role of CX3CL1, a molecule abundantly expressed in endometrium, which has been shown to stimulate human trophoblast migration