Macrophage Migration Inhibitory Factor Antagonist Blocks the Development of Endometriosis In Vivo

Endometriosis, a disease of reproductive age women, is a major cause of infertility, menstrual disorders and pelvic pain. Little is known about its etiopathology, but chronic pelvic inflammation is a common feature in affected women. Beside symptomatic treatment of endometriosis-associated pain, only two main suboptimal therapeutic approaches (hormonal and invasive surgery) are generally recommended to patients and no specific targeted treatment is available. Our studies led to the detection of a marked increase in the expression of macrophage migration inhibitory factor (MIF) in the eutopic endometrium, the peripheral blood and the peritoneal fluid of women with endometriosis, and in early, vascularized and active endometriotic lesions. Herein, we developed a treatment model of endometriosis, where human endometrial tissue was first allowed to implant into the peritoneal cavity of nude mice, to assess in vivo the effect of a specific antagonist of MIF (ISO-1) on the progression of endometriosis and evaluate its efficacy as a potential therapeutic tool. Administration of ISO-1 led to a significant decline of the number, size and in situ dissemination of endometriotic lesions. We further showed that ISO-1 may act by significantly inhibiting cell adhesion, tissue remodeling, angiogenesis and inflammation as well as by altering the balance of pro- and anti-apoptotic factors. Actually, mice treatment with ISO-1 significantly reduced the expression of cell adhesion receptors αv and ß3 integrins (P<0.05), matrix metalloproteinases (MMP) 2 and 9 (P<0.05), vascular endothelial cell growth factor (VEGF) (P<0.01), interleukin 8 (IL8) (P<0.05), cyclooxygenease (COX)2 (P<0.001) and the anti-apoptotic protein Bcl2 (P<0.01), but significantly induced the expression of Bax (P<0.05), a potent pro-apoptotic protein. These data provide evidence that specific inhibition of MIF alters endometriotic tissue growth and progression in vivo and may represent a promising potential therapeutic avenue

Atrial Heterogeneity Generates Re-entrant Substrate during Atrial Fibrillation and Anti-arrhythmic Drug Action: Mechanistic Insights from Canine Atrial Models

Anti-arrhythmic drug therapy is a frontline treatment for atrial fibrillation (AF), but its success rates are highly variable. This is due to incomplete understanding of the mechanisms of action of specific drugs on the atrial substrate at different stages of AF progression. We aimed to elucidate the role of cellular, tissue and organ level atrial heterogeneities in the generation of a re-entrant substrate during AF progression, and their modulation by the acute action of selected anti-arrhythmic drugs. To explore the complex cell-to-organ mechanisms, a detailed biophysical models of the entire 3D canine atria was developed. The model incorporated atrial geometry and fibre orientation from high-resolution micro-computed tomography, region-specific atrial cell electrophysiology and the effects of progressive AF-induced remodelling. The actions of multi-channel class III anti-arrhythmic agents vernakalant and amiodarone were introduced in the model by inhibiting appropriate ionic channel currents according to experimentally reported concentration-response relationships. AF was initiated by applied ectopic pacing in the pulmonary veins, which led to the generation of localized sustained re-entrant waves (rotors), followed by progressive wave breakdown and rotor multiplication in both atria. The simulated AF scenarios were in agreement with observations in canine models and patients. The 3D atrial simulations revealed that a re-entrant substrate was typically provided by tissue regions of high heterogeneity of action potential duration (APD). Amiodarone increased atrial APD and reduced APD heterogeneity and was more effective in terminating AF than vernakalant, which increased both APD and APD dispersion. In summary, the initiation and sustenance of rotors in AF is linked to atrial APD heterogeneity and APD reduction due to progressive remodelling. Our results suggest that anti-arrhythmic strategies that increase atrial APD without increasing its dispersion are effective in terminating AF

Neuroendocrine–immune disequilibrium and endometriosis: an interdisciplinary approach

Endometriosis, a chronic disease characterized by endometrial tissue located outside the uterine cavity, affects one fourth of young women and is associated with chronic pelvic pain and infertility. However, an in-depth understanding of the pathophysiology and effective treatment strategies of endometriosis is still largely elusive. Inadequate immune and neuroendocrine responses are significantly involved in the pathophysiology of endometriosis, and key findings are summarized in the present review. We discuss here the role of different immune mechanisms particularly adhesion molecules, protein–glycan interactions, and pro-angiogenic mediators in the development and progression of the disease. Finally, we introduce the concept of endometrial dissemination as result of a neuroendocrine-immune disequilibrium in response to high levels of perceived stress caused by cardinal clinical symptoms of endometriosis

Electrostatic interactions inside the aqueous core of spherical reversed micelles (L2 phase)

We propose a model for describing electrostatic interactions in the aqueous core of a spherical reversed micelle. Some counterions are located at the surface of the aqueous core, the others are distributed inside the core following a Boltzmann law. The nonlinearized Poisson-Boltzmann equation is solved in spherical geometry; an asymptotic expansion of its solution is found near a logarithmic divergence. We give an evaluation of the enthalpy of association of a counterion to the surface of the aqueous core. Assuming that the area by polar head remains constant, we obtain the electrostatic energy of the micelle and we show that the electrostatic energy by monomer is a function of the aggregation number.Nous proposons un modèle qui décrit les interactions électrostatiques dans le coeur aqueux d'une micelle inverse sphérique. Nous supposons que certains contre-ions sont situés à la surface du coeur aqueux, les autres étant répartis à l'intérieur suivant une loi de Boltzmann. L'équation de Poisson-Boltzmann non linéarisée est résolue et nous donnons un développement asymptotique de sa solution près d'une divergence logarithmique mise ici en évidence. L'enthalpie d'association d'un contre-ion, à la surface du cœur aqueux est évaluée. Quand la surface par tête polaire reste constante, l'énergie électrostatique par monomère est une fonction du nombre d'agrégation de la micelle

Recovery of trypsin inhibitor and soy milk protein concentration by dynamic filtration

This paper investigates the feasibility of producing a soy milk fraction enriched in trypsin inhibitor (STI) which could serve as a feed material for chromatographic purification of STI. This STI is also a soy antinutritional factor which is valuable for its medical and scientific applications. We have used a shear-enhanced filtration system with a disk rotating at high speed near the membrane. Stabilized permeate fluxes at 2500 rpm, with a disk equipped with vanes and a transmembrane pressure (TMP) of 67 kPa were 92 L h-1 m-2 with a 50 kDa MWCO PES membrane against 60 L h-1 m-2 with a 300 kDa one, under the same conditions. STI rejection by the 50 kDa membrane was 98.6%. With a smooth disk at a TMP of 107 kPa, fluxes fell to 30 L h-1 m-2 for both membranes, and rejection remained close to 98% for the 50 kDa membrane. During concentration tests, the permeate flux obeyed the logarithmic decay with concentration factor (CF), with a theoretical maximum CF of 4.85. © 2006 Elsevier B.V. All rights reserved.Articl

Recovery of trypsin inhibitor by soy milk ultrafiltration using a rotating disk system

Defatted soy milk was ultrafiltered at 50 kDa using a shear-enhanced rotating disk filtration system developed at the Technological University of Compiegne. The objectives were to concentrate soy milk proteins while removing in the permeate soy trypsin inhibitor (STI) which is an anti-nutritional factor, but can be used for medical applications. Maximum permeate flux at a rotation speed of 2500 rpm, a TMP of 140 kPa and initial concentration, was 37 L h-1m-2 when a smooth disk was used and rose to 95 L h-1m-2 when the disk was equipped with 6 mm high vanes. In concentration tests without permeate recycling, the permeate flux decayed logarithmically with increasing volume reduction ratio (VRR).The maximum theoretical VRR extrapolated to zero flux was found to be 5 for both disks. © 2006.Articl