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

Deconstructing Insight: EEG Correlates of Insightful Problem Solving

Background: Cognitive insight phenomenon lies at the core of numerous discoveries. Behavioral research indicates four salient features of insightful problem solving: (i) mental impasse, followed by (ii) restructuring of the problem representation, which leads to (iii) a deeper understanding of the problem, and finally culminates in (iv) an “Aha!” feeling of suddenness and obviousness of the solution. However, until now no efforts have been made to investigate the neural mechanisms of these constituent features of insight in a unified framework. Methodology/Principal Findings: In an electroencephalographic study using verbal remote associate problems, we identified neural correlates of these four features of insightful problem solving. Hints were provided for unsolved problems or after mental impasse. Subjective ratings of the restructuring process and the feeling of suddenness were obtained on trial-by-trial basis. A negative correlation was found between these two ratings indicating that sudden insightful solutions, where restructuring is a key feature, involve automatic, subconscious recombination of information. Electroencephalogram signals were analyzed in the space×time×frequency domain with a nonparametric cluster randomization test. First, we found strong gamma band responses at parieto-occipital regions which we interpreted as (i) an adjustment of selective attention (leading to a mental impasse or to a correct solution depending on the gamma band power level) and (ii) encoding and retrieval processes for the emergence of spontaneous new solutions. Secondly, we observed an increased upper alpha band response in right temporal regions (suggesting active suppression of weakly activated solution relevant information) for initially unsuccessful trials that after hint presentation led to a correct solution. Finally, for trials with high restructuring, decreased alpha power (suggesting greater cortical excitation) was observed in right prefrontal area. Conclusions/Significance: Our results provide a first account of cognitive insight by dissociating its constituent components and potential neural correlates

Psychosocial factors and health as determinants of quality of life in community-dwelling older adults.

PURPOSE: It is important to understand the determinants of differences in quality of life in old age and to include a wide range of possible predictors. The present study investigated the determinants of quality of life in two groups of older adults for whom there was an unusually informative set of possible predictor variables. METHOD: Participants were members of the Lothian Birth Cohorts of 1921 (n = 550) or 1936 (n = 1,091). Four facets of quality of life (QoL) and general QoL were measured using the WHOQOL-BREF. Possible determinants included personality traits, measured with the International Personality Item Pool (IPIP) scales; childhood and old age general cognitive ability, measured with the Moray House Test; minor psychological symptoms, measured with the Hospital Anxiety and Depression Scale (HADS); physical health, assessed by grip strength and cardiovascular disease history; and sociodemographic factors, assessed by interview. RESULTS: Linear regression analyses revealed that HADS depression had the greatest influence on quality of life. Personality traits, most notably Emotional Stability, also predicted quality of life to varying degrees, along with factors reflecting current life circumstances. There were differences between the two cohorts in the variables which predicted quality of life. There were different, conceptually relevant, contributions to the different QoL facets. CONCLUSIONS: Personality traits and minor depressive symptoms have an important influence on self-reported quality of life in old age. Quality of life may be influenced more by current than past circumstances, and this relationship may change with age

Evidence for widespread hydrated minerals on asteroid (101955) Bennu

Early spectral data from the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission reveal evidence for abundant hydrated minerals on the surface of near-Earth asteroid (101955) Bennu in the form of a near-infrared absorption near 2.7 µm and thermal infrared spectral features that are most similar to those of aqueously altered CM-type carbonaceous chondrites. We observe these spectral features across the surface of Bennu, and there is no evidence of substantial rotational variability at the spatial scales of tens to hundreds of metres observed to date. In the visible and near-infrared (0.4 to 2.4 µm) Bennu’s spectrum appears featureless and with a blue (negative) slope, confirming previous ground-based observations. Bennu may represent a class of objects that could have brought volatiles and organic chemistry to Earth

The dynamic geophysical environment of (101955) Bennu based on OSIRIS-REx measurements

The top-shaped morphology characteristic of asteroid (101955) Bennu, often found among fast-spinning asteroids and binary asteroid primaries, may have contributed substantially to binary asteroid formation. Yet a detailed geophysical analysis of this morphology for a fast-spinning asteroid has not been possible prior to the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission. Combining the measured Bennu mass and shape obtained during the Preliminary Survey phase of the OSIRIS-REx mission, we find a notable transition in Bennu’s surface slopes within its rotational Roche lobe, defined as the region where material is energetically trapped to the surface. As the intersection of the rotational Roche lobe with Bennu’s surface has been most recently migrating towards its equator (given Bennu’s increasing spin rate), we infer that Bennu’s surface slopes have been changing across its surface within the last million years. We also find evidence for substantial density heterogeneity within this body, suggesting that its interior is a mixture of voids and boulders. The presence of such heterogeneity and Bennu’s top shape are consistent with spin-induced failure at some point in its past, although the manner of its failure cannot yet be determined. Future measurements by the OSIRIS-REx spacecraft will provide insight into and may resolve questions regarding the formation and evolution of Bennu’s top-shape morphology and its link to the formation of binary asteroids

Novel roles for GAPDH in cell death and carcinogenesis

Publicado en línea el 25 de septiembre de 2009Growing evidence points to the fact that glucose metabolism has a central role in carcinogenesis. Among the enzymes controlling this energy production pathway, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest. Initially identified as a glycolytic enzyme and considered as a housekeeping gene, this enzyme is actually tightly regulated and is involved in numerous cellular functions. Particularly intriguing are recent reports describing GAPDH as a regulator of cell death. However, its role in cell death is unclear; whereas some studies point toward a proapoptotic function, others describe a protective role and suggest its participation in tumor progression. In this study, we highlight recent findings and discuss potential mechanisms through which cells regulate GAPDH to fulfill its diverse functions to influence cell fate.This work was supported in part by l’Association pour la Recherche sur le Cancer, by l’Agence Nationnal de la Recherche, la Fondation de France, Plan Nacional I+D SAF2008-04974 and by grants from The U.S. National Institutes of Health. J-E.R. is a recipient of a contrat d’interface INSERM-CHU de Nice.Peer reviewe

Would Physicians Override a Do-Not-Resuscitate Order When a Cardiac Arrest Is Iatrogenic?

OBJECTIVE: To assess whether physicians would be more likely to override a do-not-resuscitate (DNR) order when a hypothetical cardiac arrest is iatrogenic. DESIGN: Mailed survey of 358 practicing physicians. SETTING: A university-affiliated community teaching hospital. PARTICIPANTS: Of 358 physicians surveyed, 285 (80%) responded. MEASUREMENTS AND MAIN RESULTS: Each survey included three case descriptions in which a patient negotiates a DNR order, and then suffers a cardiac arrest. The arrests were caused by the patient’s underlying disease, by an unexpected complication of treatment, and by the physician’s error. Physicians were asked to rate the likelihood that they would attempt cardiopulmonary resuscitation for each case description. Physicians indicated that they would be unlikely to override a DNR order when the arrest was caused by the patient’s underlying disease (mean score 2.55 on a scale from 1 “certainly would not” to 7 “certainly would”). Physicians reported they would be much more likely to resuscitate when the arrest was due to a complication of treatment (5.24 vs 2.55; difference 95% confidence interval [CI] 2.44, 2.91; p < .001), and that they would be even more likely to resuscitate when the arrest was due to physician error (6.32 vs 5.24; difference 95% CI 0.88, 1.20; p < .001). Eight percent, 29%, and 69% of physicians, respectively, said that they “certainly would” resuscitate in these three vignettes (p < .001). CONCLUSIONS: Physicians may believe that DNR orders do not apply to iatrogenic cardiac arrests and that patients do not consider the possibility of an iatrogenic arrest when they negotiate a DNR order. Physicians may also believe that there is a greater obligation to treat when an illness is iatrogenic, and particularly when an illness results from the physician’s error. This response to iatrogenic cardiac arrests, and its possible generalization to other iatrogenic complications, deserves further consideration and discussion