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Objectif A fortes doses, les glucocorticoides sont a l’origine d’effets secondaires tels qu’un diabete cortico-induit et une lipodystrophie. Notre etude porte sur l’implication du recepteur adipocytaire des glucocorticoides (GR) dans ces complications, ainsi que les mecanismes impliques dans le developpement pathologique du tissu adipeux (TA), en soulevant plus specifiquement l’hypothese d’un impact sur sa vascularisation. Materiel et methodes Nous avons genere un modele murin inductible d’invalidation specifique du GR dans le TA (AdipoGR-KO). Ces souris ont ete soumises pendant 4 semaines a un traitement par la corticosterone (CORT), ligand naturel du GR chez le rongeur, et avec ou sans anticorps bloquant anti-VEGF-A, l’Aflibercept. Resultats L’invalidation du GR adipocytaire entraine une expansion massive du TA par rapport aux temoins traites CORT. Elle s’accompagne paradoxalement d’une meilleure sensibilite a l’insuline et tolerance au glucose mais aussi d’une amelioration des profils lipidiques circulants et hepatiques (Dalle et al, Diabetes 2019). Nos resultats indiquent egalement un fort developpement du reseau vasculaire dans les TA des souris AdipoGR-KO, associe a une induction de l’expression du facteur pro-angiogenique VEGF-A. Aussi, nous montrons que chez des souris AdipoGR-KO traitees par la CORT, le blocage du VEGF-A limite l’expansion du TA et reduit l’effet benefique du KO sur le phenotype metabolique. Discussion Ces resultats mettent en exergue le role majeur et limitant du GR adipocytaire dans l’expansion saine et le developpement d’une vascularisation harmonieuse du TA, via la regulation du facteur VEGF-A. Il s’agit clairement d’un nouveau mecanisme par lequel les glucocorticoides perturbent l’homeostasie energetique.

Second-generation antipsychotics (SGAs) are well known for their metabolic side effects in humans, including obesity and diabetes. These compounds are maintained during pregnancy to prevent the relapse of psychoses, but they readily diffuse across the placenta to the fetus, as documented with the widely-prescribed drug olanzapine (OLZ). However, observational studies have provided conflicting results on the potential impact of SGAs on fetal growth and body weight, and their effects on metabolic regulation in the offspring. For this reason, our study has tested whether antenatal exposure of CD1 mice to OLZ influenced metabolic outcomes in the offspring of the first (F1) and second (F2) generations. In F1 mice, OLZ antenatal treatment caused a decrease in neonatal body weight in both genders, an effect that persisted throughout life only in male animals. Interestingly, F1 female mice also displayed altered glucose homoeostasis. F2 mice, generated by mating normal males with F1 female mice exposed to OLZ during antenatal life, exhibited higher neonatal body weights which persisted only in F2 female animals. This was associated with expansion of fat mass and a concordant pattern of adipose tissue gene expression. Moreover, male and female F2 mice were glucose-intolerant. Thus, our study has demonstrated that antenatal OLZ exposure induces multigenerational and gender-specific programming of glucose tolerance in the offspring mice as adults, and points to the need for careful monitoring of children exposed to SGAs during pregnancy.

L’identification de nouvelles adipokines faisant le lien entre obesite et insulino-resistance represente un enjeu majeur. Nous avons montre recemment que NOV/CCN3, une proteine matricellulaire multifonctionnelle est synthetisee et secretee par le tissu adipeux, avec des taux plasmatiques correles avec l’IMC. NOV a ete anterieurement impliquee dans les processus de reparation tissulaire, la fibrose, les maladies inflammatoires et le cancer. Cependant, son role dans l’homeostasie energetique restait inconnu. Nous avons ainsi etudie le phenotype de souris NOV-/- soumises a un regime normal ou hyperlipidique (HFD). De facon tres nette, le poids des souris NOV-/- est nettement plus faible que celui des souris temoins, mais seulement en HFD. Ceci est lie a une reduction de masse grasse, avec des adipocytes plus petits, et une plus forte expression des acteurs de la thermogenese au sein des depots adipeux blancs, et en particulier d’UCP1. Ceci va de pair avec une depense energetique accrue des souris invalidees. Les souris NOV-/- en HFD ameliorent par ailleurs leur tolerance au glucose et leur sensibilite a l’insuline. De facon remarquable, les animaux NOV-/- ont un changement de phenotype macrophagique (M1 vers M2) et lymphocytaire dans leur tissu adipeux epididymaire, associe a une chute d’expression des cytokines pro-inflammatoires. Les animaux invalides ont egalement une amelioration de leur signalisation insulinique in vivo. L’ensemble de ces donnees montre que NOV est une nouvelle adipokine impliquee dans la resistance a l’insuline associee a l’obesite.

An original algorithm has been developed which applies several new concepts to the problem of local models. The algorithm is fully simulator independent and user-transparent. It uses a sequential least squares procedure to build appropriate approximating formulae from a general model that contains all the terms necessary to represent any particular mixture. No a priori information on the type of mixture (ideal/non ideal, narrow/wide boiling, …) or operating conditions of the process is necessary. Though, it is found that sophisticated simulators and integrators can suffer from the discontinuities introduced when parameters are updated or the local model is changed. In this regard, a regressive least squares method would lead to better results. Finally, local models algorithms are proposed as a new tool for the interpolation of properties in raw experimental tables.

A compressor, an expander and an arbitrary separator model have been added to the BELSIM-COL70 steady state simulation package for multi-stage separation processes. The performance of the dogleg method applied to the global equation system of an extended version of Cavett's problem is compared to the classical Wegstein method and the dogleg method applied to the torn variables only. The results of the simulation of a C3-splitter are compared to industrial measurements. Finally, the algorithm is applied to an azeotrope separation process with demixion in the liquid phase.

Introduction Le tissu adipeux (TA) joue un role central dans l’homeostasie lipidique. L’augmentation de la concentration systemique des acides gras conduit au developpement d’une insulino-resistance. Les fonctions adipocytaires (stockage des acides gras, isulino-sensibilite) sont liees au statut inflammatoire du TA. RORα est un facteur de transcription implique dans differents processus notamment le metabolisme lipidique et l’inflammation. La souris Staggerer, mutant naturel de perte de fonction de RORα, presente une meilleure sensibilite a l’insuline musculaire et resiste a l’obesite induite par un regime hyperlipidique. Materiels et methodes En comparant des souris Staggerer a des souris sauvages, en regime normal et apres un regime diabetogene (40 % lipides, 40 % glucides), le but de notre etude consiste a visualiser les effets de la perte de fonction de RORα sur le tissu adipeux, au niveau du statut inflammatoire et de la reponse a l’insuline ; puis, le lien avec l’insulino-sensibilite et la tolerance au glucose systemiques. Resultats En regime normal, le TA epididymaire (TAE) des souris staggerer presente une diminution de l’expression de cytokines pro- et anti-inflammatoire, accompagnee d’une meilleure sensibilite a l’insuline locale. En reponse a un regime diabetogene, le TAE des souris staggerer est resistant a l’inflammation et l’insulino-resistance induites chez les souris sauvages. Parallelement les souris staggerer conservent une bonne sensibilite a l’insuline et une bonne tolerance au glucose contrairement aux souris sauvages. Conclusion Nos resultats suggerent que RORα est un acteur negatif dans le TAE, tant au niveau inflammatoire qu’au niveau de la sensibilite a l’insuline. Ainsi, RORα pourrait etre une nouvelle cible therapeutique antidiabetique.

Alcoholism is a worldwide problem. Many strategies for alcohol detoxification and relapse prevention exist, but each alcohol treatment center has its own program. The objective of this study was to analyze and compare the financial cost and effectiveness of alcohol treatment programs from inpatient stay to follow-up 1 year later. This was a prospective, open, nonrandomized study of 4 specialized alcohol treatment centers and 267 patients admitted for alcohol detoxification.We recorded all medical and nonmedical interventions related to the program during patient stay in the hospital and every 3 months after discharge for 1 year and recorded the occurrence of alcohol relapse. Financial evaluation was based on the prices of refund from the French national health insurance service.The mean cost of hospitalization ranged from 1326 euros to 1917 euros(p = 0.001), a variation mainly due to the difference in the length of hospital stay but also to the cost of the inpatient program, routine medical checkups, and drugs administered. The mean cost of 1 year of follow-up per patient ranged from 419 euros to 1704 euros (p = 0.001). The efficiency, corresponding to the money spent to prevent the relapse of one patient during 1 month, was approximately 500 euros/month in three centers and 658 euros in the fourth. However, for a similar efficiency, the effectiveness, assessed by the mean time without relapse, was significantly (p = 0.001) different; center 1, which had the highest total cost, had an effectiveness 1.56 times higher than center 3, which had the lowest cost.This work emphasizes the heterogeneity of the costs and effectiveness of alcoholism treatment programs and suggests that research should be conducted to determine which program is the most rational, cost-efficient, and beneficial for patients and the public health office economy.

Introduction Les antipsychotiques induisent des effets secondaires metaboliques majeurs, notamment obesogenes et diabetogenes. Bien qu’ils soient prescrits chez la femme enceinte et passent la barriere placentaire, leur consequences metaboliques sur la descendance sont actuellement inconnues. Objectifs Etudier l’impact metabolique trans-generationnel de souris exposees aux antipsychotiques pendant leur gestation. Methodes Les antipsychotiques (olanzapine ou haloperidol) ont ete administres par minipompes osmotiques a des souris CD1 pendant les 2 dernieres semaines de gestation. La descendance femelle F1 obtenue a ete croisee avec des mâles non exposes pour obtenir la generation F2. Les descendances F1 et F2 ont ete suivies en termes de poids, tolerance au glucose, sensibilite a l’insuline, et composition corporelle. Resultats La descendance F1 exposee aux antipsychotiques a un poids de naissance plus faible, suggerant un retard de croissance intra-uterin. Des 5 semaines existe un dimorphisme sexuel avec une reduction ponderale chez les mâles et une prise ponderale chez les femelles. A 3 mois, aucune alteration du metabolisme glucidique n’est observee. A 1 an, le dimorphisme persiste avec chez les mâles, une reduction ponderale, un profil glucidique normal associe a une dyslipidemie, et chez les femelles une prise de poids associee a une intolerance au glucose avec insulinoresistance. Il existe en parallele des modifications d’expression des facteurs adipogeniques. Etonnamment, la descendance F2 presente des 3 mois une alteration du metabolisme glucidique associee a une prise de poids. Conclusion L’exposition antenatale aux antipsychotiques modifie de facon sexe-specifique la programmation trans-generationnelle de la vulnerabilite metabolique.

Introduction la physiopathologie de l’insulino-resistance associee a l’obesite reste encore mal comprise. L’identification de nouvelles adipokines impliquees dans ce phenomene reste ainsi un enjeu essentiel. Nos resultats recents suggerent que NOV, une proteine matricielle multi-fonctionnelle, est synthetisee et secretee par le tissu adipeux, avec des taux plasmatiques correles a l’IMC et a la masse grasse, et reduits apres chirurgie bariatrique (Pakradouni et al., PlosOne 2013). NOV est impliquee dans les processus de cicatrisation, fibrose, inflammation, et tumorigenese. Cependant, son role dans le tissu adipeux et l’homeostasie energetique demeure inconnu. Objectifs et methodes Nous avons etabli le phenotype metabolique de souris invalidees pour le gene de NOV (NOV-/-), et nourries par un regime normal ou hyperlipidique. Resultats Les souris sauvages et NOV-/- nourries par un regime normal ont un gain de poids similaire. Par contre, en regime hyperlipidique, la prise de poids des souris NOV-/- est beaucoup moins importante, en rapport avec une forte reduction de la masse grasse. Ce phenotype n’est pas associe a une modification de prise alimentaire, d’activite locomotrice ou de depense energetique. En regime hyperlipidique, les souris NOV-/- presentent une meilleure tolerance au glucose, et une sensibilite accrue a l’insuline. On observe une forte baisse d’expression de plusieurs cytokines et chemokines pro-inflammatoires dans le tissu adipeux des animaux NOV-/-. En accord avec cette observation, NOV induit in vitro l’expression de ces cyto-/chemokines dans l’adipocyte mature. Conclusion Ces resultats suggerent que NOV est une nouvelle adipokine impliquee dans l’insulino-resistance associee a l’obesite.

PURPOSE: To retrospectively evaluate survival, progression-free survival (PFS) and biological response in a series of patients irradiated with mixed neutron/photon beams for locally advanced prostate cancer in our institution. PATIENTS AND METHODS: Three hundred and eight patients were treated between January 1990 and December 1996. Fifty-five of these were recruited for pT3 or pN1 tumors after radical prostatectomy. Neoadjuvant androgen deprivation was given in 106 patients. The treatment protocol consisted of a mixed photon/neutron irradiation in a two-to-three proportion, up to a total equivalent dose of 66 Gy (assuming a clinical RBE value of 2.8). Pre- and post-treatment PSA determinations were available in practically all cases. Study endpoints were overall survival (OAS) and progression-free survival (PFS). The Cox proportional hazard regression model was used to investigate the prognostic value of baseline characteristics on survival and progression-free survival were a progression was defined as local, regional, metastatic or biological progression. Mean age was 69 years (49-86); mean pretreatment PSA was 15 (0.5-330) in all patients and 14 (0.5-160) in those receiving neoadjuvant hormonotherapy; seven patients only had an initial PSA < or = 4 ng/mL; 15% were T1, 46% were T2, 28% were T3 or pT3 and 4% were T4 (7% unspecified); WHO grade of differentiation was I in 38%, II in 38% and III in 14% (5% unspecified). RESULTS: The median follow-up was 2.8 years (0-7.8). Five-year overall survival (OAS) was 79% (95% CI: 71-87%) and 5-year progression-free survival (PFS) was 64% (95% CI: 54-74%) for the entire series. PFS in patients with an initial PSA > or = 20 ng/mL was the same. PFS could be predicted by two optimal Cox regression models, one including histological grade (p = 0.003) and initial PSA (p = 0.0009) as cofactors, the other including histological grade (p = 0.003) and T stage (p = 0.02). The main prognostic factors for overall survival were PSA and age. Biological responses with PSA < 1.5 ng/mL, < 1 ng/mL and < 0.5 ng/mL at any time after treatment were documented in 70%, 61% and 47% of the patients, respectively. CONCLUSION: Five-year OAS was 79%, PFS was 64%, and biological response was 70% for prostate cancer patients treated with mixed photon/neutron beams as applied at Louvain-la-Neuve, which are good results as compared with the literature. The usual prognostic factors were confirmed.

The incidence of pancreatic adenocarcinomas (PA) is increased in the setting of chronic pancreatitis. Distinguishing chronic pancreatitis from pancreatic adenocarcinomas is often difficult, and is based on routine brush cytological specimens provided during endoscopic retrograde cholangiopancreatography (ERCP). Reactive epithelial changes in chronic pancreatitis may appear similar to those of a well-differentiated cancer. Brush cytology specimens were obtained during ERCP from 49 patients with diseases for which the differential diagnosis included chronic pancreatitis and/or pancreatic adenocarcinoma Image cytometry was performed involving the assessment of between 200-400 Feulgen-stained nuclei per case; for each case, 40 quantitative cytometric variables were generated. Data analysis was performed using artificial intelligence methods of data classification that produced decision trees and production rule systems. Different classification models were produced for a subset of 34 patients. The best models were identified by the use of a sampling technique (leave-one-out), and were tested on the remaining 15 patients. These models were based on 5 of the 40 variables associated with a significant discriminatory function. Pancreatic adenocarcinoma was diagnosed in the training data set of 34 patients during a leave-one-out process with an estimated sensitivity of 91% and specificity of 87%. Both sensitivity and specificity were 80% in the independent test set of 15 patients. We conclude that inflammatory and malignant pancreatic epithelia exhibit distinct morphological features that can be distinguished by decision tree-based classifiers employing image-cytometric numerical data.

BACKGROUND: Alcoholism is a worldwide problem. Many strategies for alcohol detoxification and relapse prevention exist, but each alcohol treatment center has its own program. The objective of this study was to analyze and compare the financial cost and effectiveness of alcohol treatment programs from inpatient stay to follow-up 1 year later. This was a prospective, open, nonrandomized study of 4 specialized alcohol treatment centers and 267 patients admitted for alcohol detoxification. METHODS: We recorded all medical and nonmedical interventions related to the program during patient stay in the hospital and every 3 months after discharge for 1 year and recorded the occurrence of alcohol relapse. Financial evaluation was based on the prices of refund from the French national health insurance service. RESULTS: The mean cost of hospitalization ranged from 1326 euros to 1917 euros(p = 0.001), a variation mainly due to the difference in the length of hospital stay but also to the cost of the inpatient program, routine medical checkups, and drugs administered. The mean cost of 1 year of follow-up per patient ranged from 419 euros to 1704 euros (p = 0.001). The efficiency, corresponding to the money spent to prevent the relapse of one patient during 1 month, was approximately 500 euros/month in three centers and 658 euros in the fourth. However, for a similar efficiency, the effectiveness, assessed by the mean time without relapse, was significantly (p = 0.001) different; center 1, which had the highest total cost, had an effectiveness 1.56 times higher than center 3, which had the lowest cost. CONCLUSIONS: This work emphasizes the heterogeneity of the costs and effectiveness of alcoholism treatment programs and suggests that research should be conducted to determine which program is the most rational, cost-efficient, and beneficial for patients and the public health office economy.