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En approuvant un texte commun, en novembre 1995 à Barcelone, vingt-sept pays d’Europe et du pourtour méditerranéen ont entamé un processus qui s’inscrit dans le cadre de la libéralisation globale des échanges économiques à l’échelle de la planète, mais aussi dans le prolongement de plusieurs initiatives euro-méditerranéennes visant à organiser un partenariat tenant compte des spécificités régionales. Concernées au premier chef, les économies maghrébines voient se profiler l’horizon 2010 (date théorique de l’instauration d’une zone de libre-échange) avec un mélange d’espoir et de crainte : s’agit-il pour elles d’une chance unique de faire partie d’une « zone de prospérité partagée », ou doivent-elles redouter au contraire d’être laminées par leur puissant voisin du nord ? Tentant d’apporter des éléments de réponse à cette question, cet ouvrage examine à la fois les contraintes nationales, régionales et internationales qui pèsent sur ces économies, les dynamiques et les résistances qu’affrontent les acteurs économiques, et pointe quelques-unes des conditions pour l’instauration d’une véritable coopération. Rassemblés sous la direction d’Abdelkader Sid Ahmed, économiste spécialiste des questions de développement, les auteurs, européens et maghrébins, apportent les données et les interprétations nécessaires à une meilleure appréhension des rapports économiques euro-maghrébins de la prochaine décennie.

Given the increasing prevalence of obesity and the metabolic syndrome, identification of intrinsic molecular programs responsible for ensuring fuel homeostasis and preventing metabolic disease is needed. We investigated whether the orphan nuclear receptor estrogen-related receptor α (ERRα), a major regulator of energy metabolism, plays a role in lipid homeostasis and the development of nonalcoholic fatty liver disease (NAFLD) in response to chronic high-fat diet (HFD) consumption and long-term fasting. Systemic ablation of ERRα in mice demonstrated clear beneficial effects for loss of ERRα function in protection from HFD-provoked body weight gain manifested not only from a reduction in white adipose tissue stores but also from an impediment in intrahepatic lipid accumulation. The prevention of HFD-induced NAFLD in ERRα-null mice was underscored by transcriptional repression of de novo lipogenesis, which was upregulated in wild-type mice, a known contributing factor to lipid-stimulated hepatic steatosis. Surprisingly, given these findings, ERRα deficiency had no significant impact on the degree of fasting-induced NAFLD, involving the mobilization of adipocyte triglyceride (TG) stores into the liver. However, the presence of ERRα was essential for acute refeeding-mediated reversal of fasting-induced hepatic TG accretion, underpinned by impaired downregulation of adipose TG lipolysis and reduced hepatic mitochondrial oxidative activity. Taken together, the regulation of lipid handling by ERRα depended on the nutritional state, suggesting that negative modulation of ERRα activity could be envisaged to prevent lipid-induced NAFLD, whereas inducing its activity would be useful to treat and reverse the instilled disease.

Objective: To evaluate the long-term persistence of anti-hepatitis B surface (HBs) antibodies and the response to a HB challenge re-vaccination in children who had received a primary series of DTaP-IPV-HB-PRP∼T (Hexaxim™) or DTaP-IPV-HB/PRP∼T (Infanrix hexa™). Methods: Two cohorts of participants who had previously received HB vaccine at birth followed by either DTaP-IPV-HB-PRP∼T or DTaP-IPV-HB/PRP∼T co-administered with PCV7 at 2, 4, 6 months of age in a randomized, Phase III, observer-blind study in Thailand, were followed up for anti-HBs antibodies (geometric mean concentrations [GMCs] and seroprotection [SP] rate [% of participants with a titer ≥10 mIU/mL]) at 12–18 months of age and 9–10 years of age. A monovalent HB challenge re-vaccination was administered at 9–10 years of age and the anamnestic response was evaluated. Results: Anti-HBs GMCs and SP rates in the DTaP-IPV-HB-PRP∼T and DTaP-IPV-HB/PRP∼T groups were high and similar post-primary vaccination series (2477 mIU/mL and 99.5% and 2442 mIU/mL and 99.5%, respectively) and declined to a similar extent in each group at 12–18 months (154.5 mIU/mL and 90.8% and 162.3 mIU/mL and 96.5%, respectively). Antibody levels further declined at 9–10 years of age (13.3 mIU/mL and 49.3% and 8.0 mIU/mL and 42.9%) and a strong anamnestic response occurred in each group post-HB challenge re-vaccination (92.8% and 98.7%, respectively). Conclusion: The kinetics of long-term anti-HBs antibody persistence were similar following a primary series of DTaP-IPV-HB-PRP∼T or DTaP-IPV-HB/PRP∼T. The response to a subsequent HB challenge re-vaccination was strong and similar in each group, demonstrating persisting immune memory.

This study assessed a pediatric mixed hexavalent diphtheria (D)-tetanus (T)-acellular pertussis (aP)-inactivated poliovirus (IPV)-hepatitis B (HB)-Haemophilus influenzae b [polyribosylribitol phosphate (PRP-T)]-pentavalent (DTaP-IPV//PRP-T)-hexavalent primary series schedule followed by a pentavalent booster.Healthy infants (N = 265) who had received a prior HB vaccination received a fully liquid, hexavalent vaccine (DTaP-IPV-HB-PRP-T) at 2 and 6 months of age and a reconstituted pentavalent vaccine (DTaP-IPV//PRP-T) at 4 months of age. Coadministered vaccines were pneumococcal vaccine at 2 and 4 months (and optionally at 6 months of age), rotavirus vaccine at 2, 4, 6 months and meningococcal serogroup C vaccine at 2 months. At 18 months, participants received DTaP-IPV//PRP-T and pneumococcal vaccine boosters. Immunogenicity was assessed using validated assays and safety by parental reports.For the hexavalent and pentavalent vaccines, the primary series and booster immune responses in terms of seroprotection and vaccine response rates were high for all antigens (generally99% and95% for the primary series and booster, respectively) and prebooster antibody persistence was good for all antigens (in particular, 92.4% of participants had prebooster anti-HB antibody ≥ 10 mIU/mL). The incidence of solicited reactions was lower after the booster vaccination (56.9%-73.1%) than the primary series (76.6%-97.4%); there were few vaccine-related unsolicited adverse events (1.9% and 1.5% for the primary series and booster, respectively), none led to participant discontinuation and none was serious.This study provides data that allow recommending authorities to consider the use of a sequential hexavalent-pentavalent-hexavalent primary vaccination series followed by a pentavalent booster in coadministration with other common childhood vaccines.

The present study aimed at analyzing the chemical composition and evaluating the in vitro and in vivo anthelmintic activity of Artemisia campestris essential oil aerial parts. The chemical composition was analysed by gaz chromatography/mass chromatography (GC/MS). Fifty compounds were identified representing 99.98% of the total oil. A. campestris essential oil was dominated by beta-pinene (36.40%) and 2-undecanone (14.7%). The in vitro anthelmintic activity tests of A. campestris essential oil were performed on Haemonchus contortus using egg hatch assay (EHA) and adult worm’s motility assay (AWMA) compared with a reference drug albendazole. In the EHA 100% inhibition was observed at 2 mg/ml after 48 h incubation (IC50 = 0.93 mg/ml). In the AWMA, essential oil induced 66.6% inhibition at 0.5 mg/ml after 8 h post exposure. The nematicidal effect of essential oil was evaluated on Heligmosomoides polygyrus. It was monitored through faecal egg count reduction (FECR) and total worm count reduction (TWCR). Three doses (2000, 4000 and 5000 mg/kg) were studied using a bioassay. The dose of 5000 mg/kg showed a high nematicidal activity (72.1% FECR and 72% TWCR), 7 days post-treatment. The results of the present study suggest that A. campestris essential oil has a potential anthelmintic activity and further studies are required in order to establish its mechanisms of action.

To support a fully liquid, diphtheria (D)-tetanus (T)-acellular pertussis (aP)-inactivated poliovirus (IPV)-hepatitis B (HB)-Haemophilus influenzae b (PRP-T) vaccine in Europe using a 2, 3, 4 month primary series and a booster at 11-15 months of age. Phase III, randomized, observer-blind studies in Germany and the Czech Republic. Participants who had not received HB vaccine were randomized to a 2, 3, 4 month primary series of DTaP-IPV-HB-PRP-T (group 1; N = 266) or a reconstituted DTaP-HB-IPV//PRP-T comparator (group 2; N = 263) and a booster of the same vaccine. Pneumococcal vaccine (PCV13) and rotavirus vaccine were coadministered at 2, 3, 4 months, and the booster was coadministered with PCV13. Noninferiority (group 1 versus group 2) was tested postprimary series for seroprotection rates (anti-HB and anti-PRP) and vaccine response rates (anti-pertussis toxin and anti-filamentous hemagglutinin). Safety was assessed by parental reports. Noninferiority was demonstrated with the lower bound of the 95% confidence interval for the difference (group 1 to group 2) being > -10% for each comparison. Primary series immune responses were high for all antigens and similar in each group. Prebooster antibody persistence was good, and there was a strong anamnestic response, both being similar for the investigational and control vaccines. Responses to PCV13 and rotavirus vaccine were similar in each group. There were no safety concerns. These data support the use of the DTaP-IPV-HB-PRP-T vaccine in a 2, 3, 4 month schedule without a birth dose of HB vaccine, with a booster dose in the second year of life administered with routine childhood vaccines.

Autophagy Session : Selected oral communication, Poster N°37 Organizing Committee: Chairs: Didier Attaix, Lydie Combaret and Daniel TaillandierAutophagy Session : Selected oral communication, Poster N°37Organizing Committee: Chairs: Didier Attaix, Lydie Combaret and Daniel Taillandier; The protein kinase GCN2 detects free tRNA during stresses of essential amino acid (EAA) deficiencies and triggers an adaptive cell response by phosphorylating eIF2α. This leads to both a decrease in protein synthesis and the emergence of an ATF4-dependent gene expression program. Our previous work provided evidence that the GCN2/p-eIF2α/ATF4 pathway plays a major role in macro-autophagy by upregulating the expression of a number of autophagy-related genes at the transcriptional level, thereby contributing to expand the process over the long term. Here, we aimed at determining whether GCN2 could be involved in the early steps of activation of the autophagic process. Our data showed that autophagy was activated within the first hour of a single EAA deficiency in both cultured cells and mouse liver, a response that required GCN2. Furthermore, we observed that the phosphorylation of eIF2α contributed to this adaptive upregulation of autophagy whereas ATF4 was dispensable. Importantly, by using experimental conditions to activate GCN2 without affecting mTORC1 activity, our data showed that the GCN2-dependent activation of autophagy occurs without requiring concomitant mTORC1 inhibition. Overall these results highlighted that the GCN2/p-eIF2α signaling was sufficient to activate early stages of autophagy upregulation.

The present study aimed to evaluate the activity of methanolic extract of Rubus ulmifolius Schott against the Acanthamoeba castellani Neff Strain as well as its antioxidant and antimicrobial effects. The tested extract has a good amoebicidal activity with low IC 50 (61.785 ± 1.322 μg/ml) and also has significant activity against both Gram-positive ( S. aureus, S. agalactiae ) and Gram-negative bacteria ( E. coli, S. typhimurium ) and against C. albicans . The inhibition zones diameters (IZD) and minimal inhibitory concentration (MIC) values were in the range of 22.5–50 mm and 02.29–4.76 mg ml −1 , respectively. In the other hand, the in vitro ROS scavenging activity was evaluated, the tested extract exhibited a good effect on the ·OH radical (89.99% at a concentration of 100 μg/ml) when compared to the ascorbic acid (68.81%). Moreover, the inhibition percentage of superoxide generation by R. ulmifolius extract at 100 μg/ml was greater than ascorbic acid (79.55; 64.79%, respectively). Also, the tested extract showed a high percentage of H 2 O 2 scavenging activity (99.95% at 100 μg/ml). Our findings suggest that R. ulmifolius could be a potential source of natural antioxidant in preventing many diseases associated with oxidative stress, amoebic and bacterial infections.

Hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-hepatitis B-Haemophilus influenzae type b (DTaP-IPV-HB-PRP-T)-containing vaccines are increasingly the standard of care. This study evaluated the primary series (NCT01177722) and booster (NCT01444781) of a fully liquid DTaP-IPV-HB-PRP-T vaccine in Latin America.Infants (N = 1375) received hepatitis B vaccine at birth and were randomized to one of 3 batches of the investigational DTaP-IPV-HB-PRP-T or licensed control vaccine (DTaP-HB-IPV//PRP-T) at 2-4 to 6 months of age, coadministered with 7-valent pneumococcal conjugate vaccine (PCV7) (2-4-6 months) and rotavirus vaccine (2-4 months). A booster of either DTaP-IPV-HB-PRP-T or control was given at 12-24 months, coadministered with PCV7. Immunogenicity was assessed by validated assays and safety from parental reports.Primary series seroprotection and vaccine response rates were equivalent for DTaP-IPV-HB-PRP-T batches. For pooled batches, noninferiority to the control vaccine was demonstrated for each antigen. There were no descriptive differences in antibody persistence or booster response between DTaP-IPV-HB-PRP-T and the control. The booster responses to either vaccine following DTaP-IPV-HB-PRP-T primary series or to DTaP-IPV-HB-PRP-T following a control vaccine primary series were similar. The anti-aP component (filamentous hemagglutinin [FHA] and pertussis toxin [PT]) vaccine response and anti-Haemophilus influenzae type b (PRP) series seroprotection (≥0.15 µg/mL) rates were ≥73.0% after 2 primary series doses. Antipyretics had no effect on the immune response, and an extra (oral) polio vaccination had no effect on the antipolio booster response. Responses to PCV7 and rotavirus vaccine were similar for each coadministration. There were no safety concerns observed with any vaccine.These results confirm the suitability of the fully liquid DTaP-IPV-HB-PRP-T vaccine for primary and booster vaccination of infants.

The present study was undertaken to report the modeling of the dosing-time-dependent adverse effects of both untreated and biologically-treated pharmaceutical wastewater in mice. The mice were housed in a room controlled at 24 °C under a 12 h/12 h dark-light cycle (light 7:00–19:00 h) for two weeks before initiating the experiments and allowed free access to food and water. A single dose of pharmaceutical or bioremediated effluent was administrated intraperitoneally (10 mL/kg) to mice divided in six circadian stages [1, 5, 9, 13, 17, and 21 hours after light onset (HALO)]. The surviving treated mice exhibited a significant circadian variation in body weight loss (p

Pancreas divisum (PD) is a common congenital anomaly of the pancreas, which results from an abnormal fusion between the ventral and dorsal pancreatic ducts during fetal development. Association with Intraductal papillary mucinous neoplasm (IPMN) is extremely rare. The treatment of this entity will depend both on the malignant potential of IPMN and on the symptoms related to pancreas divisum. We report a rare case of Intraductal papillary mucinous carcinoma of the pancreas associated with pancreas divisum, one of the most difficult situations which the surgeon can be confronted to in his practice.

International audience; This work presents an updated experimental and kinetic modeling study of n-heptane oxidation. In the experiments, ignition delay times of stoichiometric n-heptane/air mixtures have been measured in two different high-pressure shock tubes in the temperature range of 726–1412 K and at elevated pressures (15, 20 and 38 bar). Meanwhile, concentration versus time profiles of species have been measured in a jet-stirred reactor at atmospheric pressure, in the temperature range of 500–1100 K at φ = 0.25, 2.0 and 4.0. These experimental results are consistent with those from the literature at similar conditions and extend the current data base describing n-heptane oxidation.Based on our experimental observations and previous modeling work, a detailed kinetic model has been developed to describe n-heptane oxidation. This kinetic model has adopted reaction rate rules consistent with those recently developed for the pentane isomers and for n-hexane. The model has been validated against data sets from both the current work and the literature using ignition delay times, speciation profiles measured in a jet-stirred reactor and laminar flame speeds over a wide range of conditions. Good agreement is observed between the model predictions and the experimental data. The model has also been compared with several recently published kinetic models of n heptane and shows an overall better performance. This model may contribute to the development of kinetic mechanisms of other fuels, as n-heptane is a widely used primary reference fuel. Since the sub-mechanisms of n pentane, n-hexane and n-heptane have adopted consistent reaction rate rules, the model is more likely to accurately simulate the oxidation of mixtures of these fuels. In addition, the successful implementation of these rate rules have indicated the possibility of their application for the development of mechanisms for larger hydrocarbon fuels, which are of great significance for practical combustion devices.

ORGANIZING COMMITTEE Chairs: Didier Attaix - Lydie Combaret - Daniel Taillandier Daniel Béchet - Agnès Claustre - Cécile Coudy-Gandilhon - Christiane Deval - Gérard Donadille - Cécile Polge SCIENTIFIC COMMITTEE Didier Attaix - Lydie Combaret - Alfred L. Goldberg - Ron Hay - Germana Meroni - Marco Sandri - Daniel Taillandier - Keiji Tanaka - Simon S. Wing Poster Session 3 - Autophagy Poster title : GCN2 can promote autophagy initiating events independently of mTORC1 inhibitionORGANIZING COMMITTEEChairs: Didier Attaix - Lydie Combaret - Daniel TaillandierDaniel Béchet - Agnès Claustre - Cécile Coudy-Gandilhon - Christiane Deval - Gérard Donadille - Cécile PolgeSCIENTIFIC COMMITTEEDidier Attaix - Lydie Combaret - Alfred L. Goldberg - Ron Hay - Germana Meroni - Marco Sandri - Daniel Taillandier - Keiji Tanaka - Simon S. WingPoster Session 3 - Autophagy; Imbalances in dietary amino acid (AA) supply, including deficits in one or more indispensable amino acids (IAA), are stressful conditions for the organism that needs to modulate a number of physiological functions to adapt to this situation. In particular, since there is no system dedicated for storing AA in the body, the release of free AA occurs by proteolysis at the expense of functional proteins, notably in the liver by up-regulating autophagy. This process can be rapidly mobilized within the cell in response to a number of stresses, by post-translational regulations of autophagy-related proteins already present in the cytosol. The protein kinase GCN2 is activated upon IAA scarcity in order to promote cell adaptation to a nutritional stress condition. In response to IAA limitation, GCN2 couples the accumulation of uncharged transfer RNAs to the phosphorylation of eIF2a on serine 51. By this mean, GCN2 diminishes the overall protein synthesis rate, while simultaneously activating a gene expression program mediated by the translational upregulation of the transcription factor ATF4. Our recent work has shown that the GCN2/p-eIF2a/ATF4 signaling pathway plays an essential role in the induction of transcription of a number of autophagy-related genes involved in the maintenance of the autophagic process in response to an IAA deficiency (B’chir et al., 2013). In the present study we sought to determine whether GCN2 could play a role in regulating the early stages of autophagy. The most upstream complex for triggering the autophagic process (initiation complex) is notably composed of the ULK kinase and the ATG13 bridging protein, and is classically viewed to be controlled by mTORC1. Indeed, the activity of the autophagy initiation complex has been shown to be modulated according to AA availability by the activity of mTORC1, which phosphorylates different sites in ULK. Here, by using a GCN2 knock-out mouse model we investigated the role of GCN2 in the upregulation of autophagy in the first hour of an IAA deficiency. Our results show that 1) GCN2 is required for upregulating liver autophagy in response to an IAA-deficient diet, which is confirmed in cell culture model; 2) this early activation of the autophagic process does not require the transcription factor ATF4; 3) moreover, while this effect can occur without concomitant inhibition of mTORC1 activity, our results suggest that ULK/ATG13 couple is involved in the GCN2-dependent activation of autophagy. Our results demonstrate that in the particular model of an IAA deficiency GCN2 plays a preponderant role in triggering the adaptive autophagy upregulation, a mechanism which can operate without concomitant inhibition of mTORC1 activity

International audience; The intestinal mucosa of Crohn disease (CD) patients is abnormally colonized by adherent-invasive E. coli (AIEC). Upon AIEC infection, autophagy is induced in host cells to restrain bacterial intracellular replication. The underlying mechanism, however, remains unknown. Here, we investigated the role of the EIF2AK4-EIF2A/eIF2 alpha-ATF4 pathway in the autophagic response to AIEC infection. We showed that infection of human intestinal epithelial T84 cells with the AIEC reference strain LF82 activated the EIF2AK4-EIF2A-ATF4 pathway, as evidenced by increased phospho-EIF2AK4, phospho-EIF2A and ATF4 levels. EIF2AK4 depletion inhibited autophagy activation in response to LF82 infection, leading to increased LF82 intracellular replication and elevated pro-inflammatory cytokine production. Mechanistically, EIF2AK4 depletion suppressed the LF82-induced ATF4 binding to promoters of several autophagy genes including MAP1LC3B, BECN1, SQSTM1, ATG3 and ATG7, and this subsequently inhibited transcription of these genes. LF82 infection of wild-type (WT), but not eif2ak4(-/-), mice activated the EIF2AK4-EIF2A-ATF4 pathway, inducing autophagy gene transcription and autophagy response in enterocytes. Consequently, eif2ak4(-/-) mice exhibited increased intestinal colonization by LF82 bacteria and aggravated inflammation compared to WT mice. Activation of the EIF2AK4-EIF2A-ATF4 pathway was observed in ileal biopsies from patients with noninflamed CD, and this was suppressed in inflamed CD, suggesting that a defect in the activation of this pathway could be one of the mechanisms contributing to active disease. In conclusion, we show that activation of the EIF2AK4-EIF2A-ATF4 pathway upon AIEC infection serves as a host defense mechanism to induce functional autophagy to control AIEC intracellular replication.

Monacrosporium salinum strain, MSO03, isolated from Omani horticultural agro-ecosystem in 2003, has been compared to patented strains, MST84, isolated in 1984 from Tunisian soils. Morpho-biometrical characteristics demonstrated that MSO03 was similar to MST84. However, conidia of MSO03 were longer as compared to those of MST84. Furthermore, MSO03 strain produce specifically single chlamydospores rounded, showing thick cell wall, while known M. salinum chlamydospores are flattened, in chains with thin cell wall. Consequently, the Omani strain MSO03 can resist to more severe stress conditions, such as drought and extreme temperature, occurring in Omani agro-ecosystems. Generally, the predatory antagonistic activity toward Tylenchulus semipenetrans and Meloidogyne javanica was similar for both M. salinum strains., La souche de Monacrosporium salinum MSO03, isolée en 2003 d’un agro-écosystème horticole au sultanat d’Oman, a été comparée à la souche tunisienne MST84, brevetée, de la même espèce et isolée depuis 1984. L’utilisation des caractéristiques morpho-biométriques a montré que la souche MSO03 est similaire à la souche MST84. Cependant, les conidies de MSO03 sont plus longues que celles de MST84. En outre, la souche omanaise produit des chlamydospores formées par une seule cellule arrondie à membrane épaisse, contrairement aux chlamydospores de Monacrosporium salinum connues et qui sont formées de cellules aplaties, en chaînes et présentant une membrane mince. Par conséquent, la souche omanaise MSO03 peut résister aux conditions adverses telles que la sécheresse et les températures extrêmes caractérisant les agro-écosystèmes omanais. L’activité prédatrice de ces champignons vis-à-vis de Tylenchulus semipenetrans et de Meloidogyne javanica est similaire pour les deux souches de M. salinum., Elfékih Samia, Kallel Sadreddine, Abdelwahed A., Al-Hinai Sulaiman, B’Chir Mohamed Mouldi. Comparaison morphologique de deux souches de Monacrosporium salinum, champignon prédateur de nématode, isolées d’un agro-écosystème tunisien et omanais. In: Ecologia mediterranea, tome 38 n°1, 2012. pp. 81-88.

The present study investigated relationships between clozapine dose, clozapine and norclozapine plasma concentrations, and clinical responses to clozapine treatment in Tunisian schizophrenics. Fourteen schizophrenia-treatment resistant patients, recruited for this study, were treated with clozapine for 45 days. Patient health improvement was assessed before and after each cycle of two weeks of clozapine therapy, using the Brief Psychiatric Rating Scale (BPRS). Plasma clozapine and norclozapine concentrations were determined by high-performance liquid chromatography (HPLC). No significant correlations between plasma clozapine and norclozapine concentrations and clinical health improvement among our schizophrenic patients were found. However, a significant correlation was observed between clinical health improvement given by BPRS scores and norclozapine plasma concentration to daily clozapine dose ratio (NCZ/D). Despite the small sample size of our study, our findings suggest that the clozapine therapy response variations observed in our patients may be, in part, explained by the interindividual differences in plasma norclozapine concentration to clozapine dose ratio (NCZ/D). So the NCZ/D parameter could be used as a good indicator for adjusting the clozapine dose-adaptation strategy and consequently for improving the clinical psychopathological state of schizophrenia-treatment resistant patients.

Bladder cancer is among the most frequently diagnosed cancer. Tobacco smoking exposures involving nitrosamines and aromatic amines are the main cause of bladder cancer. Although cigarette consumption has gradually decreased, an increased incidence of bladder cancer was registered among males Tunisian for the last two decades. A similar increased incidence of lung adenocarcinoma and bladder cancer was registered among Tunisian males. Epidemiological results suggest that changes in cigarette smoking may be the cause of the increased incidence of bladder cancer. The relationship between CYP1A2 enzyme activities, a key enzyme for activation of bladder carcinogens, and bladder cancer risk was investigated. Variations in CYP1 A2 activities measured in patients with bladder cancer and healthy smokers showed a signifycantly higher CYP1A2 metabolic activity in patient group. Changing in cigarette smoking habits associated to the variation in CYP1A2 activity seem to explain partly the increase incidence of bladder cancer observed in Tunisian male population.

The intestinal mucosa of Crohn disease (CD) patients is abnormally colonized by adherent-invasive E. coli (AIEC). Upon AIEC infection, autophagy is induced in host cells to restrain bacterial intracellular replication. The underlying mechanism, however, remains unknown. Here, we investigated the role of the EIF2AK4-EIF2A/eIF2α-ATF4 pathway in the autophagic response to AIEC infection. We showed that infection of human intestinal epithelial T84 cells with the AIEC reference strain LF82 activated the EIF2AK4-EIF2A-ATF4 pathway, as evidenced by increased phospho-EIF2AK4, phospho-EIF2A and ATF4 levels. EIF2AK4 depletion inhibited autophagy activation in response to LF82 infection, leading to increased LF82 intracellular replication and elevated pro-inflammatory cytokine production. Mechanistically, EIF2AK4 depletion suppressed the LF82-induced ATF4 binding to promoters of several autophagy genes including MAP1LC3B, BECN1, SQSTM1, ATG3 and ATG7, and this subsequently inhibited transcription of these genes. LF82 infection of wild-type (WT), but not eif2ak4−/−, mice activated the EIF2AK4-EIF2A-ATF4 pathway, inducing autophagy gene transcription and autophagy response in enterocytes. Consequently, eif2ak4−/− mice exhibited increased intestinal colonization by LF82 bacteria and aggravated inflammation compared to WT mice. Activation of the EIF2AK4-EIF2A-ATF4 pathway was observed in ileal biopsies from patients with noninflamed CD, and this was suppressed in inflamed CD, suggesting that a defect in the activation of this pathway could be one of the mechanisms contributing to active disease. In conclusion, we show that activation of the EIF2AK4-EIF2A-ATF4 pathway upon AIEC infection serves as a host defense mechanism to induce functional autophagy to control AIEC intracellular replication.

Resume Introduction Nous rapportons une observation originale par la survenue d’une leucemie aigue myeloblastique deux mois apres les premieres manifestations vasculaires d’une arterite de Takayasu. Exegese Une patiente de 21 ans, aux antecedents d’erytheme noueux et d’episclerite, a ete hospitalisee pour tumefaction cervicale gauche en rapport avec un anevrisme de la carotide interne gauche. L’exploration vasculaire a en outre mis en evidence une stenose de l’artere sous-claviere gauche. L’examen anatomopathologique de l’anevrisme a montre une arterite granulomateuse a cellules geantes, concluant au diagnostic d’arterite de Takayasu. Deux semaines apres sa sortie, une numeration formule sanguine a montre une hyperleucocytose a 440 000 elements/mm 3 en rapport avec une leucemie aigue myeloblastique. La patiente est decedee d’une hemorragie intracerebrale. Conclusion Des vascularites leucocytoclasiques et des periarterites noueuses ont ete decrites au cours des leucemies aigues myeloblastiques, mais l’association a une arterite de Takayasu est exceptionnelle. A notre connaissance, seules deux observations faisant etat d’une telle association ont ete publiees. (J Mal Vasc 2006; 31: 280-283)

La reponse de deux porte-greffes de Citrus les plus utilises en agrumiculture a ete etudiee sur le plan histologique. Le nematode des citrus, Tylenchulus semipenetrans, induit sur le bigaradier (Citrus aurantium L.) la formation de cellules trophiques dans la region corticale radiculaire. Le Poncirus trifoliata presente une resistance par necrose cellulaire. Le greffage du Poncirus trifoliata confere aux racines du bigaradier une resistance par necrose cellulaire au biotype mediterraneen du nematode des citrus. La resistance de P. trifoliata vis-a-vis de T. semipenetrans est liee a une action allelochimique.

Nous avons étudié le rythme nycthéméral de sécrétion du cortisol et la réponse du cortisol à la 1-24 corticotropine pendant le ramadan chez 11 sujets volontaires sains, de sexe masculin, âgés de 20 à 35 ans. Ceux-ci ont d’abord été explorés deux semaines avant le ramadan par deux tests à 250 mg de 1-24 corticotropine pratiqués l’un à 8 h et l’autre à 20 h, puis après 16 à 22 jours de jeûne, par un dosage de la cortisolémie à 8 h et un test à la 1-24 corticotropine à 20 h. Avant le ramadan, le taux de cortisol de base était significativement plus élevé à 8 h qu’à 20 h et la réponse du cortisol à la 1-24 corticotropine était également plus élevée à 8 h qu’à 20 h mais cette différence était non significative. Pendant le ramadan, le taux de cortisol à 8 h s’abaisse par rapport à sa valeur à la même heure avant le ramadan ; le taux de 20 h s’élève légèrement par rapport à sa valeur à la même heure avant le ramadan. La réponse du cortisol à la 1-24 corticotropine à 20 h pendant le ramadan ne présente pas de différence significative avec les réponses avant le ramadan à 20 h et à 8 h

Muscle fitness is an important determinant of health and disease. However, the molecular mechanisms involved in the coordinate regulation of the metabolic and structural determinants of muscle endurance are still poorly characterized. Herein, we demonstrate that estrogen-related receptor α (ERRα, NR3B1) is essential for skeletal muscle fitness. Notably, we show that ERRα-null animals are hypoactive and that genetic or therapeutic disruption of ERRα in mice results in reduced exercise tolerance. Mice lacking ERRα also exhibited lactatemia at exhaustion. Gene expression profiling demonstrates that ERRα plays a key role in various metabolic processes important for muscle function including energy substrate transport and use (Ldhd, Slc16a1, Hk2, and Glul), the tricarboxylic acid cycle (Cycs, and Idh3g), and oxidative metabolism (Pdha1, and Uqcrq). Metabolomics studies revealed impairment in replenishment of several amino acids (eg, glutamine) during recovery to exercise. Moreover, loss of ERRα was found to alter the expression of genes involved in oxidative stress response (Hmox1), maintenance of muscle fiber integrity (Trim63, and Hspa1b), and muscle plasticity and neovascularization (Vegfa). Taken together, our study shows that ERRα plays a key role in directing transcriptional programs required for optimal mitochondrial oxidative potential and muscle fitness, suggesting that modulation of ERRα activity could be used to manage metabolic myopathies and/or promote the adaptive response to physical exercise.

International audience; The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and metabolism. It controls many cell functions by integrating nutrient availability and growth factor signals. Amino acids, and in particular leucine, are among the main positive regulators of mTORC1 signaling. The current model for the regulation of mTORC1 by amino acids involves the movement of mTOR to the lysosome mediated by the Rag-GTPases. Here, we have examined the control of mTORC1 signaling and mTOR localization by amino acids and leucine in serum-fed cells, because both serum growth factors (or, e.g., insulin) and amino acids are required for full activation of mTORC1 signaling. We demonstrate that mTORC1 activity does not closely correlate with the lysosomal localization of mTOR. In particular, leucine controls mTORC1 activity without any detectable modification of the lysosomal localization of mTOR, indicating that the signal(s) exerted by leucine is likely distinct from those exerted by other amino acids. In addition, knock-down of the Rag-GTPases attenuated the inhibitory effect of amino acid- or leucine-starvation on the phosphorylation of mTORC1 targets. Furthermore, data from cells where Rag expression has been knocked down revealed that leucine can promote mTORC1 signaling independently of the lysosomal localization of mTOR Our data complement existing models for the regulation of mTORC1 by amino acids and provide new insights into this important topic.

Les variations pluriannuelles de la croissance vegetative (orthotrope et plagiotrope) et de la production et du taux d'infestation des citrus par Tylenchulus semipenetrans suivent une evolution cyclique et des amplitudes decalees les unes par rapport aux autres. Ces variations presentent deux phases distinctes. La premiere se caracterise par une diminution de la population des nematodes dans les racines, une augmentation de la croissance plagiotrope aux depens de la croissance orthotrope et une production annuelle stable. La deuxieme phase se caracterise par contre par une augmentation de l'infestation, une croissance orthotrope plus dominante et une alternance annuelle de la production des agrumes. L'intervention chimique a l'aldicarbe permet de reduire l'incidence des nematodes sur les agrumes, mais seuls les traitements appliques au cours de la deuxieme phase sont efficaces contre les nematodes.