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International audience; Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.

International audience; Background: Allergic asthma is more severe and frequent in women than in men. In male mice, androgens negatively control group 2 innate lymphoid cell (ILC2) development and function by yet unknown mechanisms.Objectives: We sought to investigate the impact of androgen on ILC2 homeostasis and IL-33-mediated inflammation in female lungs. We evaluated the role of androgen receptor (AR) signaling and the contribution of the putative inhibitory receptor killer cell lectin-like receptor G1 (KLRG1).Methods: Subcutaneous pellets mimicking physiological levels of androgen were used to treat female mice together with mice expressing a reporter enzyme under the control of androgen response elements and mixed bone marrow chimeras to assess the cell-intrinsic role of AR activation within ILC2s. We generated KLRG1-deficient mice.Results: We established that lung ILC2s express a functionally active AR that can be in vivo targeted with exogenous androgens to negatively control ILC2 homeostasis, proliferation, and function. Androgen signaling upregulated KLRG1 on ILC2s, which inhibited their proliferation on E-cadherin interaction. Despite evidence that KLRG1 impaired the competitive fitness of lung ILC2s during inflammation, KLRG1 deficiency neither alters in vivo ILC2 numbers and functions, nor did it lead to hyperactive ILC2s in either sexes.Conclusions: AR agonists can be used in vivo to inhibit ILC2 homeostatic numbers and ILC2-dependent lung inflammation through cell-intrinsic AR activation. Although androgen signals in ILC2s to upregulate KLRG1, we demonstrate that KLRG1 is dispensable for androgen-mediated inhibition of pulmonary ILC2s.

Background Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. Objectives To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. Methods A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. Results A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. Conclusions A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.

International audience; Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to intervention-induced weight loss. It is driven by AT progenitors with dual fibro/adipogenic potential, but pro-fibrogenic pathways activated in obesity remain to be deciphered. To investigate the role of macroautophagy/autophagy in AT fibrogenesis, we used Pdgfra-CreErt2 transgenic mice to create conditional deletion of Atg7 alleles in AT progenitor cells (atg7 cKO) and examined sex-dependent, depot-specific AT remodeling in high-fat diet (HFD)-fed mice. Mice with atg7 cKO had markedly decreased extracellular matrix (ECM) gene expression in visceral, subcutaneous, and epicardial adipose depots compared to Atg7lox/lox littermates. ECM gene program regulation by autophagy inhibition occurred independently of changes in the mass of fat tissues or adipocyte numbers of specific depots, and cultured preadipocytes treated with pharmacological or siRNA-mediated autophagy disruptors could mimic these effects. We found that autophagy inhibition promotes global cell-autonomous remodeling of the paracrine TGF-BMP family landscape, whereas ECM gene modulation was independent of the autophagic regulation of GTF2IRD1. The progenitor-specific mouse model of ATG7 inhibition confirms the requirement of autophagy for white/beige adipocyte turnover, and combined to in vitro experiments, reveal progenitor autophagy dependence for AT fibrogenic response to HFD, through the paracrine remodeling of TGF-BMP factors balance. Abbreviations: CQ: chloroquine; ECM: extracellular matrix; EpiAT: epididymal adipose tissue; GTF2IRD1: general transcription factor II I repeat domain-containing 1; HFD: high-fat diet; KO: knockout; OvAT: ovarian adipose tissue; PDGFR: platelet derived growth factor receptor; ScAT: subcutaneous adipose tissue; TGF-BMP: transforming growth factor-bone morphogenic protein.

International audience; Obesity and metabolic-related diseases, among which diabetes, are prominent public health challenges of the 21st century. It is now well acknowledged that pollutants are a part of the equation, especially endocrine-disrupting chemicals (EDCs) that interfere with the hormonal aspect. The aim of the review is to focus on adipose tissue, a central regulator of energy balance and metabolic homeostasis, and to highlight the significant differences in the endocrine and metabolic aspects of adipose tissue between males and females which likely underlie the differences of the response to exposure to EDCs between the sexes. Moreover, the study also presents an overview of several mechanisms of action by which pollutants could cause adipose tissue dysfunction. Indeed, a better understanding of the mechanism by which environmental chemicals target adipose tissue and cause metabolic disturbances, and how these mechanisms interact and sex specificities are essential for developing mitigating and sex-specific strategies against metabolic diseases of chemical origin. In particular, considering that a scenario without pollutant exposure is not a realistic option in our current societies, attenuating the deleterious effects of exposure to pollutants by acting on the gut-adipose tissue axis may constitute a new direction of research.

International audience; Suicide is the leading cause of non-natural death worldwide, and major depressive disorder (MDD) is the mood disorder with the highest prevalence among individuals with suicidal behaviour (SB). The role of inflammation and immunomodulation in mood disorders has raised interest in recent years, as inflammation biomarkers have been reported to be increased in mood disorder patients, suggesting a role of inflammation in their pathogenesis. The influence of inflammation on the haematopoietic production is well known; however, a comprehensive study of the haematopoietic production in patients with major depressive episodes (MDE) is lacking. We examined global haematopoietic parameters from complete blood counts (CBC) of patients with MDE, in search of prognostic patterns. MDE patients presented differences in several CBC parameters, differences that were clearly pronounced and/or significant in concurrence with suicide attempts (SA). Red and white blood cell lineage parameters were affected, suggesting general haematopoietic modulation or imbalance. We observed distinct haematological parameter changes in women versus men, with men presenting milder alterations than women. Interestingly, we found that the List of Threatening Experiences (LTE) score, but not the Childhood Trauma Questionnaire (CTQ), was associated with the haematopoietic alterations observed exclusively in women and, more importantly, served as a parameter to stratify female MDE patients based on concurrence or non-concurrence with SA. In conclusion, grades of haematopoietic modulation in MDE patients are associated with absence or presence of SA. Haematopoietic manifestations differ between men and women and, in the latter, are markedly influenced by late, and not early, traumatic events.

Summary Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remain incompletely understood. Here, we use the intestine of Drosophila melanogaster to investigate how gut-derived signals contribute to sex differences in whole-body physiology. We find that carbohydrate handling is male-biased in a specific portion of the intestine. In contrast to known sexual dimorphisms in invertebrates, the sex differences in intestinal carbohydrate metabolism are extrinsically controlled by the adjacent male gonad, which activates JAK-STAT signaling in enterocytes within this intestinal portion. Sex reversal experiments establish roles for this male-biased intestinal metabolic state in controlling food intake and sperm production through gut-derived citrate. Our work uncovers a male gonad-gut axis coupling diet and sperm production, revealing that metabolic communication across organs is physiologically important. The instructive role of citrate in inter-organ communication might be significant in more biological contexts than previously recognized., Graphical Abstract, Highlights • Intestinal carbohydrate metabolism is male-biased and region-specific • Testes masculinize gut sugar handling by promoting enterocyte JAK-STAT signaling • The male intestine secretes citrate to the adjacent testes • Gut-derived citrate promotes food intake and sperm maturation, Inter-organ communication couples diet with gamete production. The male gonad promotes sex differences in carbohydrate metabolism within an adjacent intestinal portion via JAK-STAT signalling. In response to this gonadal signal, gut-derived citrate controls food intake and sperm maturation.

International audience; Objective: To explore the prevalence and clinical profile of males and females who develop antidepressant treatment-emergent mania (ATEM).Method: From an original sample of 754 patients with BD, we identified ATEM+ cases (n = 75) and ATEM- controls (n = 135) that met stringent criteria. We specifically examined the combinations of clinical factors that best classified males and females as ATEM+ cases.Results: Seventy-five individuals were classified as ATEM+; 87% of ATEM events occurred during antidepressant monotherapy. Regression analyses demonstrated that the presence of an alcohol and/or substance use disorder [Odds Ratio (OR) 6.37], a history of one or more suicide attempts (OR 4.19) and higher number of depressive episodes per year of illness (OR 1.71) correctly classified 73% of males. In contrast, 84% of females were correctly classified on the basis of a positive history of thyroid disorder (OR 3.23), a positive family history of BD I (OR 2.68) and depressive onset polarity (OR 2.01).Conclusion: Using stringent definitions of ATEM status to reduce the probability of inclusion of false-positive cases and false-negative controls, we identified for the first time that the risk profiles for the development of an ATEM differ significantly according to gender.

Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case–control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [95% confidence interval (CI), 1.27–7.16; Ptrend = 0.02] compared with men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (Ptrend = 0.21). Results were similar across cohorts (Pheterogeneity = 0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18–2.02; multiple hypothesis-corrected P = 0.03). No SNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasma leptin were associated with an elevated risk of pancreatic cancer among men, but not among women. Cancer Res; 76(24); 7160–7. ©2016 AACR.

Background Epigenetic biomarkers of aging (the “epigenetic clock”) have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors. Results We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue. Conclusions Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1030-0) contains supplementary material, which is available to authorized users.

We present a draft sequence of the genome of Aedes aegypti , the primary vector for yellow fever and dengue fever, which at ∼1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae . Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of ∼4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster . Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of ∼2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.

International audience

Resume Introduction Le but de cette etude etait de determiner si l’existence d’un diabete avait une influence sur les manifestations cliniques et le pronostic du cancer du pancreas (CP). Patients et methodes Nous avons analyse retrospectivement les dossiers de 122 patients ayant un CP. Les patients ont ete repartis en deux groupes, ceux ayant un diabete (56 cas) et ceux n’ayant pas de diabete (66 cas). Les donnees demographiques, les manifestations cliniques du CP, les caracteristiques de la tumeur et le temps de survie ont ete compares entre les deux groupes de patients. Resultats L’âge moyen des patients, le pourcentage d’hommes, l’indice de masse corporelle au diagnostic, la prevalence de l’hypertension arterielle, de la dyslipidemie, la consommation du tabac, la prevalence de l’amaigrissement, des douleurs abdominales, des douleurs lombaires et des signes de dyspepsie etaient similaires dans les deux groupes, de meme que l’histologie et la taille de la tumeur. Le cancer etait situe dans la tete du pancreas chez 50 % des patients diabetiques contre 80 % chez les non-diabetiques ( p = 0,04). Le temps moyen de survie etait similaire. Conclusion Les manifestations cliniques, la taille de la tumeur et le pronostic du CP ne sont pas differents chez les patients diabetiques comparativement aux patients non diabetiques. La presence du diabete ne semble pas favoriser un diagnostic precoce du CP.

International audience; Silver European eels (Anguilla anguilla L.) need to develop important aerobic capacities to cope with their long fasting spawning migration at depth, particularly males which are about half the size of females. Moreover, they have to face potential oxidative stress because reactive oxygen species (ROS) production is linked to the increase in metabolic rate. Thus, aerobic metabolism was globally evaluated in male and female silver eels exposed to a 10.1 MPa hydrostatic pressure (1,000 m depth). Oxygen consumption (MO(2)), ROS production and antioxidant enzyme activities were measured in the muscle fibres. Males showed a trend in both higher rate of aerobic metabolism and ROS production than females. After pressure exposure, ROS production was inversely correlated to metabolic rate only in males. By facilitating MO(2) rise with no harmful effects by ROS, the supposed enhanced aerobic capacities of males could speed up the sustained swimming. In females, the tendency to lower metabolic rate and higher catalase activity would make them less vulnerable to ROS effects. These results are in agreement with the hypothesis for different migration depths between genders.

International audience; The aim of this review is to examine the relationship between endocrine fluctuation and cognitive functioning. A plethora of in vitro and in vivo studies has demonstrated the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented post-menopausal women suggest a temporary positive effect (notably on verbal memory), and four recent meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomised controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Several methodological differences between observation studies and controlled trials with regard to patient group, type, timing and duration of HRT, cognitive measures and analyses, are discussed to explain these discrepancies. The association between hormonal serum level and cognitive functioning remains controversial suggesting high inter-individual vulnerability in risk. Moreover, research on the impact of endocrine functioning on cognition during the female reproductive cycle suggests life-long fluctuations in vulnerability. Etiological models taking into account the interaction of clinical, reproductive, and menstrual events throughout life may provide a more valid approach in understanding the effects of steroids on the brain and in determining sub-groups at heightened risk. Cognitive disorders in the elderly are more likely be related to cumulated lifelong exposure to steroids, rather than to a specific exposure to a given steroid. Multifactorial models based on an exhaustive view of all hormonal events throughout reproductive life together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.

In the Budgerigar Melopsittacus undulatus, the significance of a conspecific alarm call was investigated in two seasons, winter and spring. Two qualitatively different behavioral responses were displayed by the receivers in reply to playbacks: call(s) and/or taking flight(s). The comparative analysis of the number of birds responding to the alarm and to the control signals revealed two major facts: 1) in both seasons, the responses to the alarm signal were only observed for females, not for males, 2) qualitatively, females exhibited a great inter-season variability in their behavioral responses to the hearing of an alarm call. In winter, the females were more predisposed to emit acoustic responses while in spring they mainly took flight.O significado de um grito de alarme do Periquito-australiano Melopsittacus undulatus foi investigado em duas estações, inverno e primavera. Duas reações comportamentais, qualitativamente diferentes, foram apresentadas pelos receptores em resposta ao play-back: grito(s) e/ou vôo(s). A análise comparativa do número de aves respondendo ao grito de alarme e aos sinais de controle revelou dois fatos principais: 1) em ambas as estações, as respostas ao grito de alarme foram observadas somente para as fêmeas, não para os machos, 2) qualitativamente, as fêmeas mostraram uma grande variação estacional nas suas respostas comportamentais à escuta de um grito de alarme. No inverno, as fêmeas eram mais predispostas a emitir uma resposta acústica, enquanto na primavera elas geralmente levantavam vôo.

International audience; In songbirds, anatomical attributes of song nuclei exhibit sexual and seasonal differences. To extend these data to physiological correlates, neurons ( n= 374) were recorded in the HVc of male and female canaries during and outside the breeding period. Surprisingly, a particular type of action potential waveforms was observed more frequently in breeding than in non-breeding birds and in males than in females. These neurons showed both a shorter action potential duration (< 0.4 ms) and a higher firing rate (2.5 1.4 spikes/s) than the other neurons. Such characteristics are usually associated with interneurons in the songbird HVc as well as in the mammalian neocortex. Thus, these results provide the first electrophysiological evidence for an alteration of the neuronal network of HVc across sexes and seasons.

International audience; Characteristics of primary-care providers have been associated with their patients' participation in breast cancer screening. A nationwide observational survey, 'EDIFICE', was conducted by telephone from December 2007 to January 2008 on a representative sample of 600 general practitioners (GPs) working in France, to investigate how a GP's characteristics may influence patient participation in screening for breast, colorectal and prostate cancer. For breast cancer screening, systematic recommendation was associated with female physicians [odds ratio (OR) =1.9; 95% confidence interval (CI) 1.2-3.1]. This systematic recommendation was also correlated with systematic referral for colorectal cancer (OR=1.5; 95% CI=1.0-2.5) and prostate cancer screening (OR=2.7; 95% CI=1.8-4.1). For colorectal cancer screening, the sex of the GP had no significant impact. However, systematic recommendation for both breast and prostate cancer screening was shown to be associated with systematic recommendation for colorectal cancer screening (OR=2.7; 95% CI=1.6-4.7 and OR=1.8; 95% CI=1.1-3.0, respectively). For prostate cancer screening, there was no significant sex specificity. However, systematic recommendation for both breast and colorectal cancer screening was associated with an advice on prostate cancer screening (OR=2.9; 95% CI=2.0-4.4 and OR=2.0; 95% CI=1.3-3.2, respectively). The age of the GP was not associated with a higher rate of systematic recommendation for screening for the three types of cancer. Male GPs were more likely than female GPs to perform digital rectal examinations on male patients (69 vs. 54%; OR=1.86; 95% CI=1.31-2.63). There is a global pattern of physicians being screening-prone (as suggested by the cross impact of recommendations from one cancer type to another). Although the frequency of systematic recommendation for breast cancer screening is higher with female GPs, systematic recommendation for prostate cancer is not higher among male GPs. The factors associated with systematic recommendation for screening are both a matter of concern and a target for action, to improve adherence of individuals through GP commitment.

International audience; Trends in Kaposi sarcoma (KS) incidence over four decades were described for Zimbabwe and Uganda. KS data were retrieved from the population-based cancer registries of Bulawayo (1963-1971) and Harare (1990-2005), Zimbabwe and Kyadondo, Uganda (1960-1971 and 1991-2007). Joinpoint regression models were used to analyze time trends of KS incidence. Trends were compared to HIV/AIDS trends and were also described as rates versus birth cohort by age. In both countries, an increased incidence of KS accompanied the emergence of the HIV/AIDS epidemic (p-value 50 years (APC after 1991 = 1.0 [-2.8; 5.0]) nor in women (APC = 1.0 [-0.6; 2.6]). In both populations, a period effect at older ages was observed, with initial increases in incidence in men followed subsequently by a downturn in rates of the same magnitude. The uniformly declining rates in younger men (aged less than 30 years) suggested that a recent cohort effect was also in operation with a reduced risk in generations born after the mid-1950s in Uganda and in the mid-1960s in Zimbabwe. The combined introduction of antiretroviral therapy and effective prevention programmes against HIV/AIDS appeared to be the key contributors to the KS decline observed in both Uganda and Zimbabwe.

International audience; Autism is the short name of a complex and heterogeneous group of disorders (autism spectrum disorders, ASD) with several lead symptoms required for classification, including compromised social interaction, reduced verbal communication and stereotyped repetitive behaviors/restricted interests. The etiology of ASD is still unknown in most cases but monogenic heritable forms exist that have provided insights into ASD pathogenesis and have led to the notion of autism as a 'synapse disorder'. Among the most frequent monogenic causes of autism are loss-of-function mutations of the NLGN4X gene which encodes the synaptic cell adhesion protein neuroligin-4X (NLGN4X). We previously described autism-like behaviors in male Nlgn4 null mutant mice, including reduced social interaction and ultrasonic communication. Here, we extend the phenotypical characterization of Nlgn4 null mutant mice to both genders and add a series of additional autism-relevant behavioral readouts. We now report similar social interaction and ultrasonic communication deficits in females as in males. Furthermore, aggression, nest-building parameters, as well as self-grooming and circling as indicators of repetitive behaviors/stereotypies were explored in both genders. The construction of a gender-specific autism severity composite score for Nlgn4 mutant mice markedly diminishes population/sample heterogeneity typically obtained for single tests, resulting in p values of 83% for female mice. Taken together, these data underscore the similarity of phenotypical consequences of Nlgn4/NLGN4X loss-of-function in mouse and man, and emphasize the high relevance of Nlgn4 null mutant mice as an ASD model with both construct and face validity.

Aflibercept (Zaltrap®) is a novel antiangiogenic agent that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-dependent tumor growth. We aimed to characterize the population pharmacokinetics (PK) of free and bound aflibercept in patients with solid tumors to examine the influence of covariates on their PK and to evaluate the proposed dosing regimens by simulation. Data from 9 clinical trials with 1,506 cancer patients receiving aflibercept (2–9 mg/kg every 2 or 3 weeks; 1 h IV infusion) as a monotherapy or in combination with various chemotherapies were included. Free and bound aflibercept concentrations were analyzed using a non-linear mixed-effects modeling approach with MONOLIX 4.1.2. An approximation of a target-mediated drug disposition model with irreversible binding of free aflibercept to VEGF adequately described the PK of free and bound aflibercept. The typical estimated clearances for free (CL f ) and bound aflibercept (CL b ) were 0.88 and 0.19 L/day, respectively. The volumes of distribution for free (V p ) and bound (V b ) aflibercept were similar (~4 L). CL f and V p increased with body weight and were lower in women. Patients with low albumin (ALB) or high alkaline phosphatase (ALK) had faster CL f compared to a typical patient. Pancreatic cancer may be associated with changes in binding of aflibercept to VEGF. Simulations of different dosing regimens showed that adequate saturation of circulating VEGF was achieved with a dose of 4 mg/kg every 2 weeks. Aflibercept kinetics was most affected by gender, body weight, ALB, ALK and pancreatic cancer. Simulations supported the rationale for the recommended dose of 4 mg/kg every 2 weeks for aflibercept.

International audience; Dioxins are persistent organic pollutants interfering with endocrine systems and causing reproductive and developmental disorders. The objective of our project was to determine the impact of an in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on reproductive function of male and female offspring in the rat with a special emphasis on the immature period. We used a low dose of TCDD (unique exposure by oral gavage of 200 ng/kg at 15.5 days of gestation) in order to mirror a response to an environmental dose of TCDD not altering fertility of the progeny. We choose a global gene expression approach using Affymetrix microarray analysis, and testes of 5 days and ovaries of 14 days of age. Less than 1% of the expressed genes in gonads were altered following embryonic TCDD exposure; specifically, 113 genes in ovaries and 56 in testes with 7 genes common to both sex gonads. It included the repressor of the aryl hydrocarbon receptor (Ahrr), the chemokines Ccl5 and Cxcl4 previously shown to be regulated by dioxin in testis, Pgds2/Hpgds and 3 others uncharacterized. To validate and extend the microarray data we realized real-time PCR on gonads at various developmental periods of interest (from 3 to 25 days for ovaries, from 5 to the adult age for testes). Overall, our results evidenced that both sex gonads responded differently to TCDD exposure. For example, we observed induction of the canonic battery of TCDD-induced genes coding enzymes of the detoxifying machinery in ovaries aged of 3-14 days of age (except Cyp1a1 induced at 3-10 days) but not in testes of 5 days (except Ahrr). We also illustrated that inflammatory pathway is one pathway activated by TCDD in gonads. Finally, we identified several new genes targeted by TCDD including Fgf13 in testis and one gene, Ptgds2/Hpgds regulated in the two sex gonads.

International audience; BACKGROUND & AIMS: Ferroportin disease is characterized by iron overload. It has an autosomal-dominant pattern of inheritance and has been associated with mutations in the SLC40A1 gene, which encodes the cellular iron exporter ferroportin. Since the first description in 2001, about 30 mutations have been reported; the heterogeneity of ferroportin disease phenotypes has led to the hypothesis that the nature of the mutation affects the function of the protein in different ways. We studied genotypes and phenotypes of a large cohort of patients with ferroportin disease. METHODS: We studied clinical, biochemical, imaging, histologic, and genetic data from 70 affected subjects from 33 families with 19 mutations. RESULTS: We found that ferroportin disease, at the time of diagnosis, has limited consequences in the absence of cofactors. Data indicated that transferrin saturation, which correlated with fibrosis and levels of alanine aminotransferase, might be a marker of disease severity. Although the study was performed in a large number of families, we observed incomplete penetrance and no correlation between genotypes and phenotypes. CONCLUSIONS: Members of families with ferroportin disease should be screened for biochemical parameters of iron metabolism as well as genotype to detect silent mutations that might cause disease with acquired or genetic cofactors. Patients should be followed up long term to identify potential complications of the disease.

International audience; OBJECTIVES: the aim of this study was to examine the factors associated with insomnia in community-dwelling elderly as a function of the nature and number of insomnia symptoms (IS), e.g., difficulty with initiating sleep (DIS), difficulty with maintaining sleep (DMS), and early morning awakening (EMA). METHODS: is were assessed in a sample of 2,673 men and 3,213 women aged 65 years and older. The participants were administered standardized questionnaires regarding the frequency of IS and other sleep characteristics (snoring, nightmares, sleeping medication, and sleepiness) and various sociodemographic, behavioral and clinical variables, and measures of physical and mental health. RESULTS: more than 70% of men and women reported at least one IS, DMS being the most prevalent symptom in both men and women. Women reported more frequently two or three IS, whereas men reported more often only one IS. Multivariate regression analyses stratified by gender showed that men and women shared numerous factors associated with IS, sleeping medication, nightmares, sleepiness, chronic diseases, and depression being independently associated with two or three IS. For both sexes, age was associated with only one IS in all age categories. Loud snoring was strongly associated with increased DMS in men only. High body mass index increased the risk for DIS in men but tended to decrease it in women. In women, hormonal replacement therapy, Mediterranean diet, and caffeine and alcohol intake had a protective effect. CONCLUSION: our data suggest that women may have specific predisposition factors of multiple IS, which may involve both behavioral and hormonal factors. Identification and treatment of these risk factors may form the basis of an intervention program for reduction of IS in the elderly.

International audience; Phagocytes play a central role in immune defense. Their dysfunction predisposes to infections. This study determined the expression level of nine receptors involved in Aspergillus immune response as well as the values of phagocytosis and production of radical oxygen species after Aspergillus stimulation, in a healthy adult population. The expression values of the CD11b, CD11c, CD14, CD18, CD35, CD181, CD182, CD282 and CD284 receptors on peripheral human monocytes and granulocytes was established. A heterogenous expression of the CD282 on granulocytes was observed as CD181, CD182 and CD284 on monocytes. Similarly, we observed considerable variation in the expression of these receptors over time. Only CD282 on granulocytes varied with sex. No variation with age was observed. Adherence of Aspergillus conidia to phagocytes was dependent of individual, sex, age and time. A better characterization of these innate immunity parameters is necessary to develop in the future an immunologic surveillance strategy for transplant recipients.

International audience; Three- to 4-month-old infants reared by female caregivers display a spontaneous preference for individual adult women's over men's faces. Here we report that this preference extends to prototype girl over boy faces. The findings suggest transfer of gender-diagnostic facial information from individual adult to prototype child faces.

International audience; OBJECTIVES: To detect the presence of Toscana virus (TOSV) circulation in Tunisia and to study its role in viral meningo-encephalitis.PATIENTS AND METHODS: A total of 315 (167 sera and 178 cerobrospinal fluid [CSF]) samples was investigated. These samples are colleted from Tunisian patients with neurological diseases during the period between January 2003 and December 2009. All samples were tested negative for enterovirus, Herpes Simplex virus and West Nile virus. Detection for IgM and IgG specific to TOSV was done by ELISA tests.RESULTS: Specific IgM for TOSV were detected in 10 % of patients with neurological diseases (31 cases). These recent infections were distributed throughout the study period and predominated during summer and automn. Patients were originated, in the majority from the coastal region. IgG were isolated in 22 cases (7 %) corresponding to previous infection.CONCLUSION: This is the first report of TOSV circulating in Tunisia and its frequent implication in neurological diseases. These results incited to include TOSV as one of the viral etiologies to target in the diagnosis of viral meningitis and encephalitis in the country.; But de l’étude : Rechercher les témoins de l’éventuelle présence du virus Toscana (TOSV) en Tunisie et étudier son implication dans les infections neuroméningées dans le pays.Patients et méthodes : Au total, 167 prélèvements de sérums et 178 LCR collectés chez 315 patients, hospitalisés pour méningite ou méningo-encéphalite virale, ont été investigués. Ces prélèvements ont été collectés durant la période allant de janvier 2003 à décembre 2009 et ont été préalablement testés négatifs vis-à-vis des entérovirus, virus Herpes Simplex de type 1 et virus West Nile. La recherche des IgM et IgG spécifiques du TOSV a été faite par Elisa indirecte.Résultats : Dix pour cent (n = 31) de ces prélèvements se sont révélés positifs en IgM anti-TOSV ; ces cas sont répartis de façon homogène sur toute la période étudiée. Une infection ancienne a été détectée dans 7 % des cas (n = 22). L’infection neuroméningée à TOSV est plus fréquente chez l’homme (20/11), en période estivo-automnale et en zone côtière.Conclusion : Il s’agit là d’une première étude rapportant la circulation du TOSV en Tunisie et son rôle non négligeable dans les infections neuroméningées. Ces résultats nous incitent à une surveillance régulière avec recherche systématique d’une infection à TOSV devant toute atteinte neurologique. Il serait même intéressant de généraliser la recherche du TOSV à d’autres tableaux cliniques où il a été également impliqué comme le syndrome fébrile aigu ou le syndrome grippal type « grippe d’été ».

International audience; The widespread use of the ankle-brachial index (ABI) enabled to reveal the high prevalence of lower extremities peripheral arterial disease (PAD) in women, even higher than in men in several series. Nonetheless, the use of a same ABI threshold for men and women may overestimate the prevalence of subclinical PAD in women. Conversely, the clinical manifestations of PAD are more often atypical in women, with as a result, a delayed diagnosis and management. The level of association between cardiovascular disease risk factors and PAD is similar in both genders. To date, there is no evidence for any association between PAD and different hormonal events in women. Despite an inverse association between hormonal replacement therapy (HRT) after menopause and PAD in epidemiological studies, the trials failed to evidence any protective effect of HRT to prevent PAD. Women with PAD are advised to discontinue HRT in case of limb revascularization. The long-term local and functional prognosis of PAD seems more severe in women, but this is partly explained by a delayed onset of the disease, occurring at a later age. Similarly, the general cardiovascular prognosis PAD is also poorer in women than in men.

International audience; Gaze aversion could be a central component of the physiopathology of social phobia. The emotions of the people interacting with a person with social phobia seem to model this gaze aversion. Our research consists of testing gaze aversion in subjects with social phobia compared to control subjects in different emotional faces of men and women using an eye tracker. Twenty-six subjects with DSM-IV social phobia were recruited. Twenty-four healthy subjects aged and sex-matched constituted the control group. We looked at the number of fixations and the dwell time in the eyes area on the pictures. The main findings of this research are: confirming a significantly lower amount of fixations and dwell time in patients with social phobia as a general mean and for the 6 basic emotions independently from gender; observing a significant correlation between the severity of the phobia and the degree of gaze avoidance. However, no difference in gaze avoidance according to subject/picture gender matching was observed. These findings confirm and extend some previous results, and suggest that eye avoidance is a robust marker of persons with social phobia, which could be used as a behavioral phenotype for brain imagery studies on this disorder.

International audience; Prenatal stress (PS) has been linked to abnormal cognitive, behavioral and psychosocial outcomes in both animals and humans. Animal studies have clearly demonstrated PS effects on the offspring's brain, however, while it has been speculated that PS most likely affects the brains of exposed human fetuses as well, no study has to date examined this possibility prospectively using an independent stressor (i.e., a stressful event that the pregnant woman has no control over, such as a natural disaster). The aim of this review is to summarize the existing animal literature by focusing on specific brain regions that have been shown to be affected by PS both macroscopically and microscopically. These regions include the hippocampus, amygdala, corpus callosum, anterior commissure, cerebral cortex, cerebellum and hypothalamus. We first discuss the mechanisms by which the effects of PS might occur. In particular, we show that maternal and fetal hypothalamic-pituitary-adrenal (HPA) axes, and the placenta, are the most likely candidates for these mechanisms. We see that, although animal studies have obvious advantages over human studies, the integration of findings in animals and the transfer of these findings to human populations remains a complex issue. Finally, we show how it is possible to circumvent these challenges by studying the effects of PS on brain development directly in humans, by taking advantage of natural or man-made disasters and assessing the impact and consequences of such stressful events on pregnant women and their offspring prospectively.

Background: Cognitive dysfunctioning (CDF) is an important issue in stroke, interfering with recovery and social dysfunctioning. We aimed to investigate the clinical and imaging correlates of CDF in patients with a first-ever subacute ischemic stroke and no dementia. Methods: We evaluated CDF 15 days after stroke in a prospective cohort of consecutive patients with a Mini Mental State Examination score ≧23 using a comprehensive neuropsychological battery. CDF was ranked into 3 categories according to Z scores calculated for each test and adjusted for age and education. CDF was analyzed in relation to stroke features. Imaging was assessed using MRI. An ordinal regression procedure was used to determine the clinical correlates of CDF and to compute probabilities. Results: Cognitive evaluation was achieved in 177 consecutive patients (age 50.0 ± 16.0 years). In bivariate analysis, CDF was associated with age, low level of education, depression, neurological deficit at day 15, stroke subtype, arterial territory and leukoaraiosis but not with stroke volume or location. The predictors of CDF were NIHSS score at day 15 (OR = 1.35; 95% CI = 1.05–1.73), middle cerebral artery infarct (OR = 2.96; 95% CI = 1.30–6.73), depression interacting with left stroke side (OR = 1.09; 95% CI = 1.03–1.15), and female gender interacting with high level of education (OR = 0.209; 95% CI = 0.085–0.514). Conclusions: Stroke features correlate with CDF in nondemented patients. These simple criteria may help to predict CDF at bedside in the subacute phase after stroke and to recommend a neuropsychological evaluation for patients’ management. Modeling CDF soon after stroke using simple neurological criteria may be a useful tool for designing clinical trials.

BackgroundAccumulating evidences suggest that sex affects lung development. Indeed, a higher incidence of respiratory distress syndrome is observed in male compared to female preterm neonates at comparable developmental stage and experimental studies demonstrated an androgen-related delay in male lung maturation. However, the precise mechanisms underlying these deleterious effects of androgens in lung maturation are only partially understood.MethodsTo build up a better understanding of the effect of androgens on lung development, we analyzed by microarrays the expression of genes showing a sexual difference and those modulated by androgens. Lungs of murine fetuses resulting from a timely mating window of 1 hour were studied at gestational day 17 (GD17) and GD18, corresponding to the period of surge of surfactant production. Using injections of the antiandrogen flutamide to pregnant mice, we hunted for genes in fetal lungs which are transcriptionally modulated by androgens.ResultsResults revealed that 1844 genes were expressed with a sexual difference at GD17 and 833 at GD18. Many genes were significantly modulated by flutamide: 1597 at GD17 and 1775 at GD18. Datasets were analyzed by using in silico tools for reconstruction of cellular pathways. Between GD17 and GD18, male lungs showed an intensive transcriptional activity of proliferative pathways along with the onset of lung differentiation. Among the genes showing a sex difference or an antiandrogen modulation of their expression, we specifically identified androgen receptor interacting genes, surfactant related genes in particularly those involved in the pathway leading to phospholipid synthesis, and several genes of lung development regulator pathways. Among these latter, some genes related to Shh, FGF, TGF-beta, BMP, and Wnt signaling are modulated by sex and/or antiandrogen treatment.ConclusionOur results show clearly that there is a real delay in lung maturation between male and female in this period, the latter pursuing already lung maturation while the proper is not yet fully engaged in the differentiation processes at GD17. In addition, this study provides a list of genes which are under the control of androgens within the lung at the moment of surge of surfactant production in murine fetal lung.

Background The sensitivity of chronic lymphocytic leukemia (CLL) cells to current treatments, both in vitro and in vivo, relies on their ability to activate apoptotic death. CLL cells resistant to DNA damage-induced apoptosis display deregulation of a specific set of genes. Methods Microarray hybridization (Human GeneChip, Affymetrix), immunofluorescent in situ labeling coupled with video-microscopy recording/analyses, chromatin-immunoprecipitation (ChIP), polymerase chain reactions (PCR), real-time quantitative PCR (RT-QPCR) and bisulfite genome sequencing were the main methods applied. Statistical analyses were performed by applying GCRMA and SAM analysis (microarray data) and Student's t-test or Mann & Whitney's U-test. Results Herein we show that, remarkably, in a resistant male CLL cells the vast majority of genes were down-regulated compared with sensitive cells, whereas this was not the case in cells derived from females. This gene down-regulation was found to be associated with an overall gain of heterochromatin as evidenced by immunofluorescent labeling of heterochromatin protein 1α (HP-1), trimethylated histone 3 lysine 9 (3metH3K9), and 5-methylcytidine (5metC). Notably, 17 genes were found to be commonly deregulated in resistant male and female cell samples. Among these, RELB was identified as a discriminatory candidate gene repressed in the male and upregulated in the female resistant cells. Conclusion The molecular defects in the silencing of RELB involve an increase in H3K9- but not CpG-island methylation in the promoter regions. Increase in acetyl-H3 in resistant female but not male CLL samples as well as a decrease of total cellular level of RelB after an inhibition of histone deacetylase (HDAC) by trichostatin A (TSA), further emphasize the role of epigenetic modifications which could discriminate two CLL subsets. Together, these results highlighted the epigenetic RELB silencing as a new marker of the progressive disease in males.

It has been suggested that age-related deterioration in trabecular microarchitecture and changes in collagen cross-link concentrations may contribute to skeletal fragility. To further explore this hypothesis, we determined the relationships among trabecular bone volume fraction (BV/TV), microarchitecture, collagen cross-link content, and bone turnover in human vertebral trabecular bone. Trabecular bone specimens from L2 vertebrae were collected from 51 recently deceased donors (54–95 years of age; 20 men and 30 women). Trabecular bone volume and microarchitecture was assessed by microCT and bone formation, reflected by osteoid surface (OS/BS, %), was measured by 2D histomorphometry. Pyridinoline (PYD), deoxypyridinoline (DPD), pentosidine (PEN) and collagen content in the cancellous bone were analysed by high-performance liquid chromatography. Associations between variables were investigated by Pearson correlations and multiple regression models, which were constructed with BV/TV and collagen cross-links as explanatory variables and microarchitecture parameters as the dependent variables. Results : Microarchitecture parameters were modestly to strongly correlated with BV/TV ( r 2 = 0.10–0.71). The amount of mature enzymatic PYD and DPD cross-links were not associated with the microarchitecture, either before or after adjustment for BV/TV. However, there was a positive correlation between PEN content and trabecular number ( r = 0.45, p = 0.001) and connectivity density ( r = 0.40, p = 0.004), and a negative correlation between PEN content and trabecular separation ( r = −0.29, p = 0.04). In the multiple regression models including BV/TV, age and PEN content was still significantly associated with several of the microarchitecture variables. In summary, this study suggests a link between trabecular microarchitecture and the collagen cross-link profile. As PEN reflects non-enzymatic glycation of collagen and generally increases with bone age, the association between PEN and trabecular architecture suggests that the preserved trabeculae may contain mainly old bone and have undergone little remodeling. Thus, vertebral fragility may not only be due to alterations in bone architecture but also to modification of collagen cross-link patterns thereby influencing bone's mechanical behavior.

International audience; This study was undertaken to characterize the toxicokinetics of p-tert-octylphenol (OP), a weak estrogenic compound, in male and female rats. Male and female Sprague-Dawley rats were given a single dose of OP either by oral gavage (50, 125 or 250 mg/kg), by intravenous (iv) injection (2, 4, or 8 mg/kg), or by subcutaneous (sc) injection (125 mg/kg). In a repeated dosing experiment, rats were given OP (oral) daily (25, 50, or 125 mg/kg) for 35 d (female) or 60 d (male). Blood and tissue samples were collected and analyzed for OP content using gas chromatography with detection by mass spectrometry. Blood OP concentrations were generally higher in female than male rats following a single oral or sc administration but were similar following a single iv injection. Tissue OP concentrations were also higher in female than male rats following oral exposure, consistent with the faster metabolism of OP observed in male rat liver microsomes. After subchronic administration, blood OP concentrations were higher at the end of exposure for female (33 d) (2.26-fold, not significant) and male (57 d) (3.47-fold) rats than single dosing but there was no change in the tissue OP concentrations. Gender differences in tissue OP concentrations may contribute, in part, to gender differences in the toxicity of OP in rats. The fact that OP was found in all reproductive tissues confirms its potential for direct endocrine-like effects.

Objectives. We examined gender differences in mortality, morbidity, and the association between the 2. Methods. We used health data from 2 studies of middle-aged men and women: the British Whitehall II cohort of employees from 20 civil service departments in London and the 1989 French GAZEL (this acronym refers to the French gas and electric companies) of employees of France's national gas and electricity company. Participants were aged 35 to 55 years when assessed for morbidity and followed up for mortality over 17 years. Results. Male mortality was higher than female mortality in Whitehall II (hazard ratio [HR] = 1.56; 95% confidence interval [CI] = 1.28, 1.91) and the GAZEL cohort (HR = 1.99; CI = 1.66, 2.40). Female excess morbidity was observed for some measures in the Whitehall II data and for 1 measure in the GAZEL data. Only self-reported sickness absence in the Whitehall II data was more strongly associated with mortality among men (P = .01). Conclusions. Mortality was lower among women than among men, but morbidity was not consistently higher. The lack of gender differences in the association between morbidity and mortality suggests that this is not a likely explanation for the gender paradox, which refers to higher morbidity but lower mortality among women than among men.

International audience; European silver eels migrate 6000 km to their supposed spawning area in the Sargasso sea. As the eel is fasting, this intense swimming activity is realised only with fat stores, involving mainly red muscle i.e. aerobic metabolism. However, eel migration is performed at depth and thus in cold water, both being known to induce changes in muscle energy metabolism. During migration, white and red muscles can operate together or separately in order to counteract the eventual effects of low temperatures and/or high pressures. We have studied the temperature sensitivity (5, 15, and 25 degrees C) of aerobic and anaerobic metabolism in both sexes. At the same temperature, migrating eels have a higher basal glycolytic flux. Moreover, there are temperature and sex effects: anaerobic glycolysis (JB) is more sensitive to cold water whereas aerobic (JA) is more affected by warm. Males, which are less sensitive to cold water, also have higher aerobic fluxes than females. As depth corresponds to low temperature, the possibility that males migrate more deeply than females is discussed. In an ecophysiological context, it is interesting to suppose that males and female eels migrate at different depths in order to optimize their energy utilization by aerobic and / or anaerobic pathways.

International audience; Germline genetics, gender and hormonal-signaling pathways are all well described modifiers of cancer risk and progression. Although an improved understanding of how germline genetic variants interact with other cancer risk factors may allow better prevention and treatment of human cancer, measuring and quantifying these interactions is challenging. In other areas of research, Information Theory has been used to quantitatively describe similar multivariate interactions. We implemented a novel information-theoretic analysis to measure the joint effect of a high frequency germline genetic variant of the p53 tumor suppressor pathway (MDM2 SNP309 T/G) and gender on clinical cancer phenotypes. This analysis quantitatively describes synergistic interactions among gender, the MDM2 SNP309 locus, and the age of onset of tumorigenesis in p53 mutation carriers. These results offer a molecular and genetic basis for the observed sexual dimorphism of cancer risk in p53 mutation carriers and a model is proposed that suggests a novel cancer prevention strategy for p53 mutation carriers.

International audience; The Alzheimer's disease (AD) is multifactorial. How to explain this group of very heterogeneous factors? Many of them can be considered as biopsychosocial risk factors. In other words, the risk factors, in link with the physiological functioning and a physiopathology, are difficultly dissociable of contingencies of psychological and/or social nature. The vital lead could be the stress bound to these variables, be it biological or psychosocial. It remains to ask the question of the preventive efficiency of treatments to relieve the impact of the traumatizing events of life that entail a depressive state or a state of posttraumatic stress. The hippocamp has to be the object of a quite particular attention. AD is a disease of the adaptation. This integrative model combines three vulnerabilities: a genetic vulnerability which would be there to dictate the type of lesions, their localization and the age of occurence; a psychobiographic vulnerability corresponding to a personality with inadequate mechanisms of defence, precarious adaptability in front of the adversity, weak impact strength and biography built on events of life during childhood, then during the grown-up life of traumatic nature, with a psychosocial environment insufficiently auxiliary; a neuroendocrinologic vulnerability which would base on a deregulation of the corticotrope axis, acquired during its infantile maturation, hampered by too premature stress. It would lead to a bad biological adaptability in stress later, at the origin of the observable lesions in the insanities.

International audience; Synthetic 2,4,5-trimethylthiazoline (TMT)--a component of red fox (Vulpes vulpes) feces--is frequently used to induce unconditioned fear in rodents. Surprisingly, direct comparison between TMT and natural fox feces odor is almost nonexistent. In this study, Experiment 1 compared the avoidance in relation to TMT concentration, natural fox feces, and gender of fox and mice. Results show that the avoidance is (a) higher with either pure or 50% TMT as compared to natural fox feces, whereas the difference is slight with 10% TMT, and (b) significantly higher for the female mouse group compared to the male mouse group with TMT as well as natural fox feces. In addition, no clear difference in effect was observed between male and female fox feces. Experiment 2 compared behavioral parameters recorded as an index of fear and anxiety, general activity, and avoidance in elevated plus-maze and open-field chamber between 10% TMT and natural fox feces in relation to the estrus cycle of the mice. Results show no cycle period effect--except for the avoidance parameter "distance to odorant"--and no different effects between 10% TMT and natural fox feces except for freezing.

0012-186X (Print) 0012-186X (Linking) Journal Article Research Support, Non-U.S. Gov't; International audience; AIMS/HYPOTHESIS: Uncoupling protein (UCP) 3 is a mitochondrial inner membrane protein expressed predominantly in glycolytic skeletal muscles. Its role in vivo remains poorly understood. The aim of the present work was to produce a mouse model with moderate overproduction and proper fibre-type distribution of UCP3. METHODS: Transgenic mice were created with a 16 kb region encompassing the human UCP3 gene. Mitochondrial uncoupling was investigated on permeabilised muscle fibres. Changes in body weight, adiposity and glucose or insulin tolerance were assessed in mice fed chow and high-fat diets. Indirect calorimetry was used to determine whole-body energy expenditure and substrate utilisation. RESULTS: Transgenic mice showed a twofold increase in UCP3 protein levels specifically in glycolytic muscles. Mitochondrial respiration revealed an increase of uncoupling in glycolytic but not in oxidative muscles. Transgenic mice gained less weight than wild-type littermates due to lower adipose tissue accretion when fed a high-fat diet. Animals showed a sexual dimorphism in metabolic responses. Female transgenic mice were more glucose-sensitive than wild-type animals, while male transgenic mice with high body weights had impaired glucose and insulin tolerance. Measurements of RQs in mice fed chow and high-fat diets suggested an impairment of metabolic flexibility in transgenic male mice. CONCLUSIONS/INTERPRETATION: Our data show that physiological overproduction of UCP3 in glycolytic muscles results in mitochondrial uncoupling, resistance to high-fat diet-induced obesity and sex specificity regarding insulin sensitivity and whole-body substrate utilisation.

International audience; Background/aims: The purpose of this work was to develop a new sensor for objective in vivo measurement of the cutaneous temperature based on micro-electro-mechanical systems (MEMS), and to compare these performances with those of a classical thermocouple. Research on this new sensor was carried out to allow the quantification of the thermal properties of the made-up skin. Methods: Sixteen female subjects divided into two different age groups (18–35 and >50 years old) were recruited for this study. Several zones of the face and forearms were made up at random with foundations containing or not a thermoregulator raw material. The quantity of foundation applied on the skin was standardized and measurements were carried out first before make-up, and then 10 s and 5 min after make-up. The new sensor and the thermocouple were used successively on each zone. The cutaneous temperature was expressed in degrees celsius. Results/conclusion: The two systems are similar in terms of repeatability and reproducibility, with some differences in sensibility. The data measured by the MEMS sensor appear lower than those measured by the thermocouple. After make-up, the MEMS sensor detects a progressive increase of the temperature in time whereas the thermocouple detects a decrease. We found the same evolution on the face but in a more attenuated way. These results tend to show that the devices do not measure the same phenomenon. The thermocouple appears more sensitive to the thermal response of the made-up surface whereas the MEMS sensor appears more sensitive to the heat transfers in the interface between the skin and make-up.

The allocation of resources to reproduction and survival is a central question of studies of life history evolution. Usually, increased allocation to current reproduction is paid in terms of reduced future reproduction and/or decreased survival. However, the proximal mechanisms underlying the cost of reproduction are poorly understood. Recently, it has been shown that increased susceptibility to oxidative stress might be one of such proximate links between reproduction and self-maintenance. Organisms possess a range of antioxidant defenses, including endogenously produced molecules (e.g., enzymes) and compounds ingested with food (e.g., carotenoids). If reproductive effort increases the production of reactive oxygen species, the availability of antioxidant defenses may partly or fully counteract the free-radical damages. One could, therefore, expect that the trade-off between reproduction and oxidative stress is modulated by the availability of antioxidant defenses. We tested this hypothesis in zebra finches. We manipulated reproductive effort by either allowing or preventing pairs to breed. Within each breeding or non-breeding group, the availability of antioxidant compounds was manipulated by supplementing or not supplementing the drinking water with carotenoids. We found that although birds in the breeding and non-breeding groups did not differ in their resistance to oxidative stress (the breakdown of red blood cells submitted to a controlled free-radical attack), one aspect of breeding effort (i.e., the number of eggs laid by birds in both breeding and non-breeding groups) was negatively correlated with resistance to oxidative stress only in birds that did not benefit from a carotenoid-supplemented diet. This result therefore suggests that carotenoid availability can modulate the trade-off between reproduction and resistance to oxidative stress., Financial support was provided by the Ministère de la Recherche (ACI Jeunes Chercheurs to GS) and the Université de Bourgogne (BQR to GD, MG, JP and BF). CA-A was funded by Ministerio de Educación, Cultura y Deporte (Spain).

International audience; Germ cells have the unique capacity to start a new life upon fertilization. They are generated during a sex-specific differentiation programme called gametogenesis. Maturation of germ cells is characterized by an impressive degree of cellular restructuring and gene regulation that involves remarkable genomic reorganization. These events are finely tuned, but are also susceptible to the introduction of various types of error. Because stable genetic transmission to future generations is essential for life, understanding the control of these processes has far-reaching implications for human health and reproduction.

Leftward occipital and rightward frontal lobe asymmetry (brain torque) and leftward planum temporale asymmetry have been consistently reported in postmortem and in vivo neuroimaging studies of the human brain. Here automatic image analysis techniques are applied to quantify global and local asymmetries, and investigate the relationship between brain torque and planum temporale asymmetries on T1-weighted magnetic resonance (MR) images of 30 right-handed young healthy subjects (15 male, 15 female). Previously described automatic cerebral hemisphere extraction and 3D interhemispheric reflection-based methods for studying brain asymmetry are applied with a new technique, LowD (Low Dimension), which enables automatic quantification of brain torque. LowD integrates extracted left and right cerebral hemispheres in columns orthogonal to the midsagittal plane (2D column maps), and subsequently integrates slices along the brain's anterior-posterior axis (1D slice profiles). A torque index defined as the magnitude of occipital and frontal lobe asymmetry is computed allowing exploratory investigation of relationships between this global asymmetry and local asymmetries found in the planum temporale. LowD detected significant torque in the 30 subjects with occipital and frontal components found to be highly correlated (P

There are no satisfactory data on circulating concentrations of inflammatory cytokines and their potential relationship with traditional and nontraditional atherosclerosis risk factors in a large healthy young population. The present study was conducted to examine, in 179 healthy families selected from the STANISLAS cohort, the association between interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), orosomucoid, haptoglobin, cell-adhesion molecules (ICAM-1, E-, L- and P-selectin) and lipid parameter concentrations. Age, BMI, white blood cells and tobacco consumption contributed to the variation of IL-6 concentrations. Age and tobacco contributed also to TNF-alpha variation. Taking into account potential covariates, we showed strong positive correlation between IL-6 and both inflammatory markers TNF-alpha and CRP in parents and in offspring (P

Polyamines are involved in the control of the cell cycle and cell growth. In murine kidney, testosterone enhances gene expression of ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis. In this study, we document the time course effect of testosterone on 1) gene expression of ODC, antizyme 1 (AZ1), and spermidine/spermine- N1-acetyltransferase ( N1-SSAT); 2) ODC activity in proximal convoluted tubules (PCT) and cortical proximal straight tubules (CPST); and 3) renal polyamine levels. Female mice were treated with testosterone for a period of 1, 2, 3, and 5 consecutive days. ODC gene expression was extremely low in kidneys of untreated female mice compared with that of males. Consequently, the renal putrescine level was sevenfold lower in females than in males, whereas spermidine and spermine levels did not differ between sexes. In female kidneys, testosterone treatment sharply increased ODC mRNA and protein levels as well as ODC activity. Testosterone increased the expression of ODC in PCT and CPST over different time courses, which suggests that ODC activity is differentially regulated in distinct tubules. The expression of AZ1 and N1-SSAT mRNA was similar in male and female mouse kidneys. Testosterone treatment enhanced AZ1 and N1-SSAT mRNA levels in a time-dependent manner by unknown molecular mechanisms. Putrescine and spermidine levels increased after testosterone treatment in female kidneys. Surprisingly, although ODC protein and activity were undetectable in female kidneys, the levels of AZ1 mRNA and protein were similar to those in males. Therefore, one may propose that ODC protein could be continuously degraded by AZ1 in female kidneys.

The ApoEurope group, collaborating centres, and their associated investigators: Portugal: Unidade de Química Clínica, Instituto Nacional de Saúde, Lisboa: Maria do Carmo Martins, Maria Odete Rodrigues, Maria Isabel Albergaria, Maria Liseta Alpendre Interindividual variation in the concentration of plasma lipids which are associated with coronary artery disease (CAD) risk is determined by a combination of genetic and environmental factors. This study investigates the effects of apoE genotype and plasma concentration on cholesterol and triglycerides (TG) levels in subjects from five countries: Finland, France, Northern Ireland, Portugal, and Spain. Age and sex significantly influenced serum cholesterol, TG and apoE concentrations. The age effect differs in males and females. The allele frequencies of the apoE gene, one of the most widely studied CAD susceptibility genes, were determined: the epsilon2 allele frequency and the apoE concentration showed a north-south increasing gradient while the epsilon4 allele frequency showed the reverse. ApoE plays an important role in lipid metabolism. Total cholesterol and TG concentrations were significantly dependent on apoE genotype in both sexes. These differences in lipids between genotypes were more pronounced when plasma apoE concentrations were taken into account.

In Drosophila , locomotor activity is sexually dimorphic and the brain area controlling this dimorphism has been mapped. The neurons of the pars intercerebralis (PI) have been suggested to participate in such differences between males and females. However, the precise physical nature of the dimorphism, the identity of the PI neurons involved, and the nature of the neuronal signal coding the dimorphism remain unknown. In this study, we used a video-tracking paradigm to characterize further the pattern of locomotor activity in Drosophila . We show that the number of activity/inactivity periods (start/stop bouts) is also sexually dimorphic, and that it can be genetically feminized in males. Moreover, the transplantation of PI neurons from a female, or of feminized PI neurons from a donor male into a receiver wild-type male is sufficient to induce the feminization of locomotor behavior, confirming that this tiny cluster of ≈10 neurons is directly responsible for the sexual dimorphism in locomotor activity. Finally, feeding males with fluvastatin, a juvenile hormone (JH) inhibitor, also led to start/stop feminization, and this effect is reversible by the simultaneous application of methoprene, a JH analog, suggesting the existence of a neuroendocrine control, by JH, of such behavioral dimorphism.

International audience; Based on neuronal recordings in the HVc, this study investigated differences between reproductively active male and sexually receptive female canaries. It is the first study to describe auditory responses and cell characteristics of HVc neurons in female songbirds and to compare them with the responses and characteristics obtained in males. Extracellular single unit recordings showed that in males HVc cells exhibited two types of auditory responses to conspecific and heterospecific song playbacks: tonic and phasic responses. The major finding of the present study is the absence of tonic responses in females. Neurons in the HVc of females only responded phasically to song playbacks. In both sexes, neurons exhibiting auditory responses had thinner action potentials than the others. As all the tonic cells recorded in males were thin spike cells (action potential < or = 0.6 ms) [corrected] and had high firing rates (6 Hz in average), they are potentially interneurons. In both sexes, two categories of nonresponsive cells were found: neurons that did not fire at song onset and had the lowest spontaneous firing rate; and neurons that did not exhibit changes in activity in response to song playbacks. Analyses of physiological characteristics of HVc neurons revealed that the rate of spontaneous activity was higher in males than in females. This study is a first step towards identifying [corrected] the cellular bases of the sexual dimorphism in HVc function and highlights the pivotal role of interneurons in HVc auditory processing.