Social status mediated variation in hypothalamic transcriptional profiles of male mice.

Animals of different social status exhibit variation in aggression, territorial and reproductive behavior as well as activity patterns, feeding, drinking and status signaling. This behavioral and physiological plasticity is coordinated by underlying changes in brain gene transcription. Using Tag-based RNA sequencing (Tag-seq), we explore RNA transcriptomes from the medial preoptic area (mPOA) and ventral hypothalamus (vHYP) of male mice of different social ranks in a dominance hierarchy and detect candidate genes and cellular pathways that underlie status-related plasticity. Within the mPOA, oxytocin (Oxt) and vasopressin (Avp) are more highly expressed in subdominant mice compared to other ranks, while nitric oxide synthase (Nos1) has lower expression in subdominant mice. Within the vHYP, we find that both orexigenic and anorexigenic genes involved in feeding behavior, including agouti-related peptide (Agrp), neuropeptide-Y (Npy), galanin (Gal), proopiomelanocortin (Pomc), and Cocaine- and Amphetamine-Regulated Transcript Protein prepropeptide (Cartpt), are less expressed in dominant animals compared to more subordinate ranks. We suggest that this may represent a reshaping of feeding circuits in dominant compared to subdominant and subordinate animals. Furthermore, we determine several genes that are positively and negatively associated with the level of despotism (aggression) in dominant males. Ultimately, we identify hypothalamic genes controlling feeding and social behaviors that are differentially transcribed across animals of varying social status. These changes in brain transcriptomics likely support phenotypic variation that enable animals to adapt to their current social status.

Postnatal maternal care predicts divergent weaning strategies and the development of social behavior.

Maternal care experienced during postnatal development predicts long-term neurobiological and behavioral outcomes. However, the cascade of behavioral changes that emerge in response to maternal care has not been elucidated. In the current study, we examine naturally occurring variation in postnatal licking/grooming (LG) in C57BL/6J mice to determine its impact on preweaning maternal and pup behavior, the weaning process, the pace of developmental change, the emergence of social behavior, and indices of anxiety-like behavior in adulthood. Our analyses indicate that lower postnatal LG is associated with truncated and more infrequent maternal behavior during the preweaning period. Moreover, compared to High LG dams, Low LG dams are observed to actively wean their offspring sooner and have offspring that play more frequently. The heightened pace of developmental change observed in offspring of Low LG dams suggests a more rapid transition to behavioral and nutritional independence, which could have implications for future reproductive strategies.

Variation in maternal and anxiety-like behavior associated with discrete patterns of oxytocin and vasopressin 1a receptor density in the lateral septum.

The relationship between anxiety and maternal behavior has been explored across species using a variety of approaches, yet there is no clear consensus on the nature or direction of this relationship. In the current study, we have assessed stable individual differences in anxiety-like behavior in a large cohort (n=57) of female F2 hybrid mice. Using open-field behavior as a continuous and categorical (high vs. low) measure we examined the relationship between the anxiety-like behavior of virgin F2 females and the subsequent maternal behavior of these females. In addition, we quantified oxytocin (OTR) and vasopressin (V1a) receptor density within the lateral septum to determine the possible correlation with anxiety-like and maternal behavior. We find that, though activity levels within the open-field do predict latency to engage in pup retrieval, anxiety-like measures on this test are otherwise not associated with subsequent maternal behavior. OTR density in the dorsal lateral septum was found to be negatively correlated with activity levels in the open-field and positively correlated with frequency of nursing behavior. V1a receptor density was significantly correlated with postpartum licking/grooming of pups. Though we do not find support for the hypothesis that individual differences in trait anxiety predict variation in maternal behavior, we do find evidence for the role of OTR and V1a receptors in predicting maternal behavior in mice and suggest possible methodological issues (such as distinguishing between trait and state anxiety) that will be a critical consideration for subsequent studies of the anxiety-maternal behavior relationship. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Impact of a bisphenol A, F, and S mixture and maternal care on the brain transcriptome of rat dams and pups.

Products containing BPA structural analog replacements have increased in response to growing public concern over adverse effects of BPA. Although humans are regularly exposed to a mixture of bisphenols, few studies have examined effects of prenatal exposure to BPA alternatives or bisphenol mixtures. In the present study, we investigate the effect of exposure to an environmentally-relevant, low-dose (150 ug/kg body weight per day) mixture of BPA, BPS, and BPF during gestation on the brain transcriptome in Long-Evans pups and dams using Tag RNA-sequencing. We also examined the association between dam licking and grooming, which also has enduring effects on pup neural development, and the transcriptomes. Associations between licking and grooming and the transcriptome were region-specific, with the hypothalamus having the greatest number of differentially expressed genes associated with licking and grooming in both dams and pups. Prenatal bisphenol exposure also had region-specific effects on gene expression and pup gene expression was affected more robustly than dam gene expression. In dams, the prelimbic cortex had the greatest number of differentially expressed genes associated with prenatal bisphenol exposure. Prenatal bisphenol exposure changed the expression of over 2000 genes in pups, with the majority being from the pup amygdala. We used Gene Set Enrichment Analysis (GSEA) to asses enrichment of gene ontology biological processes for each region. Top GSEA terms were diverse and varied by brain region and included processes known to have strong associations with steroid hormone regulation, cilium-related terms, metabolic/biosynthetic process terms, and immune terms. Finally, hypothesis-driven analysis of genes related to estrogen response, parental behavior, and epigenetic regulation of gene expression revealed region-specific expression associated with licking and grooming and bisphenol exposure that were distinct in dams and pups. These data highlight the effects of bisphenols on multiple physiological process that are highly dependent on timing of exposure (prenatal vs. adulthood) and brain region, and reiterate the contributions of multiple environmental and experiential factors in shaping the brain.

Behavioural and physiological plasticity in social hierarchies.

Individuals occupying dominant and subordinate positions in social hierarchies exhibit divergent behaviours, physiology and neural functioning. Dominant animals express higher levels of dominance behaviours such as aggression, territorial defence and mate-guarding. Dominants also signal their status via auditory, visual or chemical cues. Moreover, dominant animals typically increase reproductive behaviours and show enhanced spatial and social cognition as well as elevated arousal. These biobehavioural changes increase energetic demands that are met via shifting both energy intake and metabolism and are supported by coordinated changes in physiological systems including the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes as well as altered gene expression and sensitivity of neural circuits that regulate these behaviours. Conversely, subordinate animals inhibit dominance and often reproductive behaviours and exhibit physiological changes adapted to socially stressful contexts. Phenotypic changes in both dominant and subordinate individuals may be beneficial in the short-term but lead to long-term challenges to health. Further, rapid changes in social ranks occur as dominant animals socially ascend or descend and are associated with dynamic modulations in the brain and periphery. In this paper, we provide a broad overview of how behavioural and phenotypic changes associated with social dominance and subordination are expressed in neural and physiological plasticity. This article is part of the theme issue 'The centennial of the pecking order: current state and future prospects for the study of dominance hierarchies'.

[PMTCT in Benin: Is the pregnant women's consent free and informed?] / Prévention de la transmission mère-enfant du VIH/sida au Bénin: le consentement des femmes au dépistage est-il libre et éclairé ?

INTRODUCTION: In international and national HIV/AIDS policies, free and informed consent is recognized as one of the major components of testing programs. For pregnant women, free and informed consent means that they should get information on prevention of mother-to-child transmission (PMTCT), understand them and make an independent choice after weighing the risks and advantages. However, no PMTCT program looked into the issue of consent. The objective of this paper is to explore the free and informed nature of pregnant women's consent with regard to testing and their rationale for accepting to be tested. METHODS: We used data collected within the framework of the analysis of the creation of the PMTCT program in Benin. This analysis is based on multiple case studies that covered six maternity homes selected from 56 operational sites. For the specific analysis of consent, we used both survey data and qualitative research data. FINDINGS: Apart from three cases of secret testing, the free nature of the consent to the test is respected on the PMTCT sites. Twenty-nine cases of refusal were recorded. The reasons put forth by most pregnant women include the fear of a positive test and its consequences on family life in 55.2% of cases and the expectation of their husbands' agreement or disagreement in 27.6% of cases. On the whole, the consent was free on all the sites but its informed nature is less respected.

Developmental shifts in the behavioral phenotypes of inbred mice: the role of postnatal and juvenile social experiences.

The interaction between genotype and environment is an important feature of the process of development. We investigate this interaction by examining the influence of postnatal cross-fostering and post-weaning cross-housing on the behavioral development of 129S and B6 mice. Following cross-fostering, we found significant alterations in the frequency of maternal care as a function of maternal strain and pup type as well as interactions between these variables. In adulthood, we find there are sex-specific and strain-specific alterations in anxiety-like behavior as a function of rearing environment, with males exhibiting more pronounced rearing-induced effects. Mixed-strain housing of weanlings was found to lead to alterations in home-cage social and feeding behavior as well as changes in adult anxiety-like responses of 129S mice. Anxiety-like behavior in B6 mice was altered as a function of the interaction between housing condition and weaning weight. These data illustrate the complex pathways through which early and later social experiences may lead to variations in behavior.

[Health Ethics in Benin and HIV-AIDS : What are the stakes]. / Chapitre 5. L?éthique en santé au Bénin et le vih-sida : quels enjeux.

As part of the fight against HIV-AIDS, an effort was made at the ethical component, namely that there are legal texts, institutional and ethical. There are ethics committees (three) that give reasoned opinions on study protocols and are endeavoring to raise awareness of the actors. But we note that there is not yet a real ownership and adoption of ethical practice by them. This study targeted research projects on HIV-AIDS and centers supported PLHIV in order to analyze ethical issues : 1) the method of recruitment of participants and beneficiaries ; 2) obtaining informed consent from them ; 2) measures of confidentiality and anonymity ; 3) the integrity of staff of these projects and centers and conflicts of interest. A thematic analysis of data collected, which is done, after semi-structured interviews, helped to highlight the issues related to the recruitment process, obtaining informed consent, confidentiality measures and anonymity, integrity and Conflict of Interest. Let us remember that what is done, not done yet in the forms of art. Constant monitoring is called for, as leaders with ethics committees.They are supposed to play fully their roles.

The functional serotonin 1a receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription.

The G/C single-nucleotide polymorphism in the serotonin 1a receptor promoter, rs6295, has previously been linked with depression, suicide and antidepressant responsiveness. In vitro studies suggest that rs6295 may have functional effects on the expression of the serotonin 1a receptor gene (HTR1A) through altered binding of a number of transcription factors. To further explore the relationship between rs6295, mental illness and gene expression, we performed dual epidemiological and biological studies. First, we genotyped a cohort of 1412 individuals, randomly split into discovery and replication cohorts, to examine the relationship between rs6295 and five psychiatric outcomes: history of psychiatric hospitalization, history of suicide attempts, history of substance or alcohol abuse, current posttraumatic stress disorder (PTSD), current depression. We found that the rs6295G allele is associated with increased risk for substance abuse, psychiatric hospitalization and suicide attempts. Overall, exposure to either childhood or non-childhood trauma resulted in increased risk for all psychiatric outcomes, but we did not observe a significant interaction between rs6295 and trauma in modulating psychiatric outcomes. In conjunction, we also investigated the potential impact of rs6295 on HTR1A expression in postmortem human brain tissue using relative allelic expression assays. We found more mRNA produced from the C versus the G-allele of rs6295 in the prefrontal cortex (PFC), but not in the midbrain of nonpsychiatric control subjects. Further, in the fetal cortex, rs6295C allele exhibited increased relative expression as early as gestational week 18 in humans. Finally, we found that the C:G allelic expression ratio was significantly neutralized in the PFC of subjects with major depressive disorder (MDD) who committed suicide as compared with controls, indicating that normal patterns of transcription may be disrupted in MDD/suicide. These data provide a putative biological mechanism underlying the association between rs6295, trauma and mental illness. Moreover, our results suggest that rs6295 may affect transcription during both gestational development and adulthood in a region-specific manner, acting as a risk factor for psychiatric illness. These findings provide a critical framework for conceptualizing the effects of a common functional genetic variant, trauma exposure and their impact on mental health.

[Migration, ethics and public health in Quebec]. / Migration, éthique et santé publique au Québec.

This article analyses the ethical issues of migration in relation to public health in Quebec. There are two objectives: to describe the progression of analysis of the migration phenomenon in public health over the last thirty years and to state the ethical debate it raises. The progression of analysis of the migration phenomenon has been characterised by various approaches: intercultural, acculturation, transcultural, and migratory journey. Although these approaches have contributed to the development of knowledge about the reality of immigration, they have also, in spite of themselves, generated stigmatisation, discrimination and the proliferation of prejudices. Generally, findings that have emerged when migration is taken into account indicate an imbalance of power. For some, to focus on the phenomenon of migration promotes the power imbalance while for others, to disregard it masks the issue.

Maternal prenatal depressive symptoms predict infant NR3C1 1F and BDNF IV DNA methylation.

Prenatal maternal psychological distress increases risk for adverse infant outcomes. However, the biological mechanisms underlying this association remain unclear. Prenatal stress can impact fetal epigenetic regulation that could underlie changes in infant stress responses. It has been suggested that maternal glucocorticoids may mediate this epigenetic effect. We examined this hypothesis by determining the impact of maternal cortisol and depressive symptoms during pregnancy on infant NR3C1 and BDNF DNA methylation. Fifty-seven pregnant women were recruited during the second or third trimester. Participants self-reported depressive symptoms and salivary cortisol samples were collected diurnally and in response to a stressor. Buccal swabs for DNA extraction and DNA methylation analysis were collected from each infant at 2 months of age, and mothers were assessed for postnatal depressive symptoms. Prenatal depressive symptoms significantly predicted increased NR3C1 1F DNA methylation in male infants (ß = 2.147, P = 0.044). Prenatal depressive symptoms also significantly predicted decreased BDNF IV DNA methylation in both male and female infants (ß = -3.244, P = 0.013). No measure of maternal cortisol during pregnancy predicted infant NR3C1 1F or BDNF promoter IV DNA methylation. Our findings highlight the susceptibility of males to changes in NR3C1 DNA methylation and present novel evidence for altered BDNF IV DNA methylation in response to maternal depression during pregnancy. The lack of association between maternal cortisol and infant DNA methylation suggests that effects of maternal depression may not be mediated directly by glucocorticoids. Future studies should consider other potential mediating mechanisms in the link between maternal mood and infant outcomes.

The role of corticotropin-releasing factor--norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress.

Naturally occurring variations in maternal care in early postnatal life are associated with the development of individual differences in behavioral and hypothalamic-pituitary-adrenal responses to stress in the rat. These effects appear to be mediated by the influence of maternal licking and grooming on the development of central corticotropin-releasing factor (CRF) systems, which regulate the expression of behavioral, endocrine, and autonomic responses to stress through activation of forebrain noradrenergic systems. These findings provide a neurobiologic basis for the observed relationship between early life events and health in adulthood. In more recent studies, we explored the behavioral transmission of individual differences in stress reactivity, and thus, vulnerability to stress-induced illness, across generations.

An integrative framework for health-related research.

Research on the manifold aspects of health and health-care delivery, economics and administration has expanded rapidly in recent years and now engages a number of disciplines. The array of theories, methods, and analytical strategies derived from such diverse sources frequently impedes effective communication between investigators and sometimes renders it impossible. We propose a conceptual framework that encompasses all health-related research and demonstrates the relationships and interfaces between the various disciplines involved. The framework emerges from a classification of health-related research into studies of health states or health interventions followed by consideration of the level of analysis (e.g. cell, individual, community) employed and the purpose of each study (development, description, explanation, or evaluation).

Like mother, like daughter: evidence for non-genomic transmission of parental behavior and stress responsivity.

Considerable evidence demonstrates that the quality of the early environment influences patterns of development that, in turn, determine the health and productivity of the individual throughout their life span. However, the processes through which early life influences health are not clearly understood. Through the activation of the hypothalamo-pituitary-adrenal (HPA) axis and corticotropin-releasing hormone (CRH) pathways, prolonged or exaggerated responses to stress have profound effects on physiological and cognitive functions. Early maternal separation or handling of neonatal rats can program widespread and lifelong changes in various transmitter systems that regulate the HPA and CRH systems. Our studies show that a high level of maternal licking/grooming, and arched-back nursing correlates with reduced CRH mRNA expression and enhanced glucocorticoid negative feedback, and lower stress responses in the adult. This behavior is stably transmitted between generations and cross-fostering studies show that the offspring inherit the behavior from the nursing mother and not the biological mother. Such intergenerational transmission of maternal behavior is seen in rodents, primates and humans, and may underlie adaptive changes in the HPA axis. The neural basis of this inheritance pattern appears to reside in the central oxytocin system which determines features of maternal behavior. Through these various adaptive neural mechanisms the environmental demand on the mother is reflected in the quality of maternal care to her offspring. This, in turn, programs stress reactivity and maternal behavior patterns of the offspring. This not only determines certain health outcomes but also establishes the relationships between mother and offspring in the next generation. These findings suggest that for neurobiologists, the function of the family is an important level of analysis and the critical question is that of how environmental events regulate neural systems that mediate the expression of parental care.

Variations in maternal behaviour are associated with differences in oxytocin receptor levels in the rat.

Female Long-Evans rats exhibit stable individual differences in maternal behaviours such as pup licking/grooming and arched-back nursing posture (LG-ABN). These variations in maternal behaviour are accompanied by differences in lactation-induced increases in oxytocin receptor levels in brain regions known to mediate the expression of maternal care in this species (i.e. the bed nucleus of the stria terminalis, the medial preoptic area and the lateral septum). Oxytocin receptor levels in the central nucleus of the amygdala were significantly higher in high compared to low LG-ABN females regardless of reproductive status. These findings suggest that individual differences in maternal behaviour may be directly related to variations in oxytocin receptor expression.

A comparative analysis of rural and urban mortality in Georgia, 1979.

This paper examines the relationship between mortality and ruralness in the state of Georgia. In 1979, the rural Standardized Mortality Ratio (SMR) for deaths from all causes was significantly higher than expected when compared to statewide levels, while the urban SMR was significantly lower (p less than 0.01). Of the 13 leading causes of death, 9 had rural SMRs significantly higher than expected, while only homicide had a significantly greater urban SMR (p less than 0.01). Although much of the rural/urban difference in overall mortality is attributed to the fact that the rural population is older, figures adjusted for age and race still reveal that the rural death rate is significantly higher than the urban rate (p less than 0.01). Furthermore, there are several specific differences when analyzed by cause of death, age, and race that remain unexplained. Specific rural health problems include congenital anomalies, motor vehicle and other accidents, heart disease, and cerebrovascular disease. Specific urban health problems include homicides and cancer. In addition to metropolitan status, a second indicator of ruralness, county population size, was used to analyze the data and produced similar results. As county population size increases, the total mortality decreases.

Determinants of health counseling practices in hospitals: the patient's perspective.

We conducted a survey of 518 patients who had been admitted to three hospitals for selected medical, surgical, and obstetrical conditions. All patients came from the same city. One of the hospitals had put forward health promotion and disease prevention as a formal goal. Almost 40% of the respondents reported that they received health counseling during their hospital stay. Logistic regression analyses revealed that medical care processes and organizational factors were more important than patient characteristics in determining health counseling. The only patient characteristic that was positively related to health counseling was "perceived poor health status." Favorable conditions for the development of health counseling included having an attending physician different from the one who treated the patient before entering the hospital, an adequate number of physician visits, and a longer length of stay. Being admitted to a medical ward rather than a surgical or an obstetrical ward also was associated with more frequent health counseling. No significant differences were found among hospitals. Finally, having a general practitioner rather than a specialist as attending physician did not make a difference. These findings support the view that although hospitals have an important and legitimate role to play in health promotion, organizational and institutional obstacles to implementing such practices must not be ignored.

Impact of receiving blood cholesterol test results on dietary change.

INTRODUCTION: The study objective was to determine the impact of receiving results of a blood cholesterol test on changes in dietary behaviors among individuals participating in a Health Risk Appraisal Program. METHODS: This randomized trial of maintenance employees at six hospitals included two groups: Group 1 received their blood cholesterol test results at the pretest; Group 2 received results only at the posttest (16-20 weeks later). The pretest interview included (1) a 24-hour dietary recall; (2) an evaluation of dietary behaviors and suggestions on how to change; (3) height, weight, and blood cholesterol measurement. Five hundred employees participated, and 429 eligible employees completed both pretest and posttest interviews. RESULTS: Blood cholesterol levels decreased by 4.8% (P < .001) and saturated fat intake decreased by 7.4% (P < .05). Regression analyses indicated that individuals more likely to have lowered saturated fat intake had higher pretest saturated fat intakes, had a family history of high blood cholesterol, and were light-maintenance employees (P < .05); no other variables were associated (receiving blood cholesterol test results, previous blood cholesterol test, pretest blood cholesterol levels, personal history of heart disease, BMI, age, gender, tobacco/alcohol use). Among subjects with normal cholesterol levels, those not receiving blood test results reduced saturated fat intake more than those receiving test results; both groups had similar saturated fat intakes (> 12%) greater than recommended intake (< 10%). CONCLUSIONS: Screening programs should include an assessment of saturated fat intake as screening for blood cholesterol may provide normocholesterolemic subjects with a false sense of security.

The economic effects of introducing vigabatrin, a new antiepileptic medication.

Epilepsy is a common disorder, the prevalence of which is estimated at between 0.1 and 1% of the population. Although there are a number of medications available for treating the disorder, 20 to 35% of affected individuals are resistant to standard treatments. Many of these patients could benefit from a new anti-epileptic, vigabatrin. Because the current indication for vigabatrin is as an adjunct in a specific subgroup of epileptic patients, which implies an increased cost of drug therapy, an ex ante economic appraisal of the expected consequences of its introduction in the treatment of epilepsy is valuable. This would provide decision makers with information to complement standard clinical data. Using administrative records of healthcare services utilisation by epileptic patients, we performed a simulation of the expected economic repercussions of vigabatrin use on direct costs related to disease management. The results show that whether or not the introduction of vigabatrin results in an increase or a reduction in costs to the healthcare system depends largely on 3 factors: (i) the administered dosage of vigabatrin; (ii) the effect that vigabatrin has on hospital admissions; and (iii) the proportion of epileptic patients who take the drug. Moreover, this study underlines the usefulness of administrative data in forecasting the economic impact of new health technologies.

Cost utility of chemotherapy and best supportive care in non-small cell lung cancer.

Polychemotherapy is the therapeutic option recommended for nonresectable, non-small cell lung cancer (NSCLC). However, the modest gains in survival, and the frequent and often serious adverse effects, associated with chemotherapy should also be considered when deciding on therapy. We therefore performed a cost-utility analysis of chemotherapy and best supportive care in NSCLC. Effectiveness and costs were analysed on 70 patients who were randomised to receive one of 3 treatments: VP (vindesine and cisplatin), CAP (cyclophosphamide, doxorubicin and cisplatin), or best supportive care. Subsequently, an assessment of the value of polychemotherapy and best supportive care was performed by oncology personnel using the time trade-off technique. Polychemotherapy was found to be more effective than best supportive care, but was also more costly and had a lower value score. Because of its cost utility and its higher value, best supportive care should not be discarded as an alternative for the treatment of NSCLC.