The peroxisome proliferator-activated receptors at the cross-road of diet and hormonal signalling.

The peroxisome proliferator-activated receptors (PPARs) are members of the steroid/thyroid nuclear receptor superfamily of ligand-activated transcription factors. To date, three isotypes have been identified, alpha, beta and gamma, encoded by three different genes. The alpha isotype is expressed at high levels in the liver where it has a role in lipid oxidation. Its expression and activity follow a diurnal rhythm that parallels the circulating levels of corticosterone in the bloodstream. The gamma isotype on the other hand, is mainly expressed in adipose tissue and has a critical role in adipocyte differentiation and lipid storage. The function of the ubiquitously expressed isotype, PPAR beta, remains to be determined. Besides fulfilling different roles in lipid metabolism, the different PPAR isotypes also have different ligand specificities. A new approach to identify ligands was developed based on the ligand-dependent interaction of PPAR with the recently characterized co-activator SRC-1. This so-called CARLA assay has allowed the identification of fatty acids and eicosanoids as PPAR ligands. Although the evidence clearly links PPAR isotypes to distinct functions, the molecular basis for this isotype-specificity is still unclear. All three isotypes are able to bind the same consensus response element, formed by a direct repeat of two AGGTCA hexamers separated by one base, though with different affinities. We recently demonstrated that besides the core DR-1 element, the 5' flanking sequence should be included in the definition of a PPRE. Interestingly, the presence of this flanking sequence is of particular importance in the context of PPAR alpha binding. Moreover, it reflects the polarity of the PPAR-RXR heterodimer on DNA, with PPAR binding to the 5' half-site and RXR binding to the 3' half-site. This unusual polarity may confer unique properties to the bound heterodimer with respect to ligand binding and interaction with co-activators and corepressors.

Cross-cultural clinical competence and post-graduate teaching: any impact(s) on doctors?

Context: Cross-cultural clinical competence (CCC) requires a mixtureof "knowledge" (K), "attitude" (A) and "skills" (S), in order to develop theability to give quality care to patients of different cultures. Theseattributes allow, while providing medical care, consideration of thepatient's medical, social, cultural and language needs. The LausanneUniversity Medical Policlinic (PMU) provides approximately 30000consultations per year to migrant patients and over the past five yearshas implemented a training course on CCC that focuses on trialogue,stereotypes and administrative procedures for the healthcare ofmigrants.Method: A quantitative survey of 18 new residents, was carried outusing a validated questionnaire, the "Multicultural AssessmentQuestionnaire" (the MAQ, 16 questions on K, A and S) to evaluate theimpact of CCC training. The questionnaire was distributed before theCCC course (J-1), three days after (J+3) and three months later (J+90).A descriptive univariate analysis of the difference in MAQ scoresbetween the times J-1 - J+3 and J-1 - J+90 was made. Three FocusGroups were conducted, at three months, to explore residents' thoughtsabout the course.Results: A significant increase was observed in global performancedeclared by residents. Following the intervention, the score of the MAQincreased from 31.4 points to 38.0 points at three days (p = 0.004) andto 37.7 points at three months (p = 0.003). This increase was mostnoticeable in the field of acquiring K: total score J-1: 118, J+3: 189,J+90: 190 (difference J-1 - J+3 and J-1 - J+90: p <0.005). There was nosignificant difference in acquiring A (J-1: 222, J+3: 228, J+90: 229), andS increases in a significant way at first (J-1: 222, J+3: 265, J-1 - J+3:p = 0.035), then comes back to the start value (J+90: 217). The residentswere interested by the course which they felt provides useful informationfor clinical practice. They had a great number of expectations in varyingfields (medical anthropology, cultural differences, epidemiology, etc.),hoping a "ready-made" solution for the approach of migrant patients.Conclusions: A unique training of CCC at the post-graduate level,upgraded K, and to a lesser extent A and S, for these 18 residents. Theywere interest and they had many expectations. Subsequent coursesshould consolidate these acquisitions. Future study should demonstratethe impact on patients' clinical outcome.

Mechanisms of cross-modal plasticity in early-blind subjects.

A variety of studies have demonstrated enhanced blood oxygenation level dependent responses to auditory and tactile stimuli within occipital cortex as a result of early blindness. However, little is known about the organizational principles that drive this cross-modal plasticity. We compared BOLD responses to a wide variety of auditory and tactile tasks (vs. rest) in early-blind and sighted subjects. As expected, cross-modal responses were larger in blind than in sighted subjects in occipital cortex for all tasks (cross-modal plasticity). Within both blind and sighted subject groups, we found patterns of cross-modal activity that were remarkably similar across tasks: a large proportion of cross-modal responses within occipital cortex are neither task nor stimulus specific. We next examined the mechanisms underlying enhanced BOLD responses within early-blind subjects. We found that the enhancement of cross-modal responses due to early blindness was best described as an additive shift, suggesting that cross-modal plasticity within blind subjects does not originate from either a scaling or unmasking of cross-modal responsivities found in sighted subjects.

Worlds of working poverty : Cross-national variation in the mechanisms that lead to poverty among workers

The objective of this paper is to distinguish between different types of working poverty, on the basis of the mechanisms that produce it. Whereas the poverty literature identifies a myriad of risk factors and of categories of disadvantaged workers, we focus on three immediate causes of working poverty, namely low wage rate, weak labour force attachment, and high needs, the latter mainly due to the presence of children (and sometimes to the increase in needs caused by a divorce). These three mechanisms are the channels through which macroeconomic, demographic and policy factors have a direct bearing on working households. The main assumption tested here is that welfare regimes strongly influence the relative weight of these three mechanisms in producing working poverty, and, hence, the composition of the working-poor population. Our figures confirm this hypothesis and show that low-wage employment is a key factor, but, by far, not the only one and that family policies broadly understood play a decisive role, as well as patterns of labour market participation and integration.

Prediction of cross-recognition of peptide-HLA A2 by Melan-A-specific cytotoxic T lymphocytes using three-dimensional quantitative structure-activity relationships.

The cross-recognition of peptides by cytotoxic T lymphocytes is a key element in immunology and in particular in peptide based immunotherapy. Here we develop three-dimensional (3D) quantitative structure-activity relationships (QSARs) to predict cross-recognition by Melan-A-specific cytotoxic T lymphocytes of peptides bound to HLA A*0201 (hereafter referred to as HLA A2). First, we predict the structure of a set of self- and pathogen-derived peptides bound to HLA A2 using a previously developed ab initio structure prediction approach [Fagerberg et al., J. Mol. Biol., 521-46 (2006)]. Second, shape and electrostatic energy calculations are performed on a 3D grid to produce similarity matrices which are combined with a genetic neural network method [So et al., J. Med. Chem., 4347-59 (1997)] to generate 3D-QSAR models. The models are extensively validated using several different approaches. During the model generation, the leave-one-out cross-validated correlation coefficient (q (2)) is used as the fitness criterion and all obtained models are evaluated based on their q (2) values. Moreover, the best model obtained for a partitioned data set is evaluated by its correlation coefficient (r = 0.92 for the external test set). The physical relevance of all models is tested using a functional dependence analysis and the robustness of the models obtained for the entire data set is confirmed using y-randomization. Finally, the validated models are tested for their utility in the setting of rational peptide design: their ability to discriminate between peptides that only contain side chain substitutions in a single secondary anchor position is evaluated. In addition, the predicted cross-recognition of the mono-substituted peptides is confirmed experimentally in chromium-release assays. These results underline the utility of 3D-QSARs in peptide mimetic design and suggest that the properties of the unbound epitope are sufficient to capture most of the information to determine the cross-recognition.

Cross talk between 2,4-diacetylphloroglucinol-producing biocontrol pseudomonads on wheat roots.

The performance of Pseudomonas biocontrol agents may be improved by applying mixtures of strains which are complementary in their capacity to suppress plant diseases. Here, we have chosen the combination of Pseudomonas fluorescens CHA0 with another well-characterized biocontrol agent, P. fluorescens Q2-87, as a model to study how these strains affect each other's expression of a biocontrol trait. In both strains, production of the antimicrobial compound 2,4-diacetylphloroglucinol (DAPG) is a crucial factor contributing to the suppression of root diseases. DAPG acts as a signaling compound inducing the expression of its own biosynthetic genes. Experimental setups were developed to investigate whether, when combining strains CHA0 and Q2-87, DAPG excreted by one strain may influence expression of DAPG-biosynthetic genes in the other strain in vitro and on the roots of wheat. DAPG production was monitored by observing the expression of lacZ fused to the biosynthetic gene phlA of the respective strain. Dual-culture assays in which the two strains were grown in liquid medium physically separated by a membrane revealed that Q2-87 but not its DAPG-negative mutant Q2-87::Tn5-1 strongly induced phlA expression in a DeltaphlA mutant of strain CHA0. In the same way, phlA expression in a Q2-87 background was induced by DAPG produced by CHA0. When coinoculated onto the roots of wheat seedlings grown under gnotobiotic conditions, strains Q2-87 and CHA0, but not their respective DAPG-negative mutants, were able to enhance phlA expression in each other. In summary, we have established that two nonrelated pseudomonads may stimulate each other in the expression of an antimicrobial compound important for biocontrol. This interpopulation communication occurs in the rhizosphere, i.e., at the site of pathogen inhibition, and is mediated by the antimicrobial compound itself acting as a signal exchanged between the two pseudomonads.

Alcohol may not "cause" partner violence but it seems to make it worse : a cross-national comparison of partner aggression involving alcohol with aggression not involving alcohol

This study assesses whether severity of physical partner aggression is associated with alcohol consumption at the time of the incident, and whether the relationship between drinking and aggression severity is the same for men and women and across different countries. National or large regional general population surveys were conducted in 13 countries as part of the GENACIS collaboration. Respondents described the most physically aggressive act done to them by a partner in the past 2 years, rated the severity of aggression on a scale of 1 to 10, and reported whether either partner had been drinking when the incident occurred. Severity ratings were significantly higher for incidents in which one or both partners had been drinking compared to incidents in which neither partner had been drinking. The relationship did not differ significantly for men and women or by country. We conclude that alcohol consumption may serve to potentiate violence when it occurs, and this pattern holds across a diverse set of cultures. Further research is needed that focuses explicitly on the nature of alcohol's contribution to intimate partner aggression. Prevention needs to address the possibility of enhanced dangers of intimate partner violence when the partners have been drinking and eliminate any systemic factors that permit alcohol to be used as an excuse. Clinical services for perpetrators and victims of partner violence need to address the role of drinking practices, including the dynamics and process of aggressive incidents that occur when one or both partners have been drinking.

Association of work related chronic stressors and psychiatric symptoms in a Swiss sample of police officers : a cross sectional questionnaire study

Purpose (1) To identify work related stressors that are associated with psychiatric symptoms in a Swiss sample of policemen and (2) to develop a model for identifying officers at risk for developing mental health problems. Method The study design is cross sectional. A total of 354 male police officers answered a questionnaire assessing a wide spectrum of work related stressors. Psychiatric symptoms were assessed using the "TST questionnaire" (Langner in J Health Hum Behav 4, 269-276, 1962). Logistic regression with backward procedure was used to identify a set of variables collectively associated with high scores for psychiatric symptoms. Results A total of 42 (11.9%) officers had a high score for psychiatric symptoms. Nearly all potential stressors considered were significantly associated (at P < 0.05) with a high score for psychiatric symptoms. A significant model including 6 independent variables was identified: lack of support from superior and organization OR = 3.58 (1.58-8.13), self perception of bad quality work OR = 2.99 (1.35-6.59), inadequate work schedule OR = 2.84 (1.22-6.62), high mental/intellectual demand OR = 2.56 (1.12-5.86), age (in decades) OR = 1.82 (1.21-2.73), and score for physical environment complaints OR = 1.30 (1.03-1.64). Conclusions Most of work stressors considered are associated with psychiatric symptoms. Prevention should target the most frequent stressors with high association to symptoms. Complaints of police officers about stressors should receive proper consideration by the management of public administration. Such complaints might be the expression of psychiatric caseness requiring medical assistance. Particular attention should be given to police officers complaining about many stressors identified in this study's multiple model. [Authors]

Influence from friends to drink more or drink less: a cross-national comparison.

Drinking habits are socially patterned and social networks influence individuals' drinking behaviors. Previous studies have focused primarily upon the influence from family members to drink less. Those studies that have focused upon peer influence have been largely confined to social norms among adolescent and college-age drinkers. By contrast, based in adult populations, this article examines exhortations from friends not only to reduce alcohol consumption but also to increase it. Survey data in 15 countries that participate in the Gender, Alcohol and Culture: An International Study project (GENACIS) were used to test whether there were country and gender differences concerning the influence to drink less or to drink more by friends and examine if this was affected by the drinking behavior. The findings revealed that those influenced to drink less had more heavy episodic drinking (HED) occasions than those who did not report such influence. By contrast, influence to drink more, originating mainly from same-sex friends, may be more the result of social situations that encourage all drinkers, regardless of their frequency of HED occasions. At the country level, influence to drink less for both sexes decreased with the proportion of drinkers in a country. Similarly, influence to drink less for both sexes also decreased in countries where gender roles were more egalitarian. Thus, in countries where alcohol use is more widespread and fewer differences are observed between male and female gender role expectations, fewer people were influenced to drink less. These findings have implications for social and behavioral strategies designed to reduce alcohol-related harm across a wide range of cultures.