Agonists of GABA(B) receptors exert a bi-directional effect on the activity of dopamine (DA) neurons of the ventral tegmental area, which can be explained by the fact that coupling between GABA(B) receptors and G protein-gated inwardly rectifying potassium (GIRK) channels is significantly weaker in DA neurons than in GABA neurons. Thus, low concentrations of agonists preferentially inhibit GABA neurons and thereby disinhibit DA neurons. This disinhibition might confer reinforcing properties on addictive GABA(B) receptor agonists such as gamma-hydroxybutyrate (GHB) and its derivatives. Here we show that, in DA neurons of mice, the low coupling efficiency reflects the selective expression of heteromeric GIRK2/3 channels and is dynamically modulated by a member of the regulator of G protein signaling (RGS) protein family. Moreover, repetitive exposure to GHB increases the GABA(B) receptor-GIRK channel coupling efficiency through downregulation of RGS2. Finally, oral self-administration of GHB at a concentration that is normally rewarding becomes aversive after chronic exposure. On the basis of these results, we propose a mechanism that might underlie tolerance to GHB.

The Millennium Development Goals (MDGs) are eight international development goals to be achieved by 2015 addressing poverty, hunger, maternal and child mortality, communicable disease, education, gender inequality, environmental damage and the global partnership. Most activities worldwide have focused on maternal and child health and communicable diseases, while less attention has been paid to environmental sustainability and the development of a global partnership. Up to now, several targets have been at least partially achieved: hunger reduction is on track, poverty has been reduced by half, living conditions of 200 million deprived people enhanced, maternal and child mortality as well as communicable diseases diminished and education improved. Nevertheless, some goals will not be met, particularly in the poorest regions, due to different challenges (e.g. the lack of synergies among the goals, the economic crisis, etc.). The post-2015 agenda is now under discussion. The new targets, whatever they will be called, should reflect today's political situation, health and environmental challenges, and an all-inclusive, intersectoral and accountable approach should be adopted.

Background When microorganisms (such as bacteria or viruses) are highly exposed to antimicrobial drugs, they can develop the capacity to defeat the drugs designed to eradicate them. Long-term accumulation of adaptations to survive drug exposure can lead to the development of antimicrobial resistance (AMR). The success of antibiotics has led to their widespread overuse and misuse in humans, animals and plants. Main text AMR is a global concern and solutions are not vertical actions in a single buy business model. Even if a transectoral approach is key, there is a lack of multi-disciplinary partnerships that allow for strategic cooperation between different sectors such as the pharmaceutical industry, agro-alimentary complex, patient care and education, NGOs and research and development. Global public health voices should lead this integration to align the progress of existing AMR successes. Maintaining the public’s trust in preventive medicine, health systems and food production safety, together with public health driven, non-profit drug development, is a key factor. In its “Call for integrated action on AMR”, signed by about 70 national and international organizations the World Federation of Public Health Associations (WFPHA) called “on all governments, the private sector, non-governmental organizations, health professionals, public and private research organizations, and all stakeholders to ensure that public health remains at the centre of all policy and scientific endeavours in the field of antimicrobial resistance”. Conclusions The “Global Charter for the Public’s Health”, developed by the WFPHA in association with WHO, is proposed in this article as a tool for implementation of complex public health actions such as AMR.

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Regulator of G-protein signaling (RGS) proteins are strong modulators of G-protein-mediated pathways in the nervous system. One function of RGS proteins is to accelerate the activationdeactivation kinetics of G-protein-coupled inwardly rectifying potassium (GIRK) channels. The opening of GIRK channels reduces the firing rates of neurons. Recent studies suggest that RGS proteins also modulate the coupling efficiency between GABA B (gamma-amino butyric acid-type B) receptors and GIRK channels in dopamine neurons of the ventral tegmental area (VTA), the initial target for addictive drugs in the brain reward pathway. Chronic drug exposure can dynamically regulate the expression levels of RGS. Functional and behavioral studies now reveal that levels of RGS2 protein, through selective association with GIRK3, critically determine whether GABA B agonists are excitatory or inhibitory in the VTA. The regulation of RGS protein in the reward pathway may underlie adaptation to different types of addictive drugs.

Improved treatments for early breast cancer have led to a significant increase in overall survival. While evidence regarding potential long-term sequelae of adjuvant treatments exists, relatively little research reports patients' own perceptions of change before and after adjuvant chemotherapy (AC). This study aimed to identify key ongoing issues associated with AC in daily life. An online survey developed for this study was completed by 198 women (mean age 49.7 years) in the UK, France and Germany who had AC 1-5 years previously for oestrogen receptor positive, HER2 negative early breast cancer. Women without AC and endocrine therapy, those treated with Trastuzumab or who had recurrent disease were excluded. A third of women who responded were currently unable to perform their former family role. The majority had needed support, particularly with child care, during treatment. While 54% were in full-time employment before diagnosis this had reduced to 32% following AC. Of those women still working, over half reported difficulties with tiredness or concentration. Most (85.8%) were satisfied with healthcare professionals' treatment information, but only 29.7% received information about returning to work. This exploratory survey highlights areas of women's lives affected 1-5 years following AC for early breast cancer. The impact on returning to work and issues surrounding childcare particularly, require further study.

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