Multiplexed neurochemical signaling by neurons of the ventral tegmental area

The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in ‘multiplexed’ neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression.     

A patient in the clinic; a person in the world. Why shared decision making needs to center on the person rather than the medical encounter

Interest in shared decision making (SDM) has increased and become widely promoted. However, from both practical and measurement perspectives, SDM’s origin as an outgrowth of patient autonomy has resulted in narrowly conceptualizing and operationalizing decision making. The narrow focus on individual patient autonomy fails in four main ways: 1) excluding several facets of the roles, actions, and influences of decision partners in decision making; 2) focusing solely on the medical encounter; 3) ignoring the informational environment to which patients have access; and 4) treating each encounter as independent of all others. In addition to creating a research agenda that could answer important outstanding questions about how decisions are made and the consequences thereof, reconceiving SDM as centered on the person rather than the medical encounter has the potential to transform how illness is experienced by patients and families and how clinicians find meaning in their work.     

C-reactive protein does not impair insulin suppression of glucose release in primary hepatocytes

Recent studies have suggested that CRP may interfere with insulin signaling in skeletal muscle and endothelial cells. The aim of this study was to determine whether highly purified CRP increased the rate of glucose appearance in primary hepatocytes in the absence or presence of insulin. Primary rat hepatocytes were provided glucose-free media containing 10 mM lactate, 1 mM pyruvate, 0, 1 or 10 nM insulin, and 0 or 10 μg/ml of purified CRP for 6h. Purified CRP did not increase glucose release in the absence of insulin and did not reduce the ability of insulin to suppress glucose release.     

Threshold and non-threshold chemical carcinogens: A survey of the present regulatory landscape

For the proper regulation of a carcinogenic material it is necessary to fully understand its mode of action, and in particular whether it demonstrates a threshold of effect. This paper explores our present understanding of carcinogenicity and the mechanisms underlying the carcinogenic response. The concepts of genotoxic and non-genotoxic and threshold and non-threshold carcinogens are fully described. We provide summary tables of the types of cancer considered to be associated with exposure to a number of carcinogens and the available evidence relating to whether carcinogenicity occurs through a threshold or non-threshold mechanism. In light of these observations we consider how different regulatory bodies approach the question of chemical carcinogenesis, looking in particular at the definitions and methodologies used to derive Occupational Exposure Levels (OELs) for carcinogens. We conclude that unless proper differentiation is made between threshold and non-threshold carcinogens, inappropriate risk management measures may be put in place - and lead also to difficulties in translating carcinogenicity research findings into appropriate health policies. We recommend that clear differentiation between threshold and non-threshold carcinogens should be made by all expert groups and regulatory bodies dealing with carcinogen classification and risk assessment.