Nicotine and ethanol activate protein kinase A synergistically via G(i) betagamma subunits in nucleus accumbens/ventral tegmental cocultures: the role of dopamine D(1)/D(2) and adenosine A(2A) receptors

Tobacco and alcohol are the most commonly used drugs of abuse and show the most serious comorbidity. The mesolimbic dopamine system contributes significantly to nicotine and ethanol reinforcement, but the underlying cellular signaling mechanisms are poorly understood. Nicotinic acetylcholine (nACh) receptors are highly expressed on ventral tegmental area (VTA) dopamine neurons, with relatively low expression in nucleus accumbens (NAcb) neurons. Because dopamine receptors D(1) and D(2) are highly expressed on NAcb neurons, nicotine could influence NAcb neurons indirectly by activating VTA neurons to release dopamine in the NAcb. To investigate this possibility in vitro, we established primary cultures containing neurons from VTA or NAcb separately or in cocultures. Nicotine increased cAMP response element-mediated gene expression only in cocultures; this increase was blocked by nACh or dopamine D(1) or D(2) receptor antagonists. Furthermore, subthreshold concentrations of nicotine with ethanol increased gene expression in cocultures, and this increase was blocked by nACh, D(2) or adenosine A(2A) receptor antagonists, Gbetagamma or protein kinase A (PKA) inhibitors, and adenosine deaminase. These results suggest that nicotine activated VTA neurons, causing the release of dopamine, which in turn stimulated both D(1) and D(2) receptors on NAcb neurons. In addition, subthreshold concentrations of nicotine and ethanol in combination also activated NAcb neurons through synergy between D(2) and A(2A) receptors. These data provide a novel cellular mechanism, involving Gbetagamma subunits, A(2A) receptors, and PKA, whereby combined use of tobacco and alcohol could enhance the reinforcing effect in humans as well as facilitate long-term neuroadaptations, increasing the risk for developing coaddiction.     

O2 sensing in the human ductus arteriosus: regulation of voltage-gated K+ channels in smooth muscle cells by a mitochondrial redox sensor

Functional closure of the human ductus arteriosus (DA) is initiated within minutes of birth by O2 constriction. It occurs by an incompletely understood mechanism that is intrinsic to the DA smooth muscle cell (DASMC). We hypothesized that O2 alters the function of an O2 sensor (the mitochondrial electron transport chain, ETC) thereby increasing production of a diffusible redox-mediator (H2O2), thus triggering an effector mechanism (inhibition of DASMC voltage-gated K+ channels, Kv). O2 constriction was evaluated in 26 human DAs (12 female, aged 9+/-2 days) studied in their normal hypoxic state or after normoxic tissue culture. In fresh, hypoxic DAs, 4-aminopyridine (4-AP), a Kv inhibitor, and O2 cause similar constriction and K+ current inhibition (I(K)). Tissue culture for 72 hours, particularly in normoxia, causes ionic remodeling, characterized by decreased O2 and 4-AP constriction in DA rings and reduced O2- and 4-AP-sensitive I(K) in DASMCs. Remodeled DAMSCs are depolarized and express less O2-sensitive channels (including Kv2.1, Kv1.5, Kv9.3, Kv4.3, and BK(Ca)). Kv2.1 adenoviral gene-transfer significantly reverses ionic remodeling, partially restoring both the electrophysiological and tone responses to 4-AP and O2. In fresh DASMCs, ETC inhibitors (rotenone and antimycin) mimic hypoxia, increasing I(K) and reversing constriction to O2, but not phenylephrine. O2 increases, whereas hypoxia and ETC inhibitors decrease H2O2 production by altering mitochondrial membrane potential (DeltaPsim). H2O2, like O2, inhibits I(K) and depolarizes DASMCs. We conclude that O2 controls human DA tone by modulating the function of the mitochondrial ETC thereby varying DeltaPsim and the production of H2O2, which regulates DASMC Kv channel activity and DA tone.     

Frailty Could Predict Death in Older Adults after Admission at Emergency Department? A 6-month Prospective Study from a Middle-Income Country

The journal of nutrition, health & aging - The number of older adults attending emergency department (ED) is increasing all over the world. Usually, those patients are potentially more complex...     

General practitioners’ views on leadership roles and challenges in primary health care: a qualitative study

Objective: To explore general practitioners’ (GPs) views on leadership roles and leadership challenges in general practice and primary health care.

Design: We conducted focus groups (FGs) with 17 GPs.

Setting: Norwegian primary health care.

Subjects: 17 GPs who attended a 5 d course on leadership in primary health care.

Results: Our study suggests that the GPs experience a need for more preparation and formal training for the leadership role, and that they experienced tensions between the clinical and leadership role. GPs recognized the need to take on leadership roles in primary care, but their lack of leadership training and credentials, and the way in which their practices were organized and financed were barriers towards their involvement.

Conclusions: GPs experience tensions between the clinical and leadership role and note a lack of leadership training and awareness. There is a need for a more structured educational and career path for GPs, in which doctors are offered training and preparation in advance.

• KEY POINTS

• Little is known about doctors’ experiences and views about leadership in general practice and primary health care. Our study suggests that:

• There is a lack of preparation and formal training for the leadership role.

• GPs experience tensions between the clinical and leadership role.

• GPs recognize leadership challenges at a system level and that doctors should take on leadership roles in primary health care.

     

Effective connectivity in target stimulus processing: a dynamic causal modeling study of visual oddball task

PURPOSE: To investigate the fundamental connectivity architecture of neural structures involved in the goal-directed processing of target events. METHODS: Twenty healthy volunteers underwent event-related functional magnetic resonance imaging (fMRI) while performing a standard oddball task. In the task, two types of visual stimuli - rare (target) and frequent - were randomly presented, and subjects were instructed to mentally count the target stimuli. Dynamic causal modeling (DCM), in combination with Bayes factors was used to compare competing neurophysiological models with different intrinsic connectivity structures and input regions within the network of brain regions underlying target stimulus processing. RESULTS: Conventional analysis of fMRI data revealed significantly greater activation in response to the target stimuli (in comparison to the frequent stimuli) in several brain regions, including the intraparietal sulci and supramarginal gyri, the anterior and posterior cingulate gyri, the inferior and middle frontal gyri, the superior temporal sulcus, the precuneus/cuneus, and the subcortical grey matter (caudate and thalamus). The most extensive cortical activations were found in the right intraparietal sulcus (IPS), the anterior cingulate cortex (ACC), and the right lateral prefrontal cortex (PFC). These three regions were entered into the DCM. A comparison on a group level revealed that the dynamic causal models in which the ACC and alternatively the IPS served as input regions were superior to a model in which the PFC was assumed to receive external inputs. No significant difference was observed between the fully connected models with ACC and IPS as input regions. Subsequent analysis of the intrinsic connectivity within two investigated models (IPS and ACC) disclosed significant parallel forward connections from the IPS to the frontal areas and from the ACC to the PFC and the IPS. CONCLUSION: Our findings indicate that during target stimulus processing there is a bidirectional frontoparietal information flow, very likely reflecting parallel activation of two distinct but partially overlapping attentional or attentional/event-encoding neural systems. Additionally, a simple hierarchy within the right frontal lobe is suggested with the ACC exerting influence over the PFC.     

Esophageal Doppler-guided fluid management decreases blood lactate levels in multiple-trauma patients: a randomized controlled trial

Introduction  

Esophageal Doppler was confirmed as a useful non-invasive tool for management of fluid replacement in elective surgery. The aim of this study was to assess the effect of early optimization of intravascular volume using esophageal Doppler on blood lactate levels and organ dysfunction development in comparison with standard hemodynamic management in multiple-trauma patients.