Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels

Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA

Theory of the NO+CO surface reaction model

We derive a pair approximation (PA) for the NO+CO model with instantaneous reactions. For both the triangular and square lattices, the PA, derived here using a simpler approach, yields a phase diagram with an active state for CO-fractions y in the interval y_1 < y < y_2, with a continuous (discontinuous) phase transition to a poisoned state at y_1 (y_2). This is in qualitative agreement with simulation for the triangular lattice, where our theory gives a rather accurate prediction for y_2. To obtain the correct phase diagram for the square lattice, i.e., no active state, we reformulate the PA using sublattices. The (formerly) active regime is then replaced by a poisoned state with broken symmetry (unequal sub- lattice coverages), as observed recently by Kortluke et al. [Chem. Phys. Lett. 275, 85 (1997)]. In contrast with their approach, in which the active state persists, although reduced in extent, we report here the first qualitatively correct theory of the NO+CO model on the square lattice. Surface diffusion of nitrogen can lead to an active state in this case. In one dimension, the PA predicts that diffusion is required for the existence of an active state.Comment: 15 pages, 9 figure

Defining malnutrition: a plea to rethink

In a recent consensus report in Clinical Nutrition the undernourished category of malnutrition was proposed to be defined and diagnosed on the basis of a low BMI or unintentional weight loss combined with low BMI or FFMI with certain cut off points. The definition was endorsed by ESPEN despite recent endorsement of a very different definition. The approach aims to assess whether nutritional intake is sufficient but is imprecise because a low BMI does not always indicate malnutrition and individuals with increasing BMI's may have decreasing FFM's. The pathophysiology of individuals, considered to be malnourished in rich countries and in areas with endemic malnutrition, results predominantly from deficient nutrition combined with infection/inflammation. Both elements jointly determine body composition and function and consequently outcome of disease, trauma or treatment. When following the consensus statement only an imprecise estimate is acquired of nutritional intake without knowing the impact of inflammation. Most importantly, functional abilities are not assessed. Consequently it will remain uncertain how well the individual can overcome stressful events, what the causes are of dysfunction, how to set priorities for treatment and how to predict the effect of nutritional support. We therefore advise to consider the pathophysiology of malnourished individuals leading to inclusion of the following elements in the definition of malnutrition: a disordered nutritional state resulting from a combination of inflammation and a negative nutrient balance, leading to changes in body composition, function and outcome. A precise diagnosis of malnutrition should be based on assessment of these element

The nebular spectrum of the type Ia supernova 2003hv: evidence for a non-standard event

The optical and near-infrared late-time spectrum of the under-luminous Type Ia supernova 2003hv is analysed with a code that computes nebular emission from a supernova nebula. Synthetic spectra based on the classical explosion model W7 are unable to reproduce the large \FeIII/\FeII\ ratio and the low infrared flux at $\sim 1$ year after explosion, although the optical spectrum of SN\,2003hv is reproduced reasonably well for a supernova of luminosity intermediate between normal and subluminous (SN\,1991bg-like) ones. A possible solution is that the inner layers of the supernova ejecta (v \lsim 8000\,\kms) contain less mass than predicted by classical explosion models like W7. If this inner region contains \sim 0.5 \Msun of material, as opposed to \sim 0.9 \Msun in Chandrasekhar-mass models developed within the Single Degenerate scenario, the low density inhibits recombination, favouring the large \FeIII/\FeII\ ratio observed in the optical, and decreases the flux in the \FeII\ lines which dominate the IR spectrum. The most likely scenario may be an explosion of a sub-Chandrasekhar mass white dwarf. Alternatively, the violent/dynamical merger of two white dwarfs with combined mass exceeding the Chandrasekhar limit also shows a reduced inner density.Comment: MNRAS, in pres

Converting simulated total dry matter to fresh marketable yield for field vegetables at a range of nitrogen supply levels

Simultaneous analysis of economic and environmental performance of horticultural crop production requires qualified assumptions on the effect of management options, and particularly of nitrogen (N) fertilisation, on the net returns of the farm. Dynamic soil-plant-environment simulation models for agro-ecosystems are frequently applied to predict crop yield, generally as dry matter per area, and the environmental impact of production. Economic analysis requires conversion of yields to fresh marketable weight, which is not easy to calculate for vegetables, since different species have different properties and special market requirements. Furthermore, the marketable part of many vegetables is dependent on N availability during growth, which may lead to complete crop failure under sub-optimal N supply in tightly calculated N fertiliser regimes or low-input systems. In this paper we present two methods for converting simulated total dry matter to marketable fresh matter yield for various vegetables and European growth conditions, taking into consideration the effect of N supply: (i) a regression based function for vegetables sold as bulk or bunching ware and (ii) a population approach for piecewise sold row crops. For both methods, to be used in the context of a dynamic simulation model, parameter values were compiled from a literature survey. Implemented in such a model, both algorithms were tested against experimental field data, yielding an Index of Agreement of 0.80 for the regression strategy and 0.90 for the population strategy. Furthermore, the population strategy was capable of reflecting rather well the effect of crop spacing on yield and the effect of N supply on product grading

Paramedic clinical decision making during high acuity emergency calls: design and methodology of a Delphi study

<p>Abstract</p> <p>Background</p> <p>The scope of practice of paramedics in Canada has steadily evolved to include increasingly complex interventions in the prehospital setting, which likely have repercussions on clinical outcome and patient safety. Clinical decision making has been evaluated in several health professions, but there is a paucity of work in this area on paramedics. This study will utilize the Delphi technique to establish consensus on the most important instances of paramedic clinical decision making during high acuity emergency calls, as they relate to clinical outcome and patient safety.</p> <p>Methods and design</p> <p>Participants in this multi-round survey study will be paramedic leaders and emergency medical services medical directors/physicians from across Canada. In the first round, participants will identify instances of clinical decision making they feel are important for patient outcome and safety. On the second round, the panel will rank each instance of clinical decision making in terms of its importance. On the third and potentially fourth round, participants will have the opportunity to revise the ranking they assigned to each instance of clinical decision making. Consensus will be considered achieved for the most important instances if 80% of the panel ranks it as important or extremely important. The most important instances of clinical decision making will be plotted on a process analysis map.</p> <p>Discussion</p> <p>The process analysis map that results from this Delphi study will enable the gaps in research, knowledge and practice to be identified.</p

Methodology for the development of a Canadian national EMS research agenda

<p>Abstract</p> <p>Background</p> <p>Many health care disciplines use evidence-based decision making to improve patient care and system performance. While the amount and quality of emergency medical services (EMS) research in Canada has increased over the past two decades, there has not been a unified national plan to enable research, ensure efficient use of research resources, guide funding decisions and build capacity in EMS research. Other countries have used research agendas to identify barriers and opportunities in EMS research and define national research priorities. The objective of this project is to develop a national EMS research agenda for Canada that will: 1) explore what barriers to EMS research currently exist, 2) identify current strengths and opportunities that may be of benefit to advancing EMS research, 3) make recommendations to overcome barriers and capitalize on opportunities, and 4) identify national EMS research priorities.</p> <p>Methods/Design</p> <p>Paramedics, educators, EMS managers, medical directors, researchers and other key stakeholders from across Canada will be purposefully recruited to participate in this mixed methods study, which consists of three phases: 1) qualitative interviews with a selection of the study participants, who will be asked about their experience and opinions about the four study objectives, 2) a facilitated roundtable discussion, in which all participants will explore and discuss the study objectives, and 3) an online Delphi consensus survey, in which all participants will be asked to score the importance of each topic discovered during the interviews and roundtable as they relate to the study objectives. Results will be analyzed to determine the level of consensus achieved for each topic.</p> <p>Discussion</p> <p>A mixed methods approach will be used to address the four study objectives. We anticipate that the keys to success will be: 1) ensuring a representative sample of EMS stakeholders, 2) fostering an open and collaborative roundtable discussion, and 3) adhering to a predefined approach to measure consensus on each topic. Steps have been taken in the methodology to address each of these <it>a priori </it>concerns.</p

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Trust, control and knowledge transfer in small business networks

The ability to transfer knowledge effectively in the networks of small and medium-sized firms (SMEs) is paramount for supporting firm competitiveness. Our research is the first one that explores the joint effect of trust and control mechanisms on knowledge transfer in the case of networks of SMEs. We use a multiple case study approach based on six Italian networks of SMEs. We analyse the joint impact of different ethical based trustworthiness factors—namely benevolence and integrity—and the levers of control (LOCs)—namely, belief, boundary, diagnostic and interactive LOCs—on knowledge transfer between SMEs in networks. We find that trust substitutes for the implementation of boundary, diagnostic, and belief tools, while it works jointly with interactive tools in order to support knowledge transfer. These insights not only provide a rich foundation for follow-up research, but also inform SME managers about how to increase the effectiveness and efficiency of knowledge transfer with their network partners