Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Balancing Organizational Regulation and Agent Autonomy: An MDE-Based Approach

The deployment of agent societies —as complex systems— in dynamic and unpredictable settings brings forth critical issues concerning their design. Organizational models have been advocated to specify open systems in dynamic environments in order to accomplish the need to represent regulating structures explicitly and independently from acting components (or agents). Despite the fact that several frameworks have been proposed for the specification of organizational models, it is still a matter of design choice how to balance between regulative design and component flexibility. We propose a design framework, discussing the advantages of having different degrees of abstraction at organizational level in the development of agent societies. That is, we illustrate how the design properties impact the flexibility of run-time systems to cope with context changes. We adopt the OperA software engineering methodology to deal with the organizational model specification, and the Model Driven Engineering (MDE) mechanisms to map concepts between different design models

Strategies for avoiding preference profiling in agent-based e-commerce environments

Agent-based electronic commerce is known to offer many advantages to users. However, very few studies have been devoted to deal with privacy issues in this domain. Nowadays, privacy is of great concern and preserving users' privacy plays a crucial role to promote their trust in agent-based technologies. In this paper, we focus on preference profiling, which is a well-known threat to users' privacy. Specifically, we review strategies for customers' agents to prevent seller agents from obtaining accurate preference proles of the former group by using data mining techniques. We experimentally show the efficacy of each of these strategies and discuss their suitability in different situations. Our experimental results show that customers can improve their privacy notably with these strategies

Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome

Objective. Tumor necrosis factor receptor (TNFR) -associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory condition caused by mutations in the TNFRSFIA gene. Unlike other autoinflammatory diseases in which anti-TNF therapy is largely a successful treatment option, therapy with the anti-TNF drug infliximab is often ineffective in patients with TRAPS. Moreover, in certain cases, infliximab actually triggers severe episodes of inflammation. The aim of this study was to elucidate the mechanisms underlying such a reaction. Methods. Peripheral blood mononuclear cells (PBMCs) were obtained from patients with TRAPS. Both caspase 3 activity and NF-kappa B subunit activity were determined by enzyme-linked immunosorbent assay. Cytokine secretion was assessed using a specific customized human multiplex bead immunoassay kit. Results. Unlike findings in controls, cells from a family of 9 patients, all of whom carried the T50M mutation in TNFRSFIA, failed to respond to infliximab through proapoptotic induction of caspase 3 activity. Instead, we observed enhanced antiapoptotic c-Rel subunit activity, accompanied by a significant increase in secretion of the proinflammatory cytokines interleukin-1 beta (IL-1 beta), IL-1 receptor, IL-6, IL-8, and IL-12. Conclusion. Altered extracellular conformation of TNFRI, resulting from the T50M mutation in TNFRSFIA, results in failure of PBMCs to induce an apoptotic response to infliximab. We hypothesize that failure to shed infliximab-bound TNF/TNFRI from the cell surface of cells from patients with the T50M mutation triggers c-Rel activation, and that this leads to a marked increase in cytokine secretion and an increased proinflammatory response. In light of these findings, we strongly advise caution when prescribing infliximab as anti-TNF therapy to patients with TRAPS

Compositional data analysis as a robust tool to delineate hydrochemical facies within and between gas-bearing aquifers

Isometric log ratios of proportions of major ions, derived from intuitive sequential binary partitions, are used to characterize hydrochemical variability within and between coal seam gas (CSG) and surrounding aquifers in a number of sedimentary basins in the USA and Australia. These isometric log ratios are the coordinates corresponding to an orthonormal basis in the sample space (the simplex). The characteristic proportions of ions, as described by linear models of isometric log ratios, can be used for a mathematical-descriptive classification of water types. This is a more informative and robust method of describing water types than simply classifying a water type based on the dominant ions. The approach allows (a) compositional distinctions between very similar water types to be made and (b) large data sets with a high degree of variability to be rapidly assessed with respect to particular relationships/compositions that are of interest. A major advantage of these techniques is that major and minor ion components can be comprehensively assessed and subtle processes-which may be masked by conventional techniques such as Stiff diagrams, Piper plots, and classic ion ratios-can be highlighted. Results show that while all CSG groundwaters are dominated by Na, HCO3, and Cl ions, the proportions of other ions indicate they can evolve via different means and the particular proportions of ions within total or subcompositions can be unique to particular basins. Using isometric log ratios, subtle differences in the behavior of Na, K, and Cl between CSG water types and very similar Na-HCO3 water types in adjacent aquifers are also described. A complementary pair of isometric log ratios, derived from a geochemically-intuitive sequential binary partition that is designed to reflect compositional variability within and between CSG groundwater, is proposed. These isometric log ratios can be used to model a hydrochemical pathway associated with methanogenesis and/or to delineate groundwater associated with high gas concentrations

ALIVE:a framework for flexible and adaptive service coordination

There is a large body of research on software services, but the issues of communication and dynamic reconfiguration have received little attention, as have adaptation to environment and dynamic combination of service building blocks into new applications. Here, we present the approach of the FP7 alive project to the use of formal models of coordination and organisation mechanisms to deliver a flexible, high-level means to describe the structure of interactions between services in the environment. Our aim is to create a framework for services engineering for “live” open systems of active services. We propose to build on the current activities in service-oriented engineering by defining three levels: (i) An organisational level models the organisational structure of executing and interlinked services and the context around them. (ii) A coordination level provides flexible ways to model interaction between the services. (iii) These two levels connect with existing (semantic) Web services, which contain semantic descriptions to make components aware of their social context and of the rules of engagement with other services