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

Design Thinking for Cyber Deception

Cyber deception tools are increasingly sophisticated but rely on a limited set of deception techniques. In current deployments of cyber deception, the network infrastructure between the defender and attacker comprises the defence/attack surface. For cyber deception tools and techniques to evolve further they must address the wider attack surface; from the network through to the physical and cognitive space. One way of achieving this is by fusing deception techniques from the physical and cognitive space with the technology development process. In this paper we trial design thinking as a way of delivering this fused approach. We detail the results from a design thinking workshop conducted using deception experts from different fields. The workshop outputs include a critical analysis of design provocations for cyber deception and a journey map detailing considerations for operationalising cyber deception scenarios that fuse deception techniques from other contexts. We conclude with recommendations for future research

The role of policy in shielding, nurturing and enabling offshore wind in The Netherlands (1973–2013)

It is widely acknowledged that many renewable energy technologies cannot (yet) compete with incumbent (fossil fuel) options e.g. in terms of price. Transitions literature argues that sustainable innovations can nevertheless break out of their ‘niches’ if properly shielded, nurtured and empowered. Most studies using this perspective have focused on how innovation champions engage in shielding, nurturing and empowering (SNE) activities: none have so far focused specifically on the role that policy plays in relation to these three processes. This paper therefore aims to analyze the way in which policy constrains and enables the shielding, nurturing and empowering of renewable energy innovations. To do so, it presents a qualitative review of the development of offshore wind power (OWP) in The Netherlands over the past four decades. Based on interpretation of a wide variety of written sources (academic histories, reports, policy documents, parliamentary debate transcripts, news media) and nine semi-structured interviews, it discerns six periods of relative stability in the history of Dutch offshore wind. It then analyzes the effects of various policies on the shielding, nurturing and empowering of offshore wind in these periods. The paper contributes to transitions literature (1) by providing an analysis of how policies can enable and constrain the shielding, nurturing and empowering of renewable energy innovations, and (2) by bringing together, for the first time, fragmented accounts of the surprisingly long history of Dutch offshore wind development and implementation. Both contributions are timely, given the recent reprioritization of OWP on the Dutch policy agenda

Role of Acetaldehyde in Ethanol Reversal of Tolerance to Morphine-Induced Respiratory Depression in Mice

BACKGROUND: Opioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol rapidly reverses tolerance to morphine-induced respiratory depression. However, recent research has suggested that the primary metabolite of ethanol, acetaldehyde, may play a key role in mediating the CNS effects seen after ethanol consumption. This research investigated the role of acetaldehyde in ethanol reversal of tolerance to morphine-induced respiratory depression. METHODS: Tolerance was induced in mice by 6-days implantation of a 75 mg morphine pellet with control mice implanted with a placebo pellet. Tolerance was assessed by acute morphine administration on day 6 and respiration measured by plethysmography. Levels of acetaldehyde were inhibited or enhanced by pre-treatments with the acetaldehyde chelator D-penicillamine and the inhibitor of acetaldehyde dehydrogenase disulfiram respectively. RESULTS: Morphine pellet implanted mice displayed tolerance to an acute dose of morphine compared to placebo pellet implanted controls. Acute acetaldehyde administration dose-dependently reversed tolerance to morphine respiratory depression. As previously demonstrated, ethanol reversed morphine tolerance, and this was inhibited by D-penicillamine pre-treatment. An acute, low dose of ethanol that did not significantly reverse morphine tolerance was able to do so following disulfiram pre-treatment. CONCLUSION: These data suggest that acetaldehyde, the primary metabolite of ethanol, is responsible for the reversal of morphine tolerance observed following ethanol administration

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations

Developing Engineering Model Cobra fiber positioners for the Subaru Telescope's Prime Focus Spectrometer

The Cobra fiber positioner is being developed by the California Institute of Technology (CIT) and the Jet Propulsion Laboratory (JPL) for the Prime Focus Spectrograph (PFS) instrument that will be installed at the Subaru Telescope on Mauna Kea, Hawaii. PFS is a fiber fed multi-object spectrometer that uses an array of Cobra fiber positioners to rapidly reconfigure 2394 optical fibers at the prime focus of the Subaru Telescope that are capable of positioning a fiber to within 5μm of a specified target location. A single Cobra fiber positioner measures 7.7mm in diameter and is 115mm tall. The Cobra fiber positioner uses two piezo-electric rotary motors to move a fiber optic anywhere in a 9.5mm diameter patrol area. In preparation for full-scale production of 2550 Cobra positioners an Engineering Model (EM) version was developed, built and tested to validate the design, reduce manufacturing costs, and improve system reliability. The EM leveraged the previously developed prototype versions of the Cobra fiber positioner. The requirements, design, assembly techniques, development testing, design qualification and performance evaluation of EM Cobra fiber positioners are described here. Also discussed is the use of the EM build and test campaign to validate the plans for full-scale production of 2550 Cobra fiber positioners scheduled to begin in late-2014

Design thinking for cyber deception

Cyber deception tools are increasingly sophisticated but rely on a limited set of deception techniques. In current deployments of cyber deception, the network infrastructure between the defender and attacker comprises the defence/attack surface. For cyber deception tools and techniques to evolve further they must address the wider attack surface; from the network through to the physical and cognitive space. One way of achieving this is by fusing deception techniques from the physical and cognitive space with the technology development process. In this paper we trial design thinking as a way of delivering this fused approach. We detail the results from a design thinking workshop conducted using deception experts from different fields. The workshop outputs include a critical analysis of design provocations for cyber deception and a journey map detailing considerations for operationalising cyber deception scenarios that fuse deception techniques from other contexts. We conclude with recommendations for future research