Multiplex serum protein analysis reveals potential mechanisms and markers of response to hyperimmune caprine serum in systemic sclerosis

BACKGROUND: Hyperimmune caprine serum (HICS) is a novel biological therapy with potential benefit for skin in established diffuse cutaneous systemic sclerosis. Here we report multiplex protein analysis of blood samples from a placebo-controlled phase II clinical trial and explore mechanisms of action and markers of response. METHODS: Patients were treated with HICS (n = 10) or placebo (n = 10) over 26 weeks, with follow-up open-label treatment to 52 weeks in 14 patients. Serum or plasma samples at baseline, 26 and 52 weeks were analysed using multiplex or individual immunoassays for 41 proteins. Patterns of change were analysed by clustering using Netwalker 1.0, Pearson coefficient and significance analysis of microarrays (SAM) correction. RESULTS: Cluster analysis, SAM multiplex testing and paired comparison of individual analytes identified proteins that were upregulated or downregulated during treatment with HICS. There was upregulation of the hypothalamo-pituitary-adrenal axis after HICS treatment evidenced by increases in α-MSH and ACTH in cases treated with HICS. Interestingly, significant increase in PIIINP was associated with HICS treatment and improved MRSS suggesting that this may be a marker of extracellular matrix turnover. Other relevant factors reduced in HICS-treated patients compared with controls, although not reaching statistical significance included COMP, CCL2, IL6, TIMP2, Fractalkine and TGFβ1 levels. CONCLUSIONS: Our results suggest mechanisms of action for HICS, including upregulation of α-MSH, that has been shown to be anti-fibrotic in preclinical models, and possible markers to be included in future trials targeting skin in diffuse cutaneous systemic sclerosis. TRIAL REGISTRATION: Eudract, No. 2007-003122-24. ClinTrials.gov, No. NCT00769028 . Registered 7 October 2008

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

Synchronisation in trust management using push authorisation

Traditional trust management authorisation decisions for distributed technologies, are, in general, based on the history of the authorisations/computation to date. We consider this a pull authorisation strategy: the authorisation decision reflects the current and/or past authorisations. In this paper, we examine this pull strategy and propose an alternative form of authorisation in a distributed environment. Instead of ‘pulling ’ the information required for the current authorisation decisions from the past, authorisation decisions are made to specify what will happen in the future. This strategy is called push authorisation. When a push decision is made, its result is pushed to just the relevant protection mechanisms. This approach allows the creation of distributed separation of duties policies, without requiring additional synchronisation between components in the execution. It allows present actions to inform future authorisation decisions, before those decisions must be made

Abstract

This paper illustrates how hash-chain based micropayment schemes can be codified within the KeyNote Trust Management system. We describe an application of this scheme to the secure WebCom system, a distributed computation architecture. This supports micropayments made by servers to clients for computations performed and, payments by clients to servers for services. 1

Automating Security Configuration for the Grid

Administration of Grid resources is a time consuming and often tedious job. Most administrative requests are predictable, and in general, handling them requires knowledge of the local resources and the requester. In this paper we discuss a system to provide automated support for administrative requests, such as resource reservation and user account management. We propose using trust metrics to help judge the merits and suitability of each request. We outline how these metrics can be implemented using trust management techniques into a practical system we call GridAdmin

GridAdmin: Decentralising Grid administration Using Trust Management

Abstract — Administration of Grid resources is a time consuming and often tedious job. Most administrative requests are predictable, and in general, handling them requires knowledge of the local resources and the requester. In this paper we discuss a system to provide automated support for administrative requests, such as resource reservation and user account management. We propose using trust metrics to help judge the merits and suitability of each request. We outline how these metrics can be implemented using trust management techniques into a practical system we call GridAdmin