Hydromorphone-3-glucuronide - A more potent neuro-excitant than its structural analogue, morphine-3-glucuronide

In humans, hydromorphone (HMOR) is metabolised principally by conjugation with glucuronic acid to form hydromorphone-3-glucuronide (H3G), a close structural analogue of morphine-3-glucuronide (M3G), the major metabolite of morphine. In a previous study we described the biochemical synthesis of H3G together with a preliminary evaluation of its pharmacology which revealed that it is a neuro-excitant in rats in a manner analogous to M3G. Thus the aims of the current study were to quantify the neuro-excitatory behaviours evoked by intracerebroventricular (icv) H3G in the rat and to define its potency relative to M3G. Groups of adult male Sprague-Dawley rats received icy injections (1 muL) of H3G (1 - 3 mug), M3G (2 - 7 mug) or vehicle via a stainless steel guide cannula that had been implanted stereotaxically seven days prior to drug administration. Behavioural excitation was monitored by scoring fifteen different behaviours (myoclonic jerks, chewing, wet-dog-shakes, rearing, tonic-clonic-convulsions, explosive motor behaviour, grooming, exploring, general activity, eating, staring, ataxia, righting reflex, body posture, touch evoked agitation) immediately prior to icy injection and at the following post-dosing times: 5, 15, 25, 35, 50, 65 and 80 min. H3G produced dose-dependent behavioural excitation in a manner analogous to that reported previously for M3G by our laboratory and reproduced herein. H3G was found to be approximately 2.5-fold more potent than M3G, such that the mean (+/- S.D.) ED50 values were 2.3 (+/- 0.1) mug and 6.1 (+/- 0.6) mug respectively. Thus, our data clearly imply that if H3G crosses the BBB with equivalent efficiency to M3G, then the myoclonus, allodynia and seizures observed in some patients dosed chronically with large systemic doses of HMOR, are almost certainly due to the accumulation of sufficient H3G in the central nervous system, to evoke behavioural excitation. (C) 2001 Elsevier Science Inc. All rights reserved.

Multi-threading and message communication in Qu-Prolog

This paper presents the multi-threading and internet message communication capabilities of Qu-Prolog. Message addresses are symbolic and the communications package provides high-level support that completely hides details of IP addresses and port numbers as well as the underlying TCP/IP transport layer. The combination of the multi-threads and the high level inter-thread message communications provide simple, powerful support for implementing internet distributed intelligent applications.

A refinement calculus for logic programs

Existing refinement calculi provide frameworks for the stepwise development of imperative programs from specifications. This paper presents a refinement calculus for deriving logic programs. The calculus contains a wide-spectrum logic programming language, including executable constructs such as sequential conjunction, disjunction, and existential quantification, as well as specification constructs such as general predicates, assumptions and universal quantification. A declarative semantics is defined for this wide-spectrum language based on executions. Executions are partial functions from states to states, where a state is represented as a set of bindings. The semantics is used to define the meaning of programs and specifications, including parameters and recursion. To complete the calculus, a notion of correctness-preserving refinement over programs in the wide-spectrum language is defined and refinement laws for developing programs are introduced. The refinement calculus is illustrated using example derivations and prototype tool support is discussed.

Catalytically active Dengue virus NS3 protease forms aggregates that are separable by size exclusion chromatography

An active form of the Dengue virus protease NS3 (CF40.Gly.NS3pro) was expressed in Escherichia coli. This construct consists of a critical 40 amino acid cofactor domain from NS2B fused to the N-terminal 184 amino acid protease domain of NS3 via a flexible, covalent linker (Gly(4)SerGly(4)). The recombinantly produced protein is soluble and has a hexa-histidine tag engineered at the N-terminus for ease of purification using metal affinity chromatography. However, the presence of lower molecular weight impurities after affinity chromatography indicated the need for additional purification steps. The consistent appearance of these impurities suggested that they may be the products of proteolysis and/or auto-proteolysis. The latter possibility was subsequently excluded by the observation of the same impurities in a purified, catalytically inactive form of the recombinant protease (CF40.Gly.NS3pro.SA). Further analysis indicated that these impurities may represent premature translation termination products. Regardless of their origin, they were shown to form various sized aggregates with full-length CF40.Gly.NS3pro that can be separated by size exclusion chromatography, yielding fractions of active protease of sufficient purity for crystallisation trials. The ultimate goal of these studies is to obtain a crystal structure of a catalytically active form of the Dengue virus NS3 protease for structure-based drug design. (C) 2002 Elsevier Science (USA). All rights reserved.

Linguistic evaluation method for the environmental assessment of infrastructure projects

A soft linguistic evaluation method is proposed for the environmental assessment of physical infrastructure projects based on fuzzy relations. Infrastructure projects are characterized in terms of linguistic expressions of 'performance' with respect to factors or impacts and the 'importance' of those factors/impacts. A simple example is developed to illustrate the method in the context of three road infrastructure projects assessed against five factors/impacts. In addition, a means to include hard or crisp factors is presented and illustrated with respect to a sixth factor.

API documentation with executable examples

The rise of component-based software development has created an urgent need for effective application program interface (API) documentation. Experience has shown that it is hard to create precise and readable documentation. Prose documentation can provide a good overview but lacks precision. Formal methods offer precision but the resulting documentation is expensive to develop. Worse, few developers have the skill or inclination to read formal documentation. We present a pragmatic solution to the problem of API documentation. We augment the prose documentation with executable test cases, including expected outputs, and use the prose plus the test cases as the documentation. With appropriate tool support, the test cases are easy to develop and read. Such test cases constitute a completely formal, albeit partial, specification of input/output behavior. Equally important, consistency between code and documentation is demonstrated by running the test cases. This approach provides an attractive bridge between formal and informal documentation. We also present a tool that supports compact and readable test cases; and generation of test drivers and documentation, and illustrate the approach with detailed case studies. (C) 2002 Elsevier Science Inc. All rights reserved.