Synthesis and biological evaluation of nonpeptide mimetics of co-conotoxin GVIA

A benzothiazole-derived compound (4a) designed to mimic the C-alpha-C-beta bond vectors and terminal functionalities of Lys2, TyrI3 and Arg17 in omega-conotoxin GVIA was synthesised, together with analogues (4b-d), which had each side-chain mimic systematically truncated or eliminated. The affinity of these compounds for rat brain N-type and P/Q-type voltage gated calcium channels (VGCCs) was determined. In terms of N-type channel affinity and selectivity, two of these compounds (4a and 4d) were found to be highly promising, first generation mimetics of omega-conotoxin. The fully functionalised mimetic (4a) showed low PM binding affinity to N-type VGCCs (IC50 = 1.9 muM) and greater than 20-fold selectivity for this channel sub-type over P/Q-type VGCCs, whereas the mimetic in which the guanidine-type side chain was truncated back to an amine (4d, IC50 = 4.1 muM) showed a greater than 25-fold selectivity for the N-type channel. (C) 2004 Elsevier Ltd. All rights reserved.

Serious adverse events in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD)

Aims The study estimated serious adverse event (SAE) rates among entrants to pharmacotherapies for opioid dependence, during treatment and after leaving treatment. Design A longitudinal study based on data from 12 trials included in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD). Participants and settings A total of 1.244 heroin users and methadone patients treated in hospital, community and GP settings. Intervention Six trials included detoxification; all included treatment with methadone, buprenorphine, levo-alpha-acetyl-methadol (LAAM) or naltrexone. Findings During 394 person-years of observation, 79 SAEs of 28 types were recorded. Naltrexone participants experienced 39 overdoses per 100 person-years after leaving treatment (44% occurred within 2 weeks after stopping naltrexone). This was eight times the rate recorded among participants who left agonist treatment. Rates of all other SAEs were similar during treatment versus out of treatment, for both naltrexone-treated and agonist-treated participants. Five deaths occurred, all among participants who had left treatment, at a rate of six per 100 person-years. Total SAE rates during naltrexone and agonist treatments were similar (20, 14 per 100 person-years, respectively). Total SAE and death rates observed among participants who had left treatment were three and 19 times the corresponding rates during treatment. Conclusions Individuals who leave pharmacotherapies for opioid dependence experience higher overdose and death rates compared with those in treatment. This may be due partly to a participant self-selection effect rather than entirely to pharmacotherapy being protective. Clinicians should alert naltrexone treatment patients in particular about heroin overdose risks. Duty of care may extend beyond cessation of dosing.

Petrology and geochemistry of early cretaceous bimodal continental flood volcanism of the NW Etendeka, Namibia. Part 1: Introduction, mafic lavas and re-evaluation of mantle source components

The bimodal NW Etendeka province is located at the continental end of the Tristan plume trace in coastal Namibia. It comprises a high-Ti (Khumib type) and three low-Ti basalt (Tafelberg, Kuidas and Esmeralda types) suites, with, at stratigraphically higher level, interstratified high-Ti latites (three units) and quartz latites (five units), and one low-Ti quartz latite. Khumib basalts are enriched in high field strength elements and light rare earth elements relative to low-Ti types and exhibit trace element affinities with Tristan da Cunha lavas. The unradiogenic Pb-206/Pb-204 ratios of Khumib basalts are distinctive, most plotting to the left of the 132 Ma Geochron, together with elevated Pb-207/Pb-204 ratios, and Sr-Nd isotopic compositions plotting in the lower Nd-143/Nd-144 part of mantle array (EM1-like). The low-Ti basalts have less coherent trace element patterns and variable, radiogenic initial Sr (similar to0.707-0.717) and Pb isotope compositions, implying crustal contamination. Four samples, however, have less radiogenic Pb and Sr that we suggest approximate their uncontaminated source. All basalt types, but particularly the low-Ti types, contain samples with trace element characteristics (e.g. Nb/Nb-*) suggesting metasediment input, considered source-related. Radiogenic isotope compositions of these samples require long-term isolation of the source in the mantle and depletions (relative to unmodified sediment) in certain elements (e.g. Cs, Pb, U), which are possibly subduction-related. A geodynamic model is proposed in which the emerging Tristan plume entrained subducted material in the Transition Zone region, and further entrained asthenosphere during plume head expansion. Mixing calculations suggest that the main features of the Etendeka basalt types can be explained without sub-continental lithospheric mantle input. Crustal contamination is evident in most low-Ti basalts, but is distinct from the incorporation of a metasedimentary source component at mantle depths.

International evaluation of current and future requirements for environmental engineering education

The field of environmental engineering is developing as a result of changing environmental requirements. In response, environmental engineering education (E3) needs to ensure that it provides students with the necessary tools to address these challenges. In this paper the current status and future development of E3 is evaluated based on a questionnaire sent to universities and potential employers of E3 graduates. With increasing demands on environmental quality, the complexity of environmental engineering problems to be solved can be expected to increase. To find solutions environmental engineers will need to work in interdisciplinary teams. Based on the questionnaire there was a broad agreement that the best way to prepare students for these future challenges is to provide them with a fundamental education in basic sciences and related engineering fields. Many exciting developments in the environmental engineering profession will be located at the interface between engineering, science, and society. Aspects of all three areas need to be included in E3 and the student needs to be exposed to the tensions associated with linking the three.

The evaluation of the spatial and temporal stability of sugarcane farm performance based on yield and commercial cane sugar

In broader catchment scale investigations, there is a need to understand and ultimately exploit the spatial variation of agricultural crops for an improved economic return. In many instances, this spatial variation is temporally unstable and may be different for various crop attributes and crop species. In the Australian sugar industry, the opportunity arose to evaluate the performance of 231 farms in the Tully Mill area in far north Queensland using production information on cane yield (t/ha) and CCS ( a fresh weight measure of sucrose content in the cane) accumulated over a 12-year period. Such an arrangement of data can be expressed as a 3-way array where a farm x attribute x year matrix can be evaluated and interactions considered. Two multivariate techniques, the 3-way mixture method of clustering and the 3-mode principal component analysis, were employed to identify meaningful relationships between farms that performed similarly for both cane yield and CCS. In this context, farm has a spatial component and the aim of this analysis was to determine if systematic patterns in farm performance expressed by cane yield and CCS persisted over time. There was no spatial relationship between cane yield and CCS. However, the analysis revealed that the relationship between farms was remarkably stable from one year to the next for both attributes and there was some spatial aggregation of farm performance in parts of the mill area. This finding is important, since temporally consistent spatial variation may be exploited to improve regional production. Alternatively, the putative causes of the spatial variation may be explored to enhance the understanding of sugarcane production in the wet tropics of Australia.

Encouraging practitioners to use resources: evaluation of the national implementation of a resource to improve the clinical management of alcohol-related problems in Indigenous primary care settings

This paper reports on the evaluation of the implementation of the National Recommendations for the Clinical Management of Alcohol-Related Problems in Indigenous Primary Care Settings undertaken in 2001 through 74 standardized workshops, which sought to determine: ( 1) whether this approach to implementation influenced the likelihood that the National Recommendations would be used; ( 2) whether it influenced participants' willingness to engage with Indigenous patients regarding alcohol-related issues; and ( 3) whether the implementation as a whole influenced both practice and clinicians' willingness to engage. Evaluation included pre-/post-workshop and follow-up questionnaires and a focus group. The findings presented indicate that distribution of clinical resources alone is not sufficient to ensure use and that, particularly for medical practitioners, appropriate introduction not only increases use but also positively influences willingness to engage with alcohol-related problems as part of primary clinical care. Further, the enthusiasm for guideline production should be tempered by the need to develop effective implementation strategies.

Field evaluation of a novel colorimetric method - Double-site enzyme-linked lactate dehydrogenase immunodetection assay - To determine drug susceptibilities of Plasmodium falciparum clinical isolates from northwestern Thailand

A double-site enzyme-linked lactate dehydrogenase enzyme inummodetection assay was tested against field isolates of Plasmodium falciparum for assessing in vitro drug susceptibilities to a wide range of antimalarial drugs. Its sensitivity allowed the use of parasite densities as low as 200 parasites/mul of blood. Being a nonisotopic, colorimetric assay, it lies within the capabilities of a modest laboratory at the district level.

Ontological evaluation of enterprise systems interoperability using ebXML

Enterprise systems interoperability (ESI) is an important topic for business currently. This situation is evidenced, at least in part, by the number and extent of potential candidate protocols for such process interoperation, viz., ebXML, BPML, BPEL, and WSCI. Wide-ranging support for each of these candidate standards already exists. However, despite broad acceptance, a sound theoretical evaluation of these approaches has not yet been provided. We use the Bunge-Wand-Weber (BWW) models, in particular, the representation model, to provide the basis for such a theoretical evaluation. We, and other researchers, have shown the usefulness of the representation model for analyzing, evaluating, and engineering techniques in the areas of traditional and structured systems analysis, object-oriented modeling, and process modeling. In this work, we address the question, what are the potential semantic weaknesses of using ebXML alone for process interoperation between enterprise systems? We find that users will lack important implementation information because of representational deficiencies; due to ontological redundancy, the complexity of the specification is unnecessarily increased; and, users of the specification will have to bring in extra-model knowledge to understand constructs in the specification due to instances of ontological excess.