Molecular classification of cutaneous malignant melanoma by gene expression profiling

The most common human cancers are malignant neoplasms of the skin(1,2). Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease(3,4). Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm(2,3). Accordingly, though melanoma is thought to present with different 'taxonomic' forms, these are considered part of a continuous spectrum rather than discrete entities(2). Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas(5). Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.

Binding of an RNA trafficking response element to heterogeneous nuclear ribonucleoproteins A1 and A2

Heterogeneous nuclear ribonucleoprotein (hnRNP) A2 binds a 21-nucleotide myelin basic protein mRNA response element, the A2RE, and A2RE-like sequences in other localized mRNAs, and is a trans-acting factor in oligodendrocyte cytoplasmic RNA trafficking. Recombinant human hnRNPs A1 and A2 were used in a biosensor to explore interactions with A2RE and the cognate oligodeoxyribonucleotide. Both proteins have a single site that bound oligonucleotides with markedly different sequences but did not bind in the presence of heparin. Both also possess a second, specific site that bound only A2RE and was unaffected by heparin, hnRNP A2 bound A2RE in the latter site with a K-d near 50 nM, whereas the K-d for hnRNP A1 was above 10 muM. UV cross-linking assays led to a similar conclusion. Mutant A2RE sequences, that in earlier qualitative studies appeared not to bind hnRNP A2 or support RNA trafficking in oligodendrocytes, had dissociation constants above 5 muM for this protein. The two concatenated RNA recognition motifs (RRMs), but not the individual RRMs, mimicked the binding behavior of hnRNP A2. These data highlight the specificity of the interaction of A2RE with these hnRNPs and suggest that the sequence-specific A2RE-binding site on hnRNP A2 is formed by both RRMs acting in cis.

Evaluating corporate performance:a critique of economic value added

There has been a revival of interest in economic techniques to measure the value of a firm through the use of economic value added as a technique for measuring such value to shareholders. This technique, based upon the concept of economic value equating to total value, is founded upon the assumptions of classical liberal economic theory. Such techniques have been subject to criticism both from the point of view of the level of adjustment to published accounts needed to make the technique work and from the point of view of the validity of such techniques in actually measuring value in a meaningful context. This paper critiques economic value added techniques as a means of calculating changes in shareholder value, contrasting such techniques with more traditional techniques of measuring value added. It uses the company Severn Trent plc as an actual example in order to evaluate and contrast the techniques in action. The paper demonstrates discrepancies between the calculated results from using economic value added analysis and those reported using conventional accounting measures. It considers the merits of the respective techniques in explaining shareholder and managerial behaviour and the problems with using such techniques in considering the wider stakeholder concept of value. It concludes that this economic value added technique has merits when compared with traditional accounting measures of performance but that it does not provide the universal panacea claimed by its proponents.

The pharmacist's contribution towards monitoring and reporting adverse drug reactions

The activities and function of the West Midlands Adverse Drug Reaction Study Group are described. The impact of the Group on the reporting of adverse drug reactions to the CSM by the yellow card system has been evaluated in several ways including a comparison with the Trent Region. The role of the pharmacist in the Group is highlighted. A nationwide survey of the hospital pharmacist's involvement in adverse drug reaction reporting and monitoring is described, the results are reported and discussed. The available sources of information on adverse drug reactions, both primary and secondary, are critically reviewed. A checklist of necessary details for case reports is developed and examples of problems in the literature are given. The contribution of the drug information pharmacist in answering enquiries and encouraging reporting is examined. A role for the ward pharmacist in identifying, reporting, documenting and following up adverse drug reactions is proposed. Studies conducted to support this role are described and the results discussed. The ward pharmacist's role in preventing adverse drug reactions is also outlined. The reporting of adverse drug reactions in Australia is contrasted with the U.K. and particular attention is drawn to the pharmacist's contribution in the former. The problems in evaluating drug safety are discussed and examples are given where serious reactions have only been recognised after many patients have been exposed. To remedy this situation a case is made for enhancing the CSM yellow card scheme by further devolution of reporting, increasing the involvement of pharmacists and improving arrangements at the CSM. It is proposed that pharmacists should undertake the responsibility for reporting reactions to the CSM in some instances.

The application of artificial neural networks to the interpretation and classification of freshwater benthic invertebrate communities

This thesis presents a thorough and principled investigation into the application of artificial neural networks to the biological monitoring of freshwater. It contains original ideas on the classification and interpretation of benthic macroinvertebrates, and aims to demonstrate their superiority over the biotic systems currently used in the UK to report river water quality. The conceptual basis of a new biological classification system is described, and a full review and analysis of a number of river data sets is presented. The biological classification is compared to the common biotic systems using data from the Upper Trent catchment. This data contained 292 expertly classified invertebrate samples identified to mixed taxonomic levels. The neural network experimental work concentrates on the classification of the invertebrate samples into biological class, where only a subset of the sample is used to form the classification. Other experimentation is conducted into the identification of novel input samples, the classification of samples from different biotopes and the use of prior information in the neural network models. The biological classification is shown to provide an intuitive interpretation of a graphical representation, generated without reference to the class labels, of the Upper Trent data. The selection of key indicator taxa is considered using three different approaches; one novel, one from information theory and one from classical statistical methods. Good indicators of quality class based on these analyses are found to be in good agreement with those chosen by a domain expert. The change in information associated with different levels of identification and enumeration of taxa is quantified. The feasibility of using neural network classifiers and predictors to develop numeric criteria for the biological assessment of sediment contamination in the Great Lakes is also investigated.

Clogging in horizontal subsurface flow constructed wetlands

Horizontal Subsurface Flow Treatment Wetlands (HSSF TWs) are used by Severn Trent Water as a low-cost tertiary wastewater treatment for rural locations. Experience has shown that clogging is a major operational problem that reduces HSSF TW lifetime. Clogging is caused by an accumulation of secondary wastewater solids from upstream processes and decomposing leaf litter. Clogging occurs as a sludge layer where wastewater is loaded on the surface of the bed at the inlet. Severn Trent systems receive relatively high hydraulic loading rates, which causes overland flow and reduces the ability to mineralise surface sludge accumulations. A novel apparatus and method, the Aston Permeameter, was created to measure hydraulic conductivity in situ. Accuracy is ±30 %, which was considered adequate given that conductivity in clogged systems varies by several orders of magnitude. The Aston Permeameter was used to perform 20 separate tests on 13 different HSSF TWs in the UK and the US. The minimum conductivity measured was 0.03 m/d at Fenny Compton (compared with 5,000 m/d clean conductivity), which was caused by an accumulation of construction fines in one part of the bed. Most systems displayed a 2 to 3 order of magnitude variation in conductivity in each dimension. Statistically significant transverse variations in conductivity were found in 70% of the systems. Clogging at the inlet and outlet was generally highest where flow enters the influent distribution and exits the effluent collection system, respectively. Surface conductivity was lower in systems with dense vegetation because plant canopies reduce surface evapotranspiration and decelerate sludge mineralisation. An equation was derived to describe how the water table profile is influenced by overland flow, spatial variations in conductivity and clogging. The equation is calibrated using a single parameter, the Clog Factor (CF), which represents the equivalent loss of porosity that would reproduce measured conductivity according to the Kozeny-Carman Equation. The CF varies from 0 for ideal conditions to 1 for completely clogged conditions. Minimum CF was 0.54 for a system that had recently been refurbished, which represents the deviation from ideal conditions due to characteristics of non-ideal media such as particle size distribution and morphology. Maximum CF was 0.90 for a 15 year old system that exhibited sludge accumulation and overland flow across the majority of the bed. A Finite Element Model of a 15 m long HSSF TW was used to indicate how hydraulics and hydrodynamics vary as CF increases. It was found that as CF increases from 0.55 to 0.65 the subsurface wetted area increases, which causes mean hydraulic residence time to increase from 0.16 days to 0.18 days. As CF increases from 0.65 to 0.90, the extent of overland flow increases from 1.8 m to 13.1 m, which reduces hydraulic efficiency from 37 % to 12 % and reduces mean residence time to 0.08 days.

Does audit improve quality in a hospital manufacturing unit?

OBJECTIVE - To establish whether auditing improves the overall quality of a hospital manufacturing unit. DESIGN - Continuous assessment of the quality level of a hospital manufacturing unit using 14 quality indicators over a nine-month period, and two periods of audit carried out towards the beginning and end of the assessment period. SETTING - The non-sterile manufacturing, sterile manufacturing and repackaging services areas at the pharmacy manufacturing unit at Queens Hospital, Burton-on- Trent. RESULTS - Compliance ratings for the second audit were better than those for the first audit, but there was no overall improvement in quality over the study period. CONCLUSION - Auditing probably improves compliance by focusing the minds of the staff involved, rather than by initiating a sustained improvement in overall quality.

The words of God: Religious texts and the Counter -Reformation in the Spanish world

This dissertation analyzes a variety of religious texts such as catechisms, confession manuals, ecclesiastical legislation, saints' lives, and sermons to determine the definitions of orthodoxy held by the Spanish clergy and the origins of such visions. The conclusion posited by this research was that there was a definite continuity between the process of Catholic reform in Spain and the process of Catholic expansion into the New World in that the objectives and concerns of the Spanish clergy in Europe and the New World were very similar. This dissertation also analyzes sources that predated the Council of Trent and demonstrates that within the Iberian context the Council of Trent cannot be used as a starting date for the attempts at Catholic reform. In essence, this work concludes the Spanish clergy's activities were influenced by humanist concepts of models and model behaviour which is reflected in their attempt to form model Catholics in Spain and the New World and in their impulse to produce written texts as standards. ^

Compilation of growth rate data for marine pelagic organisms

The metabolic rate of organisms may either be viewed as a basic property from which other vital rates and many ecological patterns emerge and that follows a universal allometric mass scaling law; or it may be considered a property of the organism that emerges as a result of the organism's adaptation to the environment, with consequently less universal mass scaling properties. Data on body mass, maximum ingestion and clearance rates, respiration rates and maximum growth rates of animals living in the ocean epipelagic were compiled from the literature, mainly from original papers but also from previous compilations by other authors. Data were read from tables or digitized from graphs. Only measurements made on individuals of know size, or groups of individuals of similar and known size were included. We show that clearance and respiration rates have life-form-dependent allometries that have similar scaling but different elevations, such that the mass-specific rates converge on a rather narrow size-independent range. In contrast, ingestion and growth rates follow a near-universal taxa-independent ~3/4 mass scaling power law. We argue that the declining mass-specific clearance rates with size within taxa is related to the inherent decrease in feeding efficiency of any particular feeding mode. The transitions between feeding mode and simultaneous transitions in clearance and respiration rates may then represent adaptations to the food environment and be the result of the optimization of tradeoffs that allow sufficient feeding and growth rates to balance mortality.

Transformational learning-environments in the post-secondary classroom: through the experience of indigenous women

This study investigated the physical, mental, emotional, and spiritual aspects of transformational learning, including the elements, attributes, factors, and catalysis of the transformational learning environment, as Indigenous women experienced them in the Indigenous Studies 3040H: The Meaning of Work in the Contemporary World (INDG 3040H) course at Trent University. Using a holistic model developed in connection with the Medicine Wheel an Indigenous epistemology is integrated into the study. Qualitative interviews were conducted with eight Indigenous women. The data collected from the interviews indicated that for Indigenous women, the transformational learning environment of the post-secondary classroom is heavily connected to the relationship students develop with themselves, their peers, and the faculty member alongside the content of the course.