Studies of the metabolism, anti tumor activity and toxicity of compounds containing N-menthyl moieties

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Studies of the mechanism of action of anitumour compounds

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Studies of the fouling of heat exchanger equipment

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Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • 6-Mercaptopurine (6-MP) and azathioprine (AZA) are both inactive prodrugs that require intracellular activation into the active 6-thioguanine nucleotides (6-TGNs). • This metabolic process undergoes three different competitive pathways that are catalysed by three different enzymes; xanthine oxidase (XO), thiopurine methyltransferase (TPMT) and inosine triphosphatase (ITPA), all of which exhibit genetic polymorphisms. • Although the impact of genetic variation in the TPMT gene on treatment outcome and toxicity has been demonstrated, the role of other polymorphisms remains less well known. WHAT THIS STUDY ADDS • New information on the allelic variation of these three enzymes (XO, TPMT and ITPA) and their influence on 6-MP/AZA metabolism and toxicity. • Confirmation of the association of TPMT polymorphism with haematological toxicity. • Identified potential genetic characteristics that may contribute to higher risk of adverse events (such as ITPA IVS2+21A→C mutation). AIMS - To examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD). METHODS - Clinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6-MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase, inosine triphosphatase (C94→A and IVS2+21A→C) and thiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined. RESULTS - Thiopurine methyltransferase variant alleles were associated with a preferential metabolism away from 6-methylmercaptopurine nucleotides (P = 0.008 in ALL patients, P = 0.038 in IBD patients) favouring 6-thioguanine nucleotides (6-TGNs) (P = 0.021 in ALL patients). Interestingly, carriers of inosine triphosphatase IVS2+21A→C variants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients, P = 0.047 in IBD patients). The study confirmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association between inosine triphosphatase IVS2+21A→C variants with thrombocytopenia (P = 0.012). CONCLUSIONS - Pharmacogenetic polymorphisms in the 6-MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization.

Kinetic studies of the photopolymerisation of acrylamide in aqueous solution:effects of bromoform as a Chain transfer agent

The effects of adding bromoform (CHBr3) as a potential chain transfer agent in the photopolymerisation of acrylamide (AM) in aqueous solution have been studied both in terms of influencing the rate of polymerisation and the molecular weight of the polyacrylamide (PAM) formed. Using 4,4′-azo-bis(4-cyanopentanoic acid) (ACPA) as photoinitiator, two different CHBr3 concentrations as chain transfer agent were compared: 0.5 and 2.0 mol % (relative to AM), the higher of which was determined by the limit of CHBr3 water solubility. The results showed that CHBr3 was an effective chain transfer agent that could regulate the molecular weight of the PAM formed without seriously affecting the polymerisation rate. It is concluded that chain transfer to CHBr3occurs by both Br and H atom transfer although Br transfer is the more favoured due to the weaker C-Br bond. Furthermore, Br transfer leads to Br-terminated chains in which the terminal C-Br bond can re-dissociate leading to re-initiation and re-propagation of the same chain, thereby maintaining the polymerisation rate. Continuing studies into how this mechanism can be exploited in order to synthesize water-soluble block copolymers of potential biomedical importance are currently in progress.

A corpus-assisted study of the discourse marker well as an indicator of judges' institutional roles in court cases with litigants in person

In this paper, I concentrate on court cases with litigants in person (lay people who act on their own behalf in legal proceedings without a counsel or solicitor) and discuss the challenges of building a corpus of courtroom discourse where it is crucial to distinguish between speakers due to their distinct institutional roles. The corpus incorporates seven sub-corpora of verbatim transcripts from different court cases with litigants in person and comprises over eleven-million tokens. The focus of this paper is on the interplay between the legal and lay discourse types and how judges project their institutional roles through well-initiated turns directed at litigants in person and counsels. As a versatile discourse marker, well provides a good opportunity to explore how judges have to adapt their roles to ensure lay litigants in person receive the necessary support and that their lack of competence does not impede on the fairness of the proceedings. Given the breadth and importance of the topic of litigation in person, I discuss how the tools and approaches of corpus linguistics can be helpful in this multi-disciplinary area where multiple functions and uses of individual linguistic features need to be explored in depth.

Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration?

Pathological lesions in the form of extracellular protein deposits, intracellular inclusions and changes in cell morphology occur in the brain in the majority of neurodegenerative disorders. Studies of the presence, distribution, and molecular determinants of these lesions are often used to define individual disorders and to establish the mechanisms of lesion pathogenesis. In most disorders, however, the relationship between the appearance of a lesion and the underlying disease process is unclear. Two hypotheses are proposed which could explain this relationship: (i) lesions are the direct cause of the observed neurodegeneration ('causal' hypothesis); and (ii) lesions are a reaction to neurodegeneration ('reaction' hypothesis). These hypotheses are considered in relation to studies of the morphology and molecular determinants of lesions, the effects of gene mutations, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies and the degeneration of anatomical pathways. The balance of evidence suggests that in many disorders, the appearance of the pathological lesions is a reaction to degenerative processes rather than being their cause. Such a conclusion has implications both for the classification of neurodegenerative disorders and for studies of disease pathogenesis.

The topographic distribution of the magnetic P100M to full- and half-field stimulation

Visual evoked magnetic responses were recorded to full-field and left and right half-field stimulation with three check sizes (70′, 34′ and 22′) in five normal subjects. Recordings were made sequentially on a 20-position grid (4 × 5) based on the inion, by means of a single-channel direct current-Superconducting Quantum Interference Device second-order gradiometer. The topographic maps were consistent on the same subjects recorded 2 months apart. The half-field responses produced the strongest signals in the contralateral hemisphere and were consistent with the cruciform model of the calcarine fissure. Right half fields produced upper-left-quadrant outgoing fields and lower-left-quadrant ingoing fields, while the left half field produced the opposite response. The topographic maps also varied with check size, with the larger checks producing positive or negative maximum position more anteriorly than small checks. In addition, with large checks the full-field responses could be explained as the summation of the two half fields, whereas full-field responses to smaller checks were more unpredictable and may be due to sources located at the occipital pole or lateral surface. In addition, dipole sources were located as appropriate with the use of inverse problem solutions. Topographic data will be vital to the clinical use of the visual evoked field but, in addition, provides complementary information to visual evoked potentials, allowing detailed studies of the visual cortex. © 1992 Kluwer Academic Publishers.

Topographic mapping and source localization of the pattern reversal visual evoked magnetic response

The topography of the visual evoked magnetic response (VEMR) to pattern reversal stimulation was studied in four normal subjects using a single channel BTI magnetometer. VEMRs were recorded from 20 locations over the occipital scalp and the topographic distribution of the most consistent component (P100M) studied. A single dipole in a sphere model was fitted to the data. Topographic maps were similar when recorded two months apart on the same subject to the same stimulus. Half field (HF) stimulation elicited responses from sources on the medial surface of the calcarine fissure mainly in the contralateral hemisphere as predicted by the cruciform model. The full field (FF) responses to large checks were approximately the sum of the HF responses. However, with small checks, FF stimulation appeared to activate a different combination of sources than the two HFs. In addition, HF topography was more consistent between subjects than FF for small check sizes. Topographic studies of the VEMR may help to explain the analogous visual evoked electrical response and will be essential to define optimal recording positions for clinical applications.

Chemical studies of plasma etchants used in integrated circuit manufacture

Plasma or "dry" etching is an essential process for the production of modern microelectronic circuits. However, despite intensive research, many aspects of the etch process are not fully understood. The results of studies of the plasma etching of Si and Si02 in fluorine-containing discharges, and the complementary technique of plasma polymerisation are presented in this thesis. Optical emission spectroscopy with argon actinometry was used as the principle plasma diagnostic. Statistical experimental design was used to model and compare Si and Si02 etch rates in CF4 and SF6 discharges as a function of flow, pressure and power. Etch mechanisms m both systems, including the potential reduction of Si etch rates in CF4 due to fluorocarbon polymer formation, are discussed. Si etch rates in CF4 /SF6 mixtures were successfully accounted for by the models produced. Si etch rates in CF4/C2F6 and CHF3 as a function of the addition of oxygen-containing additives (02, N20 and CO2) are shown to be consistent with a simple competition between F, 0 and CFx species for Si surface sites. For the range of conditions studied, Si02 etch rates were not dependent on F-atom concentration, but the presence of fluorine was essential in order to achieve significant etch rates. The influence of a wide range of electrode materials on the etch rate of Si and Si02 in CF4 and CF4 /02 plasmas was studied. It was found that the Si etch rate in a CF4 plasma was considerably enhanced, relative to an anodised aluminium electrode, in the presence of soda glass or sodium or potassium "doped" quartz. The effect was even more pronounced in a CF4 /02 discharge. In the latter system lead and copper electrodes also enhanced the Si etch rate. These results could not be accounted for by a corresponding rise in atomic fluorine concentration. Three possible etch enhancement mechanisms are discussed. Fluorocarbon polymer deposition was studied, both because of its relevance to etch mechanisms and its intrinsic interest, as a function of fluorocarbon source gas (CF4, C2F6, C3F8 and CHF3), process time, RF power and percentage hydrogen addition. Gas phase concentrations of F, H and CF2 were measured by optical emission spectroscopy, and the resultant polymer structure determined by X-ray photoelectron spectroscopy and infrared spectroscopy. Thermal and electrical properties were measured also. Hydrogen additions are shown to have a dominant role in determining deposition rate and polymer composition. A qualitative description of the polymer growth mechanism is presented which accounts for both changes in growth rate and structure, and leads to an empirical deposition rate model.

A political economy of the ethnic chinese catering industry

The present political climate in which the ideals of entrepreneurship and self-help are strongly encouraged has drawn attention to those ethnic minorities noted for their entrepreneurial activity. Since the Chinese appear to be an exemplary case in point, this thesis focusses upon the historical material conditions which have led to the formation of a Chinese 'business* community in Britain, both past and present As such, it rejects the theories of cultural determinism which characterise most studies of the Chinese. For rather than representing the endurance of cultural norms, the existence of the contemporary Chinese 'niche' of ethnically exclusive firms in the catering industry is due to the conjunction of a number of historical processes. The first is the imperialist expansion into China of Britain's capitalist empire during the nineteenth century which established a relationship of dependency upon the interests of British capital by colonial Chinese labour. The second is the post war development of the catering industry and its demand for cheap labour as administered by the British state together with the contemporaneous development of the agricultural economy of colonial Hong Kong. Far from representing a source of material benefit to all, the ethnic Chinese 'niche' in catering is highly exploitative and merely underlines the racial oppression of Chinese in Britain. Attempts to promote business interests within the ethnic community therefore serve merely to entrench the structures of oppression.

The evaluation and development of the lead authority partnership scheme as a central intervention strategy for health and safety enforcement by local authorities

The research comprises a suite of studies that examines and develops the Lead Authority Partnership Scheme (LAPS) as a central intervention strategy for health and safety by local authority (LA) enforcers. Partnership working is a regulatory concept that in recent years has become more popular but there has been little research conducted to investigate, explore and evaluate its practical application. The study reviewed two contrasting approaches to partnership working between LAs and businesses, both of which were intended to secure improvements in the consistency of enforcement by the regulators and in the health and safety management systems of the participating businesses. The first was a well-established and highly prescriptive approach that required a substantial resource commitment on the part of the LA responsible for conducting a safety management review (SMR) of the business. As a result of his evaluation of the existing ‘full SMR’ scheme, the author developed a second, more flexible approach to partnership working. The research framework was based upon a primarily qualitative methodology intended to investigate and explore the impact of the new flexible arrangements for partnership working. The findings from this study of the flexible development of the scheme were compared and contrasted with those from studies of the established ‘full SMR’ scheme. A substantial degree of triangulation was applied in an attempt to strengthen validity and broaden applicability of the research findings. Key informant interviews, participant observation, document/archive reviews, questionnaires and surveys all their particular part to play in the overall study. The findings from this research revealed that LAPS failed to deliver consistency of LA enforcement across multiple-outlet businesses and the LA enforced business sectors. Improvement was however apparent in the safety management systems of the businesses participating in LAPS. Trust between LA inspector and safety professional was key to the success of the partnerships as was the commitment of these key individuals. Competition for precious LA resources, the priority afforded to food safety over health and safety, the perceived high resource demands of LAPS, and the structure and culture of LAs were identified as significant barriers to LA participation. Flexible approaches, whilst addressing the resource issues, introduced some fresh concerns relating to credibility and delivery. Over and above the stated aims of the scheme, LAs and businesses had their own reasons for participation, notably the personal development of individuals and kudos for the organisation. The research has explored the wider implications for partnership working with the overall conclusion it is most appropriately seen as a strategic level element within a broader structured intervention strategy.

Mesozoic to recent evolution of the Andean forearc of northern Chile (22-24 s)

The Andean forearc of northern Chile comprises four morphotectonic units, which include from east to west: 1) The Cordillera de la Costa: composed of Jurassic granites and andesites, thought to represent a volcanic arc, the Mejillones terrane, an accreted allochthonous terrane, and the Lower Cretaceous Coloso basin, which formed through forearc extension along the suture between the Mejillones terrane and the Jurassic arc. Palaeomagnetic studies of the above units have identified approximately 29+/-11 degrees of clockwise rotation. Rotation is due to extension (caused by subduction roll back and slab pull), at an angle to the direction of absolute motion of the South American Plate. 2) The Central Depression: a large arid basin containing isolated fault-bounded blocks of pre-Mesozoic metamorphosed igneous rocks, Triassic sediments and volcanics, and Jurassic carbonates, deposited in a. back-arc basin setting. The isolated blocks formed through extension along previous thrust faults, these originated through compression of the back-arc basin due to accretion of the Jurassic volcanic arc. 3) The Precordillera.: composed of Permian-Triassic rift-related sediments and volcanics, Jurassic continental sediments synchronous with back-arc basin sedimentation, and Cretaceous and Oligo-Miocene continental sediments deposited in foreland basins. Palaeomagnetism has identified clockwise rotation in rocks ranging in age from Jurassic-Miocene. Rotation in the Precordillera. affected larger structural blocks than in the Cordillera de la Costa. 4) The Salar Depression: a. series of arid continental basins developed on continental crust. These basins nay have originated in the Triassic, when rifting of the South American craton is thought to have taken place. In conclusion, palaeomagnetic and geological evidence is consistent with the view that the north Chilean forearc was largely under an extensional stress regime. However, the presence of extensive compressional structures in Palaeocene and older rocks in the forearc together with the currently active foreland thrust belt of Argentina. indicate that throughout the evolution of the Andean Orogen, a delicate balance between compressional and extensional tectonic regimes has existed.

Genetic studies of Cu-Pb-Zn mineralisation in Triassic red beds of Western Europe

Continental red bed sequences are host, on a worldwide scale, to a characteristic style of mineralisation which is dominated by copper, lead, zinc, uranium and vanadium. This study examines the features of sediment-hosted ore deposits in the Permo-Triassic basins of Western Europe, with particular reference to the Cu-Pb-Zn-Ba mineralisation in the Cheshire Basin, northwest England, the Pb-Ba-F deposits of the Inner Moray Firth Basin, northeast Scotland, and the Pb-rich deposits of the Eifel and Oberpfalz regions, West Germany. The deposits occur primarily but not exclusively in fluvial and aeolian sandstones on the margins of deep, avolcanic sedimentary basins containing red beds, evaporites and occasionally hydrocarbons. The host sediments range in age from Permian to Rhaetian and often contain (or can be inferred to have originally contained) organic matter. Textural studies have shown that early diagenetic quartz overgrowths precede the main episode of sulphide deposition. Fluid inclusion and sulphur isotope data have significantly constrained the genetic hypotheses for the mineralisation and a model involving the expulsion of diagenetic fluids and basinal brines up the faulted margins of sedimentary basins is favoured. Consideration of the development of these sedimentary basins suggests that ore emplacement occurred during the tectonic stage of basin evolution or during basin inversion in the Tertiary. ð34S values for barite in the Cheshire Basin range from 13.8% to 19.3% and support the theory that the Upper Triassic evaporites were the principal sulphur source for the mineralisation and provided the means by which mineralising fluids became saline. In contrast, δ34S values for barite in the Inner Moray Firth Basin (mean δ34S = + 29%) are not consistent with simple derivation of sulphur from the evaporite horizons in the basin and it is likely that sulphur-rich Jurassic shales supplied the sulphur for the mineralisation at Elgin. Possible sources of sulphur for the mineralisation in West Germany include hydrothermal vein sulphides in the underlying Devonian sediments and evaporites in the overlying Muschelkalk. Textural studies of the deeply buried sandstones in the Cheshire Basin reveal widespread dissolution and replacement of detrital phases and support the theory that red bed diagenetic processes are responsible for the release of metals into pore fluids. The ore solutions are envisaged as being warm (60-150%C), saline (9-22 wt % equiv NaCl) fluids in which metals were transported as chloride complexes. The distribution of δ34S values for sulphides in the Cheshire Basin (-1.8% to + 16%), the Moray Firth Basin (-4.8% to + 27%) and the German Permo-Triassic Basins (-22.2% to -12.2%) preclude a magmatic source for the sulphides and support the contention that sulphide precipitation is thought to result principally from sulphate reduction processes, although a decrease in temperature of the ore fluid or reaction with carbonates may also be important. Methane is invoked as the principal reducing agent in the Cheshire Basin, whilst terrestrial organic debris and bacterial reduction processes are thought to have played a major part in the genesis of the German ore deposits.