An Experimental Model of Porphyria

1. The porphyrias are a group of disorders of haem metabolism, due to an enzymatic defect in the haem biosynthetic pathway. Two current hypotheses regarding the underlying causes of the neuropathy of the acute type of porphyria were examined. Firstly, are the haem precursors d-aminolaevulinic acid (ALA) and porphobilinogen (PBG) neurotoxic? Secondly, is acute porphyric neuropathy a consequence of a reduction in essential haemoproteins? 2. The responses of a variety of in vitro rabbit nerve/muscle preparations, whose responses are mediated by different neurotransmitters, were unaffected by ALA in concentrations ranging from 1muM. to 10mM. In isolated nerve/muscle preparations taken from rats that had received porphyrinogenic drug treatment, which disrupted haem biosynthesis, 10nM. to 300muM. ALA did not alter the responses of the muscles to electrical field stimulation of their intrinsic nerves. 3.30muM. to 1mM. PBG did not significantly alter the response of the rat anococcygeus muscle to electrical field stimulation of the intrinsic inhibitory nerves. 4. The results of these experiments provide no evidence that ALA or PBG are neurotoxic. 5. In the second group of experiments the porphyrinogenic drugs (succinylacetone; allylisopropylacetamide; DDC and its 4-ethyl analogue 4-ethyl DDC; phenobarbitone; lead) were employed, in various combinations, for periods ranging from 3 to 44 days, in an attempt to produce a haem deficiency neuropathy, in rats, by inhibiting haem synthesis. 6. A range of rat in vitro nerve/muscle preparations were examined, the responses of which are mediated by different neurotransmitters, one of which, the nitrergically-mediated inhibitory response of the anococcygeus muscle results from activation of a cytosolic haemoprotein, guanylate cyclase. 7. The results of this group of experiments provide no evidence that the porphyrinogenic compounds employed, in this study, reduce essential haemoproteins to levels where a neuropathy ensues. 8. The third group of experiments examined liver, blood and brain haemoproteins, following porphyrinogenic drug treatment for periods ranging between 14 and 44 days. Hepatic respiratory cytochrome levels and catalase activity, blood haemoglobin content and catalase activity and brain respiratory cytochromes were measured. These tissues give a measure of haemoproteins in the two major haem containing organs, the liver and blood and a measure of haemoproteins in neural tissue where a deficit, in these cytochromes, could lead to neuropathy. 9. Treatments which included the use of either 4-ethyl DDC or N-methyl protoporphyrin, both of which inhibit hepatic ferrochelatase, caused a significant reduction in hepatic haemoproteins, but were ineffective in reducing blood or brain levels. Lead treatment did cause a reduction in whole blood haemoglobin content and a rise in catalase activity, but was also incapable of reducing brain respiratory cytochrome levels. 10. The failure of these porphyrinogenic compounds to alter brain haemoproteins may be due to their inability to cross the blood brain barrier. 11. The last group of experiments examined both hepatic and brain mitochondrial function following porphyrinogenic treatment, which was known, from the previous group of experiments, to reduce hepatic respiratory cytochromes. Additionlly, to circumvent the blood brain barrier, the ferrochelatase inhibitor, N-methyl protoporphyrin was administered directly into the ventricular system. Treatments which significantly reduced hepatic respiratory cytochromes also caused a reduction in the Respiratory Control Ratio (RCR) in liver mitochondria, while all other respiratory parameters were unaltered. All brain mitochondrial function parameters were unaltered by these systemic treatments. Central administration of N-methyl protoporphyrin, caused a reduction in brain mitochondrial RCRs, while all other respiratory parameters in this tissue remained unaltered. Hepatic mitochondrial function was unaffected by centrally-administered N-methyl protoporphyrin. 12. The results of these experiments show that some porphyrinogenic drugs are capable of altering some aspects of mitochondrial function, in this case the Respiratory Control Ratio (RCR). Although systemically-administered compounds were unable to alter brain mitochondrial function, while doing so in liver, N-methyl protoporphyin did reduce RCR's in brain mitochondria when administered centrally. This latter observation suggests that when porphyrinogenic drugs gain access to neural tissue they can exert similar effects. 13. The failure, in this study, to produce a neuropharmacological model of acute porphyria is most probably due to the inability of the porphyrinogenic compounds employed to reduce neural respiratory cytochromes to levels where a functional deficit occurs. This problem may be overcome by a longer period of treatment. The results of the present set of experiments indicate that succinylacetone is not a suitable compound for use in in vivo haemoprotein depletion. N-methyl protoporphyrin at larger concentrations than used in this study may be more effective in producing a model of a haem deficiency neuropathy

Church Discipline and Social Satire in Medieval Portugal

The principal aim of this study is to clarify the topic of clerical abuse as it is depicted in the satirical literature of the thirteenth, fourteenth and fifteenth centuries. In Chapter One we examine the satirical works of medieval Portugal (deemed to begin with the Galician-Portuguese satirical lyric, and to close with the works of the poet and dramatist, Gil Vicente). This analysis will establish which are the predominant stereotypes of the clergy and to construct a view of the kinds of representations of the Church that are found in a wide range of writings. Because of the scarcity of medieval Portuguese examples and information, it is essential to refer to the literatures of other, parallel Western European societies: the total volume of extant literary works in medieval Portuguese is too slight to permit us to draw realistically founded conclusions. Also included are comparisons of attitudes to the clergy and the Church, to allow insights into variations of local history and circumstance, and to supply the means to measure the performance of the Portuguese clergy against that of their peers. Once the survey has been carried out, it becomes clear that there are two distinct and opposing images of the clergy in medieval literature. The first of these corresponds to the ecclesiastical ideal, that of the Good Shepherd, the cleric who performs his duties and follows the rules and recommendations of his institution. The other stereotype, found in more than one genre and throughout the period under investigation, tends to be that of the corrupt cleric, a person who falls short of the Church's own clearly stated ideals. Much of the medieval anticlerical satire discussed derives from a perceived discrepancy between ideal and reality. It does not necessarily stem from a ridiculing of normal human weakness, but rather from the failure of the clergy to live up to the proclaimed ideals of their own institution. In Chapter Two, we compare the literary stereotypes of members of the clergy with more reliable, objective views and depictions. Literary descriptions, comments and criticisms of the clergy are set against opinions and views found in other kinds of documents and sources, principally in the writings of the clergy itself. By following this methodology, we are able, to some extent, to determine whether the vision of the clergy that emerges from the literature corresponds to the social reality of the Middle Ages. In order to gauge clerical success or failure in matching Church ideals, certain fundamental areas of clerical activity are singled out for examination: the duties of attending and convoking councils and synods and carrying out visitations. The conclusion reached is that clerical performance is not uniform or regular. This patchiness may be partially due to the uneven pattern of survival of medieval texts and documents, but even taking this factor into account, we must conclude that the Portuguese clergy did not always carry out these specific duties with the assiduity that was expected of them. After a careful review of copious listings of councils, synods, visitations and sermons, it was concluded that the weakest area of performance was that of convening councils and synods. There is documentation to show that visitations were carried out, in order to maintain the discipline of the Church, and to safeguard Church privileges and property. In Chapter Three, we explore another sphere of clerical endeavour, the preaching of sermons. The very small numbers of extant medieval Portuguese sermons might at first cause us to assume that the clergy neglected this obligation. However, a careful scrutiny of a range of source materials (letters, supplications, chronicles, exemplum collections, synodal statutes, ecclesiastical arbitrations, secular legislation) leads us to the conclusion that preaching, in general, is treated seriously and carried out regularly. Standards of preaching inevitably vary at different times and within different sectors of the clergy, but there is never a period within the three hundred years when an extensive variety of sermons are not being preached to an equally wide section of the population. In this respect, the clergy live up to the ideals of their own institution. Chapter Four contains discussion of a specific type of misconduct, and allows us to assess the official responses of the Church (and State) to delinquent behaviour by both clergy and laity. The area selected for scrutiny, superstitious beliefs and practices, lends itself to analysis because of the volume of documentation available for the period in question. This documentation serves a double function: it reveals clerical delinquency, but equally it reveals the mechanisms of ecclesiastical discipline in action, brought to bear as much against the clergy as against the laity. The fifth and final chapter of the thesis presents a review of gambling in medieval Portugal, drawing principally on the literature and legislation of the period. It becomes clear that this was a significant area of clerical abuse, but equally, we find, that the Church made serious and sustained efforts to denounce and punish those members of the laity and clergy who contravene the ecclesiastical laws against gaming. The conclusions reached are that the Portuguese clergy did, on the whole, carry out their duties as prescribed by the Church. (Abstract shortened by ProQuest.)

Trading with the Hudson's Bay Company, a case study of the Nipigon House Post, 1828-1838

This thesis critically examines generalizations offered in the fur trade literature regarding the impact of the amalgamation of the Northwest Company and Hudson's Bay Company upon Aboriginal trade partners. There are essentially two schools of thought. One asserts that Aboriginal trappers had become dependent upon European technology by the time of the 1821 amalgamation, and were forced to continue the trade exchange accepting the changes imposed by the Hudson's Bay Company during the monopoly period. The second perspective holds that Aboriginal trade partners were not dependent upon European technology and were adaptable, choosing to opt out of the trade exchange, focusing instead upon subsistence hunting and trapping to satisfy finite wants and needs. The focus of this research project is to evaluate these competing ideas about the amalgamation phase of the fur trade, using the records of Nipigon House Post dating between 1828 and 1838. The fur trade is typically characterized by several predominant periods: the early fur trade, the competition phase, and finally the amalgamation phase. As each phase of the trade progressed, Aboriginal trade partners were affected in various ways. It is thought that in the post-amalgamation phase, there was a loss of Aboriginal bargaining power, and an extended time of hardship due to a widespread collapse in the viability of fur and food resources. This thesis examines how the Anishinabe community at Nipigon House Post was affected by the amalgamation. Data derived from the Journals of the Nipigon House are used to explore the Anishinabe community and their trade activities. Contrary to expectations deriving from the conventional fur trade literature that emphasize growing dependence upon the HBC, the Nipigon House data indicate adaptability to the monopoly period. This involved a limited demand for a narrow range of goods in keeping with the modest fur returns generated. Indeed many people focused heavily upon satisfying their subsistence needs, and sharply reduced their efforts at fur trapping. This contributed to a shift of the settlement system, with much more time spent along the lakeshore. These data suggest that the Lake Nipigon Anishinabe were not dependent upon European goods for survival. It can be concluded that reconsideration of generalizations about Aboriginal dependency during the monopoly phase of the fur trade is required

Modes of address: translation strategies or the black hole

The title of this paper is perhaps deceptively succint: although it indicates the object of study it does not immediately suggest the transdisciplinary nature of its subject matter. Any consideration of the problems posed and the lexical or syntactical options available when one sets out to translate forms of address from one language to another must necessarily involve some awareness not only of issues of translation theory, but also of a series of questions usually discussed under the rubrics of sociolinguistics, pragmatics and discourse analysis.The title of this paper is perhaps deceptively succint: although it indicates the object of study it does not immediately suggest the transdisciplinary nature of its subject matter. Any consideration of the problems posed and the lexical or syntactical options available when one sets out to translate forms of address from one language to another must necessarily involve some awareness not only of issues of translation theory, but also of a series of questions usually discussed under the rubrics of sociolinguistics, pragmatics and discourse analysis