Drug Analysis without Primary Reference Standards : Application of LC-TOFMS and LC-CLND to Biofluids and Seized Material

Drug Analysis without Primary Reference Standards: Application of LC-TOFMS and LC-CLND to Biofluids and Seized Material Primary reference standards for new drugs, metabolites, designer drugs or rare substances may not be obtainable within a reasonable period of time or their availability may also be hindered by extensive administrative requirements. Standards are usually costly and may have a limited shelf life. Finally, many compounds are not available commercially and sometimes not at all. A new approach within forensic and clinical drug analysis involves substance identification based on accurate mass measurement by liquid chromatography coupled with time-of-flight mass spectrometry (LC-TOFMS) and quantification by LC coupled with chemiluminescence nitrogen detection (LC-CLND) possessing equimolar response to nitrogen. Formula-based identification relies on the fact that the accurate mass of an ion from a chemical compound corresponds to the elemental composition of that compound. Single-calibrant nitrogen based quantification is feasible with a nitrogen-specific detector since approximately 90% of drugs contain nitrogen. A method was developed for toxicological drug screening in 1 ml urine samples by LC-TOFMS. A large target database of exact monoisotopic masses was constructed, representing the elemental formulae of reference drugs and their metabolites. Identification was based on matching the sample component s measured parameters with those in the database, including accurate mass and retention time, if available. In addition, an algorithm for isotopic pattern match (SigmaFit) was applied. Differences in ion abundance in urine extracts did not affect the mass accuracy or the SigmaFit values. For routine screening practice, a mass tolerance of 10 ppm and a SigmaFit tolerance of 0.03 were established. Seized street drug samples were analysed instantly by LC-TOFMS and LC-CLND, using a dilute and shoot approach. In the quantitative analysis of amphetamine, heroin and cocaine findings, the mean relative difference between the results of LC-CLND and the reference methods was only 11%. In blood specimens, liquid-liquid extraction recoveries for basic lipophilic drugs were first established and the validity of the generic extraction recovery-corrected single-calibrant LC-CLND was then verified with proficiency test samples. The mean accuracy was 24% and 17% for plasma and whole blood samples, respectively, all results falling within the confidence range of the reference concentrations. Further, metabolic ratios for the opioid drug tramadol were determined in a pharmacogenetic study setting. Extraction recovery estimation, based on model compounds with similar physicochemical characteristics, produced clinically feasible results without reference standards.

Long-term results of operative treatment for Hirschsprung's disease and internal anal sphincter achalasia

The aim of the study was to evaluate long-term results of operative treatment for Hirschsprung's disease(HD) and internal anal sphincter achalasia. Fecal continence and quality of life were evaluated by a questionnaire in 100 adult patients who had undergone surgery for HD, during 1950-75. Fecal continence was evaluated using a numerical scoring described by Holschneider. Fifty-four of the 100 patients underwent clinical examination, rigid sigmoidoscopy and manometric evaluation. In anorectal manometry basal resting pressure(BRP)and maximal squeeze pressure(MSP) were measured and voluntary sphincter force(VSF) was calculated by subtracting the BRP from MSP. The results of operative treatment for adult HD were compared with the results of the patients operated in childhood. In adult HD the symptoms are such mild that the patients attain adolescence or even adulthood. The patients with HD and cartilage-hair-hypoplasia were specifically evaluated. The outcome of the patients with internal anal sphincter achalasia operated on by myectomy was evaluated by a questionnaire and continence was evaluated using a numerical scoring described by Holschneider. Of the 100 patients operated on for HD 38 patients had completely normal bowel habits. A normal or good continence score was found in 91 our of 100 patients. Nine patients had fair continence. One of the patients with fair continence had Down's syndrome and two were mentally retarded for other reasons. Only one patient suffered from constipation. In anorectal manometry the difference in BRP between patients with normal and good continence was statistically significant, whereas the difference between good and fair continence groups was not statistically significant. The differences on MSP and VSF between patient groups with different continence outcome were not statistically significant. The differences between patient groups and normal controls were statistically significant in BRP and MSP. In VSF there was not statistically significant difference between the patients and the normal controls. The VSF reflects the working power of the muscles including external sphincter, levator ani and gluteal muscles. The patients operated at adult age had as good continence as patients operated in childhood. The patients with HD and cartilage-hair-hypoplasia had much more morbidity and mortality than non-cartilage-hair-hypoplasia HD patients. The mortality was as high as 38%. In patients with internal anal sphincter achalasia the constipation was cured or alleviated by myectomy whereas a significant number suffered from soiling-related social problems.

Use of Standards for CAD Layers in Building

One of the central issues in making efficient use of IT in the design, construction and maintenance of buildings is the sharing of the digital building data across disciplines and lifecycle stages. One technology which enables data sharing is CAD layering, which to be of real use requires the definition of standards. This paper focuses on the background, objectives and effectiveness of the International standard ISO 13567, Organisation and naming of layers for CAD. In particular the efficiency and effectiveness of the standardisation and standard implementation process are in focus, rather than the technical details. The study was conducted as a qualitative study with a number of experts who responded to a semi-structured mail questionnaire, supplemented by personal interviews. The main results were that CAD layer standards based on the ISO standard have been implemented, particularly in northern European countries, but are not very widely used. A major problem which was identified was the lack of resources for marketing and implementing the standard as national variations, once it had been formally accepted.

Essays on Corporate Governance and the Quality of Disclosed Earnings: Across Transitional Europe

A growing body of empirical research examines the structure and effectiveness of corporate governance systems around the world. An important insight from this literature is that corporate governance mechanisms address the excessive use of managerial discretionary powers to get private benefits by expropriating the value of shareholders. One possible way of expropriation is to reduce the quality of disclosed earnings by manipulating the financial statements. This lower quality of earnings should then be reflected by the stock price of firm according to value relevance theorem. Hence, instead of testing the direct effect of corporate governance on the firm’s market value, it is important to understand the causes of the lower quality of accounting earnings. This thesis contributes to the literature by increasing knowledge about the extent of the earnings management – measured as the extent of discretionary accruals in total disclosed earnings - and its determinants across the Transitional European countries. The thesis comprises of three essays of empirical analysis of which first two utilize the data of Russian listed firms whereas the third essay uses data from 10 European economies. More specifically, the first essay adds to existing research connecting earnings management to corporate governance. It testifies the impact of the Russian corporate governance reforms of 2002 on the quality of disclosed earnings in all publicly listed firms. This essay provides empirical evidence of the fact that the desired impact of reforms is not fully substantiated in Russia without proper enforcement. Instead, firm-level factors such as long-term capital investments and compliance with International financial reporting standards (IFRS) determine the quality of the earnings. The result presented in the essay support the notion proposed by Leuz et al. (2003) that the reforms aimed to bring transparency do not correspond to desired results in economies where investor protection is lower and legal enforcement is weak. The second essay focuses on the relationship between the internal-control mechanism such as the types and levels of ownership and the quality of disclosed earnings in Russia. The empirical analysis shows that the controlling shareholders in Russia use their powers to manipulate the reported performance in order to get private benefits of control. Comparatively, firms owned by the State have significantly better quality of disclosed earnings than other controllers such as oligarchs and foreign corporations. Interestingly, market performance of firms controlled by either State or oligarchs is better than widely held firms. The third essay provides useful evidence on the fact that both ownership structures and economic characteristics are important factors in determining the quality of disclosed earnings in three groups of countries in Europe. Evidence suggests that ownership structure is a more important determinant in developed and transparent countries, while economic determinants are important determinants in developing and transitional countries.

A Relationship Mediated Theory of Internal Marketing (summary section only)

This report presents a new theory of internal marketing. The thesis has developed as a case study in retrospective action research. This began with the personal involvement of the author in an action research project for customer service improvement at a large Australian retail bank. In other words, much of the theory generating ‘research’ took place after the original project ‘action’ had wound down. The key theoretical proposition is that internal marketing is a relationship development strategy for the purpose of knowledge renewal. In the banking case, exchanges of value between employee participants emerged as the basis for relationship development, with synergistic benefits for customers, employees and the bank. Relationship development turned out to be the mediating variable between the learning activity of employee participants at the project level and success in knowledge renewal at the organisational level. Relationship development was also a pivotal factor in the motivation and customer consciousness of employees. The conclusion reached is that the strength of relationship-mediated internal marketing is in combining a market focused commitment and employee freedom in project work to achieve knowledge renewal. The forgotten truth is that organisational knowledge can be renewed through dialogue and learning, through being trustworthy, and by gaining the trust of employees in return.

Critical Incidents in Internal Relationships

Critical incidents have had an important role in service quality and service management research. The focus of critical-incident studies has gradually shifted from separate acts and episodes towards relationships, and even switching from one relationship to another. The Critical Incident Technique has mainly been used when studying the service sector, concentrating on the customer's perception of critical incidents. Although some studies have considered the perceptions of employees important, critical incidents have not been considered a tool for studying internal relationships to any larger extent. This paper takes a process approach and shifts the focus from an external to an internal setting. It puts forward a new technique for analysing internal relationships from a critical-incident perspective. The technique captures the dynamism in relationships through considering internal critical incidents as micro-processes affecting not only internal but also external relationships.

The Far Eastern Question at the Washington Conference (1921-1922) with an outline of its implications for internal politics in China

This dissertation is a narrative account of the negotiations concerning the question of the Far East and the Shandong issue at the Washington Conference, leading to treaties, agreements and resolutions. In this dissertation, a certain stress is laid on the interaction between the Conference and the internal situation in China, particularly concerning the question of the implications of the Conference for Cabinet politics in Peking. Through the narrative account of the Conference, the general aim is an attempt to reassess the achievements of the Washington Conference. Too often the Washington Conference has been viewed negatively. The political aim behind the legal framework was to open the door to China as a sovereign State member of the international community whose territorial integrity was internationally recognized, despite its chaotic internal situation. It is undeniable that the Washington Conference opened a new chapter in modern Chinese history. The violations of the agreements concerning China that occurred in the 1930s should not lead to the belief that these agreements were of no value. Peace may not be lasting and evolves according to circumstances; agreements are transitory, and new situations need new arrangements. This dissertation tries to demonstrate that the agreements in themselves were not the cause of their failure, but the failure was due to the lack of determination on the part of the Signatories Powers to defend them.

Nationalism Circumscribed : Transnational Governance of Minority Rights in Post-Cold War Europe

For the past two centuries, nationalism has been among the most influential legitimizing principles of political organization. According to its simple definition, nationalism is a principle or a way of thinking and acting which holds that the world is divided into nations, and that national and political units should be congruent. Nationalism can thus be divided into two aspects: internal and external. Internally, the political units, i.e., states, should be made up of only one nation. Externally each nation-state should be sovereign. Transnational national governance of rights of national minorities violates both these principles. This study explores the formation, operation, and effectiveness of the European post-Cold War minorities system. The study identifies two basic approaches to minority rights: security and justice. These approaches have been used to legitimize international minority politics and they also inform the practice of transnational governance. The security approach is based on the recognition that the norm of national self-determination cannot be fulfilled in all relevant cases, and so minority rights are offered as a compensation to the dissatisfied national groups, reducing their aspiration to challenge the status quo. From the justice perspective, minority rights are justified as a compensatory strategy against discrimination caused by majority nation-building. The research concludes that the post-Cold War minorities system was justified on the basis of a particular version of the security approach, according to which only Eastern European minority situations are threatening because of the ethnic variant of nationalism that exists in that region. This security frame was essential in internationalising minority issues and justifying the swift development of norms and institutions to deal with these issues. However, from the justice perspective this approach is problematic, since it justified double standards in European minority politics. Even though majority nation-building is often detrimental to minorities also in Western Europe, Western countries can treat their minorities more or less however they choose. One of the main contributions of this thesis is the detailed investigation of the operation of the post-Cold War minorities system. For the first decade since its creation in the early 1990s, the system operated mainly through its security track, which is based on the field activities of the OSCE that are supported by the EU. The study shows how the effectiveness of this track was based on inter-organizational cooperation in which various transnational actors compensate for each other s weaknesses. After the enlargement of the EU and dissolution of the membership conditionality this track, which was limited to Eastern Europe from the start, has become increasingly ineffective. Since the EU enlargement, the focus minorities system has shifted more and more towards its legal track, which is based on the Framework Convention for the Protection of National Minorities (Council of Europe). The study presents in detail how a network of like-minded representatives of governments, international organizations, and independent experts was able strengthen the framework convention s (originally weak) monitoring system considerably. The development of the legal track allows for a more universal and consistent, justice-based approach to minority rights in contemporary Europe, but the nationalist principle of organization still severely hinders the materialization of this possibility.