Expression of cytochrome P450 enzymes and metabolism of timolol in human ocular tissue

Glaucoma is a group of progressive optic neuropathies causing irreversible blindness if not diagnosed and treated in the early state of progression. Disease is often, but not always, associated with increased intraocular pressure (IOP), which is also the most important risk factor for glaucoma. Ophthlamic timolol preparations have been used for decades to lower increased intraocular pressure (IOP). Timolol is locally well tolerated but may cause e.g. cardiovascular and pulmonary adverse effects due to systemic absorption. It has been reported that approximately 80% of a topically administered eye drop is systemically absorbed. However, only limited information is available on timolol metabolism in the liver or especially in the human eye. The aim of this work was to investigate metabolism of timolol in human liver and human ocular tissues. The expression of drug metabolizing cytochrome P450 (CYP) enzymes in the human ciliary epithelial cells was studied. The metabolism of timolol and the interaction potential of timolol with other commercially available medicines were investigated in vitro using different liver preparations. The absorption of timolol to the aqueous humor from two commercially available products: 0.1% eye gel and 0.5% eye drops and the presence of timolol metabolites in the aqueous humor were investigated in a clinical trial. Timolol was confirmed to be metabolized mainly by CYP2D6 as previously suggested. Potent CYP2D6 inhibitors especially fluoxetine, paroxetine and quinidine inhibited the metabolism of timolol. The inhibition may be of clinical significance in patients using ophthalmic timolol products. CYP1A1 and CYP1B1 mRNAs were expressed in the human ciliary epithelial cells. CYP1B1 was also expressed at protein level and the expression was strongly induced by a known potent CYP1B1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The CYP1B1 induction is suggested to be mediated by aryl hydrocarbon receptor (AHR). Low levels of CYP2D6 mRNA splice variants were expressed in the human ciliary epithelial cells and very low levels of timolol metabolites were detected in the human aqueous humor. It seems that negligible amount of CYP2D6 protein is expressed in the human ocular tissues. Timolol 0.1% eye gel leads to aqueous humor concentration high enough to achieve therapeutic effect. Inter-individual variation in concentrations is low and intraocular as well as systemic safety can be increased when using this product with lower timolol concentration instead of timolol 0.5% eye drops.

The Homeless Etiquette : Social Interaction and Behavior Among the Homeless in Taito Ward, Tokyo

The thesis focuses on the social interaction and behavior of the homeless living in Tokyo's Taito Ward. The study is based on the author's own ethnographic field research carried out in the autumn 2003. The chosen methodologies were based on the methodology called "participant observation", and they were used depending on the context. The ethnographic field research was carried out from the mid-August to the beginning of the October in 2003. The most important targets of the research were three separate loosely knit groups placed in certain parts of Taito Ward. One of these groups was based in proximity to the Ueno train station, one group gathered every morning around a homeless support organization called San'yûkai, and one was based in Tamahime Park located in the old San'ya area of Tokyo. The analysis is based on the aspects of Takie Sugiyama Lebra's theory of "social relativism". Lebra's theory consists of the following, arguably universal aspects: belongingness, empathy, dependence, place in the society, and reciprocity. In addition, all the interaction and behavior is tied to the context and the situation. According to Lebra, ritual and intimate situations produce similar action, which is socially relative. Of these, the norms of the ritual behavior are more regulated, while the intimate bahavior is less spontaneous. On the contrary, an anomic situation produces anomic behavior, which is not socially relative. Lebra's theory is critically reviewed by the author of the thesis, and the author has attempted to modify the theory to make it more adaptable to the present-day society and to the analysis. Erving Goffman's views of the social interaction and Anthony Giddens' theories about the social structures have been used as complementary thoretical basis. The aim of the thesis is to clarify, how and why the interaction and the behavior of some homeless individuals in some situations follow the aspects of Lebra's "social relativism", and on the other hand, why in some situations they do not. In the latter cases the answers can be sought from regional and individual differences, or from the inaptness of the theory to analyze the presented situation. Here, a significant factor is the major finding of the field study: the so called "homeless etiquette", which is an abstract set of norms and values that influences the social interaction and behavior of the homeless, and with which many homeless individuals presented in the study complied. The fundamental goal of the thesis is to reach profound understanding about the daily life of the homeless, whose lives were studied. The author argues that this kind of profound understanding is necessary in looking for sustainable solutions in the areas of social and housing policy to improve the position of the homeless and the qualitative functioning of the society.

Studies of working memory in interrupted human-computer interaction

Distraction in the workplace is increasingly more common in the information age. Several tasks and sources of information compete for a worker's limited cognitive capacities in human-computer interaction (HCI). In some situations even very brief interruptions can have detrimental effects on memory. Nevertheless, in other situations where persons are continuously interrupted, virtually no interruption costs emerge. This dissertation attempts to reveal the mental conditions and causalities differentiating the two outcomes. The explanation, building on the theory of long-term working memory (LTWM; Ericsson and Kintsch, 1995), focuses on the active, skillful aspects of human cognition that enable the storage of task information beyond the temporary and unstable storage provided by short-term working memory (STWM). Its key postulate is called a retrieval structure an abstract, hierarchical knowledge representation built into long-term memory that can be utilized to encode, update, and retrieve products of cognitive processes carried out during skilled task performance. If certain criteria of practice and task processing are met, LTWM allows for the storage of large representations for long time periods, yet these representations can be accessed with the accuracy, reliability, and speed typical of STWM. The main thesis of the dissertation is that the ability to endure interruptions depends on the efficiency in which LTWM can be recruited for maintaing information. An observational study and a field experiment provide ecological evidence for this thesis. Mobile users were found to be able to carry out heavy interleaving and sequencing of tasks while interacting, and they exhibited several intricate time-sharing strategies to orchestrate interruptions in a way sensitive to both external and internal demands. Interruptions are inevitable, because they arise as natural consequences of the top-down and bottom-up control of multitasking. In this process the function of LTWM is to keep some representations ready for reactivation and others in a more passive state to prevent interference. The psychological reality of the main thesis received confirmatory evidence in a series of laboratory experiments. They indicate that after encoding into LTWM, task representations are safeguarded from interruptions, regardless of their intensity, complexity, or pacing. However, when LTWM cannot be deployed, the problems posed by interference in long-term memory and the limited capacity of the STWM surface. A major contribution of the dissertation is the analysis of when users must resort to poorer maintenance strategies, like temporal cues and STWM-based rehearsal. First, one experiment showed that task orientations can be associated with radically different patterns of retrieval cue encodings. Thus the nature of the processing of the interface determines which features will be available as retrieval cues and which must be maintained by other means. In another study it was demonstrated that if the speed of encoding into LTWM, a skill-dependent parameter, is slower than the processing speed allowed for by the task, interruption costs emerge. Contrary to the predictions of competing theories, these costs turned out to involve intrusions in addition to omissions. Finally, it was learned that in rapid visually oriented interaction, perceptual-procedural expectations guide task resumption, and neither STWM nor LTWM are utilized due to the fact that access is too slow. These findings imply a change in thinking about the design of interfaces. Several novel principles of design are presented, basing on the idea of supporting the deployment of LTWM in the main task.

Interaction in the Multicultural Classroom : Towards Culturally Sensitive Home Economics Education

Continuous growth in the number of immigrant students has changed the Finnish school environment. The resulting multicultural school environment is new for both teachers and students. In order to develop multicultural learning environments, there is a need to understand immigrant students everyday lives in school. In this study, home economics is seen as a fruitful school subject area for understanding these immigrant students lives as they cope with school and home cultures that may be very different from each other. Home economics includes a great deal of knowledge and skills that immigrant students need during their everyday activities outside of school. -- The main aim of the study is to clarify the characteristics of multicultural home economics classroom practices and the multicultural contacts and interaction that take place between the students and the teacher. The study includes four parts. The first part, an ethnographical prestudy, aims to understand the challenges of multicultural schoolwork with the aid of ethnographical fieldwork done in one multicultural school. The second part outlines the theoretical frames of the study and focuses on the sociocultural approach. The third part of the study presents an analysis of videodata collected in a multicultural home economics classroom. The teacher s and students interaction in the home economics classroom is analyzed through the concepts of the sociocultural approach and the cultural-historical activity theory. Firstly, this is done by analyzing the focusedness of the teacher s and the students actions as well as the questions presented and apparent disturbances during classroom interaction. Secondly, the immigrant students everyday experiences and cultural background are examined as they appear during discussions in the home economics lessons. Thirdly, the teacher s tool-use and actions as a human mediator are clarified during interaction in the classroom. The fourth part presents the results, according to which a practice-based approach in the multicultural classroom situation is a prerequisite for the teacher s and the students shared object during classroom interaction. Also, the practice-based approach facilitates students understanding during teaching and learning situations. Practice in this study is understood as collaborative teaching and learning situations that include 1) guided activating learning, 2) establishing connections with students everyday lives and 3) multiple tool-use. Guided activating learning in the classroom is defined as situations that occur and assignments that are done with a knowledgeable adult or peer and include action. The teacher s demonstrations during the practical part of the lessons seemed to be fruitful in the teaching and learning situations in the multicultural classroom. Establishing connections with students everyday lives motivated students to follow the lesson and supported understanding of meaning. Furthermore, if multiple tools (both psychological and material) were used, the students managed better with new and sometimes difficult concepts and different working habits, and accomplished the practical work more smoothly . The teacher s tool-use and role as a mediator of meaning are also highlighted in the data analysis. Hopefully, this study can provide a seedbed for situations in which knowledge produced together, as well as horizontally oriented tool-use, can make school-learned knowledge more relevant to immigrant students everyday lives, and help students to better cope with both classroom work and outside activities. KEY WORDS: home economics education, multicultural education, sociocultural perspective, classroom interaction, videoanalysis

Understanding the organic chain : The framework of the interaction between the actors in organic chains in relation to ecological modernisation of food production

The sustainability of food production has increasingly attracted the attention of consumers, farmers, food and retailing companies, and politicians. One manifestation of such attention is the growing interest in organic foods. Organic agriculture has the potential to enhance the ecological modernisation of food production by implementing the organic method as a preventative innovation that simultaneously produces environmental and economic benefits. However, in addition to the challenges to organic farming, the small market share of organic products in many countries today and Finland in particular risks undermining the achievement of such benefits. The problems identified as hindrances to the increased consumption of organic food are the poor availability, limited variety and high prices of organic products, the complicated buying decisions and the difficulties in delivering the intangible value of organic foods. Small volumes and sporadic markets, high costs, lack of market information, as well as poor supply reliability are obstacles to increasing the volume of organic production and processing. These problems shift the focus from a single actor to the entire supply chain and require solutions that involve more interaction among the actors within the organic chain. As an entity, the organic food chain has received very little scholarly attention. Researchers have mainly approached the organic chain from the perspective of a single actor, or they have described its structure rather than the interaction between the actors. Consequently, interaction among the primary actors in organic chains, i.e. farmers, manufacturers, retailers and consumers, has largely gone unexamined. The purpose of this study is to shed light on the interaction of the primary actors within a whole organic chain in relation to the ecological modernisation of food production. This information is organised into a conceptual framework to help illuminate this complex field. This thesis integrates the theories and concepts of three approaches: food system studies, supply chain management and ecological modernisation. Through a case study, a conceptual system framework will be developed and applied to a real life-situation. The thesis is supported by research published in four articles. All examine the same organic chains through case studies, but each approaches the problem from a different, complementary perspective. The findings indicated that regardless of the coherent values emphasising responsibility, the organic chains were loosely integrated to operate as a system. The focus was on product flow, leaving other aspects of value creation largely aside. Communication with consumers was rare, and none of the actors had taken a leading role in enhancing the market for organic products. Such a situation presents unsuitable conditions for ecological modernisation of food production through organic food and calls for contributions from stakeholders other than those directly involved in the product chain. The findings inspired a revision of the original conceptual framework. The revised framework, the three-layer framework , distinguishes the different layers of interaction. By gradually enlarging the chain orientation the different but interrelated layers become visible. A framework is thus provided for further research and for understanding practical implications of the performance of organic food chains. The revised framework provides both an ideal model for organic chains in relation to ecological modernisation and demonstrates a situation consistent with the empirical evidence.

Capillary electrochromatography: a versatile instrumental technique for nanodomain interaction studies

This doctoral thesis describes the development of a miniaturized capillary electrochromatography (CEC) technique suitable for the study of interactions between various nanodomains of biological importance. The particular focus of the study was low-density lipoprotein (LDL) particles and their interaction with components of the extracellular matrix (ECM). LDL transports cholesterol to the tissues through the blood circulation, but when the LDL level becomes too high the particles begin to permeate and accumulate in the arteries. Through binding sites on apolipoprotein B-100 (apoB-100), LDL interacts with components of the ECM, such as proteoglycans (PGs) and collagen, in what is considered the key mechanism in the retention of lipoproteins and onset of atherosclerosis. Hydrolytic enzymes and oxidizing agents in the ECM may later successively degrade the LDL surface. Metabolic diseases such as diabetes may provoke damage of the ECM structure through the non-enzymatic reaction of glucose with collagen. In this work, fused silica capillaries of 50 micrometer i.d. were successfully coated with LDL and collagen, and steroids and apoB-100 peptide fragments were introduced as model compounds for interaction studies. The LDL coating was modified with copper sulphate or hydrolytic enzymes, and the interactions of steroids with the native and oxidized lipoproteins were studied. Lipids were also removed from the LDL particle coating leaving behind an apoB-100 surface for further studies. The development of collagen and collagen decorin coatings was helpful in the elucidation of the interactions of apoB-100 peptide fragments with the primary ECM component, collagen. Furthermore, the collagen I coating provided a good platform for glycation studies and for clarification of LDL interactions with native and modified collagen. All methods developed are inexpensive, requiring just small amounts of biomaterial. Moreover, the experimental conditions in CEC are easily modified, and the analyses can be carried out in a reasonable time frame. Other techniques were employed to support and complement the CEC studies. Scanning electron microscopy and atomic force microscopy provided crucial visual information about the native and modified coatings. Asymmetrical flow field-flow fractionation enabled size measurements of the modified lipoproteins. Finally, the CEC results were exploited to develop new sensor chips for a continuous flow quartz crystal microbalance technique, which provided complementary information about LDL ECM interactions. This thesis demonstrates the potential of CEC as a valuable and flexible technique for surface interaction studies. Further, CEC can serve as a novel microreactor for the in situ modification of LDL and collagen coatings. The coatings developed in this study provide useful platforms for a diversity of future investigations on biological nanodomains.