The Pharmacology of Oxycodone : Studies In Vitro, In Vivo and In Humans

The antinociceptive properties of oxycodone and its metabolites were studied in models of thermal and mechanical nociception and in the spinal nerve ligation (SNL) model of neuropathic pain in rats. Oxycodone induced potent antinociception after subcutaneous (s.c.) administration in all models of nociception used in rats compared with morphine, methadone and its enantiomers. In the SNL model of neuropathic pain in rats, oxycodone produced dose dependent antinociception after s.c. administration. The antinociceptive effects of s.c. oxycodone were antagonized by naloxone but not by nor-binaltorphimine (Nor-BNI) a selective κ-opioid receptor antagonist indicating that the antinociceptive properties of oxycodone are predominantly μ-opioid receptor-mediated. The antinociceptive activity of oxymorphone, noroxycodone, and noroxymorphone, oxidative metabolites of oxycodone, were studied to determine their role in the oxycodone-induced antinociception in the rat. Of the metabolites of oxycodone s.c. administration of oxymorphone produced potent thermal and mechanical antinociception. Noroxycodone had a poor antinociceptive effect and noroxymorphone was inactive. Oxycodone produced naloxone-reversible antinociception after intrathecal (i.t) administration with a poor potency compared with morphine and oxymorphone. This seems to be related to the low efficacy and potency of oxycodone to stimulate μ-opioid receptor activation in the spinal cord in μ-opioid receptor agonist-stimulated (GTP)γ[S] autoradiography, compared with morphine and oxymorphone. All metabolites studied were more potent than oxycodone after i.t. administration. I.t. noroxymorphone induced a significantly longer lasting antinociceptive effect compared with the other drugs studied. The role of cytochrome P450 (CYP) 2D6-mediated metabolites on the analgesic activity of oxycodone in humans was studied by blocking the CYP2D6-mediated metabolism of oxycodone with paroxetine. Paroxetine co-administration had no effect on the analgesic effect of oxycodone compared with placebo in chronic pain patients, indicating that oxycodone-induced analgesia and adverse-effects are not dependent of the CYP2D6-mediated metabolism in humans. Although oxycodone has many pharmacologically active metabolites, they seem to have an insignificant role in oxycodone-induced antinociception in humans and rats.

Community, Power, and Colonialism: The U.S. Army in Southern Arizona and New Mexico, 1866-1886

Empire is central to U.S. history. When we see the U.S. projecting its influence on a global scale in today s world it is important to understand that U.S. empire has a long history. This dissertation offers a case study of colonialism and U.S. empire by discussing the social worlds, labor regimes, and culture of the U.S. Army during the conquest of southern Arizona and New Mexico (1866-1886). It highlights some of the defining principles, mentalities, and characteristics of U.S. imperialism and shows how U.S. forces have in years past constructed their power and represented themselves, their missions, and the places and peoples that faced U.S. imperialism/colonialism. Using insights from postcolonial studies and whiteness studies, this work balances its attention between discursive representations (army stories) and social experience (army actions), pays attention to silences in the process of historical production, and focuses on collective group mentalities and identities. In the end the army experience reveals an empire in denial constructed on the rule of difference and marked by frustration. White officers, their wives, and the white enlisted men not only wanted the monopoly of violence for the U.S. regime but also colonial (mental/cultural) authority and power, and constructed their identity, authority, and power in discourse and in the social contexts of the everyday through difference. Engaged in warfare against the Apaches, they did not recognize their actions as harmful or acknowledge the U.S. invasion as the bloody colonial conquest it was. White army personnel painted themselves and the army as liberators, represented colonial peoples as racial inferiors, approached colonial terrain in terms of struggle, and claimed that the region was a terrible periphery with little value before the arrival of white civilization. Officers and wives also wanted to place themselves at the top of colonial hierarchies as the refined and respectable class who led the regeneration of the colony by example: they tried to turn army villages into islands of civilization and made journeys, leisure, and domestic life to showcase their class sensibilities and level of sophistication. Often, however, their efforts failed, resulting in frustration and bitterness. Many blamed the colony and its peoples for their failures. The army itself was divided by race and class. All soldiers were treated as laborers unfit for self-government. White enlisted men, frustrated by their failures in colonial warfare and by constant manual labor, constructed worlds of resistance, whereas indigenous soldiers sought to negotiate the effects of colonialism by working in the army. As colonized labor their position was defined by tension between integration and exclusion and between freedom and colonial control.

Is a Majority Enough? Psychological Well-being and Its Relation to Academic and Prosocial Motivation, Self-regulation and Achievement at school

This cross-sectional study analyzed psychological well-being at school using the Self-Determination theory as a theoretical frame-work. The study explored basic psychological needs fulfillment (BPNS), academic (SRQ-A), prosocial self-regulation (SRQ-P) and motivation, and their relationship with achievement in general, special and selective education (N=786, 444 boys, 345 girls, mean age 12 yrs 8 mths). Motivation starts behavior which becomes guided by self-regulation. The perceived locus of control (PLOC) affects how self-determined this behavior will be; in other words, to what extent it is autonomously regulated. In order learn and thus to be able to accept external goals, a student has to feel emotionally safe and have sufficient ego-flexibility—all of which builds on satisfied psychological needs. In this study those conditions were explored. In addition to traditional methods Self-organizing maps (SOM), was used in order to cluster the students according to their well-being, self-regulation, motivation and achievement scores. The main impacts of this research were: a presentation of the theory based alternative of studying psychological well-being at school and usage of both the variable and person-oriented approach. In this Finnish sample the results showed that the majority of students felt well, but the well-being varied by group. Overall about for 11–15% the basic needs were deprived depending on the educational group. Age and educational group were the most effective factors; gender was important in relation to prosocial identified behavior. Although the person-oriented SOM-approach, was in a large extent confirming what was no-ticed by using comparison of the variables: the SEN groups had lower levels of basic needs fulfillment and less autonomous self-regulation, interesting deviations of that rule appeared. Some of the SEL- and GEN-group members ended up in the more unfavorable SOM-clusters, and not all SEN-group members belonged to the poorest clusters (although not to the best either). This evidence refines the well-being and self-regulation picture, and may re-direct intervention plans, and turn our focus also on students who might otherwise remain unnoticed. On the other hand, these results imply simultaneously that in special education groups the average is not the whole truth. On the basis of theoretical and empirical considerations an intervention model was sug-gested. The aim of the model was to shift amotivation or external motivation in a more intrinsic direction. According to the theoretical and empirical evidence this can be achieved first by studying the self-concept a student has, and then trying to affect both inner and environmental factors—including a consideration of the basic psychological needs. Keywords: academic self-regulation, prosocial self-regulation, basic psychological needs, moti-vation, achievement

Trafficking and ethanol-induced inhibition of AMPA receptors

AMPA receptors are an important class of ionotropic glutamate receptors which participate in fast excitatory synaptic transmission in most brain areas. They have a pivotal role in adjustment of cell membrane excitability as their cell membrane expression levels is altered in brain physiology such as in learning and memory formation. AMPA receptor function and trafficking is regulated by several proteins, such as transmembrane AMPA receptor regulatory proteins (TARPs). NMDA-type glutamate receptors are important target molecules of ethanol. The role of AMPA receptors in the actions of ethanol has not been clarified as thoroughly. Furthermore, the regulation of AMPA receptor synthesis and their possible adaptation in neurons with altered inhibitory mechanisms are poorly understood. In this thesis work AMPA receptor pharmacology, trafficking and synaptic localization was studied using patch-clamp electrophysiology. Both native and recombinant AMPA receptors were studied. Hippocampal slices from transgenic Thy1alfa6 mice with altered inhibition were used to study adaptation of AMPA receptors. Ethanol was found to inhibit AMPA receptor function by increasing desensitization of the receptor, as the steady-state current was inhibited more than the peak current. Ethanol inhibition was reduced when cyclothiazide was used to block desensitization and when non-desensitizing mutant receptors were studied. Ethanol also increased the rate of desensitization, which was increased further by the coexpression of TARP-proteins. We found that the agonist binding capability is important for trafficking AMPA receptors from endoplasmic reticulum to the cell membrane. TARP rescues the surface expression of non-binding AMPA receptor mutants in HEK293 cells, but not in native neurons. Studies with Thy1alfa6 mice revealed that decreased inhibition decrease AMPA receptor mediated excitation keeping the neurotransmission in balance. Thy1alfa6 mice also had lower sensitivity to electroshock convulsions, presumably due to the decreased AMPA receptor function. The results suggest that during alcohol intoxication ethanol may inhibit AMPA receptors by increasing the rate and the extent of desensitization. TARPs appear to enhance ethanol inhibition. TARPs also participate in trafficking of AMPA receptors upon their synthesis in the cell. AMPA receptors mediate also long-term adaptation to altered neuronal excitability, which adds to their well-known role in synaptic plasticity.

Early Childhood Caries and a Community Trial of its Prevention in Tehran, Iran

Varhaislapsuuden karies ja sen ehkäisy kehittyvän terveydenhuollon maassa Varhaislapsuuden karies on merkittävä kansanterveysongelma varsinkin lapsirikkaissa maissa ja väestöissä. Karieksen hoitaminen vie paljon voimavaroja ja aiheuttaa mittavia taloudellisia seuraamuksia. Karies voi ilmaantua lapselle jo vauvaikäisenä, pian ensimmäisten maitohampaiden puhjettua suuhun. Alle 3-vuotiaiden karieksesta on kuitenkin niukasti tilastotietoja. Maailman terveysjärjestökin suosittaa tietojen keräämistä vasta 3-vuotiaiden ikäryhmästä. Heistä kariesta sairastaa Suomessa 16 %, Yhdysvalloissa 25 %, Englannissa 30 %, Iranissa 46 % ja Saudi-Arabiassa 61 %. Tämä väitöstutkimus selvitti karieksen esiintymistä ja sen vaaratekijöitä 1─3-vuotiailla Teheranissa. Lisäksi tutkimus arvioi perusterveydenhuoltoon sisällytetyn karieksen ehkäisyn tuloksellisuutta. Tutkimuskohteiksi arvottiin Teheranista 18 neuvolaa. Jokaisessa oltiin 4 päivää, jolloin kaikkia rokotuksiin tulleita 1─3-vuotiaita äiteineen pyydettiin osallistumaan tutkimukseen. Kahta lukuun ottamatta kaikki äidit suostuivat, ja aineistoon tuli kaikkiaan 504 lasta äiteineen. Kaikki 1-vuotiaat, 242 lasta äiteineen, valittiin karieksen ehkäisykokeiluun. Sitä varten neuvolat jaettiin kolmeen ryhmään, joista kaksi (A ja B) oli koeryhmiä ja yksi (C) oli vertailuryhmä. Tutkimus alkoi äidin haastattelulla. Siinä selvitettiin perheen koulutus- ja tulotaso sekä lapsen ruokinnasta imetyksen kesto, yösyötöt ja päiväaikaan nautitut makeat. Vielä kysyttiin lapsen ja äidin suuhygieniatavoista ja äidin kokemuksista lapsen suun puhdistamisessa. Sitten hammaslääkäri tutki lapsen suun ja kirjasi karieksen ja hammasplakin esiintymät. Suun tutkimuksen jälkeen äiti ja lapsi siirtyivät rokotushuoneeseen. Koeryhmissä (A ja B) äidit saivat terveydenhoitajalta suunterveyttä koskevan esitteen ja kehotuksen lukea se huolellisesti. Lisäksi ryhmässä A terveydenhoitaja kertoi suun ja hampaiden terveydenhoidosta saman esitteen avulla, ja neuvolan henkilökunta muistutti suunhoidon tärkeydestä puhelimitse kahdesti seuraavan puolen vuoden kuluessa. Vertailuryhmässä äideille ei annettu suunhoidon ohjeita. Kaikissa ryhmissä äitejä muistutettiin seuraavan rokotuskerran ajankohdasta, muttei mainittu tulevaa toista hammastarkastusta. Varhaislapsuuden kariesta sairasti ikäryhmästä riippuen 3─26 % tutkituista 1─3-vuotiaista, ja 65─76 %:lla oli hammasplakkia. Äideistä 68 % harjasi hampaansa päivittäin ja 39 % puhdisti lapsensa suun päivittäin. Mitä useammin äiti harjasi omat hampaansa, sitä paremmin hän huolehti lapsen suun puhtaudesta. Rintaruokinta oli yleistä eikä lisännyt kariesvaaraa. Yöllä pullomaitoa saavilla karies oli 5 kertaa yleisempää kuin muilla. Neuvolassa saatu ohjeistus ehkäisi selvästi karieksen syntyä puolen vuoden kokeessa.

Preadolescents and Their Mothers as Oral Health-Promoting Actors : Non-biologic Determinants of Oral Health among Turkish and Finnish Preadolescents

Is oral health becoming a part of the global health culture? Oral health seems to turn out to be part of the global health culture, according to the findings of a thesis-research, Institute of Dentistry, University of Helsinki. The thesis is entitled as “Preadolescents and Their Mothers as Oral Health-Promoting Actors: Non-biologic Determinants of Oral Health among Turkish and Finnish Preadolescents.” The research was supervised by Prof.Murtomaa and led by Dr.A.Basak Cinar. It was conducted as a cross-sectional study of 611 Turkish and 223 Finnish school preadolescents in Istanbul and Helsinki, from the fourth, fifth, and sixth grades, aged 10 to 12, based on self-administered and pre-tested health behavior questionnaires for them and their mothers as well as the youth’s oral health records. Clinically assessed dental status (DMFT) and self-reported oral health of Turkish preadolescents was significantly poorer than the Finns`. A similar association occurred for well-being measures (height and weight, self-esteem), but not for school performance. Turkish preadolescents were more dentally anxious and reported lower mean values of toothbrushing self-efficacy and dietary self-efficacy than did Finns. The Turks less frequently reported recommended oral health behaviors (twice daily or more toothbrushing, sweet consumption on 2 days or less/week, decreased between-meal sweet consumption) than did the Finns. Turkish mothers reported less frequently dental health as being above average and recommended oral health behaviors as well as regular dental visits. Their mean values for dental anxiety was higher and self-efficacy on implementation of twice-daily toothbrushing were lower than those of the Finnish. Despite these differences between the Turks and Finns, the associations found in common for all preadolescents, regardless of cultural differences and different oral health care systems, assessed for the first time in a holistic framework, were as follows: There seems to be interrelation between oral health and general-well being (body height-weight measures, school performance, and self-esteem) among preadolescents: • The body height was an explanatory factor for dental health, underlining the possible common life-course factors for dental health and general well-being. • Better school performance, high levels of self-esteem and self-efficacy were interrelated and they contributed to good oral health. • Good school performance was a common predictor for twice-daily toothbrushing. Self-efficacy and maternal modelling have significant role for maintenance and improvement of both oral- and general health- related behaviors. In addition, there is need for integration of self-efficacy based approaches to promote better oral health. • All preadolescents with high levels of self-efficacy were more likely to report more frequent twice-daily toothbrushing and less frequent sweet consumption. • All preadolescents were likely to imitate toothbrushing and sweet consumption behaviors of their mothers. • High levels of self-efficacy contributed to low dental anxiety in various patterns in both groups. As a conclusion: • Many health-detrimental behaviors arise from the school age years and are unlikely to change later. Schools have powerful influences on children’s development and well-being. Therefore, oral health promotion in schools should be integrated into general health promotion, school curricula, and other activities. • Health promotion messages should be reinforced in schools, enabling children and their families to develop lifelong sustainable positive health-related skills (self-esteem, self-efficacy) and behaviors. • Placing more emphasis on behavioral sciences, preventive approaches, and community-based education during undergraduate studies should encourage social responsibility and health-promoting roles among dentists. Attempts to increase general well-being and to reduce oral health inequalities among preadolescents will remain unsuccessful if the individual factors, as well as maternal and societal influences, are not considered by psycho-social holistic approaches.

Associations among working conditions and behavioral risk factors : The Helsinki Health Study with International Comparisons

Adverse health behaviors as well as obesity are key risk factors for chronic diseases. Working conditions also contribute to health outcomes. It is possible that the effects of psychosocially strenuous working conditions and other work-related factors on health are, to some extent, explained by adverse behaviors. Previous studies about the associations between several working conditions and behavioral outcomes are, however, inconclusive. Moreover, the results are derived mostly from male populations, one national setting only, and with limited information about working conditions and behavioral risk factors. Thus, with an interest in employee health, this study was set to focus on behavioral risk factors among middle-aged employees. More specifically, the main aim was to shed light on the associations of various working conditions with health behaviors, weight gain, obesity, and symptoms of angina pectoris. In addition to national focus, international comparisons were included to test the associations across countries thereby aiming to produce a more comprehensive picture. Furthermore, a special emphasis was on gaining new evidence in these areas among women. The data derived from the Helsinki Health Study, and from collaborative partners at the Whitehall II Study, University College London, UK, and the Toyama University, Japan. In Helsinki, the postal questionnaires were mailed in 2000-2002 to employees of the City of Helsinki, aged 40 60 years (n=8960). The questionnaire data covered e.g., socio-economic indicators and working conditions such as Karasek s job demands and job control, work fatigue, working overtime, work-home interface, and social support. The outcome measures consisted of smoking, drinking, physical activity, food habits, weight gain, obesity, and symptoms of angina pectoris. The international cohorts included comparable data. Logistic regression analysis was used. The models were adjusted for potential confounders such as age, education, occupational class, and marital status subject to specific aims. The results showed that working conditions were mostly unassociated with health behaviors, albeit some associations were found. Low job strain was associated with healthy food habits and non-smoking among women in Helsinki. Work fatigue, in turn, was related to drinking among men and physical inactivity among women. Work fatigue and working overtime were associated with weight gain in Helsinki among both women and men. Finally, work fatigue, low job control, working overtime, and physically strenuous work were associated with symptoms of angina pectoris among women in Helsinki. Cross-country comparisons confirmed mostly non-existent associations. High job strain was associated with physical inactivity and smoking, and passive work with physical inactivity and less drinking. Working overtime, in turn, related to non-smoking and obesity. All these associations were, however, inconsistent between cohorts and genders. In conclusion, the associations of the studied working conditions with the behavioral risk factors lacked general patters, and were, overall, weak considering the prevalence of psychosocially strenuous work and overtime hours. Thus, based on this study, the health effects of working conditions are likely to be mediated by adverse behaviors only to a minor extent. The associations of work fatigue and working overtime with weight gain and symptoms of angina pectoris are, however, of potential importance to the subsequent health and work ability of employees.

Serum uric acid and metabolic risk factors in three ethnic groups: Asian Indians and Creoles in Mauritius and Chinese in Qingdao, China

In humans with a loss of uricase the final oxidation product of purine catabolism is uric acid (UA). The prevalence of hyperuricemia has been increasing around the world accompanied by a rapid increase in obesity and diabetes. Since hyperuricemia was first described as being associated with hyperglycemia and hypertension by Kylin in 1923, there has been a growing interest in the association between elevated UA and other metabolic abnormalities of hyperglycemia, abdominal obesity, dyslipidemia, and hypertension. The direction of causality between hyperuricemia and metabolic disorders, however, is unceartain. The association of UA with metabolic abnormalities still needs to be delineated in population samples. Our overall aims were to study the prevalence of hyperuricemia and the metabolic factors clustering with hyperuricemia, to explore the dynamical changes in blood UA levels with the deterioration in glucose metabolism and to estimate the predictive capability of UA in the development of diabetes. Four population-based surveys for diabetes and other non-communicable diseases were conducted in 1987, 1992, and 1998 in Mauritius, and in 2001-2002 in Qingdao, China. The Qingdao study comprised 1 288 Chinese men and 2 344 women between 20-74, and the Mauritius study consisted of 3 784 Mauritian Indian and Mauritian Creole men and 4 442 women between 25-74. In Mauritius, re-exams were made in 1992 and/or 1998 for 1 941 men (1 409 Indians and 532 Creoles) and 2 318 non pregnant women (1 645 Indians and 673 Creoles), free of diabetes, cardiovascular diseases, and gout at baseline examinations in 1987 or 1992, using the same study protocol. The questionnaire was designed to collect demographic details, physical examinations and standard 75g oral glucose tolerance tests were performed in all cohorts. Fasting blood UA and lipid profiles were also determined. The age-standardized prevalence in Chinese living in Qingdao was 25.3% for hyperuricemia (defined as fasting serum UA > 420 μmol/l in men and > 360 μmol/l in women) and 0.36% for gout in adults between 20-74. Hyperuricemia was more prevalent in men than in women. One standard deviation increase in UA concentration was associated with the clustering of metabolic risk factors for both men and women in three ethnic groups. Waist circumference, body mass index, and serum triglycerides appeared to be independently associated with hyperuricemia in both sexes and in all ethnic groups except in Chinese women, in whom triglycerides, high-density lipoprotein cholesterol, and total cholesterol were associated with hyperuricemia. Serum UA increased with increasing fasting plasma glucose levels up to a value of 7.0 mmol/l, but significantly decreased thereafter in mainland Chinese. An inverse relationship occurred between 2-h plasma glucose and serum UA when 2-h plasma glucose higher than 8.0 mmol/l. In the prospective study in Mauritius, 337 (17.4%) men and 379 (16.4%) women developed diabetes during the follow-up. Elevated UA levels at baseline increased 1.14-fold in risk of incident diabetes in Indian men and 1.37-fold in Creole men, but no significant risk was observed in women. In conclusion, the prevalence of hyperuricemia was high in Chinese in Qingdao, blood UA was associated with the clustering of metabolic risk factors in Mauritian Indian, Mauritian Creole, and Chinese living in Qingdao, and a high baseline UA level independently predicted the development of diabetes in Mauritian men. The clinical use of UA as a marker of hyperglycemia and other metabolic disorders needs to be further studied. Keywords: Uric acid, Hyperuricemia, Risk factors, Type 2 Diabetes, Incidence, Mauritius, Chinese

VEGF-C and angiopoietins in lymphangiogenesis

Angiogenesis and lymphangiogenesis occur during development as the result of tightly coordinated signalling programs to generate two hierarchically organised vascular systems. All tissues and organs are dependent on a functional blood vasculature for oxygen and nutrients, whereas the lymphatic vasculature functions to collect excess tissue fluid, passing it through lymph nodes for immune surveillance, and returning it to the blood circulation. Effectors that control developmental angiogenesis and lymphangiogenesis are also involved in pathological settings, and therefore potential targets for therapy. Vascular endothelial growth factor (VEGF) and angiopoietin (Ang) growth factors, signalling through endothelial VEGFR and Tie receptors, have been established as key regulators of angiogenic and lymphangiogenic processes in development and disease. In this study, we aimed to obtain a clearer understanding of the vascular effects of stimulation by VEGF-C, Ang1 and Ang2, all known to be involved in lymphangiogenesis. In cell culture models, we found that both intrinsic and microenvironmental regulatory mechanisms are involved in the regulation of endothelial cell phenotypes, and distinct responses to VEGF signalling are induced by specific receptor pathways in different endothelial cell types. Surprisingly, we also found that Ang1 induces sprouting lymphangiogenesis in vivo by a VEGFR-3 dependent mechanism, establishing Ang1 as a novel lymphangiogenic factor. Using inducible transgenic mouse models, we found that VEGF-C-induced lymphatic hyperplasia persisted independently of the growth factor, indicating that short pro-lymphangiogenic therapy could lead to lasting improvements in tissue oedema. While VEGF-C had blood vessel effects in embryos, no angiogenic side effects were observed in adult tissues. Furthermore, inducible transgenic expression of Ang2 during embryonic development confirmed Ang2 as an important regulator of lymphatic remodelling and mural cell contacts. The unexpected similarity of the lymphatic maturation defects caused by excess Ang2 to those observed in Ang2 deficient mice demonstrated that correct doses of Ang2 are crucial for the control of lymphatic development. Unlike Ang1, Ang2 did not induce lymphatic sprouting. Although Ang1 has been shown to be able to substitute for Ang2 during developmental lymphangiogenesis, their lymphatic effects are not identical. These findings further our understanding of the basic mechanisms of angiogenesis and lymphangiogenesis, important for the future development of targeted therapies for vascular diseases such as cancer, inflammation, lymphoedema and ischemia. VEGF-C and Ang1 especially emerged as promising candidates for pro-lymphangiogenic therapy.

Physical characterization of plastic surfaces in wearing and cleanability research

Plastic surfaces are a group of materials used for many purposes. The present study was focused on methods for investigation of surface topography, wearing and cleanability of polyvinyl chloride (PVC) model surfaces and industrial plastic surfaces. Contact profilometry, scanning electron microscopy (SEM) and atomic force microscopy (AFM) are powerful methods for studying the topography of plastic surfaces. Although they have their own limitations, they are together an effective tool providing useful information on surface topography, especially when studying laboratory-made PVC model surfaces with known chemical compositions and structures. All examined laboratory-made PVC plastic surfaces examined in this work could be considered as smooth according to both AFM and profilometer measurements because height differences are in the nanoscale on every surface. Industrial plastic surfaces are a complex group of materials because of their chemical and topographical heterogeneity, but they are nevertheless important reference materials when developing cleaning and wearing methods. According to the results of this study the Soiling and Wearing Drum and the Frick-Taber methods are very useful when simulating three-body wearing of plastic surfaces. Both the investigated wearing methods can be used to compare the wearing of different plastic materials using appropriate evaluation methods of wearing and industrial use. In this study, physical methods were developed and adapted from other fields of material research to cleanability studies. The thesis focuses on the methodology for investigating the cleanability of plastic surfaces under realistic conditions, where surface topography and the effect of wear cleanability were among the major topics. A colorimetric method proved to be suitable for examining the cleanability of the industrial plastic surfaces. The results were utilized to evaluate the relationship between cleanability and the surface properties of plastic surfaces. The devices and methods used in the work can be utilized both in material research and product development.

Protein cross-linking with oxidative enzymes and transglutaminase : Effects in meat protein systems

The effects of tyrosinase, laccase and transglutaminase (TG) were studied in different meat protein systems. The study was focused on the effects of the enzymes on the gel formation properties of myofibrils, and on the textural and water-holding properties of the heated meat systems. The cross-linking efficiency of a novel Trichoderma reesei tyrosinase was compared to that of the commercial Agaricus bisporus tyrosinase. Trichoderma tyrosinase was found to be superior compared to the Agaricus enzyme in its protein cross-linking efficiency and in the incorporation of a small molecule into a complex proteinaceous substrate. Tyrosinase, laccase and TG all polymerised myofibrillar proteins, but laccase was also found to cause protein fragmentation. A positive connection between covalent cross-link and gel formation was observed with tyrosinase and TG. Laccase was able to increase the gel formation only slightly. With an excessive laccase dosage the gel formation declined due to protein fragmentation. Tyrosinase, laccase and TG had different effects on the texture and water-holding of the heated chicken breast meat homogenates. Tyrosinase improved the firmness of the homogenate gels free of phosphate and with a low amount of meat. TG improved the firmness of all studied homogenates. Laccase weakened the gel firmness of the low-meat, low-salt and low-salt/phosphate homogenates and maintained the firmness on the control level in the homogenate free of phosphate. Tyrosinase was the only enzyme capable of reducing the weight loss in the homogenates containing a low amount of meat and a low amount of NaCl. TG was the only enzyme that could positively affect the firmness of the homogenate gel containing both low NaCl and phosphate amounts. In pilot scale the test products were made of coarsely ground chicken breast fillet with a moderate amount of salt. Increasining the amount of meat, salt and TG contents favoured the development of firmness of the test products. The evaporation loss decreased slightly along with increasing TG and NaCl amounts in the experimental conditions used, indicating a positive interaction between these two factors. In this work it was shown that tyrosinase, laccase and TG affected the same myofibrillar proteins, i.e. myosin and troponin T. However, these enzymes had distinguishable effects on the gel formation of a myofibril system as well as on the textural and water-holding properties of the finely ground meat homogenates, reflecting distinctions at least in the reaction mechanisms and target amino acid availability in the protein substrates for these enzymes.

Evaluation of methods and applications for behavioural profiling of transgenic mice

During the last 10-15 years interest in mouse behavioural analysis has evolved considerably. The driving force is development in molecular biological techniques that allow manipulation of the mouse genome by changing the expression of genes. Therefore, with some limitations it is possible to study how genes participate in regulation of physiological functions and to create models explaining genetic contribution to various pathological conditions. The first aim of our study was to establish a framework for behavioural phenotyping of genetically modified mice. We established comprehensive battery of tests for the initial screening of mutant mice. These included tests for exploratory and locomotor activity, emotional behaviour, sensory functions, and cognitive performance. Our interest was in the behavioural patterns of common background strains used for genetic manipulations in mice. Additionally we studied the behavioural effect of sex differences, test history, and individual housing. Our findings highlight the importance of careful consideration of genetic background for analysis of mutant mice. It was evident that some backgrounds may mask or modify the behavioural phenotype of mutants and thereby lead to false positive or negative findings. Moreover, there is no universal strain that is equally suitable for all tests, and using different backgrounds allows one to address possible phenotype modifying factors. We discovered that previous experience affected performance in several tasks. The most sensitive traits were the exploratory and emotional behaviour, as well as motor and nociceptive functions. Therefore, it may be essential to repeat some of the tests in naïve animals for assuring the phenotype. Social isolation for a long time period had strong effects on exploratory behaviour, but also on learning and memory. All experiments revealed significant interactions between strain and environmental factors (test history or housing condition) indicating genotype-dependent effects of environmental manipulations. Several mutant line analyses utilize this information. For example, we studied mice overexpressing as well as those lacking extracellular matrix protein heparin-binding growth-associated molecule (HB-GAM), and mice lacking N-syndecan (a receptor for HB-GAM). All mutant mice appeared to be fertile and healthy, without any apparent neurological or sensory defects. The lack of HB-GAM and N-syndecan, however, significantly reduced the learning capacity of the mice. On the other hand, overexpression of HB-GAM resulted in facilitated learning. Moreover, HB-GAM knockout mice displayed higher anxiety-like behaviour, whereas anxiety was reduced in HB-GAM overexpressing mice. Changes in hippocampal plasticity accompanied the behavioural phenotypes. We conclude that HB-GAM and N-syndecan are involved in the modulation of synaptic plasticity in hippocampus and play a role in regulation of anxiety- and learning-related behaviour.

Environmental effects of thermal and radioactive discharges from nuclear power plants in the boreal brackish-water conditions of the northern Baltic Sea

During recent decades, thermal and radioactive discharges from nuclear power plants into the aquatic environment have become the subject of lively debate as an ecological concern. The target of this thesis was to summarize the large quantity of results obtained in extensive monitoring programmes and studies carried out in recipient sea areas off the Finnish nuclear power plants at Loviisa and Olkiluoto during more than four decades. The Loviisa NPP is located on the coast of the Gulf of Finland and Olkiluoto NPP on that of the Bothnian Sea. The state of the Gulf of Finland is clearly more eutrophic; the nutrient concentrations in the surface water are about 1½ 2 times higher at Loviisa than at Olkiluoto, and the total phosphorus concentrations still increased in both areas (even doubled at Loviisa) between the early 1970s and 2000. Thus, it is a challenge to distinguish the local effects of thermal discharges from the general eutrophication process of the Gulf of Finland. The salinity is generally low in the brackish-water conditions of the northern Baltic Sea, being however about 1 higher at Olkiluoto than at Loviisa (the salinity of surface water varying at the latter from near to 0 in early spring to 4 6 in late autumn). Thus, many marine and fresh-water organisms live in the Loviisa area close to their limit of existence, which makes the biota sensitive to any additional stress. The characteristics of the discharge areas of the two sites differ from each other in many respects: the discharge area at Loviisa is a semi-enclosed bay in the inner archipelago, where the exchange of water is limited, while the discharge area at Olkiluoto is more open, and the exchange of water with the open Bothnian Sea is more effective. The effects of the cooling water discharged from the power plants on the temperatures in the sea were most obvious in winter. The formation of a permanent ice cover in the discharge areas has been delayed in early winter, and the break-up of the ice occurs earlier in spring. The prolonging of the growing season and the disturbance of the overwintering time, in conditions where the biota has adjusted to a distinct rest period in winter, have been the most significant biological effects of the thermal pollution. The soft-bottom macrofauna at Loviisa has deteriorated to the point of almost total extinction at many sampling stations during the past 40 years. A similar decline has been reported for the whole eastern Gulf of Finland. However, the local eutrophication process seems to have contributed into the decline of the zoobenthos in the discharge area at Loviisa. Thermal discharges have increased the production of organic matter, which again has led to more organic bottom deposits. These have in turn increased the tendency of the isolated deeps to a depletion of oxygen, and this has further caused strong remobilization of phosphorus from the bottom sediments. Phytoplankton primary production and primary production capacity doubled in the whole area between the late 1960s and the late 1990s, but started to decrease a little at the beginning of this century. The focus of the production shifted from spring to mid- and late summer. The general rise in the level of primary production was mainly due to the increase in nutrient concentrations over the whole Gulf of Finland, but the thermal discharge contributed to a stronger increase of production in the discharge area compared to that in the intake area. The eutrophication of littoral vegetation in the discharge area has been the most obvious, unambiguous and significant biological effect of the heated water. Myriophyllum spicatum, Potamogeton perfoliatus and Potamogeton pectinatus, and vigorous growths of numerous filamentous algae as their epiphytes have strongly increased in the vicinity of the cooling water outlet, where they have formed dense populations in the littoral zone in late summer. However, the strongest increase of phytobenthos has extended only to a distance of about 1 km from the outlet, i.e., the changes in vegetation have been largest in those areas that remain ice-free in winter. Similar trends were also discernible at Olkiluoto, but to a clearly smaller extent, which was due to the definitely weaker level of background eutrophy and nutrient concentrations in the Bothnian Sea, and the differing local hydrographical and biological factors prevailing in the Olkiluoto area. The level of primary production has also increased at Olkiluoto, but has remained at a clearly lower level than at Loviisa. In spite of the analogous changes observed in the macrozoobenthos, the benthic fauna has remained strong and diversified in the Olkiluoto area. Small amounts of local discharge nuclides were regularly detected in environmental samples taken from the discharge areas: tritium in seawater samples, and activation products, such as 60Co, 58Co, 54Mn, 110mAg, 51Cr, in suspended particulate matter, bottom sediments and in several indicator organisms (e.g., periphyton and Fucus vesiculosus) that effectively accumulate radioactive substances from the medium. The tritium discharges and the consequent detection frequency and concentrations of tritium in seawater were higher at Loviisa, but the concentrations of the activation products were higher at Olkiluoto, where traces of local discharge nuclides were also observed over a clearly wider area, due to the better exchange of water than at Loviisa, where local discharge nuclides were only detected outside Hästholmsfjärden Bay quite rarely and in smaller amounts. At the farthest, an insignificant trace amount (0.2 Bq kg-1 d.w.) of 60Co originating from Olkiluoto was detected in Fucus at a distance of 137 km from the power plant. Discharge nuclides from the local nuclear power plants were almost exclusively detected at the lower trophic levels of the ecosystems. Traces of local discharge nuclides were very seldom detected in fish, and even then only in very low quantities. As a consequence of the reduced discharges, the concentrations of local discharge nuclides in the environment have decreased noticeably in recent years at both Loviisa and Olkiluoto. Although the concentrations in environmental samples, and above all, the discharge data, are presented as seemingly large numbers, the radiation doses caused by them to the population and to the biota are very low, practically insignificant. The effects of the thermal discharges have been more significant, at least to the wildlife in the discharge areas of the cooling water, although the area of impact has been relatively small. The results show that the nutrient level and the exchange of water in the discharge area of a nuclear power plant are of crucial importance.

Human parvovirus B19: tissue persistence and prevalence of prototypic and new variants

Human parvovirus B19 is a minute ssDNA virus causing a wide variety of diseases, including erythema infectiosum, arthropathy, anemias, and fetal death. After primary infection, genomic DNA of B19 has been shown to persist in solid tissues of not only symptomatic but also of constitutionally healthy, immunocompetent individuals. In this thesis, the viral DNA was shown to persist as an apparently intact molecule of full length, and without persistence-specific mutations. Thus, although the mere presence of B19 DNA in tissue can not be used as a diagnostic criterion, a possible role in the pathogenesis of diseases e.g. through mRNA or protein production can not be excluded. The molecular mechanism, the host-cell type and the possible clinical significance of B19 DNA tissue persistence are yet to be elucidated. In the beginning of this work, the B19 genomic sequence was considered highly conserved. However, new variants were found: V9 was detected in 1998 in France, in serum of a child with aplastic crisis. This variant differed from the prototypic B19 sequences by ~10 %. In 2002 we found, persisting in skin of constitutionally healthy humans, DNA of another novel B19 variant, LaLi. Genetically this variant differed from both the prototypic sequences and the variant V9 also by ~10%. Simultaneously, B19 isolates with DNA sequences similar to LaLi were introduced by two other groups, in the USA and France. Based on phylogeny, a classification scheme based on three genotypes (B19 types 1-3) was proposed. Although the B19 virus is mainly transmitted via the respiratory route, blood and plasma-derived products contaminated with high levels of B19 DNA have also been shown to be infectious. The European Pharmacopoeia stipulates that, in Europe, from the beginning of 2004, plasma pools for manufacture must contain less than 104 IU/ml of B19 DNA. Quantitative PCR screening is therefore a prerequisite for restriction of the B19 DNA load and obtaining of safe plasma products. Due to the DNA sequence variation among the three B19 genotypes, however, B19 PCR methods might fail to detect the new variants. We therefore examined the suitability of the two commercially available quantitative B19 PCR tests, LightCycler-Parvovirus B19 quantification kit (Roche Diagnostics) and RealArt Parvo B19 LC PCR (Artus), for detection, quantification and differentiation of the three B19 types known, including B19 types 2 and 3. The former method was highly sensitive for detection of the B19 prototype but was not suitable for detection of types 2 and 3. The latter method detected and differentiated all three B19 virus types. However, one of the two type-3 strains was detected at a lower sensitivity. Then, we assessed the prevalence of the three B19 virus types among Finnish blood donors, by screening pooled plasma samples derived from >140 000 blood-donor units: none of the pools contained detectable levels of B19 virus types 2 or 3. According to the results of other groups, B19 type 2 was absent also among Danish blood-donors, and extremely rare among symptomatic European patients. B19 type 3 has been encountered endemically in Ghana and (apparently) in Brazil, and sporadical cases have been detected in France and the UK. We next examined the biological characteristics of these virus types. The p6 promoter regions of virus types 1-3 were cloned in front of a reporter gene, the constructs were transfected into different cell lines, and the promoter activities were measured. As a result, we found that the activities of the three p6 promoters, although differing in sequence by >20%, were of equal strength, and most active in B19-permissive cells. Furthermore, the infectivity of the three B19 types was examined in two B19-permissive cell lines. RT-PCR revealed synthesis of spliced B19 mRNAs, and immunofluorescence verified the production of NS1 and VP proteins in the infected cells. These experiments suggested similar host-cell tropism and showed that the three virus types are strains of the same species, i.e. human parvovirus B19. Last but not least, the sera from subjects infected in the past either with B19 type 1 or type 2 (as evidenced by tissue persistence of the respective DNAs), revealed in VP1/2- and VP2-EIAs a 100 % cross-reactivity between virus types 1 and 2. These results, together with similar studies by others, indicate that the three B19 genotypes constitute a single serotype.

Total hip arthroplasty in young patients : with special references to patients under 55 years of age and to patients with developmental dysplasia of the hip

There is an ongoing controversy as to which methods in total hip arthroplasty (THA) could provide young patients with best long-term results. THA is an especially demanding operation in patients with severely dysplastic hips. The optimal surgical treatment for these patients also remains controversial. The aim of this study was to evaluate the long-term survival of THA in young patients (<55 years at the time of the primary operation) on a nation-wide level, and to analyze the long-term clinical and radio-graphical outcome of uncemented THA in patients with severely dysplastic joints. Survival of 4661 primary THAs performed for primary osteoarthritis (OA), 2557 primary THAs per-formed for rheumatoid arthritis (RA), and modern uncemented THA designs performed for primary OA in young patients, were analysed from the Finnish Arthroplasty Register. A total of 68 THAs were per-formed in 56 consecutive patients with high congenital hip dislocation between 1989-1994, and 68 THAs were performed in 59 consecutive patients with severely dysplastic hips and a previous Schanz osteotomy of the femur between 1988-1995 at the Orton Orthopaedic Hospital, Helsinki, Finland. These patients underwent a detailed physical and radiographical evaluation at a mean of 12.3 years and 13.0 years postoperatively, respectively. The risk of stem revision due to aseptic loosening in young patients with primary OA was higher for cemented stems than for proximally porous-coated or HA-coated uncemented stems implanted over the 1991-2001 period. There was no difference in the risk of revision between all-poly cemented-cups and press-fit porous-coated uncemented cups implanted during the same period, when the end point was defined as any revision (including exchange of liner). All uncemented stem designs studied in young patients with primary OA had >90% survival rates at 10 years. The Biomet Bi-Metric stem had a 95% (95% CI 93-97) survival rate even at 15 years. When the end point was defined as any revision, 10 year survival rates of all uncemented cup designs except the Harris-Galante II decreased to <80%. In young patients with RA, the risk of stem revision due to aseptic loosening was higher with cemented stems than with proximally porous-coated uncemented stems. In contrast, the risk of cup revision was higher for all uncemented cup concepts than for all-poly cemented cups with any type of cup revision as the end point. The Harris hip score increased significantly (p<0.001) both in patients with high con-genital hip dislocation and in patients with severely dysplastic hips and a previous Schanz osteotomy, treated with uncemented THA. There was a negative Trendelenburg sign in 92% and in 88% of hips, respectively. There were 12 (18%) and 15 (22%) perioperative complications. The rate of survival for the CDH femoral components, with revision due to aseptic loosening as the end point, was 98% (95% CI 97-100) at 10 years in patients with high hip dislocation and 92% (95% CI, 86-99) at 14 years in patients with a previous Schanz osteotomy. The rate of survival for press-fit, porous-coated acetabular components, with revision due to aseptic loosening as the end point, was 95% (95% CI 89-100) at 10 years in patients with high hip dislocation, and 98% (95% CI 89-100) in patients with a previous Schanz osteotomy. When revision of the cup for any reason was defined as the end point, 10 year sur-vival rates declined to 88% (95% CI 81-95) and to 69% (95% CI, 56-82), respectively. For young patients with primary OA, uncemented proximally circumferentially porous- and HA-coated stems are the implants of choice. However, survival rates of modern uncemented cups are no better than that of all-poly cemented cups. Uncemented proximally circumferentially porous-coated stems and cemented all-poly cups are currently the implants of choice for young patients with RA. Uncemented THA, with placement of the cup at the level of the true acetabulum, distal advancement of the greater trochanter and femoral shortening osteotomy provided patients with high congenital hip dislocation good long-term outcomes. Most of the patients with severely dysplastic hips and a previous Schanz osteotomy can be successfully treated with the same method. However, the subtrochanteric segmental shortening with angular correction gives better leg length correction for the patients with a previous low-seated unilateral Schanz osteotomy.