Studies on Matrix Metalloproteinase (MMP-2, -9 and -14) and β2 Integrin Targeting as Potential Anticancer Therapeutics

Proteolytic enzymes, such as matrix metalloproteinases (MMP), are associated to the progression of several cancers. They degrade extracellular components, which helps tumors to expand and cancer cells to escape from the primary site. Of all MMPs, gelatinases (MMP-2 and -9) and membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14), in particular, are often associated to more aggressive types of head and neck carcinomas as well as to a poorer outcome in patient survival. Although therapies during the last decades have advanced, the mortality of the disease is still rather high and adjuvant therapies are searched for continuously. MMP-9 and MT1-MMP are also involved in neo-angiogenesis, which is necessary for tumor expansion. For this reason, we have identified synthetic peptides-targeting gelatinases and MT1-MMP, and have also evaluated their anticancer effects in vitro and in vivo. Antigelatinolytic peptides effectively inhibited tongue-carcinoma cell invasion and reduced the growth of xenografted tumors. In tumor samples of mice that were treated with antigelatinolytic peptides, the micro-vessel density was significantly reduced. We also identified a novel MT1-MMP targeting peptide and demonstrated that it exerted anticancer effects against several malignant cell lines in vitro. The effects of MT1-MMP inhibition on tongue-squamous cell carcinomas were evaluated by using xenograft tumors, which it effectively inhibited. Tranexamic acid was also demonstrated to inhibit tongue-squamous cell carcinoma invasion, most probably due to its ability to prevent the plasmin-mediated activation of proMMP-9. Leukocyte β2 integrins are another interesting option when evaluating targets for the therapeutic intervention of inflammatory conditions or malignancies of hematopoietic origin, since β2 integrins are expressed mainly by leukocytes. We identified a novel technique for screening small-molecule libraries against β2 integrins, and by using this technique we identified a novel αMβ2 integrin-binding chemical (IMB-10). IMB-10 significantly enhances leukocyte adhesion and inhibits their motility. We also demonstrated that IMB-10 can be used to inhibit inflammation and lymphoma growth in vivo. Interestingly, IMB-10 also reduced leukocyte tumor infiltration and inhibited tumor invasion.

Democracy, Participation, and Deliberation in China : The discussion about democratic centralism in the official Chinese press, 1978-1981

This study examines the Chinese press discussion about democratic centralism in 1978-1981 in newspapers, political journals and academic journals distributed nationwide. It is thus a study of intellectual trends during the Hua Guofeng period and of methods, strategies, and techniques of public political discussion of the time. In addition, this study presents democratic centralism as a comprehensive theory of democracy and evaluates this theory. It compares the Chinese theory of democratic centralism with Western traditions of democracy, not only with the standard liberal theory but also with traditions of participatory and deliberative democracy, in order to evaluate whether the Chinese theory of democratic centralism forms a legitimate theory of democracy. It shows that the Chinese theory comes close to participatory types of democracy and shares a conception of democracy as communication with the theory of deliberative democracy. Therefore, the Chinese experience provides some empirical evidence of the practicability of these traditions of democracy. Simultaneously, this study uses experiences of participatory democracies outside of China to explain some earlier findings about the Chinese practices. This dissertation also compares Chinese theory with some common Western theories and models of Chinese society as well as with Western understandings of Chinese political processes. It thus aims at opening more dialogue between Chinese and Western political theories and understandings about Chinese polity. This study belongs to scholarly traditions of the history of ideas, political philosophy, comparative politics, and China studies. The main finding of this study is that the Chinese theory of democratic centralism is essentially a theory about democracy, but whether its scrupulous practicing alone would be sufficient for making a country a democracy depends on which established definition of democracy one applies and on what kind of democratic deficits are seen as being acceptable within a truly democratic system. Nevertheless, since the Chinese theory of democratic centralism fits well with some established definitions of democracy and since democratic deficits are a reality in all actual democracies, the Chinese themselves are talking about democracy in terms acceptable to Western political philosophy as well.

Dancing and Professional Dancers in Roman Egypt

The main aim of the study is to create a many-sided view of dancing in Roman Egypt (1st - early 4th centuries AD) and especially of the dancers who earned their living by dancing as hired performers. Even though dancers and other performers played a central part in many kinds of festivities throughout the ancient world, research on ancient professional dancers is rare and tends to rest on the ancient literature, which reflects the opinions of the elite. Documentary written sources (i.e., papyri, ostraka) the core of the present study are mentioned rather superficially, easily resulting in a stereotypical view of the dancers. This study will balance the picture of professional dancers in antiquity and of ancient dancing in a more general sense. The second aim characterizes this study as basic research: to provide a corpus of written sources from Greco-Roman Egypt on dancing and to discuss pictorial sources contemporary with the texts. The study also takes into account the theoretical discussion that centres on dancing as a nonverbal communicative mode. Dancers are seen as significant conveyors of social and cultural matters. This study shows that dancers were hired to perform especially in religious contexts, where the local associations on the village level also played an important part as the employers of the performers. These performers had a better standard of living in economic terms than the average hired worker, and dancers were better paid than other performers. In the Egyptian villages and towns, where the dancers performed and lived, the dancers do not seem to have been marginal because they were professionals or because of some ethnic or social background. However, their possible marginality may have occurred for reasons related to the practicalities of their profession (e.g., the itinerant life style). The oriental background of performers was a literary topos reflecting partly the situation in the centres of the empire, especially Rome, where many performers were of other than Roman origin. The connection of dancing, prostitution and slavery reflects the essential link between dance, body and gender: dancers are equated with such professions or socio-legal statuses where the body is the focus of attention, a commodity and a source of sensual pleasure; this dimension is clearly observable in ancient literature. According to the Egyptian documentary sources, there is no watertight evidence that professional dancers would have been engaged in prostitution and very little, if any, evidence that the disapproval of the professional dancers expressed by the ancient authors was shared by the Egyptians. From the 4th century onwards the dancers almost disappear from the documentary sources, reflecting the political and religious changes in the Mediterranean east.

A Sketch of the Phonology and Grammar of Rajbanshi

This dissertation is a synchronic description of the phonology and grammar of two dialects of the Rajbanshi language (Eastern Indo-Aryan) as spoken in Jhapa, Nepal. I have primarily confined the analysis to the oral expression, since the emerging literary form is still in its infancy. The grammatical analysis is therefore based, for the most part, on a corpus of oral narrative text which was recorded and transcribed from three informants from north-east Jhapa. An informant, speaking a dialect from south-west Jhapa cross checked this text corpus and provided additional elicited material. I have described the phonology, morphology and syntax of the language, and also one aspect of its discourse structure. For the most part the phonology follows the basic Indo-Aryan pattern. Derivational morphology, compounding, reduplication, echo formation and onomatopoeic constructions are considered, as well as number, noun classes (their assignment and grammatical function), pronouns, and case and postpositions. In verbal morphology I cover causative stems, the copula, primary and secondary agreement, tense, aspect, mood, auxiliary constructions and non-finite forms. The term secondary agreement here refers to genitive agreement, dative-subject agreement and patient (and sometimes patient-agent) agreement. The breaking of default agreement rules has a range of pragmatic inferences. I argue that a distinction, based on formal, semantic and statistical grounds, should be made between conjunct verbs, derivational compound verbs and quasi-aspectual compound verbs. Rajbanshi has an open set of adjectives, and it additionally makes use of a restricted set of nouns which can function as adjectives. Various particles, and the emphatic and conjunctive clitics are also considered. The syntactic structures studied include: non-declarative speech acts, phrase-internal and clause-internal constituent order, negation, subordination, coordination and valence adjustment. I explain how the future, present and past tenses in Rajbanshi oral narratives do not seem to maintain a time reference, but rather to indicate a distinction between background and foreground information. I call this tense neutralisation .

Complicated Presence : The Unity of Being in Parmenides and Heidegger

The attempt to refer meaningful reality as a whole to a unifying ultimate principle - the quest for the unity of Being - was one of the basic tendencies of Western philosophy from its beginnings in ancient Greece up to Hegel's absolute idealism. However, the different trends of contemporary philosophy tend to regard such a speculative metaphysical quest for unity as obsolete. This study addresses this contemporary situation on the basis of the work of Martin Heidegger (1889-1976). Its methodological framework is Heidegger's phenomenological and hermeneutical approach to the history of philosophy. It seeks to understand, in terms of the metaphysical quest for unity, Heidegger's contrast between the first (Greek) beginning or "onset" (Anfang) of philosophy and another onset of thinking. This other onset is a possibility inherent in the contemporary situation in which, according to Heidegger, the metaphysical tradition has developed to its utmost limits and thereby come to an end. Part I is a detailed interpretation of the surviving fragments of the Poem of Parmenides of Elea (fl. c. 500 BC), an outstanding representative of the first philosophical beginning in Heidegger's sense. It is argued that the Poem is not a simple denial of apparent plurality and difference ("mortal acceptances," doxai) in favor of an extreme monism. Parmenides' point is rather to show in what sense the different instances of Being can be reduced to an absolute level of truth or evidence (aletheia), which is the unity of Being as such (to eon). What in prephilosophical human experience is accepted as being is referred to the source of its acceptability: intelligibility as such, the simple and undifferentiated presence to thinking that ultimately excludes unpresence and otherness. Part II interprets selected key texts from different stages in Heidegger's thinking in terms of the unity of Being. It argues that one aspect of Heidegger's sustained and gradually deepening philosophical quest was to think the unity of Being as singularity, as the instantaneous, context-specific, and differential unity of a temporally meaningful situation. In Being and Time (1927) Heidegger articulates the temporal situatedness of the human awareness of meaningful presence. His later work moves on to study the situational correlation between presence and the human awareness. Heidegger's "postmetaphysical" articulation seeks to show how presence becomes meaningful precisely as situated, in an event of differentiation from a multidimensional context of unpresence. In resigning itself to this irreducibly complicated and singular character of meaningful presence, philosophy also faces its own historically situated finitude. This resignation is an essential feature of Heidegger's "other onset" of thinking.

"Han är en trollkarl. Alla skriver laudatur som går på hans lektioner" : en studie om elevernas uppfattningar om orsakerna till toppresultat i svenska i tre finska gymnasier

Tämä pro gradu -tutkielma on tehty osana Svenska i toppen -projektia, joka alkoi syksyllä 2008 Pohjoismaisten kielten ja pohjoismaisen kirjallisuuden laitoksella. Tutkimuksen tavoitteena on selvittää, mitkä tekijät vaikuttavat lukiolaisten näkökulmasta hyvien tulosten saavuttamiseen ruotsin ylioppilaskirjoituksissa kolmessa suomenkielisessä lukiossa, jotka sijaitsevat Turun, Tampereen ja Joensuun seuduilla. Lisäksi tavoitteena on selvittää, miten maantieteelliset tekijät vaikuttavat opiskelijoiden ruotsin kielen osaamiseen sekä mitä eroja on keskipitkän ja pitkän ruotsin oppimäärän opiskelijoiden asenteissa kieltä kohtaan. Tutkielman aineistona on kolme ryhmähaastattelua, joihin on osallistunut 14 lukiolaista, 11 tyttöä ja 3 poikaa. Haastattelut on tehty joulukuussa 2008 sekä tammi- ja maaliskuussa 2009. Haastatteluissa on käytetty strukturoitua kyselylomaketta, jossa kysytään opiskelijoiden näkemyksiä ruotsin opiskelusta. Tutkimusmenetelmänä on kvalitatiivinen tutkimusote, jossa on piirteitä kolmesta eri menetelmästä: tapaustutkimuksesta, etnografisesta tutkimuksesta sekä temaattisesta analyysistä. Tärkeimpänä teoriataustana on ruotsi toisena kielenä -tutkimus, oppiminen sosiokonstruktivistisena ilmiönä sekä motivaatiotutkimus. Tarkastelen kielenoppijaa luokkahuoneessa sosiaalisena osallistujana omassa oppimisprosessissaan. Oppiminen nähdään kokonaisuutena, johon kuuluu eri osa-alueita, esimerkiksi koulujen käytännöt, yhteisön vaikutus oppimiseen sekä opiskelijan identiteetin muokkautuminen kouluyhteisössä. Motivaatiota tarkastelen kielenoppimisen näkökulmasta, ja se koostuu erilaisista dynaamisista vaiheista, esimerkiksi tavoitteiden asettamisesta oppimisprosessin alussa, valintojen tekemisestä sekä motivaation ylläpitämisestä oppimisprosessin kuluessa. Tutkimuksen tulokset osoittavat, että suurin yksittäinen syy menestykseen opiskelijoiden näkökulmasta on opettaja, joka omalla toiminnallaan voi merkittävästi parantaa opiskelijoiden oppimisedellytyksiä. Työhön panostaminen, opiskelijoiden yksilöllinen kohtaaminen myös luokkahuoneen ulkopuolella ja esimerkiksi omien oppimateriaalien valmistaminen ovat opettajaan liittyviä tekijöitä, jotka voivat nostaa opiskelijoiden motivaatiota huomattavasti. Myös lukion maantieteellisellä sijainnilla on vaikutusta. Paikkakunnilla, joilla ruotsin kieltä käytetään vähän, korostuu opettajan rooli kielellisen oppimisympäristön luomisessa. Keskipitkän ja pitkän ruotsin opiskelijoiden välillä ei tutkimuksessa ilmene eroja asenteissa kieltä kohtaan.

Fatigued driving : prevalence, risk factors and groups, and the law

Fatigue and sleepiness are major causes of road traffic accidents. However, precise data is often lacking because a validated and reliable device for detecting the level of sleepiness (cf. the breathalyzer for alcohol levels) does not exist, nor does criteria for the unambiguous detection of fatigue/sleepiness as a contributing factor in accident causation. Therefore, identification of risk factors and groups might not always be easy. Furthermore, it is extremely difficult to incorporate fatigue in operationalized terms into either traffic or criminal law. The main aims of this thesis were to estimate the prevalence of fatigue problems while driving among the Finnish driving population, to explore how VALT multidisciplinary investigation teams, Finnish police, and courts recognize (and prosecute) fatigue in traffic, to identify risk factors and groups, and finally to explore the application of the Finnish Road Traffic Act (RTA), which explicitly forbids driving while tired in Article 63. Several different sources of data were used: a computerized database and the original folders of multidisciplinary teams investigating fatal accidents (VALT), the driver records database (AKE), prosecutor and court decisions, a survey of young male military conscripts, and a survey of a representative sample of the Finnish active driving population. The results show that 8-15% of fatal accidents during 1991-2001 were fatigue related, that every fifth Finnish driver has fallen asleep while driving at some point during his/her driving career, and that the Finnish police and courts punish on average one driver per day on the basis of fatigued driving (based on the data from the years 2004-2005). The main finding regarding risk factors and risk groups is that during the summer months, especially in the afternoon, the risk of falling asleep while driving is increased. Furthermore, the results indicate that those with a higher risk of falling asleep while driving are men in general, but especially young male drivers including military conscripts and the elderly during the afternoon hours and the summer in particular; professional drivers breaking the rules about duty and rest hours; and drivers with a tendency to fall asleep easily. A time-of-day pattern of sleep-related incidents was repeatedly found. It was found that VALT teams can be considered relatively reliable when assessing the role of fatigue and sleepiness in accident causation; thus, similar experts might be valuable in the court process as expert witnesses when fatigue or sleepiness are suspected to have a role in an accident’s origins. However, the application of Article 63 of the RTA that forbids, among other things, fatigued driving will continue to be an issue that deserves further attention. This should be done in the context of a needed attitude change towards driving while in a state of extreme tiredness (e.g., after being awake for more than 24 hours), which produces performance deterioration comparable to illegal intoxication (BAC around 0.1%). Regarding the well-known interactive effect of increased sleepiness and even small alcohol levels, the relatively high proportion (up to 14.5%) of Finnish drivers owning and using a breathalyzer raises some concern. This concern exists because these drivers are obviously more focused on not breaking the “magic” line of 0.05% BAC than being concerned about driving impairment, which might be much worse than they realize because of the interactive effects of increased sleepiness and even low alcohol consumption. In conclusion, there is no doubt that fatigue and sleepiness problems while driving are common among the Finnish driving population. While we wait for the invention of reliable devices for fatigue/sleepiness detection, we should invest more effort in raising public awareness about the dangerousness of fatigued driving and educate drivers about how to recognize and deal with fatigue and sleepiness when they ultimately occur.

Learning challenges of NGOs in development : Co-operation of Finnish NGOs in Morogoro, Tanzania

Non-governmental organisations (NGOs) have gained an important role in development co-operation during the last two decades. The development funding channelled through NGOs has increased and the number of NGOs engaged in development activities, both North and South, has been growing. Supporting NGOs has been seen as one way to strengthen civil society in the South and to provide potential for enhancing more effective development than the state, and to exercise participatory development and partnership in their North-South relationships. This study focuses on learning in the co-operation practices of small Finnish NGOs in Morogoro, Tanzania. Drawing on the cultural-historical activity theory and the theory of expansive learning, in this study I understand learning as a qualitative change in the actual co-operation practices. The qualitative change, for its part, emerges out of attempts to deal with the contradictions in the present activity. I use the concept of developmental contradiction in exploring the co-operation of the small Finnish NGOs with their Tanzanian counterparts. Developmental contradiction connects learning to actual practice and its historical development. By history, in this study I refer to multiple developmental trajectories, such as trajectories of individual participants, organisations, co-operation practices and the institutional system in which the NGO-development co-operation is embedded. In the empirical chapters I explore the co-operation both in the development co-operation projects and in micro-level interaction between partners taking place within the projects. I analyse the perceptions of the Finnish participants about the different developmental trajectories, the tensions, inclusions and exclusions in the evolving object of co-operation in one project, the construction of power relations in project meetings in three projects, and the collision of explicated partnership with the emerging practice of trusteeship in one project. On the basis of the empirical analyses I elaborate four developmental contradictions and learning challenges for the co-operation. The developmental contradictions include: 1) implementing a ready-made Finnish project idea vs. taking the current activities of Tanzanian NGO as a starting point; 2) gaining experiences and cultural interaction vs. access to outside funding; 3) promoting the official tools of development co-operation in training vs. use of tools and procedures taken from the prior activities of both partners in actual practice; and 4) asymmetric relations between the partners vs. rhetoric of equal partnership. Consequently, on the basis of developmental contradictions four learning challenges are suggested: a shift from legitimation of Finnish ideas to negotiation, transcending the separate objects and finding a partly joint object, developing locally shared tools for the co-operation, and identification and reflection of the power relations in the practice of co-operation. Keywords: activity theory; expansive learning; NGO development co-operation; partnership; power

Koulukasvatusta teknologisoituvaan yhteiskuntaan : Kansakoulun opetussuunnitelman rakentuminen, 1945-1952

Education for a Technological Society. Public School Curriculum Construction, 1945-1952. The subject of my research is the significance of technology in the construction process of the public school curriculum during the years 1945-1952. During the period the war reparation and rebuilding placed demands and actions to rationalise and dramatise industry and agriculture. Thereby the ambitions of building a technological country and the reformation of curriculum took place simultaneously. Fordistian terms of reference, of which the principles were mass production, rationalisation and standardisation, a hierarchical division of labour and partition of assignments, provided a model for the developing curriculum. In the research the curriculum is examined as an artefact, which shapes socio-technically under the influence of social and technical factors. In the perspective of socio-technical construction the artefact is represented by the viewpoints of members of relevant social groups. The groups give meaning to the curriculum artefact, which determines the components of the curriculum. The weakness of the curriculum was its ineffectiveness, which was due to three critical problems. Firstly, the curriculum was to be based on scientific work, which meant the development of schools through experiments and scientific research. Secondly, the civilised conseption in the curriculum was to be composed of theoretical knowledge, as well as practical skills. Practical education was useful for both the individual and society. Thirdly, the curriculum was to be reformed in a way that the individuality of the pupil would be taken into account. It was useful for the society that talents and natural abilities of every pupil were observed and used to direct the pupil to the proper place in the social division of labour, according to the "right man in a right place" principle. The solutions to critical problems formed the instructions of the public school curriculum, which described the nature and content of education. Technology and its development were on essential part of the whole school curriculum process. The quality words connected to the development of technology - progress, rationality and effectiveness - were also suitable qualifiers and reasons for the reform of the curriculum. On the other hand, technology set a point of comparison and demand for the development of all phases of education. The view of technology was not clearly deterministic - it was also possible to shape technological society with the help of education. The public school curriculum process indicates how originally the principles of technological systems were shaped to the language of education and accepted in educational content.

Self-Concept and School Achievement of Pupils with Cleft Lip, Cleft Palate or Both : A longitudinal study

The goal of this research was to survey the self-concept and school achievement of pupils with cleft lip, cleft palate or both from juvenile age to adolescence. Longitudinal researches of self-concept and school achievement among pupils with cleft lip, cleft palate or both are uncommon. This research was the first longitudinal research ever conducted in Finland among this population. This research can be considered to be a special educational study because of the target group involved. Self-concept consists of the person s entire personality. Personality is biological and deterministic. Self-concept includes concepts, attitudes and feelings that the person has about him or her qualities, abilities and relations to the environment. The individual associates experiences to this personality with earlier observations through the social interaction. The individual will have the consciousness of the person s existence and action. The target group in this study consisted of Finnish children with clefts, who were comprised of four different age groups. The questionnaire was sent to all subjects (N1 = 419) both times. A total of 74 % of children returned the questionnaire in 1988 (N2=305). 48 % of children returned the questionnaire in 1993 (N3=203). 42% of children returned the questionnaire both times (N4=175) . These 175 children formed the research subjects. The survey was conducted in 1988, and again in 1993. In 1988, the pupils surveyed were 9 to 12 years of age, while in 1993 they were between 14 and 17 years old. The data was collected through the use of a questionnaire, which consisted of common questions and a personality inventory test that was developed for Finnish students by professor Maija-Liisa Rauste-von Wright. Quantitative analysis methods were used to examine the structure of self-concept and school achievement. Structures found in this research were observed in relation to disorder, gender and maturation. According to these results, structures of self-concepts and school achievement are in fact stable. Basic self-concept elements are seen to be formed at an early age. The developmental aspects of self-concept following puberty are observed as the stability of self-concept and as the forming of a general self. The level of school achievement is stable, but the structure of school achievement changes. From these results, it is possible to state that the gender of the child has a statistical significance regarding self-concept and school achievement. However, the experienced disorder does not have statistical significance as regards to self-concept and school achievement. Results of self-concept support the research of self-concept conducted earlier in Finland.

Effects of dairy proteins and calcium on diet-induced obesity in mice

Diet high in dairy products is inversely associated with body mass index, risk of metabolic syndrome and prevalence of type 2 diabetes in several populations. Also a number of intervention studies support the role of increased dairy intake in the prevention and treatment of obesity. Dairy calcium has been suggested to account for the effect of dairy on body weight, but it has been repeatedly shown that the effect of dairy is superior to the effect of supplemental calcium. Dairy proteins are postulated to either enhance the effect of calcium or have an independent effect on body weight, but studies in the area are scarce. The aim of this study was to evaluate the potential of dairy proteins and calcium in the prevention and treatment of diet-induced obesity in C57Bl/6J mice. The effect of dairy proteins and calcium on the liver and adipose tissue was also investigated in order to characterise the potential mechanisms explaining the reduction of risk for metabolic syndrome and type 2 diabetes. A high-calcium diet (1.8%) in combination with dietary whey protein inhibited body weight and fat gain and accelerated body weight and fat loss in high-fat-fed C57Bl/6J mice during long-term studies of 14 to 21 weeks. α-lactalbumin, one of the major whey proteins, was the most effective whey protein fraction showing significantly accelerated weight and fat loss during energy restriction and reduced the amount of visceral fat gain during ad libitum feeding after weight loss. The microarray data suggest sensitisation of insulin signalling in the adipose tissue as a result of a calcium-rich whey protein diet. Lipidomic analysis revealed that weight loss on whey protein-based high-calcium diet was characterised by significant decreases in diabetogenic diacylglycerols and lipotoxic ceramide species. The calcium supplementation led to a small, but statistically significant decrease in fat absorption independent of the protein source of the diet. This augments, but does not fully explain the effects of the studied diets on body weight. A whey protein-containing high-calcium diet had a protective effect against a high-fat diet-induced decline of β3 adrenergic receptor expression in adipose tissue. In addition, a high-calcium diet with whey protein increased the adipose tissue leptin expression which is decreased in this obesity-prone mouse strain. These changes are likely to contribute to the inhibition of weight gain. The potential sensitisation of insulin signalling in adipose tissue together with the less lipotoxic and diabetogenic hepatic lipid profile suggest a novel mechanistic link to explain why increased dairy intake is associated with a lower prevalence of metabolic syndrome and type 2 diabetes in epidemiological studies. Taken together, the intake of a high-calcium diet with dairy proteins has a body weight lowering effect in high-fat-fed C57Bl/6J mice. High-calcium diets containing whey protein prevent weight gain and enhance weight loss, α-lactalbumin being the most effective whey protein fraction. Whey proteins and calcium have also beneficial effects on hepatic lipid profile and adipose tissue gene expression, which suggest a novel mechanistic link to explain the epidemiological findings on dairy intake and metabolic syndrome. The clinical relevance of these findings and the precise mechanisms of action remain an intriguing field of future research.

Microarrays in molecular profiling of cancer - focus on head and neck squamous cell carcinoma

Microarrays have a wide range of applications in the biomedical field. From the beginning, arrays have mostly been utilized in cancer research, including classification of tumors into different subgroups and identification of clinical associations. In the microarray format, a collection of small features, such as different oligonucleotides, is attached to a solid support. The advantage of microarray technology is the ability to simultaneously measure changes in the levels of multiple biomolecules. Because many diseases, including cancer, are complex, involving an interplay between various genes and environmental factors, the detection of only a single marker molecule is usually insufficient for determining disease status. Thus, a technique that simultaneously collects information on multiple molecules allows better insights into a complex disease. Since microarrays can be custom-manufactured or obtained from a number of commercial providers, understanding data quality and comparability between different platforms is important to enable the use of the technology to areas beyond basic research. When standardized, integrated array data could ultimately help to offer a complete profile of the disease, illuminating mechanisms and genes behind disorders as well as facilitating disease diagnostics. In the first part of this work, we aimed to elucidate the comparability of gene expression measurements from different oligonucleotide and cDNA microarray platforms. We compared three different gene expression microarrays; one was a commercial oligonucleotide microarray and the others commercial and custom-made cDNA microarrays. The filtered gene expression data from the commercial platforms correlated better across experiments (r=0.78-0.86) than the expression data between the custom-made and either of the two commercial platforms (r=0.62-0.76). Although the results from different platforms correlated reasonably well, combining and comparing the measurements were not straightforward. The clone errors on the custom-made array and annotation and technical differences between the platforms introduced variability in the data. In conclusion, the different gene expression microarray platforms provided results sufficiently concordant for the research setting, but the variability represents a challenge for developing diagnostic applications for the microarrays. In the second part of the work, we performed an integrated high-resolution microarray analysis of gene copy number and expression in 38 laryngeal and oral tongue squamous cell carcinoma cell lines and primary tumors. Our aim was to pinpoint genes for which expression was impacted by changes in copy number. The data revealed that especially amplifications had a clear impact on gene expression. Across the genome, 14-32% of genes in the highly amplified regions (copy number ratio >2.5) had associated overexpression. The impact of decreased copy number on gene underexpression was less clear. Using statistical analysis across the samples, we systematically identified hundreds of genes for which an increased copy number was associated with increased expression. For example, our data implied that FADD and PPFIA1 were frequently overexpressed at the 11q13 amplicon in HNSCC. The 11q13 amplicon, including known oncogenes such as CCND1 and CTTN, is well-characterized in different type of cancers, but the roles of FADD and PPFIA1 remain obscure. Taken together, the integrated microarray analysis revealed a number of known as well as novel target genes in altered regions in HNSCC. The identified genes provide a basis for functional validation and may eventually lead to the identification of novel candidates for targeted therapy in HNSCC.

Associations among Emdogain®, human oral carcinoma cells and oral proteolytic enzymes

The Enamel matrix derivative Emdogain® (EMD) is a commercially available tissue extract preparation of porcine enamel origin. Studies have shown EMD to be clinically useful in promoting periodontal regeneration. EMD has been widely used in periodontal therapy for over ten years, but the mechanism of its action and the exact composition are not completely clear. EMD is predominantly amelogenin (>90%). However, unlike amelogenin, EMD has a number of growth factor-like effects and it has been shown to enhance the proliferation, migration and other cellular functions of periodontal ligament fibroblasts and osteoblasts. In contrast, the effects of EMD on epithelial cell lines and in particular on oral malignant cells have not been adequately studied. In addition, EMD has effects on the production of cytokines by several oral cell lines and the product is in constant interaction with different oral enzymes. Regardless of the various unknown properties of EMD, it is said to be clinically safe in regenerative procedures, also in medically compromised patients. The aim of the study was to examine whether gingival crevicular fluid (GCF), which contains several different proteolysis enzymes, could degrade EMD and alter its biological functions. In addition, the objective was to study the effects of EMD on carcinogenesis-related factors, in particular MMPs, using in vitro and in vivo models. This study also aimed to contribute to the understanding of the composition of EMD. GCF was capable of degrading EMD, depending on the periodontal status, with markedly more degradation in all states of periodontal disease compared to healthy controls. EMD was observed to stimulate the migration of periodontal ligament fibroblasts (PLF), whereas EMD together with GCF could not stimulate this proliferation. In addition, recombinant amelogenin, the main component of EMD, decreased the migration of PLFs. A comparison of changes induced by EMD and TGF-β1 in the gene profiles of carcinoma cells showed TGF-β1 to regulate a greater number of genes than EMD. However, both of the study reagents enhanced the expression of MMP-10 and MMP-9. Furthermore, EMD was found to induce several factors closely related to carcinogenesis on gene, protein, cell and in vivo levels. EMD enhanced the production of MMP-2, MMP-9 and MMP-10 proteins by cultured carcinoma cells. In addition, EMD stimulated the migration and in vitro wound closure of carcinoma cells. EMD was also capable of promoting metastasis formation in mice. In conclusion, the diseased GCF, containing various proteases, causes degradation of EMD and decreased proliferation of PLFs. Thus, this in vitro study suggests that the regenerative effect of EMD may decrease due to proteases present in periodontal tissues during the inflammation and healing of the tissues in vivo. Furthermore, EMD was observed to enhance several carcinoma-related factors and in particular the production of MMPs by benign and malignant cell lines. These findings suggest that the clinical safety of EMD with regard to dysplastic mucosal lesions should be further investigated.

Evidence-based perspective on CP rehabilitation : Reviews on physiotherapy, physiotherapy-related motor-based interventions and orthotic devices

This thesis utilises an evidence-based approach to critically evaluate and summarize effectiveness research on physiotherapy, physiotherapy-related motor-based interventions and orthotic devices in children and adolescents with cerebral palsy (CP). It aims to assess the methodological challenges of the systematic reviews and trials, to evaluate the effectiveness of interventions in current use, and to make suggestions for future trials Methods: Systematic reviews were searched from computerized bibliographic databases up to August 2007 for physiotherapy and physiotherapy-related interventions, and up to May 2003 for orthotic devices. Two reviewers independently identified, selected, and assessed the quality of the reviews using the Overview Quality Assessment Questionnaire complemented with decision rules. From a sample of 14 randomized controlled trials (RCT) published between January 1990 and June 2003 we analysed the methods of sampling, recruitment, and comparability of groups; defined the components of a complex intervention; identified outcome measures based on the International Classification of Functioning, Disability and Health (ICF); analysed the clinical interpretation of score changes; and analysed trial reporting using a modified 33-item CONSORT (Consolidated Standards of Reporting Trials) checklist. The effectiveness of physiotherapy and physiotherapy-related interventions in children with diagnosed CP was evaluated in a systematic review of randomised controlled trials that were searched from computerized databases from January 1990 up to February 2007. Two reviewers independently assessed the methodological quality, extracted the data, classified the outcomes using the ICF, and considered the level of evidence according to van Tulder et al. (2003). Results: We identified 21 reviews on physiotherapy and physiotherapy-related interventions and five on orthotic devices. These reviews summarized 23 or 5 randomised controlled trials and 104 or 27 observational studies, respectively. Only six reviews were of high quality. These found some evidence supporting strength training, constraint-induced movement therapy or hippotherapy, and insufficient evidence on comprehensive interventions. Based on the original studies included in the reviews on orthotic devices we found some short-term effects of lower limb casting on passive range of movement, and of ankle-foot orthoses on equinus walk. Long term effects of lower limb orthoses have not been studied. Evidence of upper limb casting or orthoses is conflicting. In the sample of 14 RCTs, most trials used simple randomisation, complemented with matching or stratification, but only three specified the concealed allocation. Numerous studies provided sufficient details on the components of a complex intervention, but the overlap of outcome measures across studies was poor and the clinical interpretation of observed score changes was mostly missing. Almost half (48%) of the applicable CONSORT-based items (range 28 32) were reported adequately. Most reporting inadequacies were in outcome measures, sample size determination, details of the sequence generation, allocation concealment and implementation of the randomization, success of assessor blinding, recruitment and follow-up dates, intention-to-treat analysis, precision of the effect size, co-interventions, and adverse events. The systematic review identified 22 trials on eight intervention categories. Four trials were of high quality. Moderate evidence of effectiveness was established for upper extremity treatments on attained goals, active supination and developmental status, and of constraint-induced therapy on the amount and quality of hand use and new emerging behaviours. Moderate evidence of ineffectiveness was found for strength training's effect on walking speed and stride length. Conflicting evidence was found for strength training's effect on gross motor function. For the other intervention categories the evidence was limited due to the low methodological quality and the statistically insignificant results of the studies. Conclusions: The high-quality reviews provide both supportive and insufficient evidence on some physiotherapy interventions. The poor quality of most reviews calls for caution, although most reviews drew no conclusions on effectiveness due to the poor quality of the primary studies. A considerable number of RCTs of good to fair methodological and reporting quality indicate that informative and well-reported RCTs on complex interventions in children and adolescents with CP are feasible. Nevertheless, methodological improvement is needed in certain areas of the trial design and performance, and the trial authors are encouraged to follow the CONSORT criteria. Based on RCTs we established moderate evidence for some effectiveness of upper extremity training. Due to limitations in methodological quality and variations in population, interventions and outcomes, mostly limited evidence on the effectiveness of most physiotherapy interventions is available to guide clinical practice. Well-designed trials are needed, especially for focused physiotherapy interventions.

Pain among employees : risk factors and consequences

The overall objective of this study was to gain epidemiological knowledge about pain among employee populations. More specifically, the aims were to assess the prevalence of pain, to identify socio-economic risk groups and work-related psychosocial risk factors, and to assess the consequences in terms of health-related functioning and sickness absence. The study was carried out among the municipal employees of the City of Helsinki. Data comprised questionnaire survey conducted in years 2000-2002 and register data on sickness absence. Altogether 8960 40-60 year old employees participated to the survey (response rate 67%). Pain is common among ageing employees. Approximately 29 per cent of employees reported chronic pain and 15 per cent acute pain, and about seven per cent reported moderately or severely limiting disabling chronic pain. Pain was more common among those with lower level of education or in a low occupational class. -- Psychosocial work environment was associated with pain reports. Job strain, bullying at workplace, and problems in combining work and home duties were associated with pain among women. Among men combining work and home duties was not associated with pain, whereas organizational injustice showed associations. Pain affects functional capacity and predicts sickness absence. Those with pain reported lower level of both mental and physical functioning than those with no pain, physical functioning being more strongly affected than mental. Bodily location of pain or whether pain was acute or chronic had only minor impact on the variation in functioning, whereas the simple count of painful locations was associated with widest variation. Pain accounted for eight per cent of short term (1-3 day) sickness absence spells among men and 13 per cent among women. Of absence spells lasting between four and 14 days pain accounted for 23 per cent among women and 25 per cent among men, corresponding figures for over 14 day absence spells being 37 and 30 per cent. The association between pain and sickness absence was relatively independent of physical and psychosocial work factors, especially among women. The results of this study provide a picture of the epidemiology of pain among employees. Pain is a significant problem that seriously affects work ability. Information on risk groups can be utilized to make prevention measures more effective among those at high risk, and to decrease pain rates and thereby narrow the differences between socio-economic groups. Furthermore, the work-related psychosocial risk factors identified in this study are potentially modifiable, and it should be possible to target interventions on decreasing pain rates among employees.