Talking About Time in Russian and Finnish

In this study I look at what people want to express when they talk about time in Russian and Finnish, and why they use the means they use. The material consists of expressions of time: 1087 from Russian and 1141 from Finnish. They have been collected from dictionaries, usage guides, corpora, and the Internet. An expression means here an idiomatic set of words in a preset form, a collocation or construction. They are studied as lexical entities, without a context, and analysed and categorized according to various features. The theoretical background for the study includes two completely different approaches. Functional Syntax is used in order to find out what general meanings the speaker wishes to convey when talking about time and how these meanings are expressed in specific languages. Conceptual metaphor theory is used for explaining why the expressions are as they are, i.e. what kind of conceptual metaphors (transfers from one conceptual domain to another) they include. The study has resulted in a grammatically glossed list of time expressions in Russian and Finnish, a list of 56 general meanings involved in these time expressions and an account of the means (constructions) that these languages have for expressing the general meanings defined. It also includes an analysis of conceptual metaphors behind the expressions. The general meanings involved turned out to revolve around expressing duration, point in time, period of time, frequency, sequence, passing of time, suitable time and the right time, life as time, limitedness of time, and some other notions having less obvious semantic relations to the others. Conceptual metaphor analysis of the material has shown that time is conceptualized in Russian and Finnish according to the metaphors Time Is Space (Time Is Container, Time Has Direction, Time Is Cycle, and the Time Line Metaphor), Time Is Resource (and its submapping Time Is Substance), Time Is Actor; and some characteristics are added to these conceptualizations with the help of the secondary metaphors Time Is Nature and Time Is Life. The limits between different conceptual metaphors and the connections these metaphors have with one another are looked at with the help of the theory of conceptual integration (the blending theory) and its schemas. The results of the study show that although Russian and Finnish are typologically different, they are very similar both in the needs of expression their speakers have concerning time, and in the conceptualizations behind expressing time. This study introduces both theoretical and methodological novelties in the nature of material used, in developing empirical methodology for conceptual metaphor studies, in the exactness of defining the limits of different conceptual metaphors, and in seeking unity among the different facets of time. Keywords: time, metaphor, time expression, idiom, conceptual metaphor theory, functional syntax, blending theory

Essays on the Role of Time in Price Discovery (summary section only)

The purpose of this thesis is to examine the role of trade durations in price discovery. The motivation to use trade durations in the study of price discovery is that durations are robust to many microstructure effects that introduce a bias in the measurement of returns volatility. Another motivation to use trade durations in the study of price discovery is that it is difficult to think of economic variables, which really are useful in the determination of the source of volatility at arbitrarily high frequencies. The dissertation contains three essays. In the first essay, the role of trade durations in price discovery is examined with respect to the volatility pattern of stock returns. The theory on volatility is associated with the theory on the information content of trade, dear to the market microstructure theory. The first essay documents that the volatility per transaction is related to the intensity of trade, and a strong relationship between the stochastic process of trade durations and trading variables. In the second essay, the role of trade durations in price discovery is examined with respect to the quantification of risk due to a trading volume of a certain size. The theory on volume is intrinsically associated with the stock volatility pattern. The essay documents that volatility increases, in general, when traders choose to trade with large transactions. In the third essay, the role of trade durations in price discovery is examined with respect to the information content of a trade. The theory on the information content of a trade is associated with the theory on the rate of price revisions in the market. The essay documents that short durations are associated with information. Thus, traders are compensated for responding quickly to information

Accurate mass-based analysis in human sport doping control : Application of liquid chromatography - time-of-flight mass spectrometry

Human sport doping control analysis is a complex and challenging task for anti-doping laboratories. The List of Prohibited Substances and Methods, updated annually by World Anti-Doping Agency (WADA), consists of hundreds of chemically and pharmacologically different low and high molecular weight compounds. This poses a considerable challenge for laboratories to analyze for them all in a limited amount of time from a limited sample aliquot. The continuous expansion of the Prohibited List obliges laboratories to keep their analytical methods updated and to research new available methodologies. In this thesis, an accurate mass-based analysis employing liquid chromatography - time-of-flight mass spectrometry (LC-TOFMS) was developed and validated to improve the power of doping control analysis. New analytical methods were developed utilizing the high mass accuracy and high information content obtained by TOFMS to generate comprehensive and generic screening procedures. The suitability of LC-TOFMS for comprehensive screening was demonstrated for the first time in the field with mass accuracies better than 1 mDa. Further attention was given to generic sample preparation, an essential part of screening analysis, to rationalize the whole work flow and minimize the need for several separate sample preparation methods. Utilizing both positive and negative ionization allowed the detection of almost 200 prohibited substances. Automatic data processing produced a Microsoft Excel based report highlighting the entries fulfilling the criteria of the reverse data base search (retention time (RT), mass accuracy, isotope match). The quantitative performance of LC-TOFMS was demonstrated with morphine, codeine and their intact glucuronide conjugates. After a straightforward sample preparation the compounds were analyzed directly without the need for hydrolysis, solvent transfer, evaporation or reconstitution. The hydrophilic interaction technique (HILIC) provided good chromatographic separation, which was critical for the morphine glucuronide isomers. A wide linear range (50-5000 ng/ml) with good precision (RSD<10%) and accuracy (±10%) was obtained, showing comparable or better performance to other methods used. In-source collision-induced dissociation (ISCID) allowed confirmation analysis with three diagnostic ions with a median mass accuracy of 1.08 mDa and repeatable ion ratios fulfilling WADA s identification criteria. The suitability of LC-TOFMS for screening of high molecular weight doping agents was demonstrated with plasma volume expanders (PVE), namely dextran and hydroxyethylstarch (HES). Specificity of the assay was improved, since interfering matrix compounds were removed by size exclusion chromatography (SEC). ISCID produced three characteristic ions with an excellent mean mass accuracy of 0.82 mDa at physiological concentration levels. In summary, by combining TOFMS with a proper sample preparation and chromatographic separation, the technique can be utilized extensively in doping control laboratories for comprehensive screening of chemically different low and high molecular weight compounds, for quantification of threshold substances and even for confirmation. LC-TOFMS rationalized the work flow in doping control laboratories by simplifying the screening scheme, expediting reporting and minimizing the analysis costs. Therefore LC-TOFMS can be exploited widely in doping control, and the need for several separate analysis techniques is reduced.

Mechanism-based inhibition of CYP2C8 by gemfibrozil in humans : characterisation of time and dose relationships

Drug-drug interactions may cause serious, even fatal clinical consequences. Therefore, it is important to examine the interaction potential of new chemical entities early in drug development. Mechanism-based inhibition is a pharmacokinetic interaction type, which causes irreversible loss of enzyme activity and can therefore lead to unusually profound and long-lasting consequences. The in vitro in vivo extrapolation (IVIVE) of drug-drug interactions caused by mechanism-based inhibition is challenging. Consequently, many of these interactions have remained unrecognised for many years. The concomitant use of the fibrate-class lipid-lowering agent gemfibrozil increases the concentrations of some drugs and their effects markedly. Even fatal cases of rhabdomyolysis occurred in patients administering gemfibrozil and cerivastatin concomitantly. One of the main mechanisms behind this effect is the mechanism-based inhibition of the cytochrome P450 (CYP) 2C8 enzyme by a glucuronide metabolite of gemfibrozil leading to increased cerivastatin concentrations. Although the clinical use of gemfibrozil has clearly decreased during recent years, gemfibrozil is still needed in some special cases. To enable safe use of gemfibrozil concomitantly with other drugs, information concerning the time and dose relationships of CYP2C8 inhibition by gemfibrozil should be known. This work was carried out as four in vivo clinical drug-drug interaction studies to examine the time and dose relationships of the mechanism-based inhibitory effect of gemfibrozil on CYP2C8. The oral antidiabetic drug repaglinide was used as a probe drug for measuring CYP2C8 activity in healthy volunteers. In this work, mechanism-based inhibition of the CYP2C8 enzyme by gemfibrozil was found to occur rapidly in humans. The inhibitory effect developed to its maximum already when repaglinide was given 1-3 h after gemfibrozil intake. In addition, the inhibition was shown to abate slowly. A full recovery of CYP2C8 activity, as measured by repaglinide metabolism, was achieved 96 h after cessation of gemfibrozil treatment. The dose-dependency of the mechanism-based inhibition of CYP2C8 by gemfibrozil was shown for the first time in this work. CYP2C8 activity was halved by a single 30 mg dose of gemfibrozil or by twice daily administration of less than 30 mg of gemfibrozil. Furthermore, CYP2C8 activity was decreased over 90% by a single dose of 900 mg gemfibrozil or twice daily dosing of approximately 100 mg gemfibrozil. In addition, with the application of physiological models to the data obtained in the dose-dependency studies, the major role of mechanism-based inhibition of CYP2C8 in the interaction between gemfibrozil and repaglinide was confirmed. The results of this work enhance the proper use of gemfibrozil and the safety of patients. The information related to time-dependency of CYP2C8 inhibition by gemfibrozil may also give new insights in order to improve the IVIVE of the drug-drug interactions of new chemical entities. The information obtained by this work may be utilised also in the design of clinical drug-drug interaction studies in the future.

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.

Rhetoric and Representation : Exploring the Cultural Meaning of the Natural Sciences in Contemporary Popular Science Writing and Literature

Kirjallisuuden- ja kulttuurintutkimus on viimeisten kolmen vuosikymmenen aikana tullut yhä enenevässä määrin tietoiseksi tieteen ja taiteen suhteen monimutkaisesta luonteesta. Nykyään näiden kahden kulttuurin tutkimus muodostaa oman kenttänsä, jolla niiden suhdetta tarkastellaan ennen kaikkea dynaamisena vuorovaikutuksena, joka heijastaa kulttuurimme kieltä, arvoja ja ideologisia sisältöjä. Toisin kuin aiemmat näkemykset, jotka pitävät tiedettä ja taidetta toisilleen enemmän tai vähemmän vastakkaisina pyrkimyksinä, nykytutkimus lähtee oletuksesta, jonka mukaan ne ovat kulttuurillisesti rakentuneita diskursseja, jotka kohtaavat usein samankaltaisia todellisuuden mallintamiseen liittyviä ongelmia, vaikka niiden käyttämät metodit eroavatkin toisistaan. Väitöskirjani keskittyy yllä mainitun suhteen osa-alueista popularisoidun tietokirjallisuuden (muun muassa Paul Davies, James Gleick ja Richard Dawkins) käyttämän kielen ja luonnontieteistä ideoita ammentavan kaunokirjallisuuden (muun muassa Jeanette Winterson, Tom Stoppard ja Richard Powers) hyödyntämien keinojen tarkasteluun nojautuen yli 30 teoksen kattavaa aineistoa koskevaan tyylin ja teemojen tekstianalyysiin. Populaarin tietokirjallisuuden osalta tarkoituksenani on osoittaa, että sen käyttämä kieli rakentuu huomattavassa määrin sellaisille rakenteille, jotka tarjoavat mahdollisuuden esittää todellisuutta koskevia argumentteja mahdollisimman vakuuttavalla tavalla. Tässä tehtävässä monilla klassisen retoriikan määrittelemillä kuvioilla on tärkeä rooli, koska ne auttavat liittämään sanotun sisällön ja muodon tiukasti toisiinsa: retoristen kuvioiden käyttö ei näin ollen edusta pelkkää tyylikeinoa, vaan se myös usein kiteyttää argumenttien taustalla olevat tieteenfilosofiset olettamukset ja auttaa vakiinnuttamaan argumentoinnin logiikan. Koska monet aikaisemmin ilmestyneistä tutkimuksista ovat keskittyneet pelkästään metaforan rooliin tieteellisissä argumenteissa, tämä väitöskirja pyrkii laajentamaan tutkimuskenttää analysoimalla myös toisenlaisten kuvioiden käyttöä. Osoitan myös, että retoristen kuvioiden käyttö muodostaa yhtymäkohdan tieteellisiä ideoita hyödyntävään kaunokirjallisuuteen. Siinä missä popularisoitu tiede käyttää retoriikkaa vahvistaakseen sekä argumentatiivisia että kaunokirjallisia ominaisuuksiaan, kuvaa tällainen sanataide tiedettä tavoilla, jotka usein heijastelevat tietokirjallisuuden kielellisiä rakenteita. Toisaalta on myös mahdollista nähdä, miten kaunokirjallisuuden keinot heijastuvat popularisoidun tieteen kerrontatapoihin ja kieleen todistaen kahden kulttuurin dynaamisesta vuorovaikutuksesta. Nykyaikaisen populaaritieteen retoristen elementtien ja kaunokirjallisuuden keinojen vertailu näyttää lisäksi, kuinka tiede ja taide osallistuvat keskusteluun kulttuurimme tiettyjen peruskäsitteiden kuten identiteetin, tiedon ja ajan merkityksestä. Tällä tavoin on mahdollista nähdä, että molemmat ovat perustavanlaatuisia osia merkityksenantoprosessissa, jonka kautta niin tieteelliset ideat kuin ihmiselämän suuret kysymyksetkin saavat kulttuurillisesti rakentuneen merkityksensä.

Focus on Form : J. J. Tikkanen, Giotto and Art Research in the 19th Century

My doctoral dissertation is on Johan Jakob Tikkanen (1857 1930), the first professor of art history in Finland, and his significance and methods in the context of late 19th and early 20th-century European art history. Tikkanen was one of the pioneering scholars in the field of medieval art research, and, along with Anton Springer, Heinrich Wölfflin, Aloïs Riegl, Adolfo Venturi, Franz Wickhoff, Julius von Schlosser, Aby Warburg, Emile Mâle and others, one of the scholars who defined art history as an independent academic discipline. Tikkanen s scholarly interests and his methods resemble those of many formalistically oriented German and Austrian art historians of his time. He became well known throughout Europe, mainly for his studies on illustrated medieval manuscripts. Tikkanen s dissertation, Der Malerische Styl Giotto s Versuch zu einer Characteristik Desselben, from 1884 was regarded in its day as the best form-analytical study on the painter. It has a central position in the present thesis, as it already included nearly all the methods that Tikkanen used and elaborated upon throughout his career. Giotto also gives a good perspective for comparing Tikkanen s ideas with a long art-historical tradition. Tikkanen was profoundly interested in artistic creativity. In his own words, he wanted to study das künstlerische Können , artistic ability, instead of das künstlerische Wollen or artistic will, which was an important theoretical issue in art history in the late 19th century. This starting point led him to the history of style and iconographical research. Along with the Danish art historian, Julius Lange, he was one of the first scholars who began to study the meaning of gestures and postures in art. In my dissertation I have emphasized the importance of Tikkanen s personal art education. I regard it as having influenced both his scholarly argumentation and his working methods. I have also written a short overview of the situation of art history in Finland and in Northern Countries before Tikkanen s time in order to give an idea of his scientific background. My thesis is a critical and historiographical study on J. J. Tikkanen s role in the development of art history and its methodology.

Ajan sisäkkäiset tilat. Arkkitehtuuri, valokuva ja menneisyyden esittäminen W. G. Sebaldin romaanissa Austerlitz

In her thesis, Kaisa Kaakinen analyzes how the German emigrant author W. G. Sebald (1944-2001) uses architecture and photography in his last novel "Austerlitz" to represent time, history and remembering. Sebald describes time in spatial terms: it is like a building, the rooms and chambers of which are connected to each other. The poetics of spatial time manifests itself on multiple levels of the text. Kaakinen traces it in architectural representations, photographic images, intertextuality, as well as in the form of the text, using the concept of spatial form by Joseph Frank. Architectural and photographic representations serve as meeting points for different aspects and angles of the novel and illustrate the idea of a layered present that has multiple connections to the past. The novel tells a story of Jacques Austerlitz, who as a small child was sent from Prague to Britain in one of the so-called Kindertransports that saved children from Central Europe occupied by the National Socialists. Only gradually he remembers his Jewish parents, who have most likely perished in Nazi concentration camps. The novel brings the problematic of writing about another person's past to the fore by the fact that Austerlitz's story is told by an anonymous narrator, Austerlitz's interlocutor, who listens to and writes down Austerlitz's story. Kaakinen devotes the final part of her thesis to study the demands of representing a historical trauma, drawing on authors such as Dominick LaCapra and Michael Rothberg. Through the analysis of architectural and photographic representations in the novel, she demonstrates how Austerlitz highlights the sense of singularity and inaccessibility of memories of an individual, while also stressing the necessity - and therefore a certain kind of possibility - of passing these memories to another person. The coexistence of traumatic narrowness and of the infinity of history is reflected in ambivalent buildings. Some buildings in the novel resemble reversible figures: they can be perceived simultaneously as ruins and as construction sites. Buildings are also shown to be able to both cover and preserve memories - an idea that also is repeated in the use of photography, which tends to both replace memories and cause an experience of the presence of an absent thing. Commenting and critisizing some recent studies on Sebald, the author develops a reading which stresses the ambivalence inherent in Sebald's view on history and historiography. Austerlitz shows the need to recognize the inevitable absence of the past as well as the distance from the experiences of others. Equally important, however, is the refusal to give up narrating the past: Sebald's novel stresses the necessity to preserve the sites of the past, which carry silent traces of vanished life. The poetics of Austerlitz reflects the paradox of the simultaneous impossibility and indispensability of writing history.

A sequential analysis of "nú" and "núna" in Icelandic conversation

This thesis is an empirical study of how two words in Icelandic, "nú" and "núna", are used in contemporary Icelandic conversation. My aims in this study are, first, to explain the differences between the temporal functions of "nú" and "núna", and, second, to describe the non-temporal functions of "nú". In the analysis, a focus is placed on comparing the sequential placement of the two words, on their syntactical distribution, and on their prosodic realization. The empirical data comprise 14 hours and 11 minutes of naturally occurring conversation recorded between 1996 and 2003. The selected conversations represent a wide range of interactional contexts including informal dinner parties, institutional and non-institutional telephone conversations, radio programs for teenagers, phone-in programs, and, finally, a political debate on television. The theoretical and methodological framework is interactional linguistics, which can be described as linguistically oriented conversation analysis (CA). A comparison of "nú" and "núna" shows that the two words have different syntactic distributions. "Nú" has a clear tendency to occur in the front field, before the finite verb, while "núna" typically occurs in the end field, after the object. It is argued that this syntactic difference reflects a functional difference between "nú" and "núna". A sequential analysis of "núna" shows that the word refers to an unspecified period of time which includes the utterance time as well as some time in the past and in the future. This temporal relation is referred to as reference time. "Nú", by contrast, is mainly used in three different environments: a) in temporal comparisons, 2) in transitions, and 3) when the speaker is taking an affective stance. The non-temporal functions of "nú" are divided into three categories: a) "nú" as a tone particle, 2) "nú" as an utterance particle, and 3) "nú" as a dialogue particle. "Nú" as a tone particle is syntactically integrated and can occur in two syntactic positions: pre-verbally and post-verbally. I argue that these instances are employed in utterances in which a speaker is foregrounding information or marking it as particularly important. The study shows that, although these instances are typically prosodically non-prominent and unstressed, they are in some cases delivered with stress and with a higher pitch than the surrounding talk. "Nú" as an utterance particle occurs turn-initially and is syntactically non-integrated. By using "nú", speakers show continuity between turns and link new turns to prior ones. These instances initiate either continuations by the same speaker or new turns after speaker shifts. "Nú" as a dialogue particle occurs as a turn of its own. The study shows that these instances register informings in prior turns as unexpected or as a departure from the normal state of affairs. "Nú" as a dialogue particle is often delivered with a prolonged vowel and a recognizable intonation contour. A comparative sequential and prosodic analysis shows that in these cases there is a correlation between the function of "nú" and the intonation contour by which it is delivered. Finally, I argue that despite the many functions of "nú", all the instances can be said to have a common denominator, which is to display attention towards the present moment and the utterances which are produced prior or after the production of "nú". Instead of anchoring the utterances in external time or reference time, these instances position the utterance in discourse internal time, or discourse time.

Nonverbal predication in Erzya : Studies on morphosyntactic variation and part of speech distinctions

This dissertation consists of four articles and an introduction. The five parts address the same topic, nonverbal predication in Erzya, from different perspectives. The work is at the same time linguistic typology and Uralic studies. The findings based on a large corpus of empirical Erzya data, which was collected using several different methods and included recordings of the spoken language, made it possible for the present study to apply, then test and finally discuss the previous theories based on cross-linguistic data. Erzya makes use of multiple predication patterns which vary from totally analytic to the morphologically very complex. Nonverbal predicate clause types are classified on the basis of propositional acts in clauses denoting class-membership, identity, property and location. The predicates of these clauses are nouns, adjectives and locational expressions, respectively. The following three predication strategies in Erzya nonverbal predication can be identified: i. the zero-copula construction, ii. the predicative suffix construction and iii. the copula construction. It has been suggested that verbs and nouns cannot be clearly distinguished on morphological grounds when functioning as predicates in Erzya. This study shows that even though predicativity must not be considered a sufficient tool for defining parts of speech in any language, the Erzya lexical classes of adjective, noun and verb can be distinguished from each other also in predicate position. The relative frequency and degree of obligation for using the predicative suffix construction decreases when moving left to right on the scale verb adjective/locative noun ( identificational statement). The predicative suffix is the main pattern in the present tense over the whole domain of nonverbal predication in Standard Erzya, but if it is replaced it is most likely to be with a zero-copula construction in a nominal predication. This study exploits the theory of (a)symmetry for the first time in order to describe verbal vs. nonverbal predication. It is shown that the asymmetry of paradigms and constructions differentiates the lexical classes. Asymmetrical structures are motivated by functional level asymmetry. Variation in predication as such adds to the complexity of the grammar. When symmetric structures are employed, the functional complexity of grammar decreases, even though morphological complexity increases. The genre affects the employment of predication strategies in Erzya. There are differences in the relative frequency of the patterns, and some patterns are totally lacking from some of the data. The clearest difference is that the past tense predicative suffix construction occurs relatively frequently in Standard Erzya, while it occurs infrequently in the other data. Also, the predicative suffixes of the present tense are used more regularly in written Standard Erzya than in any other genre. The genre also affects the incidence of the translative in uľ(ń)ems copula constructions. In translations from Russian to Erzya the translative case is employed relatively frequently in comparison to other data. This study reveals differences between the two Mordvinic languages Erzya and Moksha. The predicative suffixes (bound person markers) of the present tense are used more regularly in Moksha in all kinds of nonverbal predicate clauses compared to Erzya. It should further be observed that identificational statements are encoded with a predicative suffix in Moksha, but seldom in Erzya. Erzya clauses are more frequently encoded using zero-constructions, displaying agreement in number only.

Expression and function of angiotensins in the regulation of intraocular pressure - an experimental study

Glaucoma is a multifactorial long-term ocular neuropathy associated with progressive loss of the visual field, retinal nerve fiber structural abnormalities and optic disc changes. Like arterial hypertension it is usually a symptomless disease, but if left untreated leads to visual disability and eventual blindness. All therapies currently used aim to lower intraocular pressure (IOP) in order to minimize cell death. Drugs with new mechanisms of action could protect glaucomatous eyes against blindness. Renin-angiotensin system (RAS) is known to regulate systemic blood pressure and compounds acting on it are in wide clinical use in the treatment of hypertension and heart failure but not yet in ophthalmological use. There are only few previous studies concerning intraocular RAS, though evidence is accumulating that drugs antagonizing RAS can also lower IOP, the only treatable risk factor in glaucoma. The main aim of this experimental study was to clarify the expression of the renin-angiotensin system in the eye tissues and to test its potential oculohypotensive effects and mechanisms. In addition, the possible relationship between the development of hypertension and IOP was evaluated in animal models. In conclusion, a novel angiotensin receptor type (Mas), as well as ACE2 enzyme- producing agonists for Mas, were described for the first time in the eye structures participating in the regulation of IOP. In addition, a Mas receptor agonist significantly reduced even normal IOP. The effect was abolished by a specific receptor antagonist. Intraocular, local RAS would thus to be involved in the regulation of IOP, probably even more in pathological conditions such as glaucoma though there was no unambiguous relationship between arterial and ocular hypertension. The findings suggest the potential as antiglaucomatous drugs of agents which increase ACE2 activity and the formation of angiotensin (1-7), or activate Mas receptors.

Familial aggregation of type 1 diabetes and diabetic nephropathy in Finland

Type 1 diabetes (T1D) is a common, multifactorial disease with strong familial clustering. In Finland, the incidence of T1D among children aged 14 years or under is the highest in the world. The increase in incidence has been approximately 2.4% per year. Although most new T1D cases are sporadic the first-degree relatives are at an increased risk of developing the same disease. This study was designed to examine the familial aggregation of T1D and one of its serious complications, diabetic nephropathy (DN). More specifically the study aimed (1) to determine the concordance rates of T1D in monozygotic (MZ) and dizygotic (DZ) twins and to estimate the relative contributions of genetic and environmental factors to the variability in liability to T1D as well as to study the age at onset of diabetes in twins; (2) to obtain long-term empirical estimates of the risk of T1D among siblings of T1D patients and the factors related to this risk, especially the effect of age at onset of diabetes in the proband and the birth cohort effect; (3) to establish if DN is aggregating in a Finnish population-based cohort of families with multiple cases of T1D, and to assess its magnitude and particularly to find out whether the risk of DN in siblings is varying according to the severity of DN in the proband and/or the age at onset of T1D: (4) to assess the recurrence risk of T1D in the offspring of a Finnish population-based cohort of patients with childhood onset T1D, and to investigate potential sex-related effects in the transmission of T1D from the diabetic parents to their offspring as well as to study whether there is a temporal trend in the incidence. The study population comprised of the Finnish Young Twin Cohort (22,650 twin pairs), a population-based cohort of patients with T1D diagnosed at the age of 17 years or earlier between 1965 and 1979 (n=5,144) and all their siblings (n=10,168) and offspring (n=5,291). A polygenic, multifactorial liability model was fitted to the twin data. Kaplan-Meier analyses were used to provide the cumulative incidence for the development of T1D and DN. Cox s proportional hazards models were fitted to the data. Poisson regression analysis was used to evaluate temporal trends in incidence. Standardized incidence ratios (SIRs) between the first-degree relatives of T1D patients and background population were determined. The twin study showed that the vast majority of affected MZ twin pairs remained discordant. Pairwise concordance for T1D was 27.3% in MZ and 3.8% in DZ twins. The probandwise concordance estimates were 42.9% and 7.4%, respectively. The model with additive genetic and individual environmental effects was the best-fitting liability model to T1D, with 88% of the phenotypic variance due to genetic factors. The second paper showed that the 50-year cumulative incidence of T1D in the siblings of diabetic probands was 6.9%. A young age at diagnosis in the probands considerably increased the risk. If the proband was diagnosed at the age of 0-4, 5-9, 10-14, 15 or more, the corresponding 40-year cumulative risks were 13.2%, 7.8%, 4.7% and 3.4%. The cumulative incidence increased with increasing birth year. However, SIR among children aged 14 years or under was approximately 12 throughout the follow-up. The third paper showed that diabetic siblings of the probands with nephropathy had a 2.3 times higher risk of DN compared with siblings of probands free of nephropathy. The presence of end stage renal disease (ESRD) in the proband increases the risk three-fold for diabetic siblings. Being diagnosed with diabetes during puberty (10-14) or a few years before (5-9) increased the susceptibility for DN in the siblings. The fourth paper revealed that of the offspring of male probands, 7.8% were affected by the age of 20 compared with 5.3% of the offspring of female probands. Offspring of fathers with T1D have 1.7 times greater risk to be affected with T1D than the offspring of mothers with T1D. The excess risk in the offspring of male fathers manifested itself through the higher risk the younger the father was when diagnosed with T1D. Young age at onset of diabetes in fathers increased the risk of T1D greatly in the offspring, but no such pattern was seen in the offspring of diabetic mothers. The SIR among offspring aged 14 years or under remained fairly constant throughout the follow-up, approximately 10. The present study has provided new knowledge on T1D recurrence risk in the first-degree relatives and the risk factors modifying the risk. Twin data demonstrated high genetic liability for T1D and increased heritability. The vast majority of affected MZ twin pairs, however, remain discordant for T1D. This study confirmed the drastic impact of the young age at onset of diabetes in the probands on the increased risk of T1D in the first-degree relatives. The only exception was the absence of this pattern in the offspring of T1D mothers. Both the sibling and the offspring recurrence risk studies revealed dynamic changes in the cumulative incidence of T1D in the first-degree relatives. SIRs among the first-degree relatives of T1D patients seems to remain fairly constant. The study demonstrates that the penetrance of the susceptibility genes for T1D may be low, although strongly influenced by the environmental factors. Presence of familial aggregation of DN was confirmed for the first time in a population-based study. Although the majority of the sibling pairs with T1D were discordant for DN, its presence in one sibling doubles and presence of ESRD triples the risk of DN in the other diabetic sibling. An encouraging observation was that although the proportion of children to be diagnosed with T1D at the age of 4 or under is increasing, they seem to have a decreased risk of DN or at least delayed onset.

Effect of waiting time on health outcomes and service utilization : A prospective randomized study on patients admitted to hospital for hip or knee replacement

Although the principle of equal access to medically justified treatment has been promoted by official health policies in many Western health care systems, practices do not completely meet policy targets. Waiting times for elective surgery vary between patient groups and regions, and growing problems in the availability of services threaten equal access to treatment. Waiting times have come to the attention of decision-makers, and several policy initiatives have been introduced to ensure the availability of care within a reasonable time. In Finland, for example, the treatment guarantee came into force in 2005. However, no consensus exists on optimal waiting time for different patient groups. The purpose of this multi-centre randomized controlled trial was to analyse health-related quality of life, pain and physical function in total hip or knee replacement patients during the waiting time and to evaluate whether the waiting time is associated with patients health outcomes at admission. This study also assessed whether the length of waiting time is associated with social and health services utilization in patients awaiting total hip or knee replacement. In addition, patients health-related quality of life was compared with that of the general population. Consecutive patients with a need for a primary total hip or knee replacement due to osteoarthritis were placed on the waiting list between August 2002 and November 2003. Patients were randomly assigned to a short waiting time (maximum 3 months) or a non-fixed waiting time (waiting time not fixed in advance, instead the patient followed the hospitals routine practice). Patients health-related quality of life was measured upon being placed on the waiting list and again at hospital admission using the generic 15D instrument. Pain and physical function were evaluated using the self-report Harris Hip Score for hip patients and a scale modified from the Knee Society Clinical Rating System for knee patients. Utilization measures were the use of home health care, rehabilitation and social services, physician visits and inpatient care. Health and social services use was low in both waiting time groups. The most common services used while waiting were rehabilitation services and informal care, including unpaid care provided by relatives, neighbours and volunteers. Although patients suffered from clear restrictions in usual activities and physical functioning, they seemed primarily to lean on informal care and personal networks instead of professional care. While longer waiting time did not result in poorer health-related quality of life at admission and use of services during the waiting time was similar to that at the time of placement on the list, there is likely to be higher costs of waiting by people who wait longer simply because they are using services for a longer period. In economic terms, this would represent a negative impact of waiting. Only a few reports have been published of the health-related quality of life of patients awaiting total hip or knee replacement. These findings demonstrate that, in addition to physical dimensions of health, patients suffered from restrictions in psychological well-being such as depression, distress and reduced vitality. This raises the question of how to support patients who suffer from psychological distress during the waiting time and how to develop strategies to improve patients initiatives to reduce symptoms and the burden of waiting. Key words: waiting time, total hip replacement, total knee replacement, health-related quality of life, randomized controlled trial, outcome assessment, social service, utilization of health services

Sindbis virus and Pogosta disease in Finland

Sindbis virus (SINV) (genus Alphavirus, family Togaviridae) is an enveloped virus with a genome of single-stranded, positive-polarity RNA of 11.7 kilobases. SINV is widespread in Eurasia, Africa, and Australia, but clinical infection only occurs in a few geographically restricted areas, mainly in Northern Europe. In Europe, antibodies to SINV were detected from patients with fever, rash, and arthritis for the first time in the early 1980s in Finland. It became evident that the causative agent of this syndrome, named Pogosta disease, was closely related to SINV. The disease is also found in Sweden (Ockelbo disease) and in Russia (Karelian fever). Since 1974, for unknown reason, the disease has occurred as large outbreaks every seven years in Finland. This study is to a large degree based on the material collected during the 2002 Pogosta disease outbreak in Finland. We first developed SINV IgM and IgG enzyme immunoassays (EIA), based on highly purified SINV, to be used in serodiagnostics. The EIAs correlated well with the hemagglutination inhibition (HI) test, and all individuals showed neutralizing antibodies. The sensitivities of the IgM and IgG EIAs were 97.6% and 100%, and specificities 95.2% and 97.6%, respectively. E1 and E2 envelope glycoproteins of SINV were shown to be recognized by IgM and IgG in the immunoblot early in infection. We isolated SINV from five patients with acute Pogosta disease; one virus strain was recovered from whole blood, and four other strains from skin lesions. The etiology of Pogosta disease was confirmed by these first Finnish SINV strains, also representing the first human SINV isolates from Europe. Phylogenetic analysis indicated that the Finnish SINV strains clustered with the strains previously isolated from mosquitoes in Sweden and Russia, and seemed to have a common ancestor with South-African strains. Northern European SINV strains could be maintained locally in disease-endemic regions, but the phylogenetic analysis also suggests that redistribution of SINV tends to occur in a longitudinal direction, possibly with migratory birds. We searched for SINV antibodies in resident grouse (N=621), whose population crashes have previously coincided with human SINV outbreaks, and in migratory birds (N=836). SINV HI antibodies were found for the first time in birds during their spring migration to Northern Europe, from three individuals: red-backed shrike, robin, and song thrush. Of the grouse, 27.4% were seropositive in 2003, one year after a human outbreak, but only 1.4% of the grouse were seropositive in 2004. Thus, grouse might contribute to the human epidemiology of SINV. A total of 86 patients with verified SINV infection were recruited to the study in 2002. SINV RNA detection or virus isolation from blood and/or skin lesions was successful in eight patients. IgM antibodies became detectable within the first eight days of illness, and IgG within 11 days. The acute phase of Pogosta disease was characterized by arthritis, itching rash, fatigue, mild fever, headache, and muscle pain. Half of the patients reported in self-administered questionnaires joint symptoms to last > 12 months. Physical examination in 49 of these patients three years after infection revealed persistent joint manifestations. Arthritis (swelling and tenderness in physical examination) was diagnosed in 4.1% (2/49) of the patients. Tenderness in palpation or in movement of a joint was found in 14.3% of the patients in the rheumatologic examination, and additional 10.2% complained persisting arthralgia at the interview. Thus, 24.5% of the patients had joint manifestations attributable to the infection three years earlier. A positive IgM antibody response persisted in 3/49 of the patients; both two patients with arthritis were in this group. Persistent symptoms of SINV infection might have considerable public health implications in areas with high seroprevalence. The age-standardized seroprevalence of SINV (1999-2003, N=2529) in the human population in Finland was 5.2%. The seroprevalence was high in North Karelia, Kainuu, and Central Ostrobothnia. The incidence was highest in North Karelia. Seroprevalence in men (6.0%) was significantly higher than in women (4.1%), however, the average annualized incidence in the non-epidemic years was higher in women than in men, possibly indicating that infected men are more frequently asymptomatic. The seroprevalence increased with age, reaching 15.4% in persons aged 60-69 years. The incidence was highest in persons aged 50-59 years.

Tree mortality and deadwood dynamics in late-successional boreal forests

Here I aimed at quantifying the main components of deadwood dynamics, i.e. tree mortality, deadwood pools, and their decomposition, in late-successional boreal forests. I focused on standing dead trees in three stand types dominated by Picea mariana and Abies balsamea in eastern Canada, and on standing and down dead trees in Picea abies-dominated stands in three areas in Northern Europe. Dead and living trees were measured on five sample plots of 1.6-ha size in each study area and stand type. Stem disks from dead trees were sampled to determine wood density and year of death, using dendrochronological methods. The results were applied to reconstruct past tree mortality and to model deadwood decay class dynamics. Site productivity, stand developmental stage, and the occurrence of episodic tree mortality influenced deadwood volume and quality. In all study areas tree mortality was continuous, leading to continuity in deadwood decay stage distribution. Episodic tree mortality due to either autogenic or allogenic causes influenced deadwood volume and quality in all but one study area. However, regardless of productivity and disturbance history deadwood was abundant, accounting for 20 53% of total wood volume in European study areas, and 15 27% of total standing volume in eastern Canada. Deadwood was a persistent structural component, since its expected residence time in early- and midstages of decay was 18 yr even in the area with the most rapid decomposition. The results indicated that in the absence of episodic tree mortality, stands may eventually develop to a steady state, in which deadwood volume fluctuates around an equilibrium state. However, in many forests deadwood is naturally variable, due to recurrent moderate-severity disturbances. This variability, the continuous tree mortality, and variation in rates of wood decomposition determine the dynamics and availability of deadwood as a habitat and carbon storage medium in boreal coniferous forest ecosystems.