Growth factor induction in intervertebral disc tissue: Observations in basic mechanisms of disc degeneration and rearrangement

The intervertebral disc is composed of concentrically arranged components: annulus fibrosus, the transition zone, and central nucleus pulposus. The major disc cell type differs in various parts of the intervertebral disc. In annulus fibrosus a spindle shaped fibroblast-like cell mainly dominates, whereas in central nucleus pulposus the more rounded chondrocyte-like disc cell is the major cell type. At birth the intervertebral disc is well vascularized, but during childhood and adolescence blood vessels become smaller and less numerous. The adult intervertebral disc is avascular and is nourished via the cartilage endplates. On the other hand, degenerated and prolapsed intervertebral discs are again vascularized, and show many changes compared to normal discs, including: nerve ingrowth, change in collagen turnover, and change in water content. Furthermore, the prolapsed intervertebral disc tissue has a tendency to decrease in size over time. Growth factors are polypeptides which regulate cell growth, extracellular matrix protease activity, and vascularization. Oncoproteins c-Fos and c-Jun heterodimerize, forming the AP-1 transcription factor which is expressed in activated cells. In this thesis the differences of growth factor expression in normal intervertebral disc, the degenerated intervertebral disc and herniated intervertebral disc were analyzed. Growth factors of particular interest were basic fibroblast growth factor (bFGF or FGF-2), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor beta (TGFβ). Cell activation was visualized by the expression of the AP-1 transcription promoters c-Fos and c-Jun. The expression was shown with either mono- or polyclonal antibodies by indirect avidin-biotin-peroxidase immunohistochemical staining method. The normal control material was collected from a tissue bank of five organ donors. The degenerated disc material was from twelve patients operated on for painful degenerative disc disease, and herniated disc tissue material was obtained from 115 patients operated on for sciatica. Normal control discs showed only TGFβ immunopositivity. All other factors studied were immunonegative in the control material. Prolapsed disc material was immunopositive for all factors studied, and this positivity was located either in the disc cells or in blood vessels. Furthermore, neovascularization was noted. Disc cell immunoreaction was shown in chondrocyte-like disc cells or in fibroblast-like disc cells, the former being expressed especially in conglomerates (clusters of disc cells). TGFβ receptor induction was prominent in prolapsed intervertebral disc tissue. In degenerated disc material, the expression of growth factors was analyzed in greater detail in various parts of the disc: nucleus pulposus, anterior annulus fibrosus and posterior annulus fibrosus. PDGF did not show any immunoreactivity, whereas all other studied growth factors were localized either in chondrocyte-like disc cells, often forming clusters, in fibroblast-like disc cells, or in small capillaries. Many of the studied degenerated discs showed tears in the posterior region of annulus fibrosus, but expression of immunopositive growth factors was detected throughout the entire disc. Furthermore, there was a difference in immunopositive cell types for different growth factors. The main conclusion of the thesis, supported by all substudies, is the occurrence of growth factors in disc cells. They may be actively participating in a network regulating disc cell growth, proliferation, extracellular matrix turnover, and neovascularization. Chondrocyte-like disc cells, in particular, expressed growth factors and oncoproteins, highlighting the importance of this cell type in the basic pathophysiologic events involved in disc degeneration and disc rearrangement. The thesis proposes a hypothesis for cellular remodelling in intervertebral disc tissue. In summary, the model presents an activation pattern of different growth factors at different intervertebral disc stages, mechanisms leading to neovascularization of the intervertebral disc in pathological conditions, and alteration of disc cell shape, especially in annulus fibrosus. Chondrocyte-like disc cells become more numerous, and these cells are capable of forming clusters, which appear to be regionally active within the disc. The alteration of the phenotype of disc cells expressing growth factors from fibroblast-like disc cells to chondrocyte-like cells in annulus fibrosus, and the numerous expression of growth factor expressing disc cells in nucleus pulposus, may be a key element both during pathological degeneration of the intervertebral disc, and during the healing process after trauma.

Reading the Texture of Reality : Chaos Theory, Literature and the Humanist Perspective

Tutkimuksessa analysoidaan kaaosteorian vaikutusta kaunokirjallisuudessa ja kirjallisuudentutkimuksessa ja esitetään, että kaaosteorian roolia kirjallisuuden kentällä voidaan parhaiten ymmärtää sen avaamien käsitteiden kautta. Suoran soveltamisen sijaan kaaosteorian avulla on käyty uudenlaisia keskusteluja vanhoista aiheista ja luonnontieteestä ammennetut käsitteet ovat johtaneet aiemmin tukkeutuneiden argumenttien avaamiseen uudesta näkökulmasta käsin. Väitöskirjassa keskitytään kolmeen osa-alueeseen: kaunokirjallisen teoksen rakenteen teoretisointiin, ihmisen (erityisesti tekijän) identiteetin hahmottamiseen ja kuvailemiseen sekä fiktion ja todellisuuden suhteen pohdintaan. Tutkimuksen tarkoituksena on osoittaa, kuinka kaaosteorian kautta näitä aiheita on lähestytty niin kirjallisuustieteessä kuin kaunokirjallisissa teoksissakin. Väitöskirjan keskiössä ovat romaanikirjailija John Barthin, dramatisti Tom Stoppardin ja runoilija Jorie Grahamin teosten analyysit. Nämä kirjailijat ammentavat kaaosteoriasta keinoja käsitteellistää rakenteita, jotka ovat yhtä aikaa dynaamisia prosesseja ja hahmotettavia muotoja. Kaunokirjallisina teemoina nousevat esiin myös ihmisen paradoksaalisesti tunnistettava ja aina muuttuva identiteetti sekä lopullista haltuunottoa pakeneva, mutta silti kiehtova ja tavoiteltava todellisuus. Näiden kirjailijoiden teosten analyysin sekä teoreettisen keskustelun kautta väitöskirjassa tuodaan esiin aiemmassa tutkimuksessa varjoon jäänyt, koherenssia, ymmärrettävyyttä ja realismia painottava humanistinen näkökulma kaaosteorian merkityksestä kirjallisuudessa.

Space in Musical Semiosis : An Abductive Theory of the Musical Composition Process

Space in musical semiosis is a study of musical meaning, spatiality and composition. Earlier studies on musical composition have not adequately treated the problems of musical signification. Here, composition is considered an epitomic process of musical signification. Hence the core problems of composition theory are core problems of musical semiotics. The study employs a framework of naturalist pragmatism, based on C. S. Peirce’s philosophy. It operates on concepts such as subject, experience, mind and inquiry, and incorporates relevant ideas of Aristotle, Peirce and John Dewey into a synthetic view of esthetic, practic, and semiotic for the benefit of grasping musical signification process as a case of semiosis in general. Based on expert accounts, music is depicted as real, communicative, representational, useful, embodied and non-arbitrary. These describe how music and the musical composition process are mental processes. Peirce’s theories are combined with current morphological theories of cognition into a view of mind, in which space is central. This requires an analysis of space, and the acceptance of a relativist understanding of spatiality. This approach to signification suggests that mental processes are spatially embodied, by virtue of hard facts of the world, literal representations of objects, as well as primary and complex metaphors each sharing identities of spatial structures. Consequently, music and the musical composition process are spatially embodied. Composing music appears as a process of constructing metaphors—as a praxis of shaping and reshaping features of sound, representable from simple quality dimensions to complex domains. In principle, any conceptual space, metaphorical or literal, may set off and steer elaboration, depending on the practical bearings on the habits of feeling, thinking and action, induced in musical communication. In this sense, it is evident that music helps us to reorganize our habits of feeling, thinking, and action. These habits, in turn, constitute our existence. The combination of Peirce and morphological approaches to cognition serves well for understanding musical and general signification. It appears both possible and worthwhile to address a variety of issues central to musicological inquiry in the framework of naturalist pragmatism. The study may also contribute to the development of Peircean semiotics.

A Literary Turn : Rethinking the Roles of Generalization and Theory in Anglo-American Moral Philosophy

This work investigates the role of narrative literature in late-20th century and contemporary Anglo-American moral philosophy. It aims to show the trend of reading narrative literature for purposes of moral philosophy from the 1970 s and early 80 s to the present day as a part of a larger movement in Anglo-American moral philosophy, and to present a view of its significance for moral philosophy overall. Chapter 1 provides some preliminaries concerning the view of narrative literature which my discussion builds on. In chapter 2 I give an outline of how narrative literature is considered in contemporary Anglo-American moral philosophy, and connect this use to the broad trend of neo-Aristotelian ethics in this context. In chapter 3 I connect the use of literature to the idea of the non-generalizability of moral perception and judgment, which is central to the neo-Aristotelian trend, as well as to a range of moral particularisms and anti-theoretical positions of late 20th century and contemporary ethics. The joint task of chapters 2 and 3 is to situate the trend of reading narrative literature for the purposes of moral philosophy in the present context of moral philosophy. In the following two chapters, 4 and 5, I move on from the particularizing power of narrative literature, which is emphasized by neo-Aristotelians and particularists alike, to a broader under-standing of the intellectual potential of narrative literature. In chapter 4 I argue that narrative literature has its own forms of generalization which are enriching for our understanding of the workings of ethical generalizations in philosophy. In chapter 5 I discuss Iris Murdoch s and Martha Nussbaum s respective ways of combining ethical generality and particularity in a philosophical framework where both systematic moral theory and narrative literature are taken seriously. In chapter 6 I analyse the controversy between contemporary anti-theoretical conceptions of ethics and Nussbaum s refutation of these. I present my suggestion for how the significance of the ethics/literature discussion for moral philosophy can be understood if one wants to overcome the limitations of both Nussbaum s theory-centred, equilibrium-seeking perspective, and the anti-theorists repudiation of theory. I call my position the inclusive approach .

Theory and Analysis of Classic Heavy Metal Harmony

This thesis explores melodic and harmonic features of heavy metal, and while doing so, explores various methods of music analysis; their applicability and limitations regarding the study of heavy metal music. The study is built on three general hypotheses according to which 1) acoustic characteristics play a significant role for chord constructing in heavy metal, 2) heavy metal has strong ties and similarities with other Western musical styles, and 3) theories and analytical methods of Western art music may be applied to heavy metal. It seems evident that in heavy metal some chord structures appear far more frequently than others. It is suggested here that the fundamental reason for this is the use of guitar distortion effect. Subsequently, theories as to how and under what principles heavy metal is constructed need to be put under discussion; analytical models regarding the classification of consonance and dissonance and chord categorization are here revised to meet the common practices of this music. It is evident that heavy metal is not an isolated style of music; it is seen here as a cultural fusion of various musical styles. Moreover, it is suggested that the theoretical background to the construction of Western music and its analysis can offer invaluable insights to heavy metal. However, the analytical methods need to be reformed to some extent to meet the characteristics of the music. This reformation includes an accommodation of linear and functional theories that has been found rather rarely in music theory and musicology.

On the Geometry of Infinite-Dimensional Grassmannian Manifolds and Gauge Theory

This PhD Thesis is about certain infinite-dimensional Grassmannian manifolds that arise naturally in geometry, representation theory and mathematical physics. From the physics point of view one encounters these infinite-dimensional manifolds when trying to understand the second quantization of fermions. The many particle Hilbert space of the second quantized fermions is called the fermionic Fock space. A typical element of the fermionic Fock space can be thought to be a linear combination of the configurations m particles and n anti-particles . Geometrically the fermionic Fock space can be constructed as holomorphic sections of a certain (dual)determinant line bundle lying over the so called restricted Grassmannian manifold, which is a typical example of an infinite-dimensional Grassmannian manifold one encounters in QFT. The construction should be compared with its well-known finite-dimensional analogue, where one realizes an exterior power of a finite-dimensional vector space as the space of holomorphic sections of a determinant line bundle lying over a finite-dimensional Grassmannian manifold. The connection with infinite-dimensional representation theory stems from the fact that the restricted Grassmannian manifold is an infinite-dimensional homogeneous (Kähler) manifold, i.e. it is of the form G/H where G is a certain infinite-dimensional Lie group and H its subgroup. A central extension of G acts on the total space of the dual determinant line bundle and also on the space its holomorphic sections; thus G admits a (projective) representation on the fermionic Fock space. This construction also induces the so called basic representation for loop groups (of compact groups), which in turn are vitally important in string theory / conformal field theory. The Thesis consists of three chapters: the first chapter is an introduction to the backround material and the other two chapters are individually written research articles. The first article deals in a new way with the well-known question in Yang-Mills theory, when can one lift the action of the gauge transformation group on the space of connection one forms to the total space of the Fock bundle in a compatible way with the second quantized Dirac operator. In general there is an obstruction to this (called the Mickelsson-Faddeev anomaly) and various geometric interpretations for this anomaly, using such things as group extensions and bundle gerbes, have been given earlier. In this work we give a new geometric interpretation for the Faddeev-Mickelsson anomaly in terms of differentiable gerbes (certain sheaves of categories) and central extensions of Lie groupoids. The second research article deals with the question how to define a Dirac-like operator on the restricted Grassmannian manifold, which is an infinite-dimensional space and hence not in the landscape of standard Dirac operator theory. The construction relies heavily on infinite-dimensional representation theory and one of the most technically demanding challenges is to be able to introduce proper normal orderings for certain infinite sums of operators in such a way that all divergences will disappear and the infinite sum will make sense as a well-defined operator acting on a suitable Hilbert space of spinors. This research article was motivated by a more extensive ongoing project to construct twisted K-theory classes in Yang-Mills theory via a Dirac-like operator on the restricted Grassmannian manifold.

Conrad Summenhart's theory of individual rights and its medieval background

This study focuses on the theory of individual rights that the German theologian Conrad Summenhart (1455-1502) explicated in his massive work Opus septipartitum de contractibus pro foro conscientiae et theologico. The central question to be studied is: How does Summenhart understand the concept of an individual right and its immediate implications? The basic premiss of this study is that in Opus septipartitum Summenhart composed a comprehensive theory of individual rights as a contribution to the on-going medieval discourse on rights. With this rationale, the first part of the study concentrates on earlier discussions on rights as the background for Summenhart s theory. Special attention is paid to language in which right was defined in terms of power . In the fourteenth century writers like Hervaeus Natalis and William Ockham maintained that right signifies power by which the right-holder can to use material things licitly. It will also be shown how the attempts to describe what is meant by the term right became more specified and cultivated. Gerson followed the implications that the term power had in natural philosophy and attributed rights to animals and other creatures. To secure right as a normative concept, Gerson utilized the ancient ius suum cuique-principle of justice and introduced a definition in which right was seen as derived from justice. The latter part of this study makes effort to reconstructing Summenhart s theory of individual rights in three sections. The first section clarifies Summenhart s discussion of the right of the individual or the concept of an individual right. Summenhart specified Gerson s description of right as power, taking further use of the language of natural philosophy. In this respect, Summenhart s theory managed to bring an end to a particular continuity of thought that was centered upon a view in which right was understood to signify power to licit action. Perhaps the most significant feature of Summenhart s discussion was the way he explicated the implication of liberty that was present in Gerson s language of rights. Summenhart assimilated libertas with the self-mastery or dominion that in the economic context of discussion took the form of (a moderate) self-ownership. Summenhart discussion also introduced two apparent extensions to Gerson s terminology. First, Summenhart classified right as relation, and second, he equated right with dominion. It is distinctive of Summenhart s view that he took action as the primary determinant of right: Everyone has as much rights or dominion in regard to a thing, as much actions it is licit for him to exercise in regard to the thing. The second section elaborates Summenhart s discussion of the species dominion, which delivered an answer to the question of what kind of rights exist, and clarified thereby the implications of the concept of an individual right. The central feature in Summenhart s discussion was his conscious effort to systematize Gerson s language by combining classifications of dominion into a coherent whole. In this respect, his treatement of the natural dominion is emblematic. Summenhart constructed the concept of natural dominion by making use of the concepts of foundation (founded on a natural gift) and law (according to the natural law). In defining natural dominion as dominion founded on a natural gift, Summenhart attributed natural dominion to animals and even to heavenly bodies. In discussing man s natural dominion, Summenhart pointed out that the natural dominion is not sufficiently identified by its foundation, but requires further specification, which Summenhart finds in the idea that natural dominion is appropriate to the subject according to the natural law. This characterization lead him to treat God s dominion as natural dominion. Partly, this was due to Summenhart s specific understanding of the natural law, which made reasonableness as the primary criterion for the natural dominion at the expense of any metaphysical considerations. The third section clarifies Summenhart s discussion of the property rights defined by the positive human law. By delivering an account on juridical property rights Summenhart connected his philosophical and theological theory on rights to the juridical language of his times, and demonstrated that his own language of rights was compatible with current juridical terminology. Summenhart prepared his discussion of property rights with an account of the justification for private property, which gave private property a direct and strong natural law-based justification. Summenhart s discussion of the four property rights usus, usufructus, proprietas, and possession aimed at delivering a detailed report of the usage of these concepts in juridical discourse. His discussion was characterized by extensive use of the juridical source texts, which was more direct and verbal the more his discussion became entangled with the details of juridical doctrine. At the same time he promoted his own language on rights, especially by applying the idea of right as relation. He also showed recognizable effort towards systematizing juridical language related to property rights.

Interactions of nandrolone and psychostimulant drugs on central monoaminergic systems

It has been hypothesized that abuse of supra-therapeutic doses of anabolic androgenic steroids (AASs) can lead to dependence and function as a gateway to abuse of other drugs. This is supported by behavioral studies on animal models and psychiatric evaluations of human subjects, although their neurochemical effects remain largely unknown. A large body of evidence suggests that the ability of the drugs to induce a strong elevation of extracellular dopamine (DA) levels in the nucleus accumbens (NAc), especially, plays a crucial role in their reinforcing effects. -- This study had four main aims. The first was to explore the effects of nandrolone decanoate on dopaminergic and serotonergic activities in the brains of rats. The second aim was to assess whether or not nandrolone pre-exposure modulates the acute neurochemical and behavioral effects of psychostimulant drugs in experimental animals. The third was to investigate if the AAS-pre-treatment induced changes in brain reward circuitry are reversible. And the fourth main goal was to evaluate the role of androgen and estrogen receptors in the modulation of the dopaminergic and serotonergic effects of acute injections of stimulant drugs by sub-chronic nandrolone treatment. The results showed that nandrolone decanoate at doses, high enough to induce erythropoiesis, significantly increased the levels of DOPAC and 5-HT in the cerebral cortex. Co-administration of AAS and psychostimulant drugs showed that the increase in extracellular DA and 5-HT concentration evoked by amphetamine, MDMA and cocaine in the NAc was attenuated dose-dependently by pretreatment with nandrolone. Nandrolone pre-exposure also attenuated the ability of stimulants to cause increased stereotyped behavior and locomotor activity. Despite the significant decrease in nandrolone concentration in blood, the attenuation of cocaine’s effects remained unchanged after a fairly long period without nandrolone, suggesting that nandrolone effects could be long lasting. Blockade of androgen receptors with flutamide abolished the attenuating effect of nandrolone pretreatment on amphetamine-induced elevation of extracellular DA concentration. --- In conclusion, the results show that AAS-pretreatment is able to inhibit the reward-related neurochemical and behavioral effects of amphetamine, MDMA and cocaine in experimental animals. Furthermore, it seems that these effects could be long lasting and it appears that the ability of nandrolone to modulate reward-related effects of stimulants is dependent on activation of androgen receptors.

Part I: Enzyme replacement versus neurotrophic factor viral vector-mediated gene therapy of Parkinson’s disease, Part II: The effects of orally dosed tolcapone and entacapone on dopamine metabolism in the dorsal striatum and nucleus accumbens in rats

Part I: Parkinson’s disease is a slowly progressive neurodegenerative disorder in which particularly the dopaminergic neurons of the substantia nigra pars compacta degenerate and die. Current conventional treatment is based on restraining symptoms but it has no effect on the progression of the disease. Gene therapy research has focused on the possibility of restoring the lost brain function by at least two means: substitution of critical enzymes needed for the synthesis of dopamine and slowing down the progression of the disease by supporting the functions of the remaining nigral dopaminergic neurons by neurotrophic factors. The striatal levels of enzymes such as tyrosine hydroxylase, dopadecarboxylase and GTP-CH1 are decreased as the disease progresses. By replacing one or all of the enzymes, dopamine levels in the striatum may be restored to normal and behavioral impairments caused by the disease may be ameliorated especially in the later stages of the disease. The neurotrophic factors glial cell derived neurotrophic factor (GDNF) and neurturin have shown to protect and restore functions of dopaminergic cell somas and terminals as well as improve behavior in animal lesion models. This therapy may be best suited at the early stages of the disease when there are more dopaminergic neurons for neurotrophic factors to reach. Viral vector-mediated gene transfer provides a tool to deliver proteins with complex structures into specific brain locations and provides long-term protein over-expression. Part II: The aim of our study was to investigate the effects of two orally dosed COMT inhibitors entacapone (10 and 30 mg/kg) and tolcapone (10 and 30 mg/kg) with a subsequent administration of a peripheral dopadecarboxylase inhibitor carbidopa (30 mg/kg) and L- dopa (30 mg/kg) on dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens of freely moving rats using dual-probe in vivo microdialysis. Earlier similarly designed studies have only been conducted in the dorsal striatum. We also confirmed the result of earlier ex vivo studies regarding the effects of intraperitoneally dosed tolcapone (30 mg/kg) and entacapone (30 mg/kg) on striatal and hepatic COMT activity. The results obtained from the dorsal striatum were generally in line with earlier studies, where tolcapone tended to increase dopamine and DOPAC levels and decrease HVA levels. Entacapone tended to keep striatal dopamine and HVA levels elevated longer than in controls and also tended to elevate the levels of DOPAC. Surprisingly in the nucleus accumbens, dopamine levels after either dose of entacapone or tolcapone were not elevated. Accumbal DOPAC levels, especially in the tolcapone 30 mg/kg group, were elevated nearly to the same extent as measured in the dorsal striatum. Entacapone 10 mg/kg elevated accumbal HVA levels more than the dose of 30 mg/kg and the effect was more pronounced in the nucleus accumbens than in the dorsal striatum. This suggests that entacapone 30 mg/kg has minor central effects. Also our ex vivo study results obtained from the dorsal striatum suggest that entacapone 30 mg/kg has minor and transient central effects, even though central HVA levels were not suppressed below those of the control group in either brain area in the microdialysis study. Both entacapone and tolcapone suppressed hepatic COMT activity more than striatal COMT activity. Tolcapone was more effective than entacapone in the dorsal striatum. The differences between dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens may be due to different properties of the two brain areas.