The Role of Genes on Chromosome Locus 4q12 in Human Central Nervous System Tumors

Human central nervous system (CNS) tumors are a heterogeneous group of tumors occurring in brain, brainstem and spinal cord. Malignant gliomas (astrocytic and oligodendroglial tumors), which arise from the neuroepithelial cells are the most common CNS neoplasms in human. Malignant gliomas are highly aggressive and invasive tumors, and have a very poor prognosis. The development and progression of gliomas involve a stepwise accumulation of genetic alterations that generally affect either signal transduction pathways activated by receptor tyrosine kinases (RTKs), or cell cycle arrest pathways. Constitutive activation or deregulated signaling by RTKs is caused by gene amplification, overexpression or mutations. The aberrant RTK signaling results in turn in the activation of several downstream pathways, which ultimately lead to malignant transformation and tumor proliferation. Many genetic abnormalities implicated in nervous system tumors involve the genes located at the chromosomal region 4q12. This locus harbors the receptor tyrosine kinases KIT, PDGFRA and VEGFR2, and other genes (REST, LNX1) with neural function. Gene amplification and protein expression of KIT, PDGFRA, and VEGFR2 was studied using clinical tumor material. REST and LNX1, as well as NUMBL, the interaction partner of LNX1, were studied for their gene mutations and amplifications. In our studies, amplification of LNX1 was associated with KIT and PDGFRA amplification in glioblastomas, and coamplification of KIT, PDGFRA and VEGFR2 was detected in medulloblastomas and CNS primitive neuroectodermal tumors. PDGFRA amplification was also correlated with poor overall survival. Coamplification of KIT, PDGFRA and VEGFR2 was observed in a subset of human astrocytic and oligodendroglial tumors. We suggest that genes at 4q12 could be a part of a larger amplified region, which is deregulated in gliomas, and could be used as a prognostic marker of tumorigenic process. The signaling pathways activated due to gene amplifications, activating gene mutations, and overexpressed proteins may be useful as therapeutic targets for glioma treatment. This study also includes the characterization of KIT overexpressing astrocytes, analyzed by various in vitro functional assays. Our results show that overexpression of KIT in mouse astrocytes promotes cell proliferation and anchorage-independent growth, as well as phenotypic changes in the cells. Furthermore, the increased proliferation is partly inhibited by imatinib, a small molecule inhibitor of KIT. These results suggest that KIT may play a role in astrocyte growth regulation, and might have an oncogenic role in brain tumorigenesis. Elucidation of the altered signaling pathways due to specific gene amplifications, activating gene mutations, and overexpressed proteins may be useful as therapeutic targets for glioma treatment.

Foreign Capital and Finland : Central government's first period of reliance on international financial markets, 1862-1938

The main objective of the study is to evaluate the Finnish central government s foreign borrowing between the years 1862 and 1938. Most of this period was characterised by deep capital market integration that bears resemblance to the liberal world financial order at the turn of the millennium. The main aim is to analyse the credit risk associated with the state and its determination by evaluating the world financial market centres perception of Finland. By doing this, the study is also expected to provide an additional dimension to Finland s political and economic history by incorporating into the research the assessments of international capital markets regarding Finland during a period that witnessed profound political and economic changes in Finnish society. The evaluation of the credit risk mainly relies on exchange-rate risk free time series of the state s foreign bonds. They have been collected from quotations in the stock exchanges in Helsinki, Hamburg, Paris and London. In addition, it investigates Finland s exposure to short-term debt and Moody s credit ratings assigned to Finland. The study emphasises the importance of the political risk. It suggests that the hey-day of the state s reliance on foreign capital markets took place during last few decades of the 19th century when Finland enjoyed a wide autonomy in the Russian Empire and prudently managed its economy, highlighted in Finland s adherence to the international gold standard. Political confrontations in Finland and, in particular, in Russia and the turbulence of the world financial system prevented the return of this beneficial position again. Through its issuance of foreign bonds the state was able to import substantial amounts of foreign capital, which was sorely needed to foster economic development in Finland. Moreover, the study argues that the state s presence in the western capital markets not only had economic benefits, but it also increased the international awareness of Finland s distinct and separate status in the Russian Empire and later underlined its position as an independent republic.

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.

Role of γ1 Laminin and Its KDI Peptide in the Central Nervous System

Since the 1980 s, laminin-1 has been linked to regeneration of the central nervous system (CNS) and promotion of neuronal migration and axon guidance during CNS development. In this thesis, we clarify the role of γ1 laminin and its KDI tripeptide in development of human embryonic spinal cord, in regeneration of adult rat spinal cord injury (SCI), in kainic acid-induced neuronal death, and in the spinal cord tissue of amyotrophic lateral sclerosis (ALS). We demonstrated that γ1 laminin together with α1, β1, and β3 laminins localize at the floor plate region in human embryonic spinal cord. This localization of γ1 laminin is in spatial and temporal correlation with development of the spinal cord and indicates that γ1 laminin may participate in commissural axon guidance during the embryonic development of the human CNS. With in vitro studies using the Matrigel culture system, we demonstrated that the KDI tripeptide of γ1 laminin provides a chemotrophic guidance cue for neurites of the human embryonic dorsal spinal cord, verifying the functional ability of γ1 laminin to guide commissural axons. Results from our experimental SCI model demonstrate that the KDI tripeptide enhanced functional recovery and promoted neurite outgrowth across the mechanically injured area in the adult rat spinal cord. Furthermore, our findings indicate that the KDI tripeptide as a non-competitive inhibitor of the ionotropic glutamate receptors can provide when administered in adequate concentrations an effective method to protect neurons against glutamate-induced excitotoxic cell death. Human postmortem samples were used to study motor neuron disease, ALS (IV), and the study revealed that in human ALS spinal cord, γ1 laminin was selectively over-expressed by reactive astrocytes, and that this over-expression may correlate with disease severity. The multiple ways by which γ1 laminin and its KDI tripeptide provide neurotrophic protection and enhance neuronal viability suggest that the over-expression of γ1 laminin may be a glial attempt to provide protection for neurons against ALS pathology. The KDI tripeptide is effective therapeutically thus far in animal models only. However, because KDI containing γ1 laminin exists naturally in the human CNS, KDI therapies are unlikely to be toxic or allergenic. Results from our animal models are encouraging, with no toxic side-effects detected even at high concentrations, but the ultimate confirmation can be achieved only after clinical trials. More research is still needed until the KDI tripeptide is refined into a clinically applicable method to treat various neurological disorders.

Search for a Light Higgs Boson in Central Exclusive Diffraction: Method and Detectors

By detecting leading protons produced in the Central Exclusive Diffractive process, p+p → p+X+p, one can measure the missing mass, and scan for possible new particle states such as the Higgs boson. This process augments - in a model independent way - the standard methods for new particle searches at the Large Hadron Collider (LHC) and will allow detailed analyses of the produced central system, such as the spin-parity properties of the Higgs boson. The exclusive central diffractive process makes possible precision studies of gluons at the LHC and complements the physics scenarios foreseen at the next e+e− linear collider. This thesis first presents the conclusions of the first systematic analysis of the expected precision measurement of the leading proton momentum and the accuracy of the reconstructed missing mass. In this initial analysis, the scattered protons are tracked along the LHC beam line and the uncertainties expected in beam transport and detection of the scattered leading protons are accounted for. The main focus of the thesis is in developing the necessary radiation hard precision detector technology for coping with the extremely demanding experimental environment of the LHC. This will be achieved by using a 3D silicon detector design, which in addition to the radiation hardness of up to 5×10^15 neutrons/cm2, offers properties such as a high signal-to- noise ratio, fast signal response to radiation and sensitivity close to the very edge of the detector. This work reports on the development of a novel semi-3D detector design that simplifies the 3D fabrication process, but conserves the necessary properties of the 3D detector design required in the LHC and in other imaging applications.

Seismic Tomography and Earthquake Mechanism Beneath the Central Fennoscandian Shield

The aim of this thesis was to study the seismic tomography structure of the earth s crust together with earthquake distribution and mechanism beneath the central Fennoscandian Shield, mainly in southern and central Finland. The earthquake foci and some fault plane solutions are correlated with 3-D images of the velocity tomography. The results are discussed in relation to the stress field of the Shield and with other geophysical, e.g. geomagnetic, gravimetric, tectonic, and anisotropy studies of the Shield. The earthquake data of the Fennoscandian Shield has been extracted from the Nordic earthquake parameter data base which was founded at the time of inception of the earthquake catalogue for northern Europe. Eight earlier earthquake source mechanisms are included in a pilot study on creating a novel technique for calculating an earthquake fault plane solution. Altogether, eleven source mechanisms of shallow, weak earthquakes are related in the 3-D tomography model to trace stresses of the crust in southern and central Finland. The earthquakes in the eastern part of the Fennoscandian Shield represent low-active, intraplate seismicity. Earthquake mechanisms with NW-SE oriented horizontal compression confirm that the dominant stress field originates from the ridge-push force in the North Atlantic Ocean. Earthquakes accumulate in coastal areas, in intersections of tectonic lineaments, in main fault zones or are bordered by fault lines. The majority of Fennoscandian earthquakes concentrate on the south-western Shield in southern Norway and Sweden. Onwards, epicentres spread via the ridge of the Shield along the west-coast of the Gulf of Bothnia northwards along the Tornio River - Finnmark fault system to the Barents Sea, and branch out north-eastwards via the Kuusamo region to the White Sea Kola Peninsula faults. The local seismic tomographic method was applied to find the terrane distribution within the central parts of the Shield the Svecofennian Orogen. From 300 local explosions a total of 19765 crustal Pg- and Sg-wave arrival times were inverted to create independent 3-D Vp and Vs tomographic models, from which the Vp/Vs ratio was calculated. The 3-D structure of the crust is presented as a P-wave and for the first time as an S-wave velocity model, and also as a Vp/Vs-ratio model of the SVEKALAPKO area that covers 700x800 km2 in southern and central Finland. Also, some P-wave Moho-reflection data was interpolated to image the relief of the crust-mantle boundary (i.e. Moho). In the tomography model, the seismic velocities vary smoothly. The lateral variations are larger for Vp (dVp =0.7 km/s) than for Vs (dVs =0.4 km/s). The Vp/Vs ratio varies spatially more distinctly than P- and S-wave velocities, usually from 1.70 to 1.74 in the upper crust and from 1.72 to 1.78 in the lower crust. Schist belts and their continuations at depth are associated with lower velocities and lower Vp/Vs ratios than in the granitoid areas. The tomography modelling suggests that the Svecofennian Orogen was accreted from crustal blocks ranging in size from 100x100 km2 to 200x200 km2 in cross-sectional area. The intervening sedimentary belts have ca. 0.2 km/s lower P- and S-wave velocities and ca. 0.04 lower Vp/Vs ratios. Thus, the tomographic model supports the concept that the thick Svecofennian crust was accreted from several crustal terranes, some hidden, and that the crust was later modified by intra- and underplating. In conclusion, as a novel approach the earthquake focal mechanism and focal depth distribution is discussed in relation to the 3-D tomography model. The schist belts and the transformation zones between the high- and low-velocity anomaly blocks are characterized by deeper earthquakes than the granitoid areas where shallow events dominate. Although only a few focal mechanisms were solved for southern Finland, there is a trend towards strike-slip and oblique strike-slip movements inside schist areas. The normal dip-slip type earthquakes are typical in the seismically active Kuusamo district in the NE edge of the SVEKALAPKO area, where the Archean crust is ca. 15-20 km thinner than the Proterozoic Svecofennian crust. Two near vertical dip-slip mechanism earthquakes occurred in the NE-SW junction between the Central Finland Granitoid Complex and the Vyborg rapakivi batholith, where high Vp/Vs-ratio deep-set intrusion splits the southern Finland schist belt into two parts in the tomography model.

Fertility in Namibia : Changes in fertility levels in North-Central Namibia 1960-2001, including an assessment of the impact of HIV

The aim of this study was to estimate the development of fertility in North-Central Namibia, former Ovamboland, from 1960 to 2001. Special attention was given to the onset of fertility decline and to the impact of the HIV epidemic on fertility. An additional aim was to introduce parish registers as a source of data for fertility research in Africa. Data used consisted of parish registers from Evangelical Lutheran congregations, the 1991 and 2001 Population and Housing Censuses, the 1992 and 2000 Namibia Demographic and Health Surveys, and the HIV sentinel surveillances of 1992-2004. Both period and cohort fertility were analysed. The P/F ratio method was used when analysing census data. The impact of HIV infection on fertility was estimated indirectly by comparing the fertility histories of women who died at an age of less than 50 years with the fertility of other women. The impact of the HIV epidemic on fertility was assessed both among infected women and in the general population. Fertility in the study population began to decline in 1980. The decline was rapid during the 1980s, levelled off in the early 1990s at the end of war of independence and then continued to decline until the end of the study period. According to parish registers, total fertility was 6.4 in the 1960s and 6.5 in the 1970s, and declined to 5.1 in the 1980s and 4.2 in the 1990s. Adjustment of these total fertility rates to correspond to levels of fertility based on data from the 1991 and 2001 censuses resulted in total fertility declining from 7.6 in 1960-79 to 6.0 in 1980-89, and to 4.9 in 1990-99. The decline was associated with increased age at first marriage, declining marital fertility and increasing premarital fertility. Fertility among adolescents increased, whereas the fertility of women in all other age groups declined. During the 1980s, the war of independence contributed to declining fertility through spousal separation and delayed marriages. Contraception has been employed in the study region since the 1980s, but in the early 1990s, use of contraceptives was still so limited that fertility was higher in North-Central Namibia than in other regions of the country. In the 1990s, fertility decline was largely a result of the increased prevalence of contraception. HIV prevalence among pregnant women increased from 4% in 1992 to 25% in 2001. In 2001, total fertility among HIV-infected women (3.7) was lower than that among other women (4.8), resulting in total fertility of 4.4 among the general population in 2001. The HIV epidemic explained more than a quarter of the decline in total fertility at population level during most of the 1990s. The HIV epidemic also reduced the number of children born by reducing the number of potential mothers. In the future, HIV will have an extensive influence on both the size and age structure of the Namibian population. Although HIV influences demographic development through both fertility and mortality, the effect through changes in fertility will be smaller than the effect through mortality. In the study region, as in some other regions of southern Africa, a new type of demographic transition is under way, one in which population growth stagnates or even reverses because of the combined effects of declining fertility and increasing mortality, both of which are consequences of the HIV pandemic.

Juvenile diversity of tree species in Theobroma cacao L. agroforestry and primary forest – Central Sulawesi, Indonesia

This thesis studies the tree species’ juvenile diversity in cacao (Theobroma cacao L.) based agroforestry and in primary forest in a natural conservation forest environment of Lore Lindu National Park, Sulawesi, Indonesia. Species’ adult composition in Lore Lindu National Park is relatively well studied, less is known about tree species’ diversity in seedling communities particularly in frequently disturbed cacao agroforestry field environment. Cacao production forms a potentially serious thread for maintaining the conservation areas pristine and forested in Sulawesi. The impacts of cacao production on natural environment are directly linked to the diversity and abundance of shade tree usage. The study aims at comparing differences between cacao agroforestry and natural forest in the surrounding area in their species composition in seedling and sapling size categories. The study was carried out in two parts. Biodiversity inventory of seedlings and saplings was combined with social survey with farmer interviews. Aim of the survey was to gain knowledge of the cacao fields, and farmers’ observations and choices regarding tree species associated with cacao. Data was collected in summer 2008. The assessment of the impact of environmental factors of solar radiation, weeding frequency, cacao tree planting density, distance to forest and distance to main park road, and type of habitat on seedling and sapling compositions was done with Non-metric Multidimensional Scaling (NMS). Outlier analysis was used to assess distorting variables for NMS, and Multi-Response Permutation Procedures (MRPP) analysis to differentiate the impact of categorical variables. Sampling success was estimated with rarefaction curves and jackknife estimate of species richness. In the inventory 135 species of trees and shrubs were found. Only some agroforestry related species were dominating. The most species rich were sapling communities in forest habitat. NMS was showing generally low linear correlation between variation of species composition and environmental variables. Solar radiation was having most significance as explaining variable. The most clearly separated in ordination were cacao and forest habitats. The results of seedling and sapling inventory were only partly coinciding with farmers’ knowledge of the tree species occurring on their fields. More research with frequent assessment of seedling cohorts is needed due to natural variability of cohorts and high mortality rate of seedlings.