Dissection of the genetic background of childhood onset progressive myoclonic epilepsies

The progressive myoclonic epilepsies (PMEs) are a clinically and etiologically heterogeneous group of symptomatic epilepsies characterized by myoclonus, tonic-clonic seizures, psychomotor regression and ataxia. Different disorders have been classified as PMEs. Of these, the group of neuronal ceroid lipofuscinoses (NCLs) comprise an entity that has onset in childhood, being the most common cause of neurodegeneration in children. The primary aim of this thesis was to dissect the molecular genetic background of patients with childhood onset PME by studying candidate genes and attempting to identify novel PME-associated genes. Another specific aim was to study the primary protein properties of the most recently identified member of the NCL-causing proteins, MFSD8. To dissect the genetic background of a cohort of Turkish patients with childhood onset PME, a screen of the NCL-associated genes PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8 and CTSD was performed. Altogether 49 novel mutations were identified, which together with 56 mutations found by collaborators raised the total number of known NCL mutations to 364. Fourteen of the novel mutations affect the recently identified MFSD8 gene, which had originally been identified in a subset of mainly Turkish patients as the underlying cause of CLN7 disease. To investigate the distribution of MFSD8 defects, a total of 211 patients of different ethnic origins were evaluated for mutations in the gene. Altogether 45 patients from nine different countries were provided with a CLN7 molecular diagnosis, denoting the wide geographical occurrence of MFSD8 defects. The mutations are private with only one having been established by a founder-effect in the Roma population from the former Czechoslovakia. All mutations identified except one are associated with the typical clinical picture of variant late-infantile NCL. To address the trafficking properties of MFSD8, lysosomal targeting of the protein was confirmed in both neuronal and non-neuronal cells. The major determinant for this lysosomal sorting was identified to be an N-terminal dileucine based signal (9-EQEPLL-14), recognized by heterotetrameric AP-1 adaptor proteins, suggesting that MFSD8 takes the direct trafficking pathway en route to the lysosomes. Expression studies revealed the neurons as the primary cell-type and the hippocampus and cerebellar granular cell layer as the predominant regions in which MFSD8 is expressed. To identify novel genes associated with childhood onset PME, a single nucleotide polymorphism (SNP) genomewide scan was performed in three small families and 18 sporadic patients followed by homozygosity mapping to determine the candidate loci. One of the families and a sporadic patient were positive for mutations in PLA2G6, a gene that had previously been shown to cause infantile neuroaxonal dystrophy. Application of next-generation sequencing of candidate regions in the remaining two families led to identification of a homozygous missense mutation in USP19 for the first and TXNDC6 for the second family. Analysis of the 18 sporadic cases mapped the best candidate interval in a 1.5 Mb region on chromosome 7q21. Screening of the positional candidate KCTD7 revealed six mutations in seven unrelated families. All patients with mutations in KCTD7 were reported to have early onset PME, rapid disease progression leading to dementia and no pathologic hallmarks. The identification of KCTD7 mutations in nine patients and the clinical delineation of their phenotype establish KCTD7 as a gene for early onset PME. The findings presented in this thesis denote MFSD8 and KCTD7 as genes commonly associated with childhood onset symptomatic epilepsy. The disease-associated role of TXNDC6 awaits verification through identification of additional mutations in patients with similar phenotypes. Completion of the genetic spectrum underlying childhood onset PMEs and understanding of the gene products functions will comprise important steps towards understanding the underlying pathogenetic mechanisms, and will possibly shed light on the general processes of neurodegeneration and nervous system regulation, facilitating the diagnosis, classification and possibly treatment of the affected cases.

Hyvinvointivaltion läpimurto : Pienviljelyhegemonian rapautumisen, kansalaisliikehdinnän ja poliittisen murroksen keskinäiset suhteet suomalaisessa yhteiskunnassa 1950-luvun loppuvuosina

A Breakthrough of Welfare State. The inter-relationships of the civic movement, political transformation, and eroding of a hegemony based on small scale farming in the Finnish society in the late 1950's. The unusually rapid and powerful structural change; the non-parliamentary civic movements of 1956 - 1963; and the left majority in the Finnish parliament between 1958 - 1962 all took place as the Finnish welfare state started to develop. The aim of my research is to analyse the inter-relationships of these processes. The research describes the way the former semi self-sufficient, semi-proletarian and labour-intensive form of production - a simple and discriminatory system in itself - made it possible for the majority of the population to survive through hard work. For some it even provided a possibility to prosper. The waning vitality of semi self-sufficiency and small scale agriculture triggered a political ferment and started a period of searching for something new. The process was so intense that it broke up most of the parties and tore down the old consensus that was based on the power of economic and political elite. The most crucial battle of the great transformation was waged over the nature of the state: Should we build a welfare state and construct social security systems, or should we revert to the old night watchman state and, for example, cancel the modest forms of redistribution of income carried out in the 1950's? The people joining the civic movements were either cottagers of the impoverishing countryside or, quite often, people who had come from the countryside and thus had grown up under conditions of some form of solidarity that included taking care of one's own family. The Finnish social insurance developed in the midst of a change in the structure of production of the society, and it became a compromise to satisfy the needs of both the waning society of small scale agriculture and the rising proletarian society based on wage labour. The hodgepodge of political schemes and use of power became a battle between different notions of the economy and the state; the distribution of national income; and the position of Finland in the international context. This battle created a shape of an interregnum - a period of transformation including two notions of society, two alternative paths for the future and the logic of a correctional move. The transformation of Finland from a poor developing country into a prosperous society has been praised as a success story. In 1956 - 1959, when the old form of governance based on the interests of small scale agriculture and wood processing industry was in decay, and when the future seemed uncertain, the projects to reduce social benefits and efforts to distribute national income even more unequally than before led to a powerful counter-movement by citizens and started an hegemonic change and a equal socia development.

Koti keskellä kaupunkia : Keskusta lapsiperheen asuinalueena, esimerkkeinä Tukholma ja Helsinki

Families with children have traditionally moved to suburbs. In the last 20 years a modest counter process has however been recognized. Families with an urban lifestyle stay in the city centres. This study looks at the phenomenon through two cases, Stockholm and Helsinki. In the first case it has already been observed that the city centre has grown in popularity among families with children. Therefore it serves as a basis for the study and as well as a point of comparison. Stockholm’s city centre is expanding as new neighbourhoods have been built and are being planned. In the city centre of Helsinki the building of two large neighbourhoods for 30 000 inhabitants will start in a few years. The first aim of the study is to look closer at what has really happened in the city centre of Stockholm, why families choose to live there with their children and how the City of Stockholm has reacted to the change. The main sources of information are secondary sources, statistics and interviews with planners, politicians and experts in the field. The main object is to look at the situation in the city centre of Helsinki. Can a preference for urban residential environments be observed in Helsinki? What are the reasons for a family to choose the city centre as a living place? How does the everyday life of a family in the city centre appear? How are these families taken into account in the planning of the city? The main sources of information here are statistics, interviews with dwellers in the neighbourhood Kruununhaka and interviews with planners. In Stockholm the birth rate has grown constantly during the 2000s and is highest in the city centre. Some of the families still move elsewhere, but many of them do not. One of the most important reasons for living in the city centre is short working distances which give working parents more time with their children. Another reason is a preference of an urban, active lifestyle. Families prefer to live close to everything, childcare, schools, shops and entertainments. The popularity of the city centre among families with children has taken politicians and planners by surprise. Helsinki has not experienced a baby boom like Stockholm. However the negative changes in the birth rate have been more modest in the central areas than in the suburbs. Statistics show, that many families move away from the city centre as the children grow. Families who stay in the city centre especially appreciate closeness to public and private services and good public transportation which means that they are not dependent on using the car. Further they find that the city centre has a tolerant climate and is a safe and beautiful place to live in. The families enjoy the social life of the neighbourhood and feel that it makes a good climate to raise children in. However they are concerned with traffic safety and the lack of stimulus in the playgrounds of the neighbourhood parks. Two large neighbourhoods with homes for about 30 000 inhabitants are now planned in the former Port Districts in the city centre of Helsinki. The other one, Jätkäsaari has been planned to become an attractive alternative for families with children. Traffic safety has been one of the main objects for the planning. The other, Kalasatama, has been planned to attract all groups in society.

Valikoiva muuttoliike Uudellamaalla

This thesis explores selective migration in Greater Helsinki region from the perspective of counterurbanisation. The aim of the study is to research whether the migration is selective by migrants age, education, income level or the rate of employment and to study any regional patterns formed by the selectivity. In the Helsinki region recent migratory developments have been shifting the areas of net migration gain away from the city of Helsinki to municipalities farther off on the former countryside. There has been discussion about Helsinki s decaying tax revenue base and whether the city s housing policy has contributed to the exodus of wealthier households. The central question of the discussion is one of selective migration: which municipalities succeed in capturing the most favourable migrants and which will lose in the competition. Selective migration means that region s in-migrants and out-migrants significantly differ from each other demographically, socially and economically. Sometimes selectivity is also understood as some individuals greater propensity to migrate than others but the proper notion for this would be differential migration. In Finnish parlance these two concepts have tended to get mixed up. The data of the study covers the total migration of the 34 municipalities of Uusimaa provinces during the years 2001 to 2003. The data was produced by Statistics Finland. Two new methods of representing the selectivity of migration as a whole were constructed during the study. Both methods look at the proportions of favourably selected migrants in regions inward and outward migrant flow. A large share in the inward flow and a small share in the outward flow is good for region s economy and demography. The first method calculates the differences of the proportions of favourably selected four migrant groups and sums the differences up. The other ranks the same proportions between regions giving value 1 to the largest proportion in inward flow and 34 to the smallest, and respectively in outward flow the smallest proportion gets value 1 and the largest 34. The total sum of the ranks or differences in proportions represents region s selectivity of migration. The results show that migration is indeed selective in the Greater Helsinki region. There also seems to be a spatial pattern centred around the Helsinki metropolitan region. The municipalities surrounding the four central communes are generally better of than those farther away. Not only these eight municipalities of the so called capital region benefit from the selective migration, but the favourable structure of migration extends to some of the small municipalities farther away. Some municipalities situated along the main northbound railway line are not coming through as well as other municipalities of the capital region. The selectivity of migration in Greater Helsinki region shows signs of counter-urbanisation. People look for suburban or small-town lifestyle no longer from Espoo or Vantaa, the neighbouring municipalities to Helsinki, but from the municipalities surrounding these two or even farther off. This kind of pattern in selective migration leads to unbalanced development in population structure and tax revenue base in the region. Migration to outskirts of the urban area also leads to urban sprawl and fragmentation of the urban structure: these issues have ecological implications. Selective migration should be studied more. Also the concept itself needs clearer definition and so do the methods to study the selectivity of migration.

Sport, body and power: Reassessing the myth of President Kekkonen

Former President of Finland Urho Kekkonen was not only a powerful politician but also a well-known sportsman and keep-fit enthusiast. The president’s sports hobbies were covered and celebrated in the media and thus became an integral part of his public persona. This paper looks at Kekkonen’s athletic and able-bodied image and its significance for his power from the perspective of gender. In his exercise activities, Kekkonen was able to display his bodily prowess and demonstrate his version of masculinity, which emphasized both physical and mental strength. The union of mind and muscle in turn buttressed his political ascendancy. Kekkonen’s athletic body served as a cornerstone of his dominance over his country and, simultaneously, as a shield protecting Finland from both internal and external threats. Furthermore, Kekkonen’s sports performances were essential elements in the myth that was created around the president during his term and which was carefully conserved after his fall from power. Drawing upon scholarship on men and masculinities, this paper reassesses the still-effective mythical image of Kekkonen as an invincible superman. The article reveals the performative nature of his athletic activities and shows that in part, his pre-eminence in them was nothing more than theatre enacted by him and his entourage. Thus, Kekkonen’s superior and super-masculine image was actually surprisingly vulnerable and dependent on the success of the performance. The president’s ageing, in particular, demonstrates the fragility of his displays of prowess, strength and masculinity, and shows how fragile the entanglement of body and power can be.

Spectroscopic investigations of phase transitions in complex solids

Spectroscopic methods have provided information of seminal importance in understanding phase transitions in solids. After briefly examining some fundamental concept related to phase transitions, we shall discuss several case studies particularly involving the use of vibrational (IR and Raman) spectroscopy. Examples will include both order-disorder and displacive transitions. Under the former are included transitions in nitrates, ammonium halides, alkylammonium salts, plastic state of C60 and superionic conductors (specially CsHSO4). In addition, we shall discuss some aspects of incommensurate phase transitions, the glass transition and electronic phase transitions. Transitions of phosphonitrilic halide tetramers and alkane dicarboxylic acids are also examined

'South-South' Remittance - Poverty reduction nexus. The Case of 'Hadiya' immigrants in South Africa, as Agents of 'Constituence development' in Ethiopia, and the policy implications of their 'remittance instrument'

This thesis explores the link between South-South remittance and development. It attempts to establish improved understanding about the role of immigrants as agents of constituency growth and development. By doing so, it illuminates the dark corners of the policy implications that the unconventional development agency of immigrants might have for countries in the Organization ft Economic Cooperation and Development (OECD). The thesis problematises the existence of state-centric international cooperation as providing the recipe for failed Aid in the face of global poverty menace. In the last half a century, the relative shi' of focus to non-state actors brought about the proliferation of NGOs. That, intrun, helped improve international access to crisis situations; however, their long-term remedial impacts on poverty and development have been contested. Major misgivings for non-governmental organizations (NGOs) are, on one hand, low level goal-bound expenditures and lack of independence from influence of the state, on the other. Therefore, the thesis enterprises to empirically verify its fundamental question whether remitting immigrants constitute an alternative development agency to the traditional players: the State and NGOs. Its main arguments are: due to state's failures in bringing sustainable development in many countries of the South, the future of poverty reduction and development also rests in immigrants' remittances. Nonetheless, in the last decade, remittance security-nexus dominated its discourse. Because of that remittance was viewed as something requiring global regime and restrictions. These temptations to tightly regulate remittance flows carry the danger of overlooking its trans-boundary nature and its strong link with livelihood of the poor. Therefore, to avoid unintended consequences of interventions, there need to be clear policy that bases itself on a discursive knowledge on the issues of North-South and South-South remittances The study involved both literature based and empirical research. It employed Discourse Analysis (C as main method for the former and snow-balling as its approach for the latter. For the first part the thesis constructed three conceptual models, these are: metrological model, police model and ecological model on remittance development-nexus. Through this modeling, the thesis achieved better deconstruction on the concepts remittance, immigrants and development agency. The protagonists of each model, the values and interests they represent, and their main arguments along various lines of dichotomies have been discussed. For instance, the main treats of meteorological model include: it sees remittance as transitional economic variable which require constant speculations and global management; it acts as meteorological station for following up or predicting the level, direction, flow and movement of global remittance. It focuses on official lines and considers the state as legitimate recipient of advic and positive consequence of remittance. On the other hand, police model views remittance as beir at best, development neutral or as an illicit activity requiring global regulations and tight control. Both immigrants and remittance viewed as subversive to establishments. It gives primacy to state stable agent of development and a partner for international cooperation. The anti-thesis to the police model is supplied by ecological model, which this thesis is a part. Ecological model on remittance and immigrants argues that, tight global regulations alone cannot be a panacea for possible abuse of informal remittance system. Ecological model, not only links remittance to poverty reduction, the main trust of development, but also considers the development agency of immigrants as critical factor for 21st century north-south development intervention. It sees immigrants as development conscious and their remittance instrument as most stable flow of finance to the developing countries. Besides, it sees remittance as effective poverty solutions than Foreign Direct Investment and international AID. This thesis focuses on the significance of South-South remittance and investigates the South Africa - Ethiopia remittance corridor, as case study; and empirically verifies the role of Ethiopian (Kembata and Hadiya) immigrants in South Africa as agents of local development back home. The study involved techniques of interview, group discussions, observations and investigative study. It also looked into the determinants of their migration to South Africa, and their remittance to Ethiopia. The theoretical models in the first part of the thesis have been operationalised throughout the empirical part to verify if the Kembata and Hadiya immigrants played the crucial role in their household poverty and local development in comparison with the Ethiopian state and the NGOs involved in the system. As evidenced by the research the thesis has made three distinct contributions to the discourse of remittance development-nexus. Fist, it systematized the debate about linkages between remittance, immigrants, development agency and policy of international cooperation by creating three conceptual models (school of thoughts); second, it singled out remitting immigrants as new agents of development in the South; third, it deconstructed concept of remittance and established South¬South remittance as additional sphere of academic investigation. In addition to the above contributions, the thesis finds that Kembata and Hadiya immigrants have engaged in various developmental activities in their locality than usually anticipated. Hence, it concludes that Ethiopian immigrants constitute an alternative development agency to the state and other non-state actors in their country, and the lesson can be applied to poverty reduction strategies in most developing countries.

Folding of a Donor-Containing Ionene by Intercalation with an Acceptor

Cationic ionenes that bear electron-rich 1,5-dialkoxynaphthalene (DAN) units within the alkylene segment were allowed to interact with different types of electron-deficient, acceptor-containing molecules in an effort to realize intercalation-induced folding of the ionenes; the collapse of the chains was expected to occur in such a way that the donor and acceptor units become arranged in an alternating fashion. Several acceptor-bearing molecules were prepared by the derivatization of pyromellitic dianhydride and naphthalene tetracarboxylic dianhydride with two different oligoethylene glycol monomethyl ether monoamines. This yielded acceptor molecules with different water solubility and allowed the examination of solvophobic effects in the folding process. UV/Vis spectroscopic studies were carried out by using a 1:1 mixture of the DAN-ionenes and different acceptor molecules in water/DMSO solvent mixtures. The intensity of the charge-transfer (CT) band was seen to increase with the water content in the solvent mixture, thereby suggesting that the intercalation is indeed aided by solvophobic effects. The naphthalene diimide (NDI) bearing acceptor molecules consistently formed significantly stronger CT complexes when compared to the pyromellitic diimide (PDI) bearing acceptor molecules, which is a reflection of the stronger pi-stacking tendency of the former. AFM studies of drop-cast films of different ionene-acceptor combinations revealed that compact folded structures are formed most effectively under conditions in which the strongest CT complex is formed.

Dependence of magnetism on GdFeO3 distortion in the t(2g) system ARuO(3) (A = Sr, Ca)

We have examined the stability of the ferromagnetic (FM) state in CaRuO3 and SrRuO3 as a function of the GdFeO3 distortion. Model calculations predict the dependence of the FM transition temperature (T-c) on the rotation angle theta to vary as cos(2)(2 theta) for e(g)-electron systems. However, here, we find an initial increase and then the expected decrease. Furthermore, a much faster decrease is found than predicted for e(g)-electron systems. Considering the specific case of CaRuO3, a larger deviation of the Ru-O-Ru angle from 180 degrees in CaRuO3 as compared to SrRuO3 should result in a more reduced bandwidth, thereby making the former more correlated. The absence of long-range magnetic order in the more correlated CaRuO3 is traced to the strong collapse of various exchange interaction strengths that arises primarily from the volume reduction and increased distortion of the RuO6 octahedra network that accompanies the presence of a smaller ion at the A site.

A23187—Channel behaviour: Fluorescence study

Pyranine entrapped soylipid liposomes have been used as a model system to study the proton transport across membrane in the presence of A23187, a carboxylic ionophore specific for electroneutral exchange of divalent cations. An apparent rate constant (k(app)) for transport of protons has been determined from the rate of change of fluorescence intensity of pyranine by stopped flow rapid kinetics in the presence of proton gradient. The variation of k(app) has been studied as a function of ionophore concentration and the results have been compared with gramicidin-a well known channel former under the similar experimental conditions. The rates thus obtained showed that A23187 is not only a simple carrier but also shows channel behaviour at high concentration of ionophore.

An unusual distribution of glucose-6-phosphate dehydrogenase deficiency of south Indian newborn population.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is seen at a higher frequency in many national and ethnic groups in areas of current or former malaria endemicity. A screening programme undertaken to evaluate the gene frequencies for this deficiency in the highly inbred South Indian population of Karnataka revealed that of the 5140 neonates screened, 7.8% were G6PD deficient with no correlation between the reported level of inbreeding and enzyme deficiency. An interesting finding was the equal number of male (198) and female (207) individuals, with G6PD activity of less than 3 IU. The possible implications of this finding with regard to the expression of G6PD gene is discussed.

Contribution of solvent effect to the optical spectra of polyanilines: has it been underestimated

The coefficient of thermochromism of polyaniline solutions has been found to be solvent dependent and the solvent effect is not negligible. Hence, thermochromism of polyaniline solutions cannot be explained solely on the basis of conformational change induced by a change in temperature. Further, comparison of the solvatochromism of polyaniline and polytoluidine shows a higher solvatochromic shift for the former. It implies that the higher energy associated with the exciton peak of polytoluidine is not due to the higher ring torsional angle induced by the higher steric repulsion of the methyl group, as widely accepted, but is due to its less solvatochromic red-shift as compared to polyaniline.

Diffusion Parameters and Growth Mechanism of Phases in the Cu-Sn System

The tracer diffusion coefficients of the elements as well as the integrated interdiffusion coefficients are determined for the Cu3Sn and Cu6Sn5 intermetallic compounds using incremental diffusion couples and Kirkendall marker shift measurements. The activation energies are determined for the former between 498 K and 623 K (225 A degrees C and 350 A degrees C) and for the latter between 423 K and 473 K (150 A degrees C and 200 A degrees C). Sn is found to be a slightly faster diffuser in Cu6Sn5, and Cu is found to be the faster diffuser in Cu3Sn. The results from the incremental couples are used to predict the behavior of a Cu/Sn couple where simultaneous growth of both intermetallics occurs. The waviness at the Cu3Sn/Cu6Sn5 interface and possible reasons for not finding Kirkendall markers in both intermetallics in the Cu/Sn couple are discussed.

Enhancement in Bath Mixing and Plume area in a New Degassing Process - A Computational Fluid Dynamic Study

Reaction between the various species in slag and metal phase is usually mass transfer controlled. There have been continuous efforts to increase the reaction efficiency in slag-metal system, especially during decarburization of steel to produce the ultra low carbon steel (ULCS) in secondary steelmaking. It has been found that the surface reaction is a dominant factor in the final stage of decarburization. In the initial stage, the inner site reaction is major factor in the refining process. The mixing of bath affects the later reaction. However, the former reaction (surface reaction) is affected by the plume size area at the top of the metal surface. Therefore, a computational study has been made to understand the fluid dynamics of a new secondary steelmaking process called Revolutionary Degasser Activator (REDA) to study the bath mixing and plume area. REDA process has been considered as it is claimed that this process can reduce the carbon content in steel below 10ppm in a less time than the other existing processes such as RH and Tank degasser. This study shows that both bath mixing and plume area are increased in REDA process facilitating it to give the desired carbon content in less time. Qualitative comments are made on slag-metal reaction system based on this finding.

Methanol oxidation on carbon-supported Pt---Sn electrodes in silicotungstic acid

Electro-oxidation of methanol was studied on carbon-supported Pt---Sn/C electrodes in silcotungstic acid (SiWA) at various concentrations. The porous-carbon electrodes employing Pt---Sn/C catalyst have been characterized using chemical analyses, X-ray powder diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) in conjunction with electrochemistry. The presence of Pt---Sn and Pt3Sn alloys along with Pt and SnO2 phases in the catalyst were identified by XRD. XPS analysis showed a lower amount of PtO species in the Pt---Sn/C catalyst with respect to the corresponding Pt/C sample. From the steady-state galvanostatic polarization data on Pt---Sn/C electrodes in SiWA, it is inferred that a one-electron process is the rate determining step. The performance of the electrodes in 0.084 M SiWA was better than in 2.5 M H2SO4 under similar conditions up to load currents of about 100 mA cm−2 indicating the promoting behaviour of the electrolyte. At currents larger than 100 mA cm−2, the performance of the electrodes in 0.084 SiWA was poorer than that in 2.5 M H2SO4 mainly due to the dominance of mass polarization in the former owing to the large size of keggin units associated with the structure of SiWA. This aspect was supported by cyclic voltammetry and ac impedance studies on Pt---Sn/C electrodes. Simulation of the electrochemical impedance response for the oxidation of methanol in SiWA was carried out using the equivalent electrical circuit model.