Long-term effects of fenofibrate on lipoproteins and surrogate markers of macrovascular and microvascular disease in people with type 2 diabetes

Background and aims. Diabetic dyslipidemia is a highly atherogenic triad of increased triglycerides, decreased HDL cholesterol, and small dense LDL. Fibrates have a beneficial effect on diabetic dyslipidemia, and they have reduced cardiovascular events in randomized trials. Fenofibrate has reduced albuminuria and markers of low-grade inflammation and endothelial dysfunction. The present studies were undertaken to characterize the alterations of VLDL and LDL subclasses and to investigate the binding of LDL to arterial wall in type 2 diabetes. Further purpose was to elucidate the effects of fenofibrate on several lipoprotein subclasses, augmentation index (AIx), carotid intima-media thickness (IMT), and renal function. Subjects. 239 type 2 diabetic subjects were recruited among participants of the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study at the Helsinki centre. The patients were randomized to fenofibrate (200mg/d) or placebo for 5 years. Additionally, a healthy control group (N = 93) was recruited. Results. VLDL1 triglycerides increased in similar proportion to total triglycerides in type 2 diabetic patients and control subjects. Despite the increase in total apoCIII levels, VLDL apoCIII was decreased in diabetic patients. Enrichment of LDL with apoCIII induced a small increase in binding of LDL to arterial wall proteoglycan. Intrinsic characteristics of diabetic LDL, rather than levels of apoCIII, were responsible for increased proteoglycan binding of diabetic LDL with high apoCIII. Fenofibrate reduced triglycerides, increased LDL size, and shifted HDL subclasses towards smaller particles with no change in levels of HDL cholesterol. High levels of homocysteine were associated with lower increase of HDL cholesterol and apoA-I during fenofibrate treatment. Long-term fenofibrate treatment did not improve IMT, AIx, inflammation, or endothelial function. Fenofibrate decreased creatinine clearance and estimated glomerular filtration rate. No effect on albuminuria was seen with fenofibrate. Instead, Cystatin C was increased during fenofibrate treatment. Conclusions. 1) Elevation of VLDL 1 triglycerides was the major determinant of plasma triglyceride concentration in control subjects and type 2 diabetic patients. 2) LDL with high apoCIII showed multiple atherogenic properties, that were only partially mediated by apoCIII per se in type 2 diabetes 3) Fenofibrate demonstrated no effect on surrogate markers of atherosclerosis. 4) Fenofibrate had no effect on albuminuria and the observed decrease in markers of renal function could complicate the clinical surveillance of the patients. 5) Fenofibrate can be used to treat severe hypertriglyceridemia or in combination therapy with statins, but not to increase HDL levels.

Features of the geomagnetic field during the Holocene and Proterozoic

The geomagnetic field is one of the most fundamental geophysical properties of the Earth and has significantly contributed to our understanding of the internal structure of the Earth and its evolution. Paleomagnetic and paleointensity data have been crucial in shaping concepts like continental drift, magnetic reversals, as well as estimating the time when the Earth's core and associated geodynamo processes begun. The work of this dissertation is based on reliable Proterozoic and Holocene geomagnetic field intensity data obtained from rocks and archeological artifacts. New archeomagnetic field intensity results are presented for Finland, Estonia, Bulgaria, Italy and Switzerland. The data were obtained using sophisticated laboratory setups as well as various reliability checks and corrections. Inter-laboratory comparisons between three laboratories (Helsinki, Sofia and Liverpool) were performed in order to check the reliability of different paleointensity methods. The new intensity results fill up considerable gaps in the master curves for each region investigated. In order to interpret the paleointensity data of the Holocene period, a novel and user-friendly database (GEOMAGIA50) was constructed. This provided a new tool to independently test the reliability of various techniques and materials used in paleointensity determinations. The results show that archeological artifacts, if well fired, are the most suitable materials. Also lavas yield reliable paleointensity results, although they appear more scattered. This study also shows that reliable estimates are obtained using the Thellier methodology (and its modifications) with reliability checks. Global paleointensity curves during Paleozoic and Proterozoic have several time gaps with few or no intensity data. To define the global intensity behavior of the Earth's magnetic field during these times new rock types (meteorite impact rocks) were investigated. Two case histories are presented. The Ilyinets (Ukraine) impact melt rocks yielded a reliable paleointensity value at 440 Ma (Silurian), whereas the results from Jänisjärvi impact melts (Russian Karelia, ca. 700 Ma) might be biased towards high intensity values because of non-ideal magnetic mineralogy. The features of the geomagnetic field at 1.1 Ga are not well defined due to problems related to reversal asymmetries observed in Keweenawan data of the Lake Superior region. In this work new paleomagnetic, paleosecular variation and paleointensity results are reported from coeval diabases from Central Arizona and help understanding the asymmetry. The results confirm the earlier preliminary observations that the asymmetry is larger in Arizona than in Lake Superior area. Two of the mechanisms proposed to explain the asymmetry remain plausible: the plate motion and the non-dipole influence.

Quantum Space-Time and Noncommutative Gauge Field Theories

Arguments arising from quantum mechanics and gravitation theory as well as from string theory, indicate that the description of space-time as a continuous manifold is not adequate at very short distances. An important candidate for the description of space-time at such scales is provided by noncommutative space-time where the coordinates are promoted to noncommuting operators. Thus, the study of quantum field theory in noncommutative space-time provides an interesting interface where ordinary field theoretic tools can be used to study the properties of quantum spacetime. The three original publications in this thesis encompass various aspects in the still developing area of noncommutative quantum field theory, ranging from fundamental concepts to model building. One of the key features of noncommutative space-time is the apparent loss of Lorentz invariance that has been addressed in different ways in the literature. One recently developed approach is to eliminate the Lorentz violating effects by integrating over the parameter of noncommutativity. Fundamental properties of such theories are investigated in this thesis. Another issue addressed is model building, which is difficult in the noncommutative setting due to severe restrictions on the possible gauge symmetries imposed by the noncommutativity of the space-time. Possible ways to relieve these restrictions are investigated and applied and a noncommutative version of the Minimal Supersymmetric Standard Model is presented. While putting the results obtained in the three original publications into their proper context, the introductory part of this thesis aims to provide an overview of the present situation in the field.

Local numerical modelling of magnetoconvection and turbulence - implications for mean-field theories

During the last decades mean-field models, in which large-scale magnetic fields and differential rotation arise due to the interaction of rotation and small-scale turbulence, have been enormously successful in reproducing many of the observed features of the Sun. In the meantime, new observational techniques, most prominently helioseismology, have yielded invaluable information about the interior of the Sun. This new information, however, imposes strict conditions on mean-field models. Moreover, most of the present mean-field models depend on knowledge of the small-scale turbulent effects that give rise to the large-scale phenomena. In many mean-field models these effects are prescribed in ad hoc fashion due to the lack of this knowledge. With large enough computers it would be possible to solve the MHD equations numerically under stellar conditions. However, the problem is too large by several orders of magnitude for the present day and any foreseeable computers. In our view, a combination of mean-field modelling and local 3D calculations is a more fruitful approach. The large-scale structures are well described by global mean-field models, provided that the small-scale turbulent effects are adequately parameterized. The latter can be achieved by performing local calculations which allow a much higher spatial resolution than what can be achieved in direct global calculations. In the present dissertation three aspects of mean-field theories and models of stars are studied. Firstly, the basic assumptions of different mean-field theories are tested with calculations of isotropic turbulence and hydrodynamic, as well as magnetohydrodynamic, convection. Secondly, even if the mean-field theory is unable to give the required transport coefficients from first principles, it is in some cases possible to compute these coefficients from 3D numerical models in a parameter range that can be considered to describe the main physical effects in an adequately realistic manner. In the present study, the Reynolds stresses and turbulent heat transport, responsible for the generation of differential rotation, were determined along the mixing length relations describing convection in stellar structure models. Furthermore, the alpha-effect and magnetic pumping due to turbulent convection in the rapid rotation regime were studied. The third area of the present study is to apply the local results in mean-field models, which task we start to undertake by applying the results concerning the alpha-effect and turbulent pumping in mean-field models describing the solar dynamo.

Conformal Field Theory Methods for Variants of Schramm-Loewner Evolutions

This thesis consists of an introduction, four research articles and an appendix. The thesis studies relations between two different approaches to continuum limit of models of two dimensional statistical mechanics at criticality. The approach of conformal field theory (CFT) could be thought of as the algebraic classification of some basic objects in these models. It has been succesfully used by physicists since 1980's. The other approach, Schramm-Loewner evolutions (SLEs), is a recently introduced set of mathematical methods to study random curves or interfaces occurring in the continuum limit of the models. The first and second included articles argue on basis of statistical mechanics what would be a plausible relation between SLEs and conformal field theory. The first article studies multiple SLEs, several random curves simultaneously in a domain. The proposed definition is compatible with a natural commutation requirement suggested by Dubédat. The curves of multiple SLE may form different topological configurations, ``pure geometries''. We conjecture a relation between the topological configurations and CFT concepts of conformal blocks and operator product expansions. Example applications of multiple SLEs include crossing probabilities for percolation and Ising model. The second article studies SLE variants that represent models with boundary conditions implemented by primary fields. The most well known of these, SLE(kappa, rho), is shown to be simple in terms of the Coulomb gas formalism of CFT. In the third article the space of local martingales for variants of SLE is shown to carry a representation of Virasoro algebra. Finding this structure is guided by the relation of SLEs and CFTs in general, but the result is established in a straightforward fashion. This article, too, emphasizes multiple SLEs and proposes a possible way of treating pure geometries in terms of Coulomb gas. The fourth article states results of applications of the Virasoro structure to the open questions of SLE reversibility and duality. Proofs of the stated results are provided in the appendix. The objective is an indirect computation of certain polynomial expected values. Provided that these expected values exist, in generic cases they are shown to possess the desired properties, thus giving support for both reversibility and duality.

Gauge Field Theories, Quantum Space-Time and Some Applications

In this thesis, the possibility of extending the Quantization Condition of Dirac for Magnetic Monopoles to noncommutative space-time is investigated. The three publications that this thesis is based on are all in direct link to this investigation. Noncommutative solitons have been found within certain noncommutative field theories, but it is not known whether they possesses only topological charge or also magnetic charge. This is a consequence of that the noncommutative topological charge need not coincide with the noncommutative magnetic charge, although they are equivalent in the commutative context. The aim of this work is to begin to fill this gap of knowledge. The method of investigation is perturbative and leaves open the question of whether a nonperturbative source for the magnetic monopole can be constructed, although some aspects of such a generalization are indicated. The main result is that while the noncommutative Aharonov-Bohm effect can be formulated in a gauge invariant way, the quantization condition of Dirac is not satisfied in the case of a perturbative source for the point-like magnetic monopole.

Perinatal mortality and maternal health in rural China

Background and context Since the economic reforms of 1978, China has been acclaimed as a remarkable economy, achieving 9% annual growth per head for more than 25 years. However, China's health sector has not fared well. The population health gains slowed down and health disparities increased. In the field of health and health care, significant progress in maternal care has been achieved. However, there still remain important disparities between the urban and rural areas and among the rural areas in terms of economic development. The excess female infant deaths and the rapidly increasing sex ratio at birth in the last decade aroused serious concerns among policy makers and scholars. Decentralization of the government administration and health sector reform impacts maternal care. Many studies using census data have been conducted to explore the determinants of a high sex ratio at birth, but no agreement has been so far reached on the possible contributing factors. No study using family planning system data has been conducted to explore perinatal mortality and sex ratio at birth and only few studies have examined the impact of the decentralization of government and health sector reforms on the provision and organization of maternal care in rural China. Objectives The general objective of this study was to investigate the state of perinatal health and maternal care and their determinants in rural China under the historic context of major socioeconomic reforms and the one child family planning policy. The specific objectives of the study included: 1) to study pregnancy outcomes and perinatal health and their correlates in a rural Chinese county; 2) to examine the issue of sex ratio at birth and its determinants in a rural Chinese county; 3) to explore the patterns of provision, utilization, and content of maternal care in a rural Chinese county; 4) to investigate the changes in the use of maternal care in China from 1991 to 2003. Materials and Methods This study is based on a project for evaluating the prenatal care programme in Dingyuan county in 1999-2003, Anhui province, China and a nationwide household health survey to describe the changes in maternal care utilization. The approaches used included a retrospective cohort study, cross sectional interview surveys, informant interviews, observations and the use of statistical data. The data sources included the following: 1) A cohort of pregnant women followed from pregnancy up to 7 days after birth in 20 townships in the study county, collecting information on pregnancy outcomes using family planning records; 2) A questionnaire interview survey given to women who gave birth between 2001 and 2003; 3) Various statistical and informant surveys data collected from the study county; 4) Three national household health interview survey data sets (1993-2003) were utilized, and reanalyzed to described the changes in maternity care utilization. Relative risks (RR) and their confidence intervals (CI) were calculated for comparison between parity, approval status, infant sex and township groups. The chi-square test was used to analyse the disparity of use of maternal care between and within urban and rural areas and its trend across the years in China. Logistic regression was used to analyse the factors associated with hospital delivery in rural areas. Results There were 3697 pregnancies in the study cohort, resulting in 3092 live births in a total population of 299463 in the 20 study townships during 1999-2000. The average age at pregnancy in the cohort was 25.9 years. Of the women, 61% were childless, 38% already had one child and 0.3% had two children before the current pregnancy. About 90% of approved pregnancies ended in a live birth while 73% of the unapproved ones were aborted. The perinatal mortality rate was 69 per thousand births. If the 30 induced abortions in which the gestational age was more than 28 weeks had been counted as perinatal deaths, the perinatal mortality rate would have been as high as 78 per thousand. The perinatal mortality rate was negatively associated with the wealth of the township. Approximately two thirds of the perinatal deaths occurred in the early neonatal period. Both the still birth rate and the early neonatal death rate increased with parity. The risk of a stillbirth in a second pregnancy was almost four times that for a first pregnancy, while the risk of early neonatal deaths doubled. The early neonatal mortality rate was twice as high for female as for male infants. The sex difference in the early neonatal mortality rate was mainly attributable to mortality in second births. The male early neonatal mortality rate was not affected by parity, while the female early neonatal mortality rate increased dramatically with parity: it was about six times higher for second births than for first births. About 82% early neonatal deaths happened within 24 hours after birth, and during that time, girls were almost three times more likely to die than boys. The death rate of females on the day of birth increased much more sharply with parity than that of males. The total sex ratio at birth of 3697 registered pregnancies was 152 males to 100 females, with 118 and 287 in first and second pregnancies, respectively. Among unapproved pregnancies, there were almost 5 live-born boys for each girl. Most prenatal and delivery care was to be taken care of in township hospitals. At the village level, there were small private clinics. There was no limitation period for the provision of prenatal and postnatal care by private practitioners. They were not permitted to provide delivery care by the county health bureau, but as some 12% of all births occurred either at home or at private clinics; some village health workers might have been involved. The county level hospitals served as the referral centers for the township hospitals in the county. However, there was no formal regulation or guideline on how the referral system should work. Whether or not a woman was referred to a higher level hospital depended on the individual midwife's professional judgment and on the clients' compliance. The county health bureau had little power over township hospitals, because township hospitals had in the decentralization process become directly accountable to the township government. In the township and county hospitals only 10-20% of the recurrent costs were funded by local government (the township hospital was funded by the township government and the county hospital was funded by the county government) and the hospitals collected user fees to balance their budgets. Also the staff salaries depended on fee incomes by the hospital. The hospitals could define the user charges themselves. Prenatal care consultations were however free in most township hospitals. None of the midwives made postnatal home visits, because of low profit of these services. The three national household health survey data showed that the proportion of women receiving their first prenatal visit within 12 weeks increased greatly from the early to middle 1990s in all areas except for large cities. The increase was much larger in the rural areas, reducing the urban-rural difference from more than 4 times to about 1.4 times. The proportion of women that received antenatal care visits meeting the Ministry of Health s standard (at least 5 times) in the rural areas increased sharply from 12% in 1991-1993 to 36% in 2001-2003. In rural areas, the proportion increase was much faster in less developed areas than in developed areas. The hospital delivery rate increased slightly from 90% to 94% in urban areas while the proportion increased from 27% to 69% in rural areas. The fastest change was found to be in type 4 rural areas, where the utilization even quadrupled. The overall difference between rural and urban areas was substantially narrowed over the period. Multiple logistic regression analysis shows that time periods, residency in rural or urban areas, income levels, age group, education levels, delivery history, occupation, health insurance and distance from the nearest health care facilities were significantly associated with hospital delivery rates. Conclusions 1. Perinatal mortality in this study was much higher than that for urban areas as well as any reported rate from specific studies in rural areas of China. Previous studies in which calculations of infant mortality were not based on epidemiological surveys have been shown to underestimate the rates by more than 50%. 2. Routine statistics collected by the Chinese family planning system proved to be a reliable data source for studying perinatal health, including still births, neonatal deaths, sex ratio at birth and among newborns. National Household Health Survey data proved to be a useful and reliable data source for studying population health and health services. Prior to this research there were few studies in these areas available to international audiences. 3.Though perinatal mortality rate was negatively associated with the level of township economic development, the excess female early neonatal mortality rate contributed much more to high perinatal mortality rate than economic factors. This was likely a result of the role of the family planning policy and the traditional preferences for sons, which leads to lethal neglect of female newborns and high perinatal mortality. 4. The selective abortions of female foetuses were likely to contribute most to the high sex ratio at birth. The underreporting of female births seemed to have played a secondary role. The higher early neonatal mortality rate in second-born as compared to first-born children, particularly in females, may indicate that neglect or poorer care of female newborn infants also contributes to the high sex ratio at birth or among newborns. Existing family planning policy proved not to effectively control the steadily increased birth sex ratio. 5. The rural-urban gap in service utilization was on average significantly narrowed in terms of maternal healthcare in China from 1991 to 2003. This demonstrates that significant achievements in reducing inequities can be made through a combination of socio-economic development and targeted investments in improving health services, including infrastructure, staff capacities, and subsidies to reduce the costs of service utilization for the poorest. However, the huge gap which persisted among cities of different size and within different types of rural areas indicated the need for further efforts to support the poorest areas. 6. Hospital delivery care in the study county was better accepted by women because most of women think delivery care was very important while prenatal and postnatal care were not. Hospital delivery care was more systematically provided and promoted than prenatal and postnatal care by township hospital in the study area. The reliance of hospital staff income on user fees gave the hospitals an incentive to put more emphasis on revenue generating activities such as delivery care instead of prenatal and postnatal care, since delivery care generated much profits than prenatal and postnatal care . Recommendations 1. It is essential for the central government to re-assess and modify existing family planning policies. In order to keep national sex balance, the existing practice of one couple one child in urban areas and at-least-one-son a couple in rural areas should be gradually changed to a two-children-a-couple policy throughout the country. The government should establish a favourable social security policy for couples, especially for rural couples who have only daughters, with particular emphasis on their pension and medical care insurance, combined with an educational campaign for equal rights for boys and girls in society. 2. There is currently no routine vital-statistics registration system in rural China. Using the findings of this study, the central government could set up a routine vital-statistics registration system using family planning routine work records, which could be used by policy makers and researchers. 3. It is possible for the central and provincial government to invest more in the less developed and poor rural areas to increase the access of pregnant women in these areas to maternal care services. Central government together with local government should gradually provide free maternal care including prenatal and postnatal as well as delivery care to the women in poor and less developed rural areas. 4. Future research could be done to explore if county and the township level health care sector and the family planning system could be merged to increase the effectiveness and efficiency of maternal and child care. 5. Future research could be done to explore the relative contribution of maternal care, economic development and family planning policy on perinatal and child health using prospective cohort studies and community based randomized trials. Key words: perinatal health, perinatal mortality, stillbirth, neonatal death, sex selective abortion, sex ratio at birth, family planning, son preference, maternal care, prenatal care, postnatal care, equity, China

Plant communities of field margins : the effects of management and environmental factors on species composition and diversity

Agri-environmental schemes have so far resulted in only minor positive implications for the biodiversity of agricultural environments, in contrast to what has been expected. Land-use intensification has decreased landscape heterogeneity and the amount of semi-natural habitats. Field margins are uncultivated areas of permanent vegetation located adjacent to fields. Since the number of these habitats is high, investing in their quality may result in more diverse agricultural landscapes. Field margins can be considered as multifunctional habitats providing agronomic, environmental and wildlife services. This thesis aimed at examining the plant communities of different types of field margin habitats and the factors affecting their species diversity and composition. The importance of edaphic, spatial and management factors was studied on regional, landscape and habitat scales. Vegetation surveys were conducted on regional and landscape scales and a field experiment on cutting management was conducted on a habitat scale. In field margin plant communities, species appeared to be indicators of high or intermediate soil fertility and moist soil conditions. The plant species diversity found was rather low, compared with most species-rich agricultural habitats in Finland, such as dry meadows. Among regions, land-use history, main production line, natural species and human induced distribution, climate and edaphic factors were elements inducing differences in species composition. The lowest regional species diversity of field margins was related to intensive and long-term cereal production. Management by cutting and removal or grazing had a positive effect on plant species diversity. The positive effect of cutting and removal on species richness was also dependent on the adjacent source of colonizing species. Therefore, in species-poor habitats and landscapes, establishment of margins with diverse seed mixtures can be recommended for enhancing the development of species richness. However, seed mixtures should include only native species preferably local origin. Management by cutting once a year for 5 years did not result in a decline in dominance of a harmful weed species, Elymus repens, showing that E. repens probably needs cutting more frequently than once per year. Agri-environmental schemes should include long-term contracts with farmers for the establishment, and management by cutting and removal or grazing, of field margins that are several metres wide. In such schemes, the timing and frequency of management should be planned so as not to harm other taxa, such as the insects and birds that are dependent on these habitats. All accidental herbicide drifts to field margins should be avoided when spraying the cultivated area to minimize the negative effects of sprayings on vegetation. The harmful effects of herbicides can be avoided by organic farming methods.

Assessment of insect occurrence in boreal forests based on satellite imagery and field measurements.

The presence/absence data of twenty-seven forest insect taxa (e.g. Retinia resinella, Formica spp., Pissodes spp., several scolytids) and recorded environmental variation were used to investigate the applicability of modelling insect occurrence based on satellite imagery. The sampling was based on 1800 sample plots (25 m by 25 m) placed along the sides of 30 equilateral triangles (side 1 km) in a fragmented forest area (approximately 100 km2) in Evo, S Finland. The triangles were overlaid on land use maps interpreted from satellite images (Landsat TM 30 m multispectral scanner imagery 1991) and digitized geological maps. Insect occurrence was explained using either environmental variables measured in the field or those interpreted from the land use and geological maps. The fit of logistic regression models varied between species, possibly because some species may be associated with the characteristics of single trees while other species with stand characteristics. The occurrence of certain insect species at least, especially those associated with Scots pine, could be relatively accurately assessed indirectly on the basis of satellite imagery and geological maps. Models based on both remotely sensed and geological data better predicted the distribution of forest insects except in the case of Xylechinus pilosus, Dryocoetes sp. and Trypodendron lineatum, where the differences were relatively small in favour of the models based on field measurements. The number of species was related to habitat compartment size and distance from the habitat edge calculated from the land use maps, but logistic regressions suggested that other environmental variables in general masked the effect of these variables in species occurrence at the present scale.