Acute Lymphoblastic Leukemia in Adolescents and Young Adults in Finland

In recent reports, adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) have had a better outcome with pediatric treatment than with adult protocols. ALL can be classified into biologic subgroups according to immunophenotype and cytogenetics, with different clinical characteristics and outcome. The proportions of the subgroups are different in children and adults. ALL subtypes in AYA patients are less well characterized. In this study, the treatment and outcome of ALL in AYA patients aged 10-25 years in Finland on pediatric and adult protocols was retrospectively analyzed. In total, 245 patients were included. The proportions of biologic subgroups in different age groups were determined. Patients with initially normal or failed karyotype were examined with oligonucleotide microarray-based comparative genomic hybridization (aCGH). Also deletions and instability of chromosome 9p were screened in ALL patients. In addition, patients with other hematologic malignancies were screened for 9p instability. aCGH data were also used to determine a gene set that classifies AYA patients at diagnosis according to their risk of relapse. Receiver operating characteristic analysis was used to assess the value of the set of genes as prognostic classifiers. The 5-year event-free survival of AYA patients treated with pediatric or adult protocols was 67% and 60% (p=0.30), respectively. White blood cell count larger than 100x109/l was associated with poor prognosis. Patients treated with pediatric protocols and assigned to an intermediate-risk group fared significantly better than those of the pediatric high-risk or adult treatment groups. Deletions of 9p were detected in 46% of AYA ALL patients. The chromosomal region 9p21.3 was always affected, and the CDKN2A gene was always deleted. In about 15% of AYA patients, the 9p21.3 deletion was smaller than 200 kb in size, and therefore, probably undetectable with conventional methods. Deletion of 9p was the most common aberration of AYA ALL patients with initially normal karyotype. Instability of 9p, defined as multiple separate areas of copy number loss or homozygous loss within a larger heterozygous area in 9p, was detected in 19% (n=27) of ALL patients. This abnormality was restricted to ALL; none of the patients with other hematologic malignancies had the aberration. The prognostic model identification procedure resulted in a model of four genes: BAK1, CDKN2B, GSTM1, and MT1F. The copy number profile combinations of these genes differentiated between AYA ALL patients at diagnosis depending on their risk of relapse. Deletions of CDKN2B and BAK1 in combination with amplification of GSTM1 and MT1F were associated with a higher probability of relapse. Unlike all previous studies, we found that the outcome of AYA patients with ALL treated using pediatric or adult therapeutic protocols was comparable. The success of adult ALL therapy emphasizes the benefit of referral of patients to academic centers and adherence to research protocols. 9p deletions and instability are common features of ALL and may act together with oncogene-activating translocations in leukemogenesis. New and more sensitive methods of molecular cytogenetics can reveal previously cryptic genetic aberrations with an important role in leukemic development and prognosis and that may be potential targets of therapy. aCGH also provides a viable approach for model design aiming at evaluation of risk of relapse in ALL.

HIV outbreak among injecting drug users in Finland

An HIV outbreak among Finnish injecting drug users (IDUs) occurred in 1998. By the end of 2005, 282 IDUs were in-fected, most of them by recombinant virus CRF01_AE of HIV. After a rapid spread, the outbreak subsided, and the prevalence of HIV among IDUs remained low (<2%). The purpose of the study was to describe the outbreak in order to recognise factors that have influenced the spread and restriction of the outbreak, and thus to find tools for HIV preven-tion. Data on Finnish IDUs newly diagnosed HIV-positive between 1998 and 2005 was collected through interviews and patient documents. Study I compared markers of disease progression between 93 Finnish IDUs and 63 Dutch IDUs. In study II, geographical spread of the HIV outbreak was examined and compared with the spatial distribution of employed males. In study III, risk behaviour data from interviews of 89 HIV-positive and 207 HIV-negative IDUs was linked, and prevalence and risk factors for unprotected sex were evaluated. In study IV, data on 238 newly diagnosed IDUs was combined with data on 675 sexually transmitted HIV cases, and risk factors for late HIV diagnosis (CD4 cell count <200/µL, or AIDS at HIV diagnosis) were analysed. Finnish IDUs infected with CRF01_AE exhibited higher viral loads than did Amsterdam IDUs infected with subtype B, but there was no difference in CD4 development. The Finnish IDU outbreak spread and was restricted socially in a marginalised IDU population and geographically in areas characterised by low proportions of employed males. Up to 40% of the cases in the two clusters outside the city centre had no contact with the centre, where needle exchange services were available since 1997. Up to 63% of HIV-positive and 80% of HIV-negative sexually active IDUs reported inconsistent condom use, which was associated with steady relationships and recent inpatient addiction care. Com-pared to other transmission groups, HIV-positive IDUs were diagnosed earlier in their infection. The proportion of late diagnosed HIV cases in all transmission groups was 23%, but was only 6% among IDUs diagnosed during the first four years of the epidemic. The high viral load in early HIV infection may have contributed to the rapid spread of recombinant virus in the Finnish outbreak. The outbreak was restricted to a marginalised IDU population, and limited spatially to local pockets of pov-erty. To prevent HIV among IDUs, these pockets should be recognised and reached early through outreach work and the distribution of needle exchange and other prevention activities. To prevent the sexual transmission of HIV among IDUs, prevention programmes should be combined with addiction care services and targeted at every IDU. The early detection of the outbreak and early implementation of needle exchange programmes likely played a crucial role in re-versing the IDU outbreak.

Generalised regression estimation for domain class frequencies

This study examines the properties of Generalised Regression (GREG) estimators for domain class frequencies and proportions. The family of GREG estimators forms the class of design-based model-assisted estimators. All GREG estimators utilise auxiliary information via modelling. The classic GREG estimator with a linear fixed effects assisting model (GREG-lin) is one example. But when estimating class frequencies, the study variable is binary or polytomous. Therefore logistic-type assisting models (e.g. logistic or probit model) should be preferred over the linear one. However, other GREG estimators than GREG-lin are rarely used, and knowledge about their properties is limited. This study examines the properties of L-GREG estimators, which are GREG estimators with fixed-effects logistic-type models. Three research questions are addressed. First, I study whether and when L-GREG estimators are more accurate than GREG-lin. Theoretical results and Monte Carlo experiments which cover both equal and unequal probability sampling designs and a wide variety of model formulations show that in standard situations, the difference between L-GREG and GREG-lin is small. But in the case of a strong assisting model, two interesting situations arise: if the domain sample size is reasonably large, L-GREG is more accurate than GREG-lin, and if the domain sample size is very small, estimation of assisting model parameters may be inaccurate, resulting in bias for L-GREG. Second, I study variance estimation for the L-GREG estimators. The standard variance estimator (S) for all GREG estimators resembles the Sen-Yates-Grundy variance estimator, but it is a double sum of prediction errors, not of the observed values of the study variable. Monte Carlo experiments show that S underestimates the variance of L-GREG especially if the domain sample size is minor, or if the assisting model is strong. Third, since the standard variance estimator S often fails for the L-GREG estimators, I propose a new augmented variance estimator (A). The difference between S and the new estimator A is that the latter takes into account the difference between the sample fit model and the census fit model. In Monte Carlo experiments, the new estimator A outperformed the standard estimator S in terms of bias, root mean square error and coverage rate. Thus the new estimator provides a good alternative to the standard estimator.

Helsingin metropolialueen maisemaekologiset muutokset vuosina 1955-2009

Landscape is shaped by natural environment and increasingly by human activity. In landscape ecology, the concept of landscape can be defined as a kilometre-scale mosaic formed by different land-use types. In Helsinki Metropolitan Region, the landscape change caused by urbanization has accelerated after the 1950s. Prior to that, the landscape of the region was mainly only shaped by agriculture. The goal of this study was in addition to describing the landscape change to discuss the factors impacting the landscape change and evaluate thelandscape ecological impacts of the change. Three study areas at different distances from Helsinki city centre were chosen in order to look at the landscape change. Study areas were Malmi, Espoo and Mäntsälä regions representing different parts of the urban-to-rural gradient in 1955, 1975, 1990 and 2009. Land-use of the maps was then digitized into five classes: agricultural lands, semi-natural grasslands, built areas, waters and others using GIS methods. First, landscape change was studied using landscape ecological indices. Indices used were PLAND i.e. the proportions of the different land-use types in the landscape; MPS, SHEI and SHDI which describe fragmentation and heterogeneity of the landscape; and MSI and ED which are measures of patch shape. Second, landscape change was studied statistically in relation to topography, soil and urban structure of the study areas. Indicators used concerning urban structure were number of residents, car ownership and travel-related zones of urban form which indicate the degree of urban sprawl within the study areas. For the statistical analyses, each of the 9.25 x 9.25 km sized study areas was further divided into grids with resolution of 0.25 x 0.25 kilometres. Third, the changes in the green structure of the study areas were evaluated. The landscape change reflected by the proportions of the land-use types was the most notable in Malmi area where a large amount of agricultural land was developed from 1955 to 2009. The proportion of semi-natural grasslands also showed an interesting pattern in relation to urbanization. When urbanization started, a great number of agricultural lands were abandoned and turned into semi-natural grasslands but as the urbanization accelerated, the number of semi-natural grasslands started to decline because of urban densification. Landscape fragmentation and heterogeneity were the most widespread in Espoo study area which is not only because of the great differences in relative heights within the region but also its location in the rural-urban fringe. According to the results, urbanization induced agricultural lands to be more regular in shape both spatially and temporally whereas for built areas and semi-natural grasslands the impact of urbanization was reverse. Changes in landscape were the most insignificant in the most rural study area Mäntsälä. In Mäntsälä, built area per resident showed the greatest values indicating a widespread urban sprawl. The values were the smallest in highly urbanized Malmi study area. Unlike other study areas, in Mäntsälä the proportion of developing land in the ecologically disadvantageous cardependent zone was on the increase. On the other hand, the green structure of the Mäntsälä study area was the most advantageous whereas Malmi study area showed the most ecologically disadvantageous structure. Considering all the landscape ecological criteria used, the landscape structure of Espoo study area proved to be the best not least because of the great heterogeneity of its landscape. Thus the study confirmed the previous results according to which landscape heterogeneity is the most significant in areas exposed to a moderate human impact.

Smoking patterns and lung function : A longitudinal twin study

In many countries, the prevalence of smoking and smokers average cigarette consumption have decreased, with occasional smoking and daily light smoking (1-4 cigarettes per day, CPD) becoming more common. Despite these changes in smoking patterns, the prevalence of chronic obstructive pulmonary disease (COPD), a disorder characterized by a progressive decline in lung function, continues to rise globally. Smoking is the most important factor causing COPD, however, not all smokers develop the disease. Genetic factors partly explain the inter-individual differences in lung function and susceptibility of some smokers to COPD. No earlier research on the genetic and environmental determinants of lung function or on the phenomenon of light smoking exists in the Finnish population. Further, the association between low-rate smoking patterns and COPD remains partly unknown. This thesis aimed to study the prevalence and consistency of light smoking longitudinally in the Finnish population, to assess the characteristics of light smokers, and to examine the risks of chronic bronchitis and COPD associated with changing smoking patterns over time. A further aim was to estimate longitudinally the proportions of genetic and environmental factors that explain the inter-individual variances in lung function. Data from the Older Finnish Twin Cohort, including same-sex twin pairs born in Finland before 1958, were used. Smoking patterns and chronic bronchitis symptoms were consistently assessed in surveys conducted in 1975, 1981, and 1990. National registry data on reimbursement eligibilities and medication purchases were used to define COPD. Lung function data were obtained from a subsample of the cohort, 217 female twin pairs, who attended spirometry in 2000 and 2003 as part of the Finnish Twin Study on Ageing. The genetic and environmental influences on lung function were estimated by using genetic modeling. This thesis found that light smokers are more often female, well-educated, and exhibit a healthier lifestyle than heavy smokers. At individual level, light smoking is rarely a constant pattern. Light smoking, reducing from heavier smoking to light smoking, and relapsing to light smoking after quitting, are among patterns associated with an increased risk of chronic bronchitis and COPD. Constant light smoking is associated with an increased use of inhaled anticholinergics, a medication for CODP. In addition to smoking, other environmental factors influence lung function in the older age. During a three-year follow-up, new environmental effects influencing spirometry values were observed, whereas the genes affecting lung function remained mostly the same. In conclusion, no safe level of daily smoking exists with regard to pulmonary diseases. Even daily light smoking in middle-age is associated with increased respiratory morbidity later in life. Smoking reduction does not decrease the risk of COPD, and should not be recommended as an alternative to quitting smoking. In elderly people, attention should also be drawn to other factors that can prevent poor lung function.

Myoblast Sheet Transplantation for Treatment of Heart Failure after Myocardial Infarction

Heart failure is a common, severe, and progressive condition associated with high mortality and morbidity. Because of population-aging in the coming decades, heart failure is estimated to reach epidemic proportions. Current medical and surgical treatments have reduced mortality, but the prognosis for patients has remained poor. Transplantation of skeletal myoblasts has raised hope of regenerating the failing heart and compensating for lost cardiac contractile tissue. In the present work, we studied epicardial transplantation of tissue-engineered myoblast sheets for treatment of heart failure. We employed a rat model of myocardial infarction-induced acute and chronic heart failure by left anterior descending coronary artery ligation. We then transplanted myoblast sheets genetically modified to resist cell death after transplantation by expressing antiapoptotic gene bcl2. In addition, we evaluated the regenerative capacity of myoblast sheets expressing the cardioprotective cytokine hepatocyte growth factor in a rat chronic heart failure model. Furthermore, we utilized in vitro cardiomyocyte and endothelial cell culture models as well as microarray gene expression analysis to elucidate molecular mechanisms mediating the therapeutic effects of myoblast sheet transplantation. Our results demonstrate that Bcl2-expression prolonged myoblast sheet survival in rat hearts after transplantation and induced secretion of cardioprotective, proangiogenic cytokines. After acute myocardial infarction, these sheets attenuated left ventricular dysfunction and myocardial damage, and they induced therapeutic angiogenesis. In the chronic heart failure model, inhibition of graft apoptosis by Bcl-2 improved cardiac function, supported survival of cardiomyocytes in the infarcted area, and induced angiogenesis in a vascular endothelial growth factor receptor 1- and 2-dependent mechanism. Hepatocyte growth factor-secreting myoblast sheets further enhanced the angiogenic efficacy of myoblast sheet therapy. Moreover, myoblast-secreted paracrine factors protected cardiomyocytes against oxidative stress in an epidermal growth factor receptor- and c-Met dependent manner. This protection was associated with induction of antioxidative genes and activation of the unfolded protein response. Our results provide evidence that inhibiting myoblast sheet apoptosis can enhance the sheets efficacy for treating heart failure after acute and chronic myocardial infarction. Furthermore, we show that myoblast sheets can serve as vehicles for delivery of growth factors, and induce therapeutic angiogenesis in the chronically ischemic heart. Finally, myoblasts induce, in a paracine manner, a cardiomyocyte-protective response against oxidative stress. Our study elucidates novel mechanisms of myoblast transplantation therapy, and suggests effective means to improve this therapy for the benefit of the heart failure patient.

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.