Type 1 and type 2 diabetes among young adults in Finland : Incidence and perinatal exposures

This study aimed to examine the incidence of young adult-onset T1DM and T2DM among Finns, and to explore the possible risk factors for young adult-onset T1DM and T2DM that occur during the perinatal period and childhood. In the studies I-II, the incidence of diabetes was examined among 15-39-year-old Finns during the years 1992-2001. Information on the new diagnoses of diabetes was collected from four sources: standardized national reports filled in by diabetes nurses, the Hospital Discharge Register, the Drug Reimbursement Register, and the Drug Prescription Register. The type of diabetes was assigned using information obtained from these four data sources. The incidence of T1DM was 18 per 100,000/year, and there was a clear male predominance in the incidence of T1DM. The incidence of T1DM increased on average 3.9% per year during 1992-2001. The incidence of T2DM was 13 per 100,000/year, and it displayed an increase of 4.3% per year. In the studies III-V, the effects of perinatal exposures and childhood growth on the risk for young adult-onset T1DM and T2DM were explored in a case-control setting. Individuals diagnosed with T1DM (n=1,388) and T2DM (n=1,121) during the period 1992-1996 were chosen as the diabetes cases for the study, and two controls were chosen for each case from the National Population Register. Data on the study subjects parents and siblings was obtained from the National Population Register. The study subjects original birth records and child welfare clinic records were traced nationwide. The risk for young adult-onset T2DM was the lowest among the offspring of mothers aged about 30 years, whereas the risk for T2DM increased towards younger and older maternal ages. Birth orders second to fourth were found protective of T2DM. In addition, the risk for T2DM was observed to decrease with increasing birth weight until 4.2 kg, after which the risk began to increase. A high body mass index (BMI) at the BMI rebound between ages 3-11 years substantially increased the risk for T2DM, and the excess weight gain in individuals diagnosed with T2DM began in early childhood. Maternal age, birth order, or body size at birth had no effect on the risk for young adult-onset T1DM. Instead, individuals with T1DM were observed to have a higher maximum BMI before the age of 3 than their control subjects. In conclusion, the increasing trend in the development of both T1DM and T2DM among young Finnish adults is alarming. The high risk for T1DM among the Finnish population extends to at least 40 years of age, and at least 200-300 young Finnish adults are diagnosed with T2DM every year. Growth during the fetal period and childhood notably affects the risk for T2DM. T2DM prevention should also target childhood obesity. Rapid growth during the first years of life may be a risk factor for late-onset T1DM.

Statistical analysis of the associations of hereditary factors with the risk of Type 1 diabetes and Diabetic Nephropathy based on the familial data collected through ascertaiment from population-based registers

In genetic epidemiology, population-based disease registries are commonly used to collect genotype or other risk factor information concerning affected subjects and their relatives. This work presents two new approaches for the statistical inference of ascertained data: a conditional and full likelihood approaches for the disease with variable age at onset phenotype using familial data obtained from population-based registry of incident cases. The aim is to obtain statistically reliable estimates of the general population parameters. The statistical analysis of familial data with variable age at onset becomes more complicated when some of the study subjects are non-susceptible, that is to say these subjects never get the disease. A statistical model for a variable age at onset with long-term survivors is proposed for studies of familial aggregation, using latent variable approach, as well as for prospective studies of genetic association studies with candidate genes. In addition, we explore the possibility of a genetic explanation of the observed increase in the incidence of Type 1 diabetes (T1D) in Finland in recent decades and the hypothesis of non-Mendelian transmission of T1D associated genes. Both classical and Bayesian statistical inference were used in the modelling and estimation. Despite the fact that this work contains five studies with different statistical models, they all concern data obtained from nationwide registries of T1D and genetics of T1D. In the analyses of T1D data, non-Mendelian transmission of T1D susceptibility alleles was not observed. In addition, non-Mendelian transmission of T1D susceptibility genes did not make a plausible explanation for the increase in T1D incidence in Finland. Instead, the Human Leucocyte Antigen associations with T1D were confirmed in the population-based analysis, which combines T1D registry information, reference sample of healthy subjects and birth cohort information of the Finnish population. Finally, a substantial familial variation in the susceptibility of T1D nephropathy was observed. The presented studies show the benefits of sophisticated statistical modelling to explore risk factors for complex diseases.

Adult-type hypolactasia: Genotype-phenotype correlation

Adult-type hypolactasia (primary lactose malabsorption, lactase non-persistence) is the most common enzyme deficiency worldwide, and manifests with symptoms of lactose intolerance such as abdominal pain, gas formation and diarrhea. In humans with adult-type hypolactasia, lactase activity is high at birth, but declines during childhood to about one-tenth of the activity at birth. In 2002, a one base polymorphism C/T-13910, located 14 kilobases from the starting codon of the lactase-phlorizin hydrolase (LPH) gene was observed to be associated with the persistence of lactase activity. The T-13910 allele (C/T-13910 and T/T-13910 genotypes) associates with persistence of lactase activity throughout life, whereas the C/C-13910 genotype associates with adult-type hypolactasia. In this thesis work, the timing and mechanism of decline of lactase enzyme activity during development was studied using the C/T-13910 polymorphism as a molecular marker. We observed an excellent correlation between low lactase activity and the C/C-13910 genotype in all subjects > 12 years of age, irrespective their ethnicity. In children of African origin, the lactase activity declined somewhat earlier than among Finnish children. Furthermore, we observed an increasing imbalance in the relative lactase mRNA expression from the C-13910 and T-13910 alleles in Finnish children beginning from five years of age. The genetic test for adult-type hypolactasia showed a sensitivity of 93% and a specificity of 100% in the Finnish children and adolescents > 12 years of age. The relation of milk consumption and the milk-related abdominal complaints to the C/T-13910 genotypes associated with lactase persistence/non-persistence was studied by a questionnaire-based approach in > 2100 Finns. Both Finnish children and adults with the C/C-13910 genotype consumed significantly less dairy products compared to those with the C/T-13910 and T/T-13910 genotypes. Flatulence was the only of the abdominal symptoms of lactose intolerance that subjects with the C/C-13910 genotype reported significantly more often than those with the C/T-13910 and T/T-13910 genotypes. A minor proportion (<10%) of subjects with the C/C-13910 genotype, nevertheless, reported drinking milk without any symptoms afterwards. There was no association between cow's milk allergy starting as a newborn and adult-type hypolactasia. In an association study an increased risk of colorectal cancer was observed among those with molecular diagnosis of adult-type hypolactasia. It warrants further studies to clarify whether the increased risk observed in the Finnish population is associated with lactose or decreased intake of dairy products in these subjects.

Nephrin and the Pathogenesis of Nephropathy - Emphasis on Type I Diabetes

End-stage renal disease is an increasingly common pathologic condition, with a current incidence of 87 per million inhabitants in Finland. It is the end point of various nephropathies, most common of which is the diabetic nephropathy. This thesis focuses on exploring the role of nephrin in the pathogenesis of diabetic nephropathy. Nephrin is a protein of the glomerular epithelial cell, or podocyte, and it appears to have a crucial function as a component of the filtration slit diaphragm in the kidney glomeruli. Mutations in the nephrin gene NPHS1 lead to massive proteinuria. Along with the originally described location in the podocyte, nephrin has now been found to be expressed in the brain, testis, placenta and pancreatic beta cells. In type 1 diabetes, the fundamental pathologic event is the autoimmune destruction of the beta cells. Autoantibodies against various beta cell antigens are generated during this process. Due to the location of nephrin in the beta cell, we hypothesized that patients with type 1 diabetes may present with nephrin autoantibodies. We also wanted to test whether such autoantibodies could be involved in the pathogenesis of diabetic nephropathy. The puromycin aminonucleoside nephrosis model in the rat, the streptozotocin model in the rat, and the non-obese diabetic mice were studied by immunochemical techniques, in situ -hybridization and the polymerase chain reaction -based methods to resolve the expression of nephrin mRNA and protein in experimental nephropathies. To test the effect of antiproteinuric therapies, streptozotocin-treated rats were also treated with aminoguanidine or perindopril. To detect nephrin antibodies we developed a radioimmunoprecipitation assay and analyzed follow-up material of 66 patients with type 1 diabetes. In the puromycin aminonucleoside nephrosis model, the nephrin expression level was uniformly decreased together with the appearance of proteinuria. In the streptozotocin-treated rats and in non-obese diabetic mice, the nephrin mRNA and protein expression levels were seen to increase in the early stages of nephropathy. However, as observed in the streptozotocin rats, in prolonged diabetic nephropathy the expression level decreased. We also found out that treatment with perindopril could not only prevent proteinuria but also a decrease in nephrin expression in streptozotocin-treated rats. Aminoguanidine did not have an effect on nephrin expression, although it could attenuate the proteinuria. Circulating antibodies to nephrin in patients with type 1 diabetes were found, although there was no correlation with the development of diabetic nephropathy. At diagnosis, 24% of the patients had these antibodies, while at 2, 5 and 10 years of disease duration the respective proportions were 23%, 14% and 18%. During the total follow-up of 16 to 19 years after diagnosis of diabetes, 14 patients had signs of nephropathy and 29% of them tested positive for nephrin autoantibodies in at least one sample. In conclusion, this thesis work could show changes of nephrin expression along with the development of proteinuria. The autoantibodies against nephrin are likely generated in the autoimmune process leading to type 1 diabetes. However, according to the present work it is unlikely that these autoantibodies are contributing significantly to the development of diabetic nephropathy.

Molecular biology of progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1)

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited disorder characterized by age of onset at 6-15 years, stimulus-sensitive myoclonus, tonic-clonic epileptic seizures and a progressive course. Mutations in the cystatin B (CSTB) gene underlie EPM1. The most common mutation underlying EPM1 is a dodecamer repeat expansion in the promoter region of CSTB. In addition, nine other mutations have been identified. CSTB, a cysteine protease inhibitor, is a ubiquitously expressed inhibitor of cathepsins, but its physiological function is unknown. The purpose of this study was to investigate CSTB gene expression and CSTB protein function in normal and pathological conditions. The basal CSTB promoter was mapped and characterized using different promoter-luciferase gene constructs. The binding activity of transcription factors to one ARE half, five Sp1 and four AP1 sites in the CSTB promoter was demonstrated. The CSTB promoter activity was clearly decreased using a CSTB promoter with "premutation" repeat expansions and in individuals with alike expansions. The expression of CSTB mRNA and protein was markedly reduced in patient cells. The endogenous CSTB protein localized to the nucleus, cytoplasm and lysosomes, and in differentiated cells merely to the cytoplasm. This suggests that the subcellular distribution of CSTB is dependent on the differentation status of the cells. The proteins representing patient missense mutations failed to associate with lysosomes, implying the importance of the lysosomal association for the proper physiological function of CSTB. Several alternatively spliced CSTB isoforms were identified. Of these CSTB2 was widely expressed with very low levels whereas the other alternatively spliced forms seemed to have limited tissue expression. In patients CSTB2 expression was reduced similarly to that of CSTB. The physiological relevance of CSTB alternative splicing remains unknown. The mouse Cstb transcript was shown to be present in all embryonic stages and adult tissues examined. The expression was highest at embryonic day 7 and in thymus, as well as in postnatal brain in the cortex, caudate putamen, thalamus, hippocampus, and in the Purkinje cell layer of the cerebellum. Our data implies that CSTB expression is tightly temporally and spatially regulated. The data presented in my thesis lay the basis for further understanding of the role of CSTB in health and disease.

Kohti hyvää suometsien hoitoa : harvennusten ja kunnostusojitusten vaikutus ojitusaluemänniköiden puuntuotokseen ja metsänkasvatuksen taloustulokseen

This thesis examines the impacts of silvicultural activities on productivity and financial returns of Scots pine (Pinus sylvestris L.) stands on drained peatlands in Finland. The effects of ditch network maintenance operations (DNM) and thinnings, with different timings and intensities, were studied. Based on stand development simulations, the best regimes for different types of stands according to site type, climatic area, and stand silvicultural status were defined from the viewpoint of both wood production and financial profitability. Certain aspects affecting the management outcomes, such as the timing of the first thinning, were examined using data from thinning experiments. Long-term predictions of the impacts of different management regimes were carried out by simulating the development of well-representative model-stands which were composed from appropriate inventory data sets. The MOTTI stand simulator used to perform the simulations enables the predictions by utilizing specific models for drained peatland stands. In addition to natural stand dynamics, these models describe the effects of silvicultural treatments on the development of a given stand. The mean annual increment of merchantable wood (MAImerch) was used as the measure of wood productivity, and the financial feasibility of the regimes was compared using net present value (NPV) analysis. Silvicultural treatments, when applied to appropriately match stand condition, increased both the productivity and financial returns of stand management. Applying DNM resulted in a small increase in MAImerch. When thinning was introduced along with DNM, their combined effect on wood productivity was considerable. According to current operational practices, DNM is generally combined with thinning. In some cases, e.g., in sites of low productivity, the need for DNM may become apparent prior to the thinning stage. As for profitability, thinnings proved to be crucial. The regimes with heavy and late thinnings were generally more profitable than those with normal thinnings. Further, early thinning (relative to stand volume) lacked appeal when seeking a financially profitable removal from the first thinning. In young stands with an initially poor silvicultural condition, however, applying even a low-yielding first thinning considerably increased the NPV when compared to a regime with no thinning at all. Generally, the regimes resulting in the best profitability included heavier thinnings and fewer DNM and thinning treatments than did the regimes resulting in the best yield results. This study demonstrates considerable potential for profitable wood production-oriented management in pine stands on drained peatlands despite their challenging circumstances and long rotations. The results can be used for defining new and more site-specific silvicultural guidelines for various types of drained, pine-dominated peatland stands within the entire range of boreal conditions.

Nuorten männiköiden kehitys - taimikonhoito ja ensiharvennus

The aim of this study was to investigate the effects of location, site type, regeneration method and precommercial thinning on the characteristics and development of young, even-aged, pure Scots pine stands. In addition, the effects of timing and intensity of first commercial thinning on the yield and profitability during the rotation period were also studied. The stand characteristics and external quality of young Scots pine stands and stand-level growth models were based on extensive inventory data of the Finnish Forest Research Institute for young Scots pine stands (3 measurement times, 192 stands). The effect of precommercial thinning on stand development was examined on the basis of long-term experiments (13 stands, 169 plots). The effect of timing and intensity of the first commercial thinning on yield and profitability were based on measurements made in first commercial thinnings (27 stands of Metsähallitus), and the further stand development was modeled using the MOTTI simulator. The thesis was based on four articles and a summary. Stand level growth models were developed for young, even-aged Scots pine stands. The models reliably predicted the development up until the first commercial thinning stage. The stand density of young Scots pine stands in Finland was moderately low compared to the target values. In addition, the external quality of pines was low on average. The low stand density and poor external quality will result in the need for quality tree selection in thinnings, if high quality sawn timber is required. In Northern Finland, only 20% of the dominant trees were classified as normal. This will lead to the situation where external quality will remain relatively poor up until the end of rotation. Early and light precommercial thinning (Hdom 3 m, to a density of 3000 trees per hectare) increased the thinning removal by 40% compared to late and more intensive precommercial thinning (at 7 meters to a density of 2000 trees per hectare). A model for the effect of precommercial thinning on merchantable thinning removal at the first commercial thinning was developed for forest management planning purposes. When the recommended time of first commercial thinning was delayed from a dominant height of 12 m to 16 m, or by ten years, the yield of merchantable wood was doubled. Simultaneously, the current value of the stumpage revenues (with 4% interest rate) was increased on the average by 65% (330 € per hectare). Variation in stumpage prices or interest rates did not have any effect on the final results. Without exception, delaying the first commercial thinning by ten years seemed to be the most profitable method. This presupposes that precommercial thinning has been carried out at the right time and that tree quality aspects do not be specially considered. Furthermore, the wood yield and economic outcome from the entire rotation were similar regardless of whether the first thinning was performed at the time currently recommended or ten years later.

Management of multi-scale forest resource data over time

During the last decades there has been a global shift in forest management from a focus solely on timber management to ecosystem management that endorses all aspects of forest functions: ecological, economic and social. This has resulted in a shift in paradigm from sustained yield to sustained diversity of values, goods and benefits obtained at the same time, introducing new temporal and spatial scales into forest resource management. The purpose of the present dissertation was to develop methods that would enable spatial and temporal scales to be introduced into the storage, processing, access and utilization of forest resource data. The methods developed are based on a conceptual view of a forest as a hierarchically nested collection of objects that can have a dynamically changing set of attributes. The temporal aspect of the methods consists of lifetime management for the objects and their attributes and of a temporal succession linking the objects together. Development of the forest resource data processing method concentrated on the extensibility and configurability of the data content and model calculations, allowing for a diverse set of processing operations to be executed using the same framework. The contribution of this dissertation to the utilisation of multi-scale forest resource data lies in the development of a reference data generation method to support forest inventory methods in approaching single-tree resolution.

Tree mortality and deadwood dynamics in late-successional boreal forests

Here I aimed at quantifying the main components of deadwood dynamics, i.e. tree mortality, deadwood pools, and their decomposition, in late-successional boreal forests. I focused on standing dead trees in three stand types dominated by Picea mariana and Abies balsamea in eastern Canada, and on standing and down dead trees in Picea abies-dominated stands in three areas in Northern Europe. Dead and living trees were measured on five sample plots of 1.6-ha size in each study area and stand type. Stem disks from dead trees were sampled to determine wood density and year of death, using dendrochronological methods. The results were applied to reconstruct past tree mortality and to model deadwood decay class dynamics. Site productivity, stand developmental stage, and the occurrence of episodic tree mortality influenced deadwood volume and quality. In all study areas tree mortality was continuous, leading to continuity in deadwood decay stage distribution. Episodic tree mortality due to either autogenic or allogenic causes influenced deadwood volume and quality in all but one study area. However, regardless of productivity and disturbance history deadwood was abundant, accounting for 20 53% of total wood volume in European study areas, and 15 27% of total standing volume in eastern Canada. Deadwood was a persistent structural component, since its expected residence time in early- and midstages of decay was 18 yr even in the area with the most rapid decomposition. The results indicated that in the absence of episodic tree mortality, stands may eventually develop to a steady state, in which deadwood volume fluctuates around an equilibrium state. However, in many forests deadwood is naturally variable, due to recurrent moderate-severity disturbances. This variability, the continuous tree mortality, and variation in rates of wood decomposition determine the dynamics and availability of deadwood as a habitat and carbon storage medium in boreal coniferous forest ecosystems.

The effect of temperature on height growth of Scots pine in northern Finland

The effect of temperature on height growth of Scots pine in the northern boreal zone in Lapland was studied in two different time scales. Intra-annual growth was monitored in four stands in up to four growing seasons using an approximately biweekly measurement interval. Inter-annual growth was studied using growth records representing seven stands and five geographical locations. All the stands were growing on a dry to semi-dry heath that is a typical site type for pine stands in Finland. The applied methodology is based on applied time-series analysis and multilevel modelling. Intra-annual elongation of the leader shoot correlated with temperature sum accumulation. Height growth ceased when, on average, 41% of the relative temperature sum of the site was achieved (observed minimum and maximum were 38% and 43%). The relative temperature sum was calculated by dividing the actual temperature sum by the long-term mean of the total annual temperature sum for the site. Our results suggest that annual height growth ceases when a location-specific temperature sum threshold is attained. The positive effect of the mean July temperature of the previous year on annual height increment proved to be very strong at high latitudes. The mean November temperature of the year before the previous had a statistically significantly effect on height increment in the three northernmost stands. The effect of mean monthly precipitation on annual height growth was statistically insignificant. There was a non-linear dependence between length and needle density of annual shoots. Exceptionally low height growth results in high needle-density, but the effect is weaker in years of average or good height growth. Radial growth and next year s height growth are both largely controlled by current July temperature. Nevertheless, their growth variation in terms of minimum and maximum is not necessarily strongly correlated. This is partly because height growth is more sensitive to changes in temperature. In addition, the actual effective temperature period is not exactly the same for these two growth components. Yet, there is a long-term balance that was also statistically distinguishable; radial growth correlated significantly with height growth with a lag of 2 years. Temperature periods shorter than a month are more effective variables than mean monthly values, but the improvement is on the scale of modest to good when applying Julian days or growing-degree-days as pointers.

Econometric models of Finnish non-industrial private forest owners' timber supply and timber stock

This dissertation examines the short- and long-run impacts of timber prices and other factors affecting NIPF owners' timber harvesting and timber stocking decisions. The utility-based Faustmann model provides testable hypotheses of the exogenous variables retained in the timber supply analysis. The timber stock function, derived from a two-period biomass harvesting model, is estimated using a two-step GMM estimator based on balanced panel data from 1983 to 1991. Timber supply functions are estimated using a Tobit model adjusted for heteroscedasticity and nonnormality of errors based on panel data from 1994 to 1998. Results show that if specification analysis of the Tobit model is ignored, inconsistency and biasedness can have a marked effect on parameter estimates. The empirical results show that owner's age is the single most important factor determining timber stock; timber price is the single most important factor in harvesting decision. The results of the timber supply estimations can be interpreted using utility-based Faustmann model of a forest owner who values a growing timber in situ.