Tampere University of Applied Sciences

We propose a novel image denoising strategy based on an enhanced sparse representation in transform domain. The enhancement of the sparsity is achieved by grouping similar 2-D image fragments (e.g., blocks) into 3-D data arrays which we call "groups." Collaborative filtering is a special procedure developed to deal with these 3-D groups. We realize it using the three successive steps: 3-D transformation of a group, shrinkage of the transform spectrum, and inverse 3-D transformation. The result is a 3-D estimate that consists of the jointly filtered grouped image blocks. By attenuating the noise, the collaborative filtering reveals even the finest details shared by grouped blocks and, at the same time, it preserves the essential unique features of each individual block. The filtered blocks are then returned to their original positions. Because these blocks are overlapping, for each pixel, we obtain many different estimates which need to be combined. Aggregation is a particular averaging procedure which is exploited to take advantage of this redundancy. A significant improvement is obtained by a specially developed collaborative Wiener filtering. An algorithm based on this novel denoising strategy and its efficient implementation are presented in full detail; an extension to color-image denoising is also developed. The experimental results demonstrate that this computationally scalable algorithm achieves state-of-the-art denoising performance in terms of both peak signal-to-noise ratio and subjective visual quality.

Magnetoencephalography (MEG) is a noninvasive technique for investigating neuronal activity in the living human brain. The time resolution of the method is better than 1 ms and the spatial discrimination is, under favorable circumstances, 2-3 mm for sources in the cerebral cortex. In MEG studies, the weak 10 fT-1 pT magnetic fields produced by electric currents flowing in neurons are measured with multichannel SQUID (superconducting quantum interference device) gradiometers. The sites in the cerebral cortex that are activated by a stimulus can be found from the detected magnetic-field distribution, provided that appropriate assumptions about the source render the solution of the inverse problem unique. Many interesting properties of the working human brain can be studied, including spontaneous activity and signal processing following external stimuli. For clinical purposes, determination of the locations of epileptic foci is of interest. The authors begin with a general introduction and a short discussion of the neural basis of MEG. The mathematical theory of the method is then explained in detail, followed by a thorough description of MEG instrumentation, data analysis, and practical construction of multi-SQUID devices. Finally, several MEG experiments performed in the authors' laboratory are described, covering studies of evoked responses and of spontaneous activity in both healthy and diseased brains. Many MEG studies by other groups are discussed briefly as well.

Abstract Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored 1,2 . FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10 –11 ) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Members of the recently recognized SRC-1 family of transcriptional coactivators interact with steroid hormone receptors to enhance ligand-dependent transcription. AIB1, a member of the SRC-1 family, was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number were elevated in human breast cancers. AIB1 amplification and overexpression were observed in four of five estrogen receptor-positive breast and ovarian cancer cell lines. Subsequent evaluation of 105 unselected specimens of primary breast cancer found AIB1 amplification in approximately 10 percent and high expression in 64 percent of the primary tumors analyzed. AIB1 protein interacted with estrogen receptors in a ligand-dependent fashion, and transfection of AIB1 resulted in enhancement of estrogen-dependent transcription. These observations identify AIB1 as a nuclear receptor coactivator whose altered expression may contribute to development of steroid-dependent cancers.

Recent theoretical work has suggested that brain oscillations in the theta band are involved in active maintenance and recall of working memory representations. To test this theoretical framework we recorded neuromagnetic responses from 10 subjects performing the Sternberg task. Subjects were required to retain a list of 1, 3, 5 or 7 visually presented digits during a 3-s retention period. During the retention period we observed ongoing frontal theta activity in the 7-8.5-Hz band recorded by sensors over frontal brain areas. The activity in the theta band increased parametrically with the number of items retained in working memory. A time-frequency analysis revealed that the task-dependent theta was present during the retention period and during memory scanning. Following the memory task the theta activity was reduced. These results suggest that theta oscillations generated in frontal brain regions play an active role in memory maintenance.

Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.DOI: http://dx.doi.org/10.7554/eLife.02242.001.

The power of genetic diversity in genome-wide association studies of lipids Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , heart disease remains the leading cause of death worldwide 3 . Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS 4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns 24 . Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine 25 , we anticipate that increased diversity of participants will lead to more accurate and equitable 26 application of polygenic scores in clinical practice.

Muscle injuries are one of the most common traumas occurring in sports. Despite their clinical importance, few clinical studies exist on the treatment of these traumas. Thus, the current treatment principles of muscle injuries have either been derived from experimental studies or been tested only empirically. Although nonoperative treatment results in good functional outcomes in the majority of athletes with muscle injuries, the consequences of failed treatment can be very dramatic, possibly postponing an athlete's return to sports for weeks or even months. Moreover, the recognition of some basic principles of skeletal muscle regeneration and healing processes can considerably help in both avoiding the imminent dangers and accelerating the return to competition. Accordingly, in this review, the authors have summarized the prevailing understanding on the biology of muscle regeneration. Furthermore, they have reviewed the existing data on the different treatment modalities (such as medication, therapeutic ultrasound, physical therapy) thought to influence the healing of injured skeletal muscle. In the end, they extend these findings to clinical practice in an attempt to propose an evidence-based approach for the diagnosis and optimal treatment of skeletal muscle injuries.

In this paper, the computational and practical aspects of a realistically-shaped multilayer model for the conductivity geometry of the human head are discussed. A novel way to handle the numerical difficulties caused by the presence of the poorly conducting skull is presented. Using our method, both the potential on the surface of the head and the magnetic field outside the head can be computed accurately. The procedure was tested with the multilayer sphere model, for which analytical expressions are available. The method is then applied to a realistically-shaped head model, and it is numerically shown that for the computation of B, produced by cerebral current sources, it is sufficient to consider a brain-shaped homogeneous conductor only since the secondary currents on the outer interfaces give only a negligible contribution to the magnetic field outside the head. Comparisons with the sphere model are also included to pinpoint areas where the homogeneous conductor model provides essential improvements in the calculation of the magnetic field outside the head.

We present an extension of the BM3D filter to volumetric data. The proposed algorithm, BM4D, implements the grouping and collaborative filtering paradigm, where mutually similar d-dimensional patches are stacked together in a (d+1)-dimensional array and jointly filtered in transform domain. While in BM3D the basic data patches are blocks of pixels, in BM4D we utilize cubes of voxels, which are stacked into a 4-D "group." The 4-D transform applied on the group simultaneously exploits the local correlation present among voxels in each cube and the nonlocal correlation between the corresponding voxels of different cubes. Thus, the spectrum of the group is highly sparse, leading to very effective separation of signal and noise through coefficient shrinkage. After inverse transformation, we obtain estimates of each grouped cube, which are then adaptively aggregated at their original locations. We evaluate the algorithm on denoising of volumetric data corrupted by Gaussian and Rician noise, as well as on reconstruction of volumetric phantom data with non-zero phase from noisy and incomplete Fourier-domain (k-space) measurements. Experimental results demonstrate the state-of-the-art denoising performance of BM4D, and its effectiveness when exploited as a regularizer in volumetric data reconstruction.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

The identification of the Drosophila melanogaster Toll pathway cascade and the subsequent characterization of TLRs have reshaped our understanding of the immune system. Ever since, Drosophila NF-κB signaling has been actively studied. In flies, the Toll receptors are essential for embryonic development and immunity. In total, nine Toll receptors are encoded in the Drosophila genome, including the Toll pathway receptor Toll. The induction of the Toll pathway by gram-positive bacteria or fungi leads to the activation of cellular immunity as well as the systemic production of certain antimicrobial peptides. The Toll receptor is activated when the proteolytically cleaved ligand Spatzle binds to the receptor, eventually leading to the activation of the NF-κB factors Dorsal-related immunity factor or Dorsal. In this study, we review the current literature on the Toll pathway and compare the Drosophila and mammalian NF-κB pathways.

We present a simple and usable noise model for the raw-data of digital imaging sensors. This signal-dependent noise model, which gives the pointwise standard-deviation of the noise as a function of the expectation of the pixel raw-data output, is composed of a Poissonian part, modeling the photon sensing, and Gaussian part, for the remaining stationary disturbances in the output data. We further explicitly take into account the clipping of the data (over- and under-exposure), faithfully reproducing the nonlinear response of the sensor. We propose an algorithm for the fully automatic estimation of the model parameters given a single noisy image. Experiments with synthetic images and with real raw-data from various sensors prove the practical applicability of the method and the accuracy of the proposed model.

Tests are proposed for detecting possible changes in parameters when the observations are obtained sequentially in time. While deriving the tests the alternative one has in mind specifies the parameter process as a martingale. The distribution theory of these tests relies on the large-sample results; that is, only the limiting null distributions are known (except in very special cases). The main tool in establishing these limiting distributions is weak convergence of stochastic processes. Suppose that we have vector-valued observations x 1, …, x n obtained sequentially in time (or ordered in some other linear fashion). Their joint distribution is described by determining the initial distribution for x 1 and the conditional distribution for each x k given the past up to x k–1. Suppose further that these distributions depend on a p-dimensional parameter vector θ. At least locally (i.e., in a short time period) this may be more or less legitimate. In the long run, however, the possibility of some changes in the observation-generating process should be taken into account. Specifically, it is assumed here that those changes occur through a parameter variation in the form of a martingale. The martingale specification has an advantage of covering several types of departure of constancy: for example, a single jump at an unknown time point (the so-called change-point model) or slow random variation (typically random walk). The tests are derived by first finding the locally most powerful test against a martingale-type alternative when the starting value of the parameter process is known. After some simplification a test having a known numerically tractable limiting distribution is developed. When the starting point is unknown an efficient estimate is substituted for it. In addition, the corresponding limiting distribution is established. The proposed tests turn out to be based on cumulative sums of the score function (the derivative of the log-likelihood).

The heterogeneity of common variable immunodeficiency (CVID) calls for a classification addressing pathogenic mechanisms as well as clinical relevance. This European multicenter trial was initiated to develop a consensus of 2 existing classification schemes based on flowcytometric B-cell phenotyping and the clinical course. The clinical evaluation of 303 patients with the established diagnosis of CVID demonstrated a significant coincidence of granulomatous disease, autoimmune cytopenia, and splenomegaly. Phenotyping of B-cell subpopulations confirmed a severe reduction of switched memory B cells in most of the patients that was associated with a higher risk for splenomegaly and granulomatous disease. An expansion of CD21(low) B cells marked patients with splenomegaly. Lymphadenopathy was significantly linked with transitional B-cell expansion. Based on these findings and pathogenic consideration of B-cell differentiation, we suggest an improved classification for CVID (EUROclass), separating patients with nearly absent B cells (less than 1%), severely reduced switched memory B cells (less than 2%), and expansion of transitional (more than 9%) or CD21(low) B cells (more than 10%). Whereas the first group contains all patients with severe defects of early B-cell differentiation, severely reduced switched memory B cells indicate a defective germinal center development as found in inducible constimulator (ICOS) or CD40L deficiency. The underlying defects of expanded transitional or CD21(low) B cells remain to be elucidated. This trial is re-gistered at http://www.uniklinik-freiburg.de/zks/live/uklregister/Oeffentlich.html as UKF000308.

Mitogen-activated protein kinase (MAPK) pathways constitute a large modular network that regulates a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. The function of the ERK pathway has been depicted as survival-promoting, in essence by opposing the proapoptotic activity of the stress-activated c-Jun NH(2)-terminal kinase (JNK)/p38 MAPK pathways. However, recently published work suggests that extracellular regulated kinase (ERK) pathway activity is suppressed by JNK/p38 kinases during apoptosis induction. In this review, we will summarize the current knowledge about JNK/p38-mediated mechanisms that negatively regulate the ERK pathway. In particular, we will focus on phosphatases (PP2A, MKPs) as inhibitors of ERK pathway activity in regulating apoptosis. A model proposed in this review places the negative regulation of the ERK pathway in a central position for the cellular decision-making process that determines whether cells will live or die in response to apoptosis-promoting signals. In addition, we will discuss the potential functional relevance of negative regulation of ERK pathway activity, for physiological and pathological conditions (e.g., cellular transformation).

In Finland, coronary heart disease (CHD) incidence was very high in the 1960s and 1970s.1 In line with this high incidence, the Seven Countries Study showed that the level of serum cholesterol in Finns was also the highest among the investigated countries in the 1960s.2 Because several studies indicated that the atherosclerotic process starts early in life, and in accord with the World Health Organization Recommendation of 19783 which stated that studies assessing atherosclerosis precursors in children should be initiated, a program was launched in Finland in the late 1970s to study cardiovascular risk in the youth.4–6 The Cardiovascular Risk in Young Finns Study was designed as a collaborative effort between five university departments of medical schools (i.e. in Helsinki, Kuopio, Oulu, Tampere and Turku) and several other institutions in Finland. The aim was to study the levels of CHD risk factors and their determinants in children and adolescents of various ages in different parts of the country. Two pilot studies were carried out in 1978 (N = 264, age 8 years) and in 1979 (N = 634, aged 3, 12 and 17 years).6,7 The first main cross-sectional (baseline) study was performed in 1980. The baseline study included 3596 children and adolescents aged 3, 6, 9, 12, 15 and 18 years.8 Between 1980 and 1992, these cohorts were followed up at 3-year intervals. The latest examination of the Cardiovascular Risk in Young Finns Study was performed in 2001, when the participants were young adults, aged 24–39 years. At the time of writing, the 27-year (i.e. 27 years since the start of the study when the participants are aged 30–45 years) follow-up field studies are being conducted, and will be completed in the beginning of 2008. The main objectives of the study have been to: (i) study risk factor levels and their possible regional differences, (ii) study the determinants of CHD risk factors and the mechanisms by which risk factor levels change into adult levels, (iii) explore risk factor tracking, i.e. the maintenance of the relative ranking of an individual with respect to his peers, (iv) study possible clustering of risk factors, (v) study the effect of the time of the study and age of subjects on the results, (vi) identify psychological and behavioural risk factors generally, and recognize their age-specificity and (vii) collect background information for future intervention strategies. In the 21-year follow-up study in 2001, non-invasive ultrasound studies were introduced to the study protocol to measure markers of sub-clinical atherosclerosis. These included carotid artery intima-media thickness (IMT), carotid artery elasticity and brachial artery endothelial-dependent flow-mediated dilation (FMD). Therefore, in recent years the main focus has been in vascular epidemiology, including analyses examining the relations between risk factors from childhood to adulthood with the markers of sub-clinical atherosclerosis. The experience gained in the observational Young Finns Study has set the stage for the Special Turku Coronary Risk Factor Intervention Project for Children (STRIP) Study.9 STRIP Study is an ongoing mainly on dietary intervention trial to reduce cardiovascular diseases (CVD) risk beginning from infancy.10 The study has been carried out in all five Finnish university cities with medical schools and their rural surroundings. The first cross-sectional study was conducted in 1980.8 Altogether 4320 children and adolescents aged 3, 6, 9, 12, 15 and 18 years were randomly chosen from the population register of these areas to produce a representative sample of Finnish children. In practice, girls and boys of each age cohort in each study community were separately placed in random order on the basis of the unique personal identification number. Every kth girl and every kth boy in each community was selected so that the sample consisted of the required number of boys and girls. The varying k factors were determined on the basis of sample size and the total number of boys and girls in the different age cohorts in each community. The final sample was designed to apply the following two considerations: (i) children and adolescents from different parts of Finland with varying CHD risk in adults should be studied and (ii) their socioeconomic background and living conditions should vary, so as to represent reasonably well all Finnish children and adolescents and allow comparisons of urban and rural and different socioeconomic groups. After the first cross-sectional study in 1980, follow-up studies have been conducted 3 years apart (Table 1). Blood sampling and physical examination were conducted for the whole cohort in 1983 and 1986. In 1989, physical examinations and blood tests were gathered in one centre (Turku). The main aim of this 9-year follow-up was to study long-term tracking of serum lipoproteins in children and adolescents. In addition, background information using questionnaires was gathered from the whole cohort. In 1992, cohorts from Helsinki, Kuopio and Turku areas (∼58% of the total cohort) were included for blood sampling. In 1992, physical examinations were performed only in the Turku area. The limitation in the sampling size in 1992 was due to economic constraints and does not imply loss to follow-up due to voluntary non-participation. Psychological data were collected in total cohort also in 1992 and 1997. Cohorts and design of the Young Finns Study aLimitations in the sampling size in 1989 and 1992 do not imply voluntary non-participation. In 1989, physical examinations and blood tests were gathered only in one centre (Turku). In 1992, the limitation in the sampling size was due to economic constraints. Cohorts and design of the Young Finns Study aLimitations in the sampling size in 1989 and 1992 do not imply voluntary non-participation. In 1989, physical examinations and blood tests were gathered only in one centre (Turku). In 1992, the limitation in the sampling size was due to economic constraints. The main study variables are shown in Table 2. In the first cross-sectional study in 1980, a comprehensive data collection was performed using questionnaires, physical measurements and blood tests, including general health status, serum lipoproteins, insulin, obesity indices, blood pressure, lifestyle factors, smoking status, alcohol use, food consumption, dietary intakes, food behaviour, physical activity, psychological and behavioural factors and socioeconomic status. In the follow-ups, serial information concerning these risk factors has been gathered. In addition, several novel risk factors, including C-reactive protein (CRP), homocysteine, asymmetric dimethlyarginine (ADMA), adiponectin and leptin, were analysed in 2001. In addition, heart rate variability measurements to study autonomic nervous system function were collected in the latest follow-up in 2001. Summary of data items in the Cardiovascular Risk in Young Finns Study Summary of data items in the Cardiovascular Risk in Young Finns Study To assess sub-clinical atherosclerosis, carotid artery IMT, carotid elasticity and brachial FMD were measured in the 21-year follow-up at the age of 24–39 years.11,12 These non-invasive vascular markers were chosen because they can be measured quickly and with relative ease in large population studies. Increased carotid IMT is a marker of structural atherosclerosis. It correlates with cardiovascular risk factors, coronary atherosclerosis and predicts cardiovascular events.13,14 Decreased carotid artery elasticity may reflect early functional changes related to atherosclerosis. It has been implicated as an independent predictor for cardiovascular mortality in high-risk individuals.15 Brachial FMD responses are thought to reflect systemic vascular endothelial function.16 Endothelial dysfunction is an early event in atherosclerosis. Impairment in brachial FMD has been shown to predict cardiovascular events,17 and an improvement in FMD in response to optimized antihypertensive control has been associated with a favourable cardiovascular outcome.18 In 2001, genomic DNA was extracted from peripheral blood leukocytes. DNA samples were genotyped by employing the 5′ nuclease assay and fluorogenic allele-specific TaqMan MGB probes,19 using the ABI Prism 7900HT Sequence Detection System. The nucleotide sequences of the primers and probes used in the polymerase chain reaction were deduced from published sequences deposited in the GenBank and Celera databases and synthesized by Applied Biosystems. The participation rates in follow-up studies have been satisfactory (Table 1). Of those invited in (N = 4320), 3596 (83%) participated in the first cross-sectional study in 1980. The main reasons for non-participation included fear of clinical examination (16%), accompanying person was unable to leave from work (12%), child was unwilling to participate (12%) and lack of interest in the study (11%). The follow-up field studies were performed for the whole study population in 1983 and 1986, when 2991 (83.2%) and 2799 (78.3%) subjects participated. In 2001, 2283 subjects (63.5%) of the original cohort participated in clinical examinations and 2620 (72.9%) subjects returned questionnaires. We have examined the representativeness of the remaining cohort on several occasions. Early in the study, the participants who dropped out tended be older, more often males and more often smokers.20 A detailed analysis of participants who dropped out was done after the 21-year follow-up study in 2001. Interestingly, the participation has been dynamic, so that many subjects lost-to follow-up early in the study have actually returned to the study later on.21 When we tested the representativeness of the participants in 2001 by comparing their baseline (1980) characteristics to those of the participants who dropped out,21 we found that the participants were more often women and older than those who dropped out. Otherwise, comparing those who dropped out and participants using age-adjusted analysis found no significant differences in either men or women in total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, blood pressure, body mass index (BMI) or parents’ study years. In addition, there was no difference in physical activity between participants and dropouts. Results from the Young Finns Study have clearly shown that individual's biological risk factor profile is significantly modified by early lifestyle-related factors. Important for strategies of primary prevention among children and adolescents is the question of whether risk factors measured at one-time point are predictive of risk factor values years later. Therefore, several analyses into risk factor tracking have been conducted in the Young Finns Study. In the 12-year follow-up between 1980 and 1992, significant tracking was found for each of the serum lipid variables.22 The range of 12-year correlation was 0.48–0.58, 0.53–0.58, 0.53–0.58 and 0.33–0.37 for serum total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides, respectively. Common risk factors of CHD such as dyslipidaemia and hypertension often co-exist in adults. This clustering is clinically important, since the harmful effects of multiple risk factors are synergistic. Observations from the 1980 and 1986 studies consistently showed that the clustering of adverse lipids, elevated blood pressure and increased obesity was more prevalent in boys compared with girls.23,24 Metabolic deviations related to insulin resistance seem to determine the clustering of biological risk variables in adults. Earlier observations from the Young Finns Study emphasize the role of insulin levels in predicting the clustering of the typical risk factor profile associated with insulin resistance syndrome also in children and adolescents. Fasting insulin concentration is associated with obesity, high triglycerides levels, low HDL cholesterol concentration and elevated blood pressure in children and adolescents,25 and predicts the development of hypertriglyceridaemia and clustering of these risk variables in young adulthood.26 In addition to metabolic risk factor clustering, risky behaviours also show significant clustering in the Young Finns population. The data gathered in the follow-up study in 1986 were used to study the clustering of several risk behaviours, such as non-prudent diet, smoking, physical inactivity and frequent inebriation by alcohol.27 In young adults, the determinants for adverse life-behaviour clustering included male sex, aggressiveness and past unemployment. On the other hand, paying a lot of attention to healthy behaviours, higher education (being a student), good self-perceived health and a high sense of responsibility seemed to be protective factors against risky behaviour clustering. The accumulation of risk behaviours was also associated with an atherogenic lipid and blood pressure profile. Thus, the concept of clustering is a complex phenomenon, where socioeconomic,28 demographic, dietary and behavioural factors29 determine the occurrence of risky behaviour clustering, which contribute to the development of an adverse metabolic risk profile. Physical activity has been an intensive research topic in the Young Finns Study. For example, tracking of physical activity has been analysed on several occasions. A significant tracking was observed in physical activity from adolescence to early adulthood.30 These observations were confirmed in the 21-year follow-up study, when we could demonstrate that high level of physical activity at ages 9–18 years, especially when continuous, significantly predicted a high level of adult physical activity.31 Health effects of physical activity have also been examined. A cross-sectional analysis in 9–24-year-old subjects in 1986 (n = 2358)32 found that a high level of physical activity was associated with high-serum HDL-cholesterol, especially HDL-2 cholesterol concentrations, and low levels of serum triglycerides, apolipoprotein B and insulin in males. Recent analysis suggests that changes in physical activity patterns during the lifetime may contribute to the development of obesity, especially in women.33 Psychological, behavioural and socioeconomic risk factors inside the families were highly accumulated comprising generally favourable and unfavourable developmental environments. Familial factors in subjects’ early childhood, such as parental job stress, Type A behaviour, life satisfaction and child rearing practices significantly predict adulthood risk factors like hostility34 and depression;35 and moderate other risk factors, such as early smoking and physical inactivity.36 In addition, a correlation between psychological and somatic risk factors of CHD is evident since childhood.37 At present, there are no prospective long-term data available that could be used to test the hypothesis that exposure to risk factors in childhood influence cardiovascular morbidity or mortality. Therefore, the main objective for the 21-year follow-up study in 2001 was to gather indirect evidence for this idea by examining how exposure to risk factors early in life influences the markers of sub-clinical atherosclerosis in young adulthood. The findings have been supportive of this hypothesis. We have observed that exposure to cardiovascular risk factors in early in life may induce changes in arteries that contribute to the development of structural and functional vascular changes related to atherosclerosis. For example, we have shown that exposure to high LDL cholesterol, elevated blood pressure, obesity and cigarette smoking in adolescence predict increased carotid IMT and decreased elasticity in young adulthood.12,38 In addition, the data suggest that elevated blood pressure during adolescence influences brachial FMD responses later on in adulthood.39 Most importantly, the effect of childhood risk factors on later sub-clinical atherosclerosis was independent of contemporaneous risk factors. Thus, these findings suggest that exposure to risk factors in childhood may increase the vulnerability of vascular wall to atherosclerosis. Cross-sectional findings in 2001 regarding the inter-relations of vascular markers and biochemical risk have also provided interesting insights into the pathophysiology of atherosclerosis. Loss of normal endothelial function is hypothesized to be a fundamental step in the atherosclerotic disease process. The response-to-injury model of atherosclerosis40 predicts that arterial endothelial damage or activation is required before risk factors can induce atherosclerotic changes in the arterial wall. We have addressed this concept at the population level in the Young Finns Study. We demonstrated that the number of risk factors was associated with increased carotid IMT only among subjects with impaired FMD but not among those with enhanced FMD.11 The data thus support the concept that systemic endothelial function reflects the propensity of arteries to develop atherosclerosis in response to exposure to cardiovascular risk factors. Of the potential biochemical markers of endothelial function, we found that the levels of asymmetric dimethylarginine were, independently of conventional risk factors, associated with decreased brachial FMD response.41 The analyses from the 21-year follow-up have also shown that socioeconomic, behavioural and psychological factors, e.g. depression and job strain are associated with cardiovascular risk factors and measures of sub-clinical atherosclerosis.42,43 For example, an association between job stress and carotid IMT was moderated by genetic dispositions, i.e. this association was related to certain genetic polymorphisms that sensitize the carriers to the stress.44 Childhood temperamental hyperactivity45 and childhood eagerness-energy (a temperament-related sub-component of Type A behaviour46 predict adult IMT over a follow-up periods of 21- and 15-years, respectively. In addition to environmental factors, several genetic polymorphisms have been linked with cardiovascular risk factors, as well as with alterations in carotid and brachial artery structure or function in the Young Finns Study. We have utilized the candidate gene approach to explore potentially interesting relations between several known single nucleotide polymorphisms and clinical traits. Recently, genetic analyses have been an active part of the study. For example, by using the Mendelian randomization technique, we found no evidence of a causal association between CRP and carotid IMT.47 However, CRP genetics may influence arterial elasticity.48 In diabetes research, we found that variation of the transcription factor 7-like two gene predicted impaired fasting glucose in young adults.49 In addition, the role of apolipoprotein E polymorphism influencing serum lipid changes from childhood to adulthood was recently confirmed in the study.50 Regarding risk factor trends over time, we observed a rapid decrease in total cholesterol levels between 1980 and 1986 and a modest decrease between 1986 and 2001.21 At the same time, a clear increase in BMI and triglycerides levels and a decrease in HDL-cholesterol and blood pressure levels was observed. In line with these findings, in 24-year-old subjects, the prevalence of the metabolic syndrome increased significantly from 1.0 to 7.5% in 15 years.51 Our reports have also shown that lifestyle adopted in childhood is clearly predictive of diet and physical activity in adulthood.31,52 Dietary patterns are established already in childhood, persist into adulthood and are significantly associated with CHD risk factors.53,54 The main strengths of the Young Finns Study include its longitudinal study design with regular follow-ups and collection of a diverse set of carefully measured phenotypes, lifestyle measures and socioeconomic background information. With the vascular measurements the study has the potential to provide important insights regarding the mechanisms of atherosclerosis, as it will be possible to test and integrate at the population level concepts that have emerged from experimental studies. The cohort provides a unique opportunity to study the development of lifestyle and risk factors from childhood to adulthood. The study makes it possible to relate the lifetime burden of risk factors on vascular ageing in these subjects. By linking morbidity and mortality statistics on the existing longitudinal database of this cohort, it will be possible to study the childhood determinants of adult health in a way that has not been previously possible. The cumulative data allow testing the hypothesis that common diseases and disorders have their origin in early life. At this time, the main weakness of the study is that so far it is not possible to study the associations between childhood risk factors with disease end points. In addition, the generalizability of the findings is limited to white European subjects. Lost to follow-up is an inevitable problem in all long-term studies. Finally, original enrolment of the subjects occurred over a wide age range 3–18 years, therefore in a large proportion of subjects early childhood data are not The Young Finns Study a unique opportunity to longitudinal measures of conventional and novel cardiovascular risk factors, genetic and psychological factors beginning from childhood with a range of in adulthood. for are and or for information should be to information the study, information and a are available on the This study was by the of Finland and the of Finland, the Turku the from the Tampere and Kuopio the of the Finnish of Cardiovascular the Finnish and the Finnish

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

We present a novel approach to still image denoising based on effective filtering in 3D transform domain by combining sliding-window transform processing with block-matching. We process blocks within the image in a sliding manner and utilize the block-matching concept by searching for blocks which are similar to the currently processed one. The matched blocks are stacked together to form a 3D array and due to the similarity between them, the data in the array exhibit high level of correlation. We exploit this correlation by applying a 3D decorrelating unitary transform and effectively attenuate the noise by shrinkage of the transform coefficients. The subsequent inverse 3D transform yields estimates of all matched blocks. After repeating this procedure for all image blocks in sliding manner, the final estimate is computed as weighed average of all overlapping blockestimates. A fast and efficient algorithm implementing the proposed approach is developed. The experimental results show that the proposed method delivers state-of-art denoising performance, both in terms of objective criteria and visual quality.

The shape-adaptive discrete cosine transform ISA-DCT) transform can be computed on a support of arbitrary shape, but retains a computational complexity comparable to that of the usual separable block-DCT (B-DCT). Despite the near-optimal decorrelation and energy compaction properties, application of the SA-DCT has been rather limited, targeted nearly exclusively to video compression. In this paper, we present a novel approach to image filtering based on the SA-DCT. We use the SA-DCT in conjunction with the Anisotropic Local Polynomial Approximation-Intersection of Confidence Intervals technique, which defines the shape of the transform's support in a pointwise adaptive manner. The thresholded or attenuated SA-DCT coefficients are used to reconstruct a local estimate of the signal within the adaptive-shape support. Since supports corresponding to different points are in general overlapping, the local estimates are averaged together using adaptive weights that depend on the region's statistics. This approach can be used for various image-processing tasks. In this paper, we consider, in particular, image denoising and image deblocking and deringing from block-DCT compression. A special structural constraint in luminance-chrominance space is also proposed to enable an accurate filtering of color images. Simulation experiments show a state-of-the-art quality of the final estimate, both in terms of objective criteria and visual appearance. Thanks to the adaptive support, reconstructed edges are clean, and no unpleasant ringing artifacts are introduced by the fitted transform.