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1.  Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase 
Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized.
This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways.
Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts.
Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03).
Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms.
PMCID: PMC4783625  PMID: 26965542
cholesterol lowering; drug development; lipoproteins; Mendelian randomization; metabolomics; CVD, cardiovascular disease; HDL, high-density lipoprotein; HMGCR, HMG-CoA reductase; IDL, intermediate-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; NMR, nuclear magnetic resonance; VLDL, very-low-density lipoprotein
2.  Screening for cardiovascular risk factors and self-rated health in a community setting: a cross-sectional study in Finland 
The British Journal of General Practice  2014;64(627):e611-e615.
Self-rated health is an independent predictor of mortality. However, general health checks in populations unselected for disease or risk factors have not been shown to reduce mortality or morbidity.
To describe new comorbidities and cardiovascular risk factors in apparently healthy people and to relate this to their self-rated health.
Design and setting
A targeted screening programme identified 462 middle-aged people with cardiovascular risk factors without previously diagnosed chronic disease in a Finnish community in 2005–2006.
Home blood pressure monitoring, oral glucose tolerance test, estimated glomerular filtration rate, and ankle brachial index were used to detect previously undiagnosed conditions. The Short-Form Health Survey and Beck’s Depression Inventory were completed by participants before the diagnostic tests were performed.
The prevalence of previously undiagnosed disease was: hypertension 113/462 (24% [95% confidence interval {CI} = 21% to 29%]), diabetes 19/462 (4% [95% CI = 2% to 6%]), renal insufficiency 23/462 (5% [95% CI = 3% to 7%]), and peripheral arterial disease 17/462 (4% [95% CI = 2% to 5%]). Of the 139 participants who regarded their health as ‘fair–poor’, 60 (43%) had a previously undetected condition affecting their vasculature.
Out of the screen-detected apparently healthy cardiovascular risk subjects, one in three had undiagnosed hypertension, diabetes, peripheral arterial disease, or renal insufficiency. Those individuals experiencing ill health tended to be at high risk of cardiovascular problems.
PMCID: PMC4173723  PMID: 25267046
cardiovascular disease; community health; health promotion; prevention; primary care; risk factors; screening
3.  Association between suicidal behaviour and impaired glucose metabolism in depressive disorders 
BMC Psychiatry  2015;15:163.
Disturbances in lipid metabolism have been linked to suicidal behaviour, but little is known about the association between suicide risk and abnormal glucose metabolism in depression. Hyperglycaemia and hyperinsulinaemia may increase the risk of depression and also the risk for suicide, we therefore studied associations between suicidal behaviour and disturbances in glucose metabolism in depressive patients who had been referred to depression nurse case managers.
Patients aged 35 years and older (N = 448, mean age 51 years) who were experiencing a new depressive episode, who were referred to depression nurse case managers in 2008–2009 and who scored ≥10 on the Beck Depression Inventory were enrolled in this study. The study was conducted in municipalities within the Central Finland Hospital District (catchment area of 274 000 inhabitants) as part of the Finnish Depression and Metabolic Syndrome in Adults study. The patients’ psychiatric diagnoses and suicidal behaviour were confirmed by the Mini-International Neuropsychiatric Interview. Blood samples, for glucose and lipid determinations, were drawn from participants after 12 h of fasting, which was followed by a 2-hour oral glucose tolerance test (OGTT) when blood was drawn at 0 and 2 h. Insulin resistance was measured by the Quantitative Insulin Sensitivity Check Index (QUICKI) method.
Suicidal ideation (49 %) and previous suicide attempts (16 %) were common in patients with major depressive disorder or dysthymia. Patients with depression and suicidal behaviour had higher blood glucose concentrations at baseline and at 2 hours in the OGTT. Glucose levels associated positively with the prevalence of suicidal behaviour, and the linearity was significant at baseline (p for linearity: 0.012, adjusted for age and sex) and for 2-hour OGTT glucose (p for linearity: 0.004, adjusted for age and sex). QUICKI levels associated with suicidal behavior (p for linearity across tertiles of QUICKI: 0.026). Total and LDL cholesterol and triglyceride levels were also higher in those patients with suicidal behaviour. Multivariate analysis revealed that blood glucose levels, BDI scores and antidepressive medications associated with suicidal behaviour.
Insulin resistance and disturbances in glucose and lipid metabolism may be more common in middle-aged depressive patients with suicidal behaviour.
PMCID: PMC4509469  PMID: 26199013
Cholesterol; Depression; Glucose; Insulin resistance; Suicidal behaviour; Ideation; Suicidality; Suicide attempt; Triglyceride
4.  The Relationship between Thyroid Function and Depressive Symptoms—the FIN-D2D Population-Based Study 
The association between thyroid function and depression is controversial. Both conditions express many similar symptoms, but the studies done give conflicting results. This study draws on a random, population-based sample of 4500 subjects aged 45–75 years old from Finland. The basic clinical study was done in 2007 for 1396 men and 1500 women (64% participation rate). Thyroid stimulating hormone (TSH), free thyroxine (F-T4), and free triiodothyronine (F-T3) were measured in 2013 from frozen samples. The 21-item Beck Depression Inventory (BDI-21) was applied to assess depressive symptoms (score ≥10 points). The prevalence of depressive symptoms was 17.5% in women and 12.5% in men. In women, the mean levels of TSH, F-T4, and F-T3 without depressive symptoms vs. with the presence of depressive symptoms were 1.92/1.97 mU/L, 13.1/13.1 pmol/L, and 3.91/3.87 pmol/L (NS), respectively. In men, the levels were 1.87/1.94 mU/L, 13.5/13.7 pmol/L, and 4.18/4.12 pmol/L (NS), respectively. In multiple regression analysis, TSH had no relationship to BDI-21 total score. We found no association between depressive symptoms and thyroid values.
PMCID: PMC4406392  PMID: 25987853
depressive symptoms; BDI-21; thyroid; population based
5.  Decreasing cholesterol levels in the community – lifestyle change with statin? 
BMC Family Practice  2015;16:29.
The Lapinlahti 2005–2010 study was carried out to explore cardiovascular disease risk factors and changes in lifestyle in Lapinlahti residents in eastern Finland. Our aim was to analyse factors influencing the level of cholesterol in the community.
In 2005, 480 subjects aged 30–65 years underwent a complete health survey (baseline study) that consisted of a structured questionnaire and a health examination. The follow-up was carried out five years later in 2010. The present study population included 326 individuals who did not use lipid-lowering medication at the baseline. A trained research nurse measured weight, height, waist circumference and blood pressure at the baseline and follow-up. Respectively, lifestyle factors (nutrition, exercise, smoking and alcohol use) were examined with a structured questionnaire. Each lifestyle item was valued as −1, 0 or 1, depending on how closely it fitted to the recommendations. Cholesterol level analyses at the baseline and follow-up were performed according to the protocol of the Kuopio University Hospital’s medical laboratory. Based on their baseline cholesterol levels, the participants were divided into tertiles. The age- and sex-adjusted linear trend between the tertiles was tested.
The change in cholesterol level was associated with lipid-lowering medication (P < 0.001). Lifestyle improvement was associated with the cholesterol level change but did not reach statistical significance (P = 0.061), although the interaction of lipid-lowering medication and lifestyle change was associated with the change in cholesterol level (P = 0.018). In multivariate analysis, a favourable change in fat consumption (P = 0.007) and lipid-lowering medication (P < 0.001) were associated with decreasing cholesterol levels.
At the population level, dyslipidaemia is one of the most easily modifiable risk factors of CHD. Lipid-lowering medication may have the most significant impact on cholesterol level in communities with primary health care with good coverage. On the other hand, the potential of health-promoting and population-based prevention strategies may be underused.
PMCID: PMC4356061  PMID: 25879518
Cholesterol; Lifestyle; Population-based study
6.  Metabolic Signatures of Adiposity in Young Adults: Mendelian Randomization Analysis and Effects of Weight Change 
PLoS Medicine  2014;11(12):e1001765.
In this study, Wurtz and colleagues investigated to what extent elevated body mass index (BMI) within the normal weight range has causal influences on the detailed systemic metabolite profile in early adulthood using Mendelian randomization analysis.
Please see later in the article for the Editors' Summary
Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.
Methods and Findings
We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16–39 y; 51% women; mean ± standard deviation BMI 24±4 kg/m2). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%–183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87%±3%; R2 = 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160%±2%; R2 = 0.92).
Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood.
Please see later in the article for the Editors' Summary
Editors' Summary
Adiposity—having excessive body fat—is a growing global threat to public health. Body mass index (BMI, calculated by dividing a person's weight in kilograms by their height in meters squared) is a coarse indicator of excess body weight, but the measure is useful in large population studies. Compared to people with a lean body weight (a BMI of 18.5–24.9 kg/m2), individuals with higher BMI have an elevated risk of developing life-shortening cardiometabolic diseases—cardiovascular diseases that affect the heart and/or the blood vessels (for example, heart failure and stroke) and metabolic diseases that affect the cellular chemical reactions that sustain life (for example, diabetes). People become unhealthily fat by consuming food and drink that contains more energy (calories) than they need for their daily activities. So adiposity can be prevented and reversed by eating less and exercising more.
Why Was This Study Done?
Epidemiological studies, which record the patterns of risk factors and disease in populations, suggest that the illness and death associated with excess body weight is partly attributable to abnormalities in how individuals with high adiposity metabolize carbohydrates and fats, leading to higher blood sugar and cholesterol levels. Further, adiposity is also associated with many other deviations in the metabolic profile than these commonly measured risk factors. However, epidemiological studies cannot prove that adiposity causes specific changes in a person's systemic (overall) metabolic profile because individuals with high BMI may share other characteristics (confounding factors) that are the actual causes of both adiposity and metabolic abnormalities. Moreover, having a change in some aspect of metabolism could also lead to adiposity, rather than vice versa (reverse causation). Importantly, if there is a causal effect of adiposity on cardiometabolic risk factor levels, it might be possible to prevent the progression towards cardiometabolic diseases by weight loss. Here, the researchers use “Mendelian randomization” to examine whether increased BMI within the normal and overweight range is causally influencing the metabolic risk factors from many biological pathways during early adulthood. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. Several gene variants are known to lead to modestly increased BMI. Thus, an investigation of the associations between these gene variants and risk factors across the systemic metabolite profile in a population of healthy individuals can indicate whether higher BMI is causally related to known and novel metabolic risk factors and higher cardiometabolic disease risk.
What Did the Researchers Do and Find?
The researchers measured the BMI of 12,664 adolescents and young adults (average BMI 24.7 kg/m2) living in Finland and the blood levels of 82 metabolites in these young individuals at a single time point. Statistical analysis of these data indicated that elevated BMI was adversely associated with numerous cardiometabolic risk factors. For example, elevated BMI was associated with raised levels of low-density lipoprotein, “bad” cholesterol that increases cardiovascular disease risk. Next, the researchers used a gene score for predisposition to increased BMI, composed of 32 gene variants correlated with increased BMI, as an “instrumental variable” to assess whether adiposity causes metabolite abnormalities. The effects on the systemic metabolite profile of a 1-kg/m2 increment in BMI due to genetic predisposition closely matched the effects of an observed 1-kg/m2 increment in adulthood BMI on the metabolic profile. That is, higher levels of adiposity had causal effects on the levels of numerous blood-based metabolic risk factors, including higher levels of low-density lipoprotein cholesterol and triglyceride-carrying lipoproteins, protein markers of chronic inflammation and adverse liver function, impaired insulin sensitivity, and elevated concentrations of several amino acids that have recently been linked with the risk for developing diabetes. Elevated BMI also causally led to lower levels of certain high-density lipoprotein lipids in the blood, a marker for the risk of future cardiovascular disease. Finally, an examination of the metabolic changes associated with changes in BMI in 1,488 young adults after a period of six years showed that those metabolic measures that were most strongly associated with BMI at a single time point likewise displayed the highest responsiveness to weight change over time.
What Do These Findings Mean?
These findings suggest that increased adiposity has causal adverse effects on multiple cardiometabolic risk markers in non-obese young adults beyond the effects on cholesterol and blood sugar. Like all Mendelian randomization studies, the reliability of the causal association reported here depends on several assumptions made by the researchers. Nevertheless, these findings suggest that increased adiposity has causal adverse effects on multiple cardiometabolic risk markers in non-obese young adults. Importantly, the results of both the causal effect analyses and the longitudinal study suggest that there is no threshold below which a BMI increase does not adversely affect the metabolic profile, and that a systemic metabolic profile linked with high cardiometabolic disease risk that becomes established during early adulthood can be reversed. Overall, these findings therefore highlight the importance of weight reduction as a key target for metabolic risk factor control among young adults.
Additional Information
Please access these websites via the online version of this summary at
The Computational Medicine Research Team of the University of Oulu has a webpage that provides further information on metabolite profiling by high-throughput NMR metabolomics
The World Health Organization provides information on obesity (in several languages)
The Global Burden of Disease Study website provides the latest details about global obesity trends
The UK National Health Service Choices website provides information about obesity, cardiovascular disease, and type 2 diabetes (including some personal stories)
The American Heart Association provides information on all aspects of cardiovascular disease and diabetes and on keeping healthy; its website includes personal stories about heart attacks, stroke, and diabetes
The US Centers for Disease Control and Prevention has information on all aspects of overweight and obesity and information about heart disease, stroke, and diabetes
MedlinePlus provides links to other sources of information on heart disease, vascular disease, and obesity (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC4260795  PMID: 25490400
7.  Serum ferritin levels and the development of metabolic syndrome and its components: a 6.5-year follow-up study 
The aim of this study was to investigate the relationship between changes in serum ferritin concentrations and the development of metabolic syndrome (MetS) and its components over a 6.5 year follow-up period in Finnish adults.
Adults born in Pieksämäki, Finland, in 1942, 1947, 1952, 1957, and 1962 (n = 1294) were invited to health checkups between 1997 and 1998 and 2003 and 2004. All of the required variables for both checkups were available from 691 (53%) subjects (289 men and 402 women). MetS was defined by the National Cholesterol Education Program criteria.
During the 6.5-year follow-up period, 122 (18%) subjects developed incident cases of MetS. Increases in serum ferritin levels were significantly higher in both women and men with incident MetS compared with women and men without MetS (p = 0.04, p = 0.03). Also, serum ferritin levels increased significantly less in women in whom the criteria for MetS resolved during the follow-up period (p = 0.01). Increases in serum ferritin levels were significantly lower in women in whom the glucose criterion for MetS resolved, and higher in women for whom the waist criterion developed (p = 0.01 and p <0.001, respectively). Serum ferritin levels decreased significantly more in men in whom the triglyceride criterion for MetS resolved during the follow-up period (p = 0.01). There was a clear and significant correlation between change in serum ferritin level and change in waist circumference both in men and women (p <0.001, p <0.01). In addition, correlations between change in serum ferritin level and change in plasma triglyceride as well as glucose levels were strongly positive in men (p <0.001). There was negative correlation between change in serum ferritin and plasma high density cholesterol level both in men and women.
Increases in serum ferritin over a 6,5 year period are associated with development of MetS in both men and women. Whereas, lower increases in serum ferritin over the same timeframe are associated with resolution of hypertriglyceridemia in men and hyperglycemia in women. Increases in waist circumference was positively correlated with increases in serum ferritin in both men and women.
PMCID: PMC4219011  PMID: 25371712
Metabolic syndrome; Ferritin; Obesity
8.  Cross-sectional and longitudinal associations of circulating omega-3 and omega-6 fatty acids with lipoprotein particle concentrations and sizes: population-based cohort study with 6-year follow-up 
Cross-sectional studies have suggested that serum omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are related to favorable lipoprotein particle concentrations. We explored the associations of serum n-3 and n-6 PUFAs with lipoprotein particle concentrations and sizes in a general population cohort at baseline and after 6 years.
The cohort included 665 adults (274 men) with a 6-year follow-up. Nutritional counseling was given at baseline. Serum n-3 and n-6 PUFAs and lipoprotein particle concentrations and the mean particle sizes of VLDL, LDL, and HDL were quantified by nuclear magnetic resonance (NMR) spectroscopy for all baseline and follow-up samples at the same time. Concentrations of n-3 and n-6 PUFAs were expressed relative to total fatty acids. At baseline, n-3 PUFAs were not associated with lipoprotein particle concentrations. A weak negative association was observed for VLDL (P = 0.021) and positive for HDL (P = 0.011) particle size. n-6 PUFA was negatively associated with VLDL particle concentration and positively with LDL (P < 0.001) and HDL particle size (P < 0.001). The 6-year change in n-3 PUFA correlated positively with the change in particle size for HDL and LDL lipoproteins but negatively with VLDL particle size. An increase in 6-year levels of n-6 PUFAs was negatively correlated with the change in VLDL particle concentration and size, and positively with LDL particle size.
Change in circulating levels of both n-3 and n-6 PUFAs, relative to total fatty acids, during 6 years of follow-up are associated with changes in lipoprotein particle size and concentrations at the population level.
PMCID: PMC3922432  PMID: 24507090
Lipoprotein profile; Fatty acid; Cohort study
9.  Circulating Metabolite Predictors of Glycemia in Middle-Aged Men and Women 
Diabetes Care  2012;35(8):1749-1756.
Metabolite predictors of deteriorating glucose tolerance may elucidate the pathogenesis of type 2 diabetes. We investigated associations of circulating metabolites from high-throughput profiling with fasting and postload glycemia cross-sectionally and prospectively on the population level.
Oral glucose tolerance was assessed in two Finnish, population-based studies consisting of 1,873 individuals (mean age 52 years, 58% women) and reexamined after 6.5 years for 618 individuals in one of the cohorts. Metabolites were quantified by nuclear magnetic resonance spectroscopy from fasting serum samples. Associations were studied by linear regression models adjusted for established risk factors.
Nineteen circulating metabolites, including amino acids, gluconeogenic substrates, and fatty acid measures, were cross-sectionally associated with fasting and/or postload glucose (P < 0.001). Among these metabolic intermediates, branched-chain amino acids, phenylalanine, and α1-acid glycoprotein were predictors of both fasting and 2-h glucose at 6.5-year follow-up (P < 0.05), whereas alanine, lactate, pyruvate, and tyrosine were uniquely associated with 6.5-year postload glucose (P = 0.003–0.04). None of the fatty acid measures were prospectively associated with glycemia. Changes in fatty acid concentrations were associated with changes in fasting and postload glycemia during follow-up; however, changes in branched-chain amino acids did not follow glucose dynamics, and gluconeogenic substrates only paralleled changes in fasting glucose.
Alterations in branched-chain and aromatic amino acid metabolism precede hyperglycemia in the general population. Further, alanine, lactate, and pyruvate were predictive of postchallenge glucose exclusively. These gluconeogenic precursors are potential markers of long-term impaired insulin sensitivity that may relate to attenuated glucose tolerance later in life.
PMCID: PMC3402262  PMID: 22563043
10.  Association between vitamin b12 levels and melancholic depressive symptoms: a Finnish population-based study 
BMC Psychiatry  2013;13:145.
An association between vitamin B12 levels and depressive symptoms (DS) has been reported in several epidemiological studies. The purpose of this study was to evaluate vitamin B12 levels in population-based samples with melancholic or non-melancholic DS as the relationship between vitamin B12 levels and different subtypes of DS has not been evaluated in previous studies.
Subjects without previously known type 2 diabetes, aged 45–74 years were randomly selected from the National Population Register as a part of the Finnish diabetes prevention programme (FIN-D2D). The study population (N = 2806, participation rate 62%) consisted of 1328 men and 1478 women. The health examinations were carried out between October and December 2007 according to the WHO MONICA protocol. The assessment of DS was based on the Beck Depression Inventory (BDI, cut-off ≥10 points). A DSM-IV- criteria based summary score of melancholic items in the BDI was used in dividing the participants with DS (N = 429) into melancholic (N = 138) and non-melancholic DS (N = 291) subgroups. In the statistical analysis we used chi-squared test, t-test, permutation test, analysis of covariance, multivariate logistic regression analysis and multinomial regression model.
The mean vitamin B12 level was 331±176 pmol/L in those without DS while the subjects with non-melancholic DS had a mean vitamin B12 level of 324 ± 135 pmol/L, and those with melancholic DS had the lowest mean vitamin B12 level of 292±112 pmol/L (p < 0.001 after adjusted for age, sex, use of antidepressive medication and chronic diseases sum index). The adjusted difference of vitamin B12 levels between the non-melancholic and the melancholic group was 33 pmol/L (95%CI 8 to 57, p = 0.008). Melancholic DS and vitamin B12 levels showed an independent linearly inverse association. The relative risk ratio (RRR) for melancholic DS was 2.75 (95%CI 1.66 to 4.56) in the lowest vitamin B12 level tertile versus the highest (p for linearity <0.001) when those without DS formed the reference group. The RRR in the non-melancholic subgroup was nonsignificant.
The vitamin B12 level was associated with melancholic DS but not with non-melancholic DS.
PMCID: PMC3674945  PMID: 23705786
Beck depression inventory; Melancholic depressive symptoms; Non-melancholic depressive symptoms; Population-based; Vitamin B12
11.  Erythropoietin, ferritin, haptoglobin, hemoglobin and transferrin receptor in metabolic syndrome: a case control study 
Increased ferritin concentrations are associated with metabolic syndrome (MetS). The association between ferritin as well as hemoglobin level and individual MetS components is unclear. Erythropoietin levels in subjects with MetS have not been determined previously. The aim of this study was to compare serum erythropoietin, ferritin, haptoglobin, hemoglobin, and transferrin receptor (sTFR) levels between subjects with and without MetS and subjects with individual MetS components.
A population based cross-sectional study of 766 Caucasian, middle-aged subjects (341 men and 425 women) from five age groups born in Pieksämäki, Finland who were invited to a health check-up in 2004 with no exclusion criteria. Laboratory analyzes of blood samples collected in 2004 were done during year 2010. MetS was defined by National Cholesterol Education Program criteria.
159 (53%) men and 170 (40%) women of study population met MetS criteria. Hemoglobin and ferritin levels as well as erythropoietin and haptoglobin levels were higher in subjects with MetS (p < 0.001, p = 0.018). sTFR level did not differ significantly between subjects with or without MetS. Hemoglobin level was significantly higher in subjects with any of the MetS components (p < 0.001, p = 0.002). Ferritin level was significantly higher in subjects with abdominal obesity or high TG or elevated glucose or low high density cholesterol component (p < 0.001, p = 0.002, p = 0.02). Erythropoietin level was significantly higher in subjects with abdominal obesity component (p = 0.015) but did not differ significantly between subjects with or without other MetS components. Haptoglobin level was significantly higher in subjects with blood pressure or elevated glucose component o MetS (p = 0.028, p = 0.025).
Subjects with MetS have elevated hemoglobin, ferritin, erythropoietin and haptoglobin concentrations. Higher hemoglobin levels are related to all components of MetS. Higher ferritin levels associate with TG, abdominal obesity, elevated glucose or low high density cholesterol. Haptoglobin levels associate with blood pressure or elevated glucose. However, erythropoietin levels are related only with abdominal obesity. Higher serum erythropoietin concentrations may suggest underlying adipose tissue hypoxemia in MetS.
PMCID: PMC3471017  PMID: 23016887
Erythropoietin; Ferritin; Hemoglobin; Metabolic syndrome
12.  Relationships between depressive symptoms and self-reported unintentional injuries: the cross-sectional population–based FIN-D2D survey 
BMC Public Health  2012;12:516.
There is a lack of knowledge on the influence of different levels of physical activity (PA) on unintentional injuries among those with depressive symptoms (DS). The aim of this study was to evaluate the relationship between PA categories and unintentional injuries among participants with and without DS based on a cross-sectional population–based FIN-D2D survey conducted in 2007.
Out of 4500, 2682 participants (60%) aged 45–74 years attended in this study. The unintentional injuries over the past year were captured in a questionnaire. DS were determined with the Beck Depression Inventory (≥ 10 points) and PA with the International Physical Activity Questionnaire. The statistical significance between DS and unintentional injury categories was evaluated by using t-test, chi-square test, or permutation test, analysis of covariance, or regression models. The factors related to unintentional injuries were estimated by univariate and multivariate logistic regression models.
The proportion of subjects with unintentional injuries was higher among those with DS (17%) compared to those without DS (10%) (age- and gender-adjusted p = 0.023). The median (range) number of activity-loss days after injury was 22 (0–365) in participants with DS and 7 (0–120) in participants without DS ( p = 0.009). The percentage of subjects with unintentional injuries was not significantly different between PA categories in participants with DS and without DS. A stepwise multivariate logistic regression analysis showed that DS, functional ability, and musculoskeletal diseases were related to unintentional injuries.
PA level was not related to unintentional injuries, whereas those with DS had a higher prevalence of unintentional injuries and prolonged activity-loss after injury. These results underline the importance of injury prevention, especially among those who have DS and additional risk factors.
PMCID: PMC3506522  PMID: 22781103
Beck depression inventory; Depressive symptoms; Injury; Physical activity
13.  Association of Depressive Symptoms With Impaired Glucose Regulation, Screen-Detected, and Previously Known Type 2 Diabetes 
Diabetes Care  2010;34(1):71-76.
To study the association between impaired glucose regulation (IGR), screen-detected type 2 diabetes, and previously known diabetes and depressive symptoms.
Altogether, 2,712 participants from three hospital districts in Finland attended a health examination. Cutoff scores ≥10 and ≥16 in the 21-item Beck Depression Inventory (BDI-21) were used for depressive symptoms. The participants were defined as having known diabetes if they reported diabetes. An oral glucose tolerance test was used to detect normal glucose regulation (NGR), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and screen-detected diabetes. The participants were defined as having IGR if they had IFG or IGT.
Prevalence of depressive symptoms, defined as a BDI-21 cutoff score ≥10, was 14.4% for those with NGR, 13.7% for those with IGR, 14.8% for those with screen-detected diabetes, and 26.4% for those with previously known diabetes. The corresponding prevalences for a cutoff score ≥16 were 3.4, 3.4, 4.2, and 7.5%, respectively. Compared with NGR and adjusted for demographic, lifestyle, and biological factors, the odds ratios for IGR, screen-detected diabetes, and previously known diabetes were 0.91 (95% CI 0.69–1.20), 0.70 (0.45–1.08), and 1.35 (0.84–2.15), respectively, for a cutoff score ≥10. For a cutoff score ≥16, the corresponding odds ratios were 1.05 (0.62–1.76), 0.87 (0.40–1.90), and 1.56 (0.69–3.50), respectively.
Participants with diagnosed diabetes had a higher prevalence of depressive symptoms than participants with NGR, IGR, and previously unknown diabetes. When potential confounding factors were included in the analysis, previously known diabetes was not significantly associated with depressive symptoms.
PMCID: PMC3005462  PMID: 20929992
14.  Price, familiarity, and availability determine the choice of drug - a population-based survey five years after generic substitution was introduced in Finland 
Mandatory generic substitution (GS) was introduced in Finland at the beginning of April 2003. However, individual patients or physicians may forbid the substitution. GS was a significant change for Finnish medicine users. It was thought it would confuse people when the names, colors, packages, etc., changed. The purpose of this study was to explore what medicine-related factors influence people's choice of prescription drugs five years after generic substitution was introduced in Finland.
A population survey was carried out during the autumn of 2008. A random sample was drawn from five mainland counties. A questionnaire was mailed to 3000 people at least 18 years old and living in Finland. The questionnaire consisted of both structured and open-ended questions. Factors that influenced the subjects' choice of medicines were asked with a structured question containing 11 propositions. Descriptive statistical analyses were performed.
In total, 1844 questionnaires were returned (response rate, 62%). The percentage of female respondents was 55%. Price, availability, and familiarity were the three most important factors that influenced the choice of medicines. For the people who had refused GS, the familiarity of the medicine was the most important factor. For the subjects who had allowed GS and for those who had both refused and allowed GS, price was the most important factor.
The present study shows that price, familiarity, and availability were important factors in the choice of prescription medicines. The external characteristics of the medicines, for instance the color and shape of the tablet/capsule or the appearance of the package, were not significant characteristics for people.
PMCID: PMC3262749  PMID: 22171800
15.  Prevalence of neck pain in subjects with metabolic syndrome - a cross-sectional population-based study 
Metabolic syndrome (MetS) is increasingly common. Obesity has been suggested to associate with neck pain but prevalence of neck pain in subjects with MetS has not been studied. Aim of this study was to analyse the association between MetS and neck pain.
The study population consisted of 1294 middle-aged subjects in Pieksämäki, Finland. A total of 399 males and 500 females participated (69%). The mean age of both males and females was 46 years. Clinical and biochemical measurements were taken. The participants filled out a standard questionnaire. Psychological distress was assessed with the 12-item General Health Questionnaire (GHQ-12). Neck pain was defined as neck pain perceived daily. MetS was defined using National Cholesterol Education Program (NCEP) criteria. Statistical comparisons between the groups were performed using a bootstrap-type t-test or Chi-Square test. Risk ratios of having neck pain were calculated using generalised linear models with age, smoking, alcohol use, exercise and GHQ-12 score as covariates.
The prevalence of MetS was 33% in males and 29% in females. Neck pain was present in 11% (N = 42) of males and 19% (N = 93) of females (P < 0.001). The prevalence of neck pain was 7.9% (95% CI, 4.9% to 12%) among male subjects without MetS and 16% (95% CI, 10% to 23%) among those with MetS. The respective proportions among females were 16% (95% CI, 12% to 20%) and 25% (95% CI, 18% to 33%). The multivariate analysis showed an increased risk of neck pain in males with MetS (RR 2.1, 95% CI, 1.2 to 3.7, P = 0.010) and in females with MetS (RR 1.5, 95% CI, 1.0 to 2.1, P = 0.040).
MetS was associated with neck pain. This association was stronger in males, but the prevalence of neck pain was higher in females. Prospective studies should explore the potential causal association between neck pain and MetS and the potential common background factors of neck pain and MetS.
PMCID: PMC2918543  PMID: 20670458
16.  Gender-specific association of psychological distress with cardiovascular risk scores 
To examine the gender differences in the association of psychological distress with cardiovascular disease (CVD) risk scores using two different CVD risk assessment models.
Design and setting
A cross-sectional, population-based study from 1997 to 1998 in Pieksämäki, Finland.
A population sample of 899 (399 male and 500 female) middle-aged subjects.
Main outcome measures
The 10-year risk for CVD events was calculated using the European SCORE model and the Framingham CVD risk prediction model. Psychological distress was measured using the 12-item General Health Questionnaire (GHQ-12). Study subjects were allocated into three groups according to their global GHQ-12 -scores: 0 points, 1–2 points, and 3–12 points.
Psychological distress was associated with higher mean CVD risk scores in men. Men in the highest GHQ group (3–12 points) had significantly higher mean European CVD risk score (3.6 [SD 3.3]) compared with men in the lowest group (0 points) (2.5 [SD 2.6]), the difference being 1.1 (95% CI 0.4 to 1.9). The p-value for linearity between the three GHQ groups was 0.003. The Framingham CVD risk prediction model yielded similar results: 15.7 (SD 10.2) vs. 12.3 (SD 9.6), the difference 3.4 (95% CI 1.0 to 6.0) and p-value for linearity 0.008. No significant association was observed in women.
A gender-specific association was found betwen psychological distress and cardiovascular risk scores. These results highlight the importance of identifying men with psychological distress when assessing CVD risk.
PMCID: PMC3440612  PMID: 20331387
Cardiovascular disease; Framingham; gender difference; general health questionnaire; psychological distress; SCORE
17.  Far from easy and accurate - detection of metabolic syndrome by general practitioners 
BMC Family Practice  2009;10:76.
Metabolic syndrome (MetS) is a major public health challenge. General practitioners (GPs) could play a key role in its recognition. However, it often remains undiagnosed in primary care. This study assesses how well GPs and patients recognise MetS among patients with coronary heart disease or at least one of its risk factors.
Twenty-six health centres around Finland were randomly selected for the purpose of identifying, over a two-week period in April 2005, patients meeting the inclusion criteria of coronary heart disease or one of its risk factors. GPs and identified patients (n = 1880) were asked to complete surveys that included a question about the patient's MetS status. A trained nurse conducted health checks (n = 1180) of the identified patients, utilising criteria of MetS modified from the National Cholesterol Program. Data from the GPs' survey were compared with those from the health check to establish the extent of congruence of identification of MetS.
Almost half (49.4%) of the patients met the criteria of MetS as established by objective measures. However, in the GPs' survey responses, only 28.5% of the patients were identified as having MetS. Additionally, these groups of MetS patients were not congruent. The sensitivity of the GPs' diagnosis of MetS was 0.31 with a specificity of 0.73. Only 7.1% of the study patients stated that they were suffering from MetS.
Detection of MetS is inaccurate among GPs in Finland. Most patients were not aware of having MetS. The practical relevance of MetS in primary care should be reconsidered.
PMCID: PMC2789713  PMID: 19948040
18.  Access to and continuity of primary medical care of different providers as perceived by the Finnish population 
To study people's views on the accessibility and continuity of primary medical care provided by different providers: a public primary healthcare centre (PPHC), occupational healthcare (OHC), and a private practice (PP).
A nationwide population-based questionnaire study.
A total of 6437 (from a sample of 10 000) Finns aged 15–74 years.
Main outcome measures
Period of time (in days) to get an appointment with any physician was assessed via a single structured question. Accessibility and continuity were evaluated with a five-category Likert scale. Values 4–5 were regarded as good.
Altogether 72% had found that they could obtain an appointment with a physician within three days, while 6% had to wait more than two weeks. Older subjects and subjects with chronic diseases perceived waiting times as longer more often than younger subjects and those without chronic diseases. The proportion of subjects who perceived access to care to be good was 35% in a PPHC, 68% in OHC, and 78% in a PP. The proportion of subjects who were able to get successive appointments with the same doctor was 45% in a PPHC, 68% in OHC, and 81% in a PP. A personal doctor system was related to good continuity and access in a PPHC.
Access to and continuity of care in Finland are suboptimal for people suffering from chronic diseases. The core features of good primary healthcare are still not available within the medical care provided by public health centres.
PMCID: PMC3389449  PMID: 17354156
Continuity of care; family practice; health service accessibility; healthcare quality assessment
19.  Head and neck cancer in primary care: presenting symptoms and the effect of delayed diagnosis of cancer cases 
Little is known about the diagnosis of head and neck carcinoma in primary care. We sought to estimate the general prevalence of symptoms reported by patients with head and neck carcinomas and to determine the association between detection patterns of head and neck cancer cases in primary care and survival.
In a cross-sectional survey, we used a questionnaire to estimate the general prevalence of symptoms associated with head and neck cancer from a sample of 5646 primary care visits in 25 randomly selected health centres over 4 weeks throughout Finland. A population-based retrospective cohort study involved the 221 patients resident in one primary health care district (population about 700 000) in whom head and neck carcinoma was diagnosed between Jan. 1, 1986, and Dec. 31, 1996. Data on the initial primary care visit, clinical characteristics and survival were obtained from patient charts.
Of 5646 visits to a primary care practitioner, 11% (617) were made because of the same symptoms as those initially reported by patients later found to have head and neck cancer. According to the cohort data, the detection rate of these carcinomas in primary care was 1 per 63 000 visits. At the initial visit of 221 patients later found to have cancer, 56% (123) received referrals, 24% (53) follow-up appointments and 20% (45) neither (“overlooked”). At 3 years, the risk of death was significantly higher among patients whose disease was overlooked (adjusted hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.03–3.45). The excess risk associated with being overlooked, however, was confined to subjects with tongue or glottic tumours (HR 4.25, 95% CI 1.59–11.4) (number needed to harm 3.0, 95% CI 1.9–6.7).
Despite the rarity of patients with head and neck carcinoma in primary care, patients with symptoms of these diseases and especially with symptoms of tongue and glottic carcinomas should be initially referred for further care or followed up.
PMCID: PMC1402394  PMID: 16534084
20.  Concomitant use of analgesics and psychotropics in home-dwelling elderly people – Kuopio 75 + study 
To investigate the extent of concomitant use of analgesic and psychotropic medicines among home-dwelling elderly people aged at least 75 years in Finland.
This was a population-based study in Finland, performed as part of Kuopio 75 + study focusing on the clinical epidemiology of diseases, medication and functional capacity. A random sample of 700 persons was drawn from the total population of the city of Kuopio, eastern Finland, aged 75 years on January 1, 1998 (n = 4518). Ninety-nine persons could not be examined and 78 were living in long-term institutions, so that the number of home-dwelling elderly persons amounted to 523. A trained nurse interviewed the participants about their use of medicines, and a geriatrician examined their overall physical and mental status. Dementia and depression were diagnosed according to the DSM IV criteria. Both regular and irregular prescribed and nonprescribed drug use was recorded.
Every fourth elderly person (27.2%) used analgesics and psychotropics concomitantly, this use becoming twice as common with advancing age (19.6% in the age group 75–79 years, 38.2% among the oldest, aged 85 + years). Concomitant use of psychotropics and opioids also became more common with increasing age (2.8% in age group 75–79 years and 9.6% in the oldest group, aged 85 + years). The use of opioids was nearly twice as common among concomitant users (19.7%) than among those using only analgesics (11.3%). Concomitant users suffered from interfering daily pain and daily pain at rest more commonly than nonusers of analgesics. Depression, sleeping problems and polypharmacy were more common among the concomitant users, who had also had more hip fractures than the rest.
Concomitant use of analgesics and psychotropics becomes more common with advancing age and is a potential risk factor for adverse drug effects.
PMCID: PMC1884761  PMID: 16120070
analgesics; elderly; psychotropics
21.  Doctor-patient interaction in Finnish primary health care as perceived by first year medical students 
In Finland, public health care is the responsibility of primary health care centres, which render a wide range of community level preventive, curative and rehabilitative medical care. Since 1990's, medical studies have involved early familiarization of medical students with general practice from the beginning of the studies, as this pre-clinical familiarisation helps medical students understand patients as human beings, recognise the importance of the doctor-patient relationship and identify practicing general practitioners (GPs) as role models for their professional development. Focused on doctor-patient relationship, we analysed the reports of 2002 first year medical students in the University of Kuopio. The students observed GPs' work during their 2-day visit to primary health care centres.
We analysed systematically the texts of 127 written reports of 2002, which represents 95.5% of the 133 first year pre-clinical medical students reports. The reports of 2003 (N = 118) and 2004 (N = 130) were used as reference material.
Majority of the students reported GPs as positive role models. Some students reported GPs' poor attitudes, which they, however, regarded as a learning opportunity. Students generally observed a great variety of responsibilities in general practice, and expressed admiration for the skills and abilities required. They appreciated the GPs' interest in patients concerns. GPs' communication styles were found to vary considerably. Students reported some factors disturbing the consultation session, such as the GP staring at the computer screen and other team members entering the room. Working with marginalized groups, the chronically and terminally ill, and dying patients was seen as an area for development in the busy Finnish primary health care centres.
During the analysis, we discovered that medical students' perceptions in this study are in line with the previous findings about the importance of role model (good or bad) in making good doctors. Therefore, medical students' pre-clinical primary health care centre visits may influence their attitudes towards primary health care work and the doctor-patient relationship. We welcome more European studies on the role of early pre-clinical general practice exposure on medical students' primary care specialty choice.
PMCID: PMC1242232  PMID: 16162300

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