Causes and consequences of variation in nestling immune function

Defence against pathogens is a vital need of all living organisms that has led to the evolution of complex immune mechanisms. However, although immunocompetence the ability to resist pathogens and control infection has in recent decades become a focus for research in evolutionary ecology, the variation in immune function observed in natural populations is relatively little understood. This thesis examines sources of this variation (environmental, genetic and maternal effects) during the nestling stage and its fitness consequences in wild populations of passerines: the blue tit (Cyanistes caeruleus) and the collared flycatcher (Ficedula albicollis). A developing organism may face a dilemma as to whether to allocate limited resources to growth or to immune defences. The optimal level of investment in immunity is shaped inherently by specific requirements of the environment. If the probability of contracting infection is low, maintaining high growth rates even at the expense of immune function may be advantageous for nestlings, as body mass is usually a good predictor of post-fledging survival. In experiments with blue tits and haematophagous hen fleas (Ceratophyllus gallinae) using two methods, methionine supplementation (to manipulate nestlings resource allocation to cellular immune function) and food supplementation (to increase resource availability), I confirmed that there is a trade-off between growth and immunity and that the abundance of ectoparasites is an environmental factor affecting allocation of resources to immune function. A cross-fostering experiment also revealed that environmental heterogeneity in terms of abundance of ectoparasites may contribute to maintaining additive genetic variation in immunity and other traits. Animal model analysis of extensive data collected from the population of collared flycatchers on Gotland (Sweden) allowed examination of the narrow-sense heritability of PHA-response the most commonly used index of cellular immunocompetence in avian studies. PHA-response is not heritable in this population, but is subject to a non-heritable origin (presumably maternal) effect. However, experimental manipulation of yolk androgen levels indicates that the mechanism of the maternal effect in PHA-response is not in ovo deposition of androgens. The relationship between PHA-response and recruitment was studied for over 1300 collared flycatcher nestlings. Multivariate selection analysis shows that it is body mass, not PHA-response, that is under direct selection. PHA-response appears to be related to recruitment because of its positive relationship with body mass. These results imply that either PHA-response fails to capture the immune mechanisms that are relevant for defence against pathogens encountered by fledglings or that the selection pressure from parasites is not as strong as commonly assumed.

The TRAM flap for breast reconstruction : Studies on perioperative cutaneous blood flow, vasoconstriction, and indices of obesity

Breast reconstruction is performed for 10-15 % of women operated on for breast cancer. A popular method is the TRAM (transverse rectus abdominis musculocutaneous) flap formed of the patient’s own abdominal tissue, a part of one of the rectus abdominis muscles and a transverse skin-subcutis area over it. The flap can be raised as a pedicled or a free flap. The pedicled TRAM flap, based on its nondominant pedicle superior epigastric artery (SEA), is rotated to the chest so that blood flow through SEA continues. The free TRAM flap, based on its dominant pedicle deep inferior epigastric artery (DIEA), is detached from the abdomen, transferred to the chest, and DIEA and vein are anastomosed to vessels on the chest. Cutaneous necrosis is seen in 5–60 % of pedicled TRAM flaps and in 0–15 % of free TRAM flaps. This study was the first one to show with blood flow measurements that the cutaneous blood flow is more generous in free than in pedicled TRAM flaps. After this study the free TRAM flap has exceeded the pedicled flap in popularity as a breast reconstruction method, although the free flap it is technically a more demanding procedure than the pedicled TRAM flap. In pedicled flaps, a decrease in cutaneous blood flow was observed when DIEA was ligated. It seems that SEA cannot provide sufficient blood flow on the first postoperative days. The postoperative cutaneous blood flow in free TRAM flaps was more stable than in pedicled flaps. Development of cutaneous necrosis of pedicled TRAM flaps could be predicted based on intraoperative laser Doppler flowmetry (LDF) measurements. The LDF value on the contralateral skin of the flap decreased to 43 ± 7 % of the initial value after ligation of the DIEA in flaps developing cutaneous necrosis during the next week. Endothelin-1 (ET-1) is a powerful vasoconstrictory peptide secreted by vascular endothelial cells. A correlation was found between plasma ET-1 concentrations and peripheral vasoconstriction developing during and after breast reconstructions with a pedicled TRAM flap. ET-1 was not associated with the development of cutaneous necrosis. Felodipine, a vasodilating calcium channel antagonist, had no effect on plasma ET-1 concentrations, peripheral vasoconstriction or development of cutaneous necrosis in free TRAM flaps. Body mass index and thickness of abdominal were not associated with cutaneous necrosis in pedicled TRAM flaps.

Gastrointestinal complications after kidney transplantation

The aim of the study was to evaluate gastrointestinal (GI) complications after kidney transplantation in the Finnish population. The adult patients included underwent kidney transplantation at Helsinki University Central Hospital in 1990-2000. Data on GI complications were collected from the Finnish Kidney Transplantation Registry, patient records and from questionnaires sent to patients. Helicobacter pylori IgG and IgA antibodies were measured from 500 patients before kidney transplantation and after a median 6.8-year follow up. Oesophagogastroduodenoscopy with biopsies was performed on 46 kidney transplantation patients suffering from gastroduodenal symptoms and 43 dyspeptic controls for studies of gastroduodenal cytomegalovirus (CMV) infection. Gallbladder ultrasound was performed on 304 patients after a median of 7.4 years post transplantation. Data from these 304 patients were also collected on serum lipids, body mass index and the use of statin medication. Severe GI complications occurred in 147 (10%) of 1515 kidney transplantations, 6% of them fatal after a median of 0.93 years. 51% of the complications occurred during the first post transplantation year, with highest incidence in gastroduodenal ulcers and complications of the colon. Patients with GI complications were older and had more delayed graft function and patients with polycystic kidney disease had more GI complications than the other patients. H.pylori seropositivity rate was 31% and this had no influence on graft or patient survival. 29% of the H.pylori seropositive patients seroreverted without eradication therapy. 74% of kidney transplantation patients had CMV specific matrix protein pp65 or delayed early protein p52 positive findings in the gastroduodenal mucosa, and 53% of the pp65 or p52 positive patients had gastroduodenal erosions without H.pylori findings. After the transplantation 165 (11%) patients developed gallstones. A biliary complication including 1 fatal cholecystitis developed in 15% of the patients with gallstones. 13 (0.9%) patients had pancreatitis. Colon perforations, 31% of them fatal, occurred in 16 (1%) patients. 13 (0.9%) developed a GI malignancy during the follow up. 2 H.pylori seropositive patients developed gastroduodenal malignancies during the follow up. In conclusion, severe GI complications usually occur early after kidney transplantation. Colon perforations are especially serious in kidney transplantation patients and colon diverticulosis and gallstones should be screened and treated before transplantation. When found, H.pylori infection should also be treated in these patients.

The brain serotonin transporter binding in young adults; methodological considerations and association with Bulimia Nervosa and acquired obesity

The neurotransmitter serotonin (5-HT) modulates many functions important for life, e.g., appetite and body temperature, and controls development of the neural system. Disturbed 5-HT function has been implicated in mood, anxiety and eating disorders. The serotonin transporter (SERT) controls the amount of effective 5-HT by removing it from the extracellular space. Radionuclide imaging methods single photon emission tomography (SPET) and positron emission tomography (PET) enable studies on the brain SERTs. This thesis concentrated on both methodological and clinical aspects of the brain SERT imaging using SPET. The first study compared the repeatability of automated and manual methods for definition of volumes of interest (VOIs) in SERT images. The second study investigated within-subject seasonal variation of SERT binding in healthy young adults in two brain regions, the midbrain and thalamus. The third study investigated the association of the midbrain and thalamic SERT binding with Bulimia Nervosa (BN) in female twins. The fourth study investigated the association of the midbrain and hypothalamic/thalamic SERT binding and body mass index (BMI) in monozygotic (MZ) twin pairs. Two radioligands for SERT imaging were used: [123I]ADAM (studies I-III) and [123I]nor-beta-CIT (study IV). Study subjects included young adult MZ and dizygotic (DZ) twins screened from the FinnTwin16 twin cohort (studies I-IV) and healthy young adult men recruited for study II. The first study validated the use of an automated brain template in the analyses of [123I]ADAM images and proved automated VOI definition more reproducible than manual VOI definition. The second study found no systematic within-subject variation in SERT binding between scans done in summer and winter in either of the investigated brain regions. The third study found similar SERT binding between BN women (including purging and non-purging probands), their unaffected female co-twins and other healthy women in both brain regions; in post hoc analyses, a subgroup of purging BN women had significantly higher SERT binding in the midbrain as compared to all healthy women. In the fourth study, MZ twin pairs were divided into twins with higher BMI and co-twins with lower BMI; twins with higher BMI were found to have higher SERT binding in the hypothalamus/thalamus than their leaner co-twins. Our results allow the following conclusions: 1) No systematic seasonal variation exists in the midbrain and thalamus between SERT binding in summer and winter. 2) In a population-based sample, BN does not associate with altered SERT status, but alterations are possible in purging BN women. 3) The higher SERT binding in MZ twins with higher BMIs as compared to their leaner co-twins suggests non-genetic association between acquired obesity and the brain 5-HT system, which may have implications on feeding behavior and satiety.

Individualized immunosuppression after renal transplantation in childhood

Pediatric renal transplantation (TX) has evolved greatly during the past few decades, and today TX is considered the standard care for children with end-stage renal disease. In Finland, 191 children had received renal transplants by October 2007, and 42% of them have already reached adulthood. Improvements in treatment of end-stage renal disease, surgical techniques, intensive care medicine, and in immunosuppressive therapy have paved the way to the current highly successful outcomes of pediatric transplantation. In children, the transplanted graft should last for decades, and normal growth and development should be guaranteed. These objectives set considerable requirements in optimizing and fine-tuning the post-operative therapy. Careful optimization of immunosuppressive therapy is crucial in protecting the graft against rejection, but also in protecting the patient against adverse effects of the medication. In the present study, the results of a retrospective investigation into individualized dosing of immunosuppresive medication, based on pharmacokinetic profiles, therapeutic drug monitoring, graft function and histology studies, and glucocorticoid biological activity determinations, are reported. Subgroups of a total of 178 patients, who received renal transplants in 1988 2006 were included in the study. The mean age at TX was 6.5 years, and approximately 26% of the patients were <2 years of age. The most common diagnosis leading to renal TX was congenital nephrosis of the Finnish type (NPHS1). Pediatric patients in Finland receive standard triple immunosuppression consisting of cyclosporine A (CsA), methylprednisolone (MP) and azathioprine (AZA) after renal TX. Optimal dosing of these agents is important to prevent rejections and preserve graft function in one hand, and to avoid the potentially serious adverse effects on the other hand. CsA has a narrow therapeutic window and individually variable pharmacokinetics. Therapeutic monitoring of CsA is, therefore, mandatory. Traditionally, CsA monitoring has been based on pre-dose trough levels (C0), but recent pharmacokinetic and clinical studies have revealed that the immunosuppressive effect may be related to diurnal CsA exposure and blood CsA concentration 0-4 hours after dosing. The two-hour post-dose concentration (C2) has proved a reliable surrogate marker of CsA exposure. Individual starting doses of CsA were analyzed in 65 patients. A recommended dose based on a pre-TX pharmacokinetic study was calculated for each patient by the pre-TX protocol. The predicted dose was clearly higher in the youngest children than in the older ones (22.9±10.4 and 10.5±5.1 mg/kg/d in patients <2 and >8 years of age, respectively). The actually administered oral doses of CsA were collected for three weeks after TX and compared to the pharmacokinetically predicted dose. After the TX, dosing of CsA was adjusted according to clinical parameters and blood CsA trough concentration. The pharmacokinetically predicted dose and patient age were the two significant parameters explaining post-TX doses of CsA. Accordingly, young children received significantly higher oral doses of CsA than the older ones. The correlation to the actually administered doses after TX was best in those patients, who had a predicted dose clearly higher or lower (> ±25%) than the average in their age-group. Due to the great individual variation in pharmacokinetics standardized dosing of CsA (based on body mass or surface area) may not be adequate. Pre-Tx profiles are helpful in determining suitable initial CsA doses. CsA monitoring based on trough and C2 concentrations was analyzed in 47 patients, who received renal transplants in 2001 2006. C0, C2 and experienced acute rejections were collected during the post-TX hospitalization, and also three months after TX when the first protocol core biopsy was obtained. The patients who remained rejection free had slightly higher C2 concentrations, especially very early after TX. However, after the first two weeks also the trough level was higher in the rejection-free patients than in those with acute rejections. Three months after TX the trough level was higher in patients with normal histology than in those with rejection changes in the routine biopsy. Monitoring of both the trough level and C2 may thus be warranted to guarantee sufficient peak concentration and baseline immunosuppression on one hand and to avoid over-exposure on the other hand. Controlling of rejection in the early months after transplantation is crucial as it may contribute to the development of long-term allograft nephropathy. Recently, it has become evident that immunoactivation fulfilling the histological criteria of acute rejection is possible in a well functioning graft with no clinical sings or laboratory perturbations. The influence of treatment of subclinical rejection, diagnosed in 3-month protocol biopsy, to graft function and histology 18 months after TX was analyzed in 22 patients and compared to 35 historical control patients. The incidence of subclinical rejection at three months was 43%, and the patients received a standard rejection treatment (a course of increased MP) and/or increased baseline immunosuppression, depending on the severity of rejection and graft function. Glomerular filtration rate (GFR) at 18 months was significantly better in the patients who were screened and treated for subclinical rejection in comparison to the historical patients (86.7±22.5 vs. 67.9±31.9 ml/min/1.73m2, respectively). The improvement was most remarkable in the youngest (<2 years) age group (94.1±11.0 vs. 67.9±26.8 ml/min/1.73m2). Histological findings of chronic allograft nephropathy were also more common in the historical patients in the 18-month protocol biopsy. All pediatric renal TX patients receive MP as a part of the baseline immunosuppression. Although the maintenance dose of MP is very low in the majority of the patients, the well-known steroid-related adverse affects are not uncommon. It has been shown in a previous study in Finnish pediatric TX patients that steroid exposure, measured as area under concentration-time curve (AUC), rather than the dose correlates with the adverse effects. In the present study, MP AUC was measured in sixteen stable maintenance patients, and a correlation with excess weight gain during 12 months after TX as well as with height deficit was found. A novel bioassay measuring the activation of glucocorticoid receptor dependent transcription cascade was also employed to assess the biological effect of MP. Glucocorticoid bioactivity was found to be related to the adverse effects, although the relationship was not as apparent as that with serum MP concentration. The findings in this study support individualized monitoring and adjustment of immunosuppression based on pharmacokinetics, graft function and histology. Pharmacokinetic profiles are helpful in estimating drug exposure and thus identifying the patients who might be at risk for excessive or insufficient immunosuppression. Individualized doses and monitoring of blood concentrations should definitely be employed with CsA, but possibly also with steroids. As an alternative to complete steroid withdrawal, individualized dosing based on drug exposure monitoring might help in avoiding the adverse effects. Early screening and treatment of subclinical immunoactivation is beneficial as it improves the prospects of good long-term graft function.

Evolutionary and conservation biology of the Finnish house sparrow

Recently it has been recognized that evolutionary aspects play a major role in conservation issues of a species. In this thesis I have combined evolutionary research with conservation studies to provide new insight into these fields. The study object of this thesis is the house sparrow, a species that has features that makes it interesting for this type of study. The house sparrow has been ubiquitous almost all over the world. Even though being still abundant, several countries have reported major declines. These declines have taken place in a relatively short time covering both urban and rural habitats. In Finland this species has declined by more than two thirds in just over two decades. In addition, as the house sparrow lives only in human inhabited areas it can also raise public awareness to conservation issues. I used both an extensive museum collection of house sparrows collected in 1980s from all over Finland as well as samples collected in 2009 from 12 of the previously collected localities. I used molecular techniques to study neutral genetic variation within and genetic differentiation between the study populations. This knowledge I then combined with data gathered on morphometric measurements. In addition I analyzed eight heavy metals from the livers of house sparrows that lived in either rural or urban areas in the 1980s and evaluated the role of heavy metal pollution as a possible cause of the declines. Even though dispersal of house sparrows is limited I found that just as the declines started in 1980s the house sparrows formed a genetically panmictic population on the scale of the whole Finland. When compared to Norway, where neutral genetic divergence has been found even with small geographic distances, I concluded that this difference would be due to contrasting landscapes. In Finland the landscape is rather homogeneous facilitating the movements of these birds and maintaining gene flow even with the low dispersal. To see whether the declines have had an effect on the neutral genetic variation of the populations I did a comparison between the historical and contemporary genetic data. I showed that even though genetic diversity has not decreased due to the drastic declines the populations have indeed become more differentiated from each other. This shows that even in a still quite abundant species the declines can have an effect on the genetic variation. It is shown that genetic diversity and differentiation may approach their new equilibriums at different rates. This emphasizes the importance of studying both of them and if the latter has increased it should be taken as a warning sign of a possible loss of genetic diversity in the future. One of the factors suggested to be responsible for the house sparrow declines is heavy metal pollution. When studying the livers of house sparrows from 1980s I discovered higher levels of heavy metal concentrations in urban than rural habitats, but the levels of the metals were comparatively low and based on that heavy metal pollution does not seem to be a direct cause for the declines in Finland. However, heavy metals are known to decrease the amount of insects in urban areas and thus in the cities heavy metals may have an indirect effect on house sparrows. Although neutral genetic variation is an important tool for conservation genetics it does not tell the whole story. Since neutral genetic variation is not affected by selection, information can be one-sided. It is possible that even neutral genetic differentiation is low, there can be substantial variation in additive genetic traits indicating local adaptation. Therefore I performed a comparison between neutral genetic differentiation and phenotypic differentiation. I discovered that two traits out of seven are likely to be under directional selection, whereas the others could be affected by random genetic drift. Bergmann s rule may be behind the observed directional selection in wing length and body mass. These results highlight the importance of estimating both neutral and adaptive genetic variation.

The Effect of Obesity on Wages and Employment: The Difference Between Having a High BMI and Being Fat

In this paper, we re-examine the relationship between overweight and labour market success, using indicators of individual body composition along with BMI (Body Mass Index). We use the dataset from Finland in which weight, height, fat mass and waist circumference are not self-reported, but obtained as part of the overall health examination. We find that waist circumference, but not weight or fat mass, has a negative effect on wages for women, whereas all measures of obesity have negative effects on women’s employment probabilities. For men, the only obesity measure that is significant for men’s employment probabilities is fat mass. One interpretation of our findings is that the negative wage effects of overweight on wages run through the discrimination channel, but that the negative effects of overweight on employment have more to do with ill health. All in all, measures of body composition provide a more refined picture about the effects of obesity on wages and employment.

Associations of interleukin-1 (IL-1) gene variation and IL-1 receptor antagonist phenotypes with immunological responses, metabolic dysregulation and type 2 diabetes

The upstream proinflammatory interleukin-1 (IL-1) cytokines, together with a naturally occurring IL-1 receptor antagonist (IL-1Ra), play a significant role in several diseases and physiologic conditions. The IL-1 proteins affect glucose homeostasis at multiple levels contributing to vascular injuries and metabolic dysregulations that precede diabetes. An association between IL-1 gene variations and IL-1Ra levels has been suggested, and genetic studies have reported associations with metabolic dysregulation and altered inflammatory responses. The principal aims of this study were to: 1) examine the associations of IL-1 gene variation and IL-1Ra expression in the development and persistence of thyroid antibodies in subacute thyroiditis; 2) investigate the associations of common variants in the IL-1 gene family with plasma glucose and insulin concentrations, glucose homeostasis measures and prevalent diabetes in a representative population sample; 3) investigate genetic and non-genetic determinants of IL-1Ra phenotypes in a cross-sectional setting in three independent study populations; 4) investigate in a prospective setting (a) whether variants of the IL-1 gene family are predictors for clinically incident diabetes in two population-based observational cohort studies; and (b) whether the IL-1Ra levels predict the progression of metabolic syndrome to overt diabetes during the median follow-up of 10.8 and 7.1 years. Results from on patients with subacte thyroiditis showed that the systemic IL-1Ra levels are elevated during a specific proinflammatory response and they correlated with C-reactive protein (CRP) levels. Genetic variation in the IL-1 family seemed to have an association with the appearance of thyroid peroxidase antibodies and persisting local autoimmune responses during the follow-up. Analysis of patients suffering from diabetes and metabolic traits suggested that genetic IL-1 variation and IL-1Ra play a role in glucose homeostasis and in the development of type 2 diabetes. The coding IL-1 beta SNP rs1143634 was associated with traits related to insulin resistance in cross-sectional analyses. Two haplotype variants of the IL-1 beta gene were associated with prevalent diabetes or incident diabetes in a prospective setting and both of these haplotypes were tagged by rs1143634. Three variants of the IL-1Ra gene and one of the IL-1 beta gene were consistently identified as significant, independent determinants of the IL-1Ra phenotype in two or three populations. The proportion of the phenotypic variation explained by the genetic factors was modest however, while obesity and other metabolic traits explained a larger part. Body mass index was the strongest predictor of systemic IL-1Ra concentration overall. Furthermore, the age-adjusted IL-1Ra concentrations were elevated in individuals with metabolic syndrome or diabetes when compared to those free of metabolic dysregulation. In prospective analyses the systemic IL-1Ra levels were found as independent predictors for the development of diabetes in people with metabolic syndrome even after adjustment for multiple other factors, including plasma glucose and CRP levels. The predictive power of IL-1Ra was better than that of CRP. The prospective results also provided some evidence for a role of common IL-1 alpha promoter SNP rs1800587 in the development of type 2 diabetes among men and suggested that the role may be gender specific. Likewise, common variations in the IL-1 beta coding region may have a gender specific association with diabetes development. Further research on the potential benefits of IL-1Ra measurements in identifying individuals at high risk for diabetes, who then could be targeted for specific treatment interventions, is warranted. It has been reported in the recent literature that IL-1Ra secreted from adipose tissue has beneficial effects on glucose homeostasis. Furthermore, treatment with recombinant human IL-1Ra has been shown to have a substantial therapeutic potential. The genetic results from the prospective analyses performed in this study remain inconclusive, but together with the cross-sectional analyses they suggest gender-specific effects of the IL-1 variants on the risk of diabetes. Larger studies with more extensive genotyping and resequencing may help to pinpoint the exact variants responsible and to further elucidate the biological mechanisms for the observed associations. This would improve our understanding of the pathways linking inflammation and obesity with glucose and insulin metabolism.

Preterm birth and risk factors for chronic disease : Helsinki Study of Very Low Birth Weight Adults

Background: The improved prognosis of early preterm birth has created a generation of surviving very low birth weight (< 1500 g, VLBW) infants whose health risks in adulthood are poorly known. Of every 1000 live-born infants in Finland, about 8 are born at VLBW. Variation in birth weight, even within the normal range, relates to considerable variation in the risk for several common adult disorders, including cardiovascular disease and osteoporosis. Small preterm infants frequently exhibit severe postnatal or prenatal growth retardation, or both. Much reason for concern thus exists, regarding adverse health effects in surviving small preterm infants later lives. We studied young adults, aiming at exploring whether VLBW birth and postnatal events after such a birth are associated with higher levels of risk factors for cardiovascular disease or osteoporosis. Subjects and Methods: A follow-up study for VLBW infants began in 1978; by the end of 1985, 335 VLBW survivors at Helsinki University Central Hospital participated in the follow-up. Their gestational ages ranged from 24 to 35 weeks, mean 29.2 and standard deviation 2.2 weeks. In 2004, we invited for a clinic visit 255 subjects, aged 18 to 27, who still lived in the greater Helsinki area. From the same birth hospitals, we also invited 314 term-born controls of similar age and sex. These two study groups underwent measurements of body size and composition, function of brachial arterial endothelium (flow-mediated dilatation, FMD) and carotid artery intima-media thickness (cIMT) by ultrasound. In addition, we measured plasma lipid concentrations, ambulatory blood pressure, fasting insulin, glucose tolerance and, by dual-energy x-ray densitometry, bone-mineral density. Results: 172 control and 166 VLBW participants underwent lipid measurements and a glucose tolerance test. VLBW adults fasting insulin (adjusted for body mass index) was 12.6% (95% confidence interval, 0.8 to 25.8) higher than that of the controls. The glucose and insulin concentrations 120 minutes after 75 g glucose ingestion showed similar differences (N=332) (I). VLBW adults had 3.9 mmHg (1.3 to 6.4) higher office systolic blood pressure, 3.5 mmHg (1.7 to 5.2) higher office diastolic blood pressure (I), and, when adjusted for body mass index and height, 3.1 mmHg (0.5 to 5.5) higher 24-hour mean systolic blood pressure (N=238) (II). VLBW birth was associated neither with HDL- or total cholesterol nor triglyceride concentrations (N=332) (I), nor was it associated with a low FMD or a high cIMT (N=160) (III). VLBW adults had 0.51-unit (0.28 to 0.75) lower lumbar spine Z scores and 0.56-unit (0.34 to 0.78) lower femoral neck Z scores (N=283). Adjustments for size attenuated the differences, but only partially (IV). Conclusions: These results imply that those born at VLBW, although mostly healthy as young adults, already bear several risk factors for chronic adult disease. The significantly higher fasting insulin level in adults with VLBW suggests increased insulin resistance. The higher blood pressure in young adults born at VLBW may indicate they later are at risk for hypertension, although their unaffected endothelial function may be evidence for some form of protection from cardiovascular disease. Lower bone mineral density around the age of peak bone mass may suggest increased risk for later osteoporotic fractures. Because cardiovascular disease and osteoporosis are frequent, and their prevention is relatively cheap and safe, one should focus on prevention now. When initiated early, preventive measures are likely to have sufficient time to be effective in preventing or postponing the onset of chronic disease.

Determinants of Cognitive Impairment in Old Age and Their Genetic Architecture

Cognitive health is of central importance for independent and balanced old age, while memory disorders represent the leading cause of intensive and long-term care among the Finnish elderly. The aims of this study were to analyse the effect of height, body mass index, weight change, metabolic conditions and coffee drinking in midlife on cognitive performance in old age among a sample of 2606 Finnish twins aged 65 years or older who had participated in a telephone interview to assess their cognitive status. Since coffee drinking associates with several metabolic conditions and Finns are known to be the greatest consumers of coffee in the world, the heritability and stability of coffee drinking was analysed in the whole Older Finnish Twin Cohort (n=10716). In order to investigate the association between height and cognitive performance in a population with more supportive childhood living conditions, a total of 2161 Danish twins were included in this study. A greater height was found to clearly associate with better cognitive performance in Finnish subjects, but less so among the Danish sample, which may reflect the childhood environmental differences between these cohorts. In the Finnish subjects, there was greater variance in cognitive performance among shorter subjects, and environmental factors were found to play a greater role in their cognitive performance, whereas the cognitive performance of taller participants was mainly explained by genetic factors. Midlife metabolic variables that were found to be significantly associated with a poorer cognitive performance in old age included a higher body mass index and three metabolic conditions: cardiovascular disease, hypertension and, most significantly of all, diabetes. Moreover, both weight gain and loss, even to a lesser degree than suggested previously, were found to be associated with poorer cognition. Furthermore, evidence of a causal relationship between midlife cardiovascular disease and cognitive performance in old age was demonstrated among discordant twin pairs. Conversely, no effect of coffee drinking in midlife on cognitive performance in old age was observed, although coffee drinking was demonstrated to be stable in the study population. The heritability of coffee drinking was found to differ across sexes and age groups, being 51% in men and 52% in women in the whole study population. This study supports the contention that cognitive performance in old age reflects the effects of multiple genetic and environmental exposures, including their complex interactions during the life-span. The demonstrated associations and evidence of a causal pathway between potentially preventable exposures and poorer cognitive performance highlight the importance of preventive medicine.

Preterm birth and risk factors for chronic disease : Helsinki Study of Very Low Birth Weight Adults

Background: The improved prognosis of early preterm birth has created a generation of surviving very low birth weight (PIENEMPI KUIN 1500 g, VLBW) infants whose health risks in adulthood are poorly known. Of every 1000 live-born infants in Finland, about 8 are born at VLBW. Variation in birth weight, even within the normal range, relates to considerable variation in the risk for several common adult disorders, including cardiovascular disease and osteoporosis. Small preterm infants frequently exhibit severe postnatal or prenatal growth retardation, or both. Much reason for concern thus exists, regarding adverse health effects in surviving small preterm infants later lives. We studied young adults, aiming at exploring whether VLBW birth and postnatal events after such a birth are associated with higher levels of risk factors for cardiovascular disease or osteoporosis. Subjects and Methods: A follow-up study for VLBW infants began in 1978; by the end of 1985, 335 VLBW survivors at Helsinki University Central Hospital participated in the follow-up. Their gestational ages ranged from 24 to 35 weeks, mean 29.2 and standard deviation 2.2 weeks. In 2004, we invited for a clinic visit 255 subjects, aged 18 to 27, who still lived in the greater Helsinki area. From the same birth hospitals, we also invited 314 term-born controls of similar age and sex. These two study groups underwent measurements of body size and composition, function of brachial arterial endothelium (flow-mediated dilatation, FMD) and carotid artery intima-media thickness (cIMT) by ultrasound. In addition, we measured plasma lipid concentrations, ambulatory blood pressure, fasting insulin, glucose tolerance and, by dual-energy x-ray densitometry, bone-mineral density. Results: 172 control and 166 VLBW participants underwent lipid measurements and a glucose tolerance test. VLBW adults fasting insulin (adjusted for body mass index) was 12.6% (95% confidence interval, 0.8 to 25.8) higher than that of the controls. The glucose and insulin concentrations 120 minutes after 75 g glucose ingestion showed similar differences (N=332) (I). VLBW adults had 3.9 mmHg (1.3 to 6.4) higher office systolic blood pressure, 3.5 mmHg (1.7 to 5.2) higher office diastolic blood pressure (I), and, when adjusted for body mass index and height, 3.1 mmHg (0.5 to 5.5) higher 24-hour mean systolic blood pressure (N=238) (II). VLBW birth was associated neither with HDL- or total cholesterol nor triglyceride concentrations (N=332) (I), nor was it associated with a low FMD or a high cIMT (N=160) (III). VLBW adults had 0.51-unit (0.28 to 0.75) lower lumbar spine Z scores and 0.56-unit (0.34 to 0.78) lower femoral neck Z scores (N=283). Adjustments for size attenuated the differences, but only partially (IV). Conclusions: These results imply that those born at VLBW, although mostly healthy as young adults, already bear several risk factors for chronic adult disease. The significantly higher fasting insulin level in adults with VLBW suggests increased insulin resistance. The higher blood pressure in young adults born at VLBW may indicate they later are at risk for hypertension, although their unaffected endothelial function may be evidence for some form of protection from cardiovascular disease. Lower bone mineral density around the age of peak bone mass may suggest increased risk for later osteoporotic fractures. Because cardiovascular disease and osteoporosis are frequent, and their prevention is relatively cheap and safe, one should focus on prevention now. When initiated early, preventive measures are likely to have sufficient time to be effective in preventing or postponing the onset of chronic disease.

Genetic polymorphisms and laboratory variables as predictors of blood pressure response to antihypertensive drugs

Hypertension is one of the major risk factors for cardiovascular morbidity. The advantages of antihypertensive therapy have been clearly demonstrated, but only about 30% of hypertensive patients have their blood pressure (BP) controlled by such treatment. One of the reasons for this poor BP control may lie in the difficulty in predicting BP response to antihypertensive treatment. The average BP reduction achieved is similar for each drug in the main classes of antihypertensive agents, but there is a marked individual variation in BP responses to any given drug. The purpose of the present study was to examine BP response to four different antihypertensive monotherapies with regard to demographic characteristics, laboratory test results and common genetic polymorphisms. The subjects of the present study are participants in the pharmacogenetic GENRES Study. A total of 208 subjects completed the whole study protocol including four drug treatment periods of four weeks, separated by four-week placebo periods. The study drugs were amlodipine, bisoprolol, hydrochlorothiazide and losartan. Both office (OBP) and 24-hour ambulatory blood pressure (ABP) measurements were carried out. BP response to study drugs were related to basic clinical characteristics, pretreatment laboratory test results and common polymorphisms in genes coding for components of the renin-angiotensin system, alpha-adducin (ADD1), beta1-adrenergic receptor (ADRB1) and beta2-adrenergic receptor (ADRB2). Age was positively correlated with BP responses to amlodipine and with OBP and systolic ABP responses to hydrochlorothiazide, while body mass index was negatively correlated with ABP responses to amlodipine. Of the laboratory test results, plasma renin activity (PRA) correlated positively with BP responses to losartan, with ABP responses to bisoprolol, and negatively with ABP responses to hydrochlorothiazide. Uniquely to this study, it was found that serum total calcium level was negatively correlated with BP responses to amlodipine, whilst serum total cholesterol level was negatively correlated with ABP responses to amlodipine. There were no significant associations of angiotensin II type I receptor 1166A/C, angiotensin converting enzyme I/D, angiotensinogen Met235Thr, ADD1 Gly460Trp, ADRB1 Ser49Gly and Gly389Arg and ADRB2 Arg16Gly and Gln27Glu polymorphisms with BP responses to the study drugs. In conclusion, this study confirmed the relationship between pretreatment PRA levels and response to three classes of antihypertensive drugs. This study is the first to note a significant inverse relation between serum calcium level and responsiveness to a calcium channel blocker. However, this study could not replicate the observations that common polymorphisms in angiotensin II type I receptor, angiotensin converting enzyme, angiotensinogen, ADD1, ADRB1, or ADRB2 genes can predict BP response to antihypertensive drugs.

Early Growth and Later Health, Focus on Metabolic Syndrome, Obesity and Physical Activity

The Developmental Origins of Health and Disease Hypothesis proposes that adverse health outcomes in adult life are in part programmed during fetal life and infancy. This means that e.g. restricted nutrition during pregnancy programmes the offspring to store fat more effectively, to develop faster and to reach puberty earlier. These adaptations are beneficial in terms of short term survival. However, in developed countries these adaptations often lead to an increased risk of obesity and metabolic disturbances in later life, due to a mismatch between the prenatal and postnatal environment. This thesis aimed to study the role of early growth in people who are obese as adults, but metabolically healthy as well as in those who are normal in weight but metabolically obese. Other study aims were to assess whether physical activity and cardiorespiratory fitness are programmed early in life. The role of socioeconomic status in the development of obesity from a life course setting was also studied. These studies included 2003 men and women born in Helsinki between 1934 and 1944 with detailed information of their prenatal and childhood growth as well as living conditions. They participated in the detailed clinical examination during the years 2001-2004. A sub-group of the subjects participated in the UKK Institute 2-kilometre walk test. Metabolic syndrome was defined according to the 2005 criteria of the International Diabetes Federation. Among the obese men and women 20 % were metabolically healthy. Those with metabolic syndrome did not differ in birth size compared to the healthy ones, but by two years of age, they were lighter and thinner, and remained so up to 11 years. The period when changes in BMIs were predictive of the metabolic syndrome was from birth to 7 years. Of the normal weight individuals 17 % were metabolically obese. Again, there were no differences in birth size. However, by the age 7 years, those men who later developed metabolic syndrome were thinner. Gains in BMI during the first two years of life were protective of the syndrome. Children who were heavier, and especially taller, were more physically active, exercised with higher intensity and had higher cardiorespiratory fitness in their adult life than those who were shorter and thinner as children. Lower educational attainment and lower adult social class were associated with obesity in both men and women. Childhood social class was inversely associated with body mass index only in men while lower household income was associated with higher BMI in women. These results support the role of early life factors in the development of metabolic syndrome and adult life style. Early detection of risk factors predisposing to these conditions is highly relevant from a public health point of view.

Dietary habits and obesity: the role of emotional and cognitive factors

In post-industrialised societies, food is more plentiful, accessible and palatable than ever before and technological development has reduced the need for physical activity. Consequently, the prevalence of obesity is increasing, which is problematic as obesity is related to a number of diseases. Various psychological and social factors have an important influence on dietary habits and the development of obesity in the current food-rich and sedentary environments. The present study concentrates on the associations of emotional and cognitive factors with dietary intake and obesity as well as on the role these factors play in socioeconomic disparities in diet. Many people cognitively restrict their food intake to prevent weight gain or to lose weight, but research on whether restrained eating is a useful weight control strategy has produced conflicting findings. With respect to emotional factors, the evidence is accumulating that depressive symptoms are related to less healthy dietary intake and obesity, but the mechanisms explaining these associations remain unclear. Furthermore, it is not fully understood why socioeconomically disadvantaged individuals tend to have unhealthier dietary habits and the motives underlying food choices (e.g., price and health) could be relevant in this respect. The specific aims of the study were to examine 1) whether obesity status and dieting history moderate the associations of restrained eating with overeating tendencies, self-control and obesity indicators; 2) whether the associations of depressive symptoms with unhealthier dietary intake and obesity are attributable to a tendency for emotional eating and a low level of physical activity self-efficacy; and 3) whether the absolute or relative importance of food choice motives (health, pleasure, convenience, price, familiarity and ethicality) contribute to the socioeconomic disparities in dietary habits. The study was based on a large population-based sample of Finnish adults: the participants were men (N=2325) and women (N=2699) aged 25-74 who took part in the DILGOM (Dietary, Lifestyle and Genetic Determinants of Obesity and Metabolic Syndrome) sub-study of the National FINRISK Study 2007. The participants weight, height, waist circumference and body fat percentage were measured in a health examination. Psychological eating styles (the Three-Factor Eating Questionnaire-R18), food choice motives (a shortened version of the Food Choice Questionnaire), depressive symptoms (the Center for Epidemiological Studies Depression Scale) and self-control (the Brief Self-Control Scale) were measured with pre-existing questionnaires. A validated food frequency questionnaire was used to assess the average consumption of sweet and non-sweet energy-dense foods and vegetables/fruit. Self-reported total years of education and gross household income were used as indicators of socioeconomic position. The results indicated that 1) restrained eating was related to a lower body mass index, waist circumference, emotional eating and uncontrolled eating, and to a higher self-control in obese participants and current/past dieters. In contrast, the associations were the opposite in normal weight individuals and those who had never dieted. Thus, restrained eating may be related to better weight control among obese individuals and those with dieting experiences, while among others it may function as an indicator of problems with eating and an attempt to solve them. 2) Emotional eating and depressive symptoms were both related to less healthy dietary intake, and the greater consumption of energy-dense sweet foods among participants with elevated depressive symptoms was attributable to the susceptibility for emotional eating. In addition, emotional eating and physical activity self-efficacy were both important in explaining the positive association between depressive symptoms and obesity. 3) The lower vegetable/fruit intake and higher energy-dense food intake among individuals with a low socioeconomic position were partly explained by the higher priority they placed on price and familiarity and the lower priority they gave to health motives in their daily food choices. In conclusion, although policy interventions to change the obesogenic nature of the current environment are definitely needed, knowledge of the factors that hinder or facilitate people s ability to cope with the food-rich environment is also necessary. This study implies that more emphasis should be placed on various psychological and social factors in weight control programmes and interventions.