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.

Psychological distress may affect nutrition indicators in Australian adults

- Objective The purpose of this research was to explore which demographic and health status variables moderated the relationship between psychological distress and three nutrition indicators: the consumption of fruits, vegetables and takeaway. - Method We analysed data from the 2009 Self-Reported Health Status Survey Report collected in the state of Queensland, Australia. Adults (N = 6881) reported several demographic and health status variables. Moderated logistic regression models were estimated separately for the three nutrition indicators, testing as moderators demographic (age, gender, educational attainment, household income, remoteness, and area-level socioeconomic status) and health status indicators (body mass index, high cholesterol, high blood pressure, and diabetes status). - Results Several significant interactions emerged between psychological distress, demographic (age, area-level socioeconomic status, and income level), and health status variables (body mass index, diabetes status) in predicting the nutrition indicators. Relationships between distress and the nutrition indicators were not significantly different by gender, remoteness, educational attainment, high cholesterol status, and high blood pressure status. - Conclusions The associations between psychological distress and several nutrition indicators differ amongst population subgroups. These findings suggest that in distressed adults, age, area-level socio-economic status, income level, body mass index, and diabetes status may serve as protective or risk factors through increasing or decreasing the likelihood of meeting nutritional guidelines. Public health interventions for improving dietary behaviours and nutrition may be more effective if they take into account the moderators identified in this study rather than using global interventions.

Peripartum management of glycemia in women with type 1 diabetes

OBJECTIVE We aimed to 1) describe the peripartum management of type 1 diabetes at an Australian teaching hospital and 2) discuss factors influencing the apparent transient insulin independence postpartum. RESEARCH DESIGN AND METHODS We conducted a retrospective review of women with type 1 diabetes delivering singleton pregnancies from 2005 to 2010. Information was collected regarding demographics, medical history, peripartum management and outcome, and breast-feeding. To detect a difference in time to first postpartum blood glucose level (BGL) >8 mmol/L between women with an early (<4 h) and late (>12 h) requirement for insulin postpartum, with a power of 80% and a type 1 error of 0.05, at least 24 patients were required. RESULTS An intravenous insulin infusion was commenced in almost 95% of women. Univariate analysis showed that increased BMI at term, lower creatinine at term, longer duration from last dose of long- or intermediate-acting insulin, and discontinuation of an insulin infusion postpartum were associated with a shorter time to first requirement of insulin postpartum (P = 0.005, 0.026, 0.026, and <0.001, respectively). There was a correlation between higher doses of insulin commenced postpartum and number of out-of-range BGLs (r[36] = 0.358, P = 0.030) and hypoglycemia (r[36] = 0.434, P = 0.007). Almost 60% had at least one BGL <3.5 mmol/L between delivery and discharge. CONCLUSIONS Changes in the pharmacodynamic profile of insulin may contribute to the transient insulin independence sometimes observed postpartum in type 1 diabetes. A dose of 50–60% of the prepregnancy insulin requirement resulted in the lowest rate of hypoglycemia and glucose excursions. These results require validation in a larger, prospective study.

Maternal perception of weight status in first-born Australian toddlers aged 12–16 months – the NOURISH and SAIDI cohorts

Background The preference amongst parents for heavier infants is in contrast to obesity prevention efforts worldwide. Parents are poor at identifying overweight in older children, but few studies have investigated maternal perception of weight status amongst toddlers and none in the Australian setting. Methods Mothers (n = 290) completed a self-administered questionnaire at child age 12–16 months, defining their child's weight status as underweight, normal weight, somewhat overweight or very overweight. Weight-for-length z-score was derived from measured weight and length, and children categorized as underweight, normal weight, at risk overweight or obese (WHO standards). Objective classification was compared with maternal perception of weight status. Mean weight-for-length z-score was compared across categories of maternal perception using one-way ANOVA. Multinomial logistic regression was used to determine child or maternal characteristics associated with inaccurate weight perception. Results Most children (83%) were perceived as normal weight. Twenty nine were described as underweight, although none were. Sixty-six children were at risk of overweight, but 57 of these perceived as normal weight. Of the 14 children who were overweight, only 4 were identified as somewhat overweight by their mother. Compared with mothers who could accurately classify their normal weight child, mothers who were older had higher odds of perceiving their normal weight child as underweight, while mothers with higher body mass index had slightly higher odds of describing their overweight/at risk child as normal weight. Conclusion The leaner but healthy weight toddler was perceived as underweight, while only the heaviest children were recognized as overweight. Mothers unable to accurately identify children at risk are unlikely to act to prevent further excess weight gain. Practitioners can lead a shift in attitudes towards weight in infants and young children, promoting routine growth monitoring and adequate but not rapid weight gain.

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 effects of height and BMI on prostate cancer incidence and mortality: A Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

Background Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality. Methods We conducted a case–control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man’s number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies. Results The genetic risk scores explained 6.31 and 1.46 % of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95 % CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95 % CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03). Conclusions We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication.

Protocol for assessing maternal, environmental and epigenetic risk factors for dental caries in children

Background Expenditure on dental and oral health services in Australia is $3.4 billion AUD annually. This is the sixth highest health cost and accounts for 7 % of total national health expenditure. Approximately 49 % of Australian children aged 6 years have caries experience in their deciduous teeth and this is rising. The aetiology of dental caries involves a complex interplay of individual, behavioural, social, economic, political and environmental conditions, and there is increasing interest in genetic predisposition and epigenetic modification. Methods The Oral Health Sub-study; a cross sectional study of a birth cohort began in November 2012 by examining mothers and their children who were six years old by the time of initiation of the study, which is ongoing. Data from detailed questionnaires of families from birth onwards and data on mothers’ knowledge, attitudes and practices towards oral health collected at the time of clinical examination are used. Subjects’ height, weight and mid-waist circumference are taken and Body Mass Index (BMI) computed, using an electronic Bio-Impedance balance. Dental caries experience is scored using the International Caries Detection and Assessment System (ICDAS). Saliva is collected for physiological measures. Salivary Deoxyribose Nucleic Acid (DNA) is extracted for genetic studies including epigenetics using the SeqCap Epi Enrichment Kit. Targets of interest are being confirmed by pyrosequencing to identify potential epigenetic markers of caries risk. Discussion This study will examine a wide range of potential determinants for childhood dental caries and evaluate inter-relationships amongst them. The findings will provide an evidence base to plan and implement improved preventive strategies.

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.

Women’s Wellness after Cancer Program Study (WWACP)– A multi centre randomised controlled trial examining the benefits and cost effectiveness of an Evidenced Based, e-health intervention

Background Advances in cancer diagnosis and treatment have significantly improved survival rates, through their subsequent health needs are often not adequately addressed by current health services. National Health and Medical Research Council (NHMRC) Partnerships Project awarded a national collaborative project to develop, trial and evaluate clinical benefits and cost effectiveness of an e-health enabled structured health promotion intervention - The Women’s Wellness after Cancer Program (WWACP). The aim of this e-health enabled multimodal intervention is to improve health related quality of life in women previously treated for target cancers. Aim The WWACP is a 12-week web based, interactive, holistic program. Primary outcomes for this project are to promote a positive change in health-related quality of life (HRQoL) and reduction in Body Mass Index (BMI) in the women undertaking WWACP compared to women who receive usual care. Secondary outcomes include managing other side effects of cancer treatment through evidence-based nutrition and exercise practices, dealing with stress, sleep, menopause and sexuality issues. Methods The single-blinded multi-center randomized controlled trial recruited a toatl of 330 women within 24 months of completion of chemotherapy and /or radiotherapy. Women were randomly assigned to either a usual care or intervention group. Women provided with the intervention were provided with an interactive iBook and journal, web interface, and three virtual consultations by experienced cancer nurses. A variety of methods were utilized, to enable positive self- efficacy and lifestyle changes. These include online coaching with a registered nurse trained in the intervention, plus written educational and health promotional information. The program has been delivered through the e-health enabled interfaces, which enables virtual delivery via desktop and mobile computing devices. Importantly this enables accessibility for rural and regional women in Australia who are frequently geographically disadvantaged in terms of health care provision. Results Research focusing on alternative methods of delivering post treatment / or survivorship care in cancer utilizing web based interfaces is limited, but emerging evidence suggests that Internet interventions can increase psychological and physical wellbeing in cancer patients. The WWACP trial aims to establish the effectiveness of delivery of the program in terms of positive patient outcomes and cost effective, flexibility. The trial will be completed in September and results will be presented at the conference. Conclusions Women after acute hematological, breast and gynecological cancer treatments demonstrate good cancer survival rates and face residual health problems which are amenable to behavioral interventions. The conclusion of active treatment is a key 'teachable moment' in which sustainable positive lifestyle change can be achieved if patients receive education and psychological support which targets key treatment related health problems and known chronic disease risk factors.

Avian diversification patterns across the K-Pg boundary: Influence of calibrations, datasets, and model misspecification

Birds represent the most diverse extant tetrapod clade, with ca. 10,000 extant species, and the timing of the crown avian radiation remains hotly debated. The fossil record supports a primarily Cenozoic radiation of crown birds, whereas molecular divergence dating analyses generally imply that this radiation was well underway during the Cretaceous. Furthermore, substantial differences have been noted between published divergence estimates. These have been variously attributed to clock model, calibration regime, and gene type. One underappreciated phenomenon is that disparity between fossil ages and molecular dates tends to be proportionally greater for shallower nodes in the avian Tree of Life. Here, we explore potential drivers of disparity in avian divergence dates through a set of analyses applying various calibration strategies and coding methods to a mitochondrial genome dataset and an 18-gene nuclear dataset, both sampled across 72 taxa. Our analyses support the occurrence of two deep divergences (i.e., the Palaeognathae/Neognathae split and the Galloanserae/Neoaves split) well within the Cretaceous, followed by a rapid radiation of Neoaves near the K-Pg boundary. However, 95% highest posterior density intervals for most basal divergences in Neoaves cross the boundary, and we emphasize that, barring unreasonably strict prior distributions, distinguishing between a rapid Early Paleocene radiation and a Late Cretaceous radiation may be beyond the resolving power of currently favored divergence dating methods. In contrast to recent observations for placental mammals, constraining all divergences within Neoaves to occur in the Cenozoic does not result in unreasonably high inferred substitution rates. Comparisons of nuclear DNA (nDNA) versus mitochondrial DNA (mtDNA) datasets and NT- versus RY-coded mitochondrial data reveal patterns of disparity that are consistent with substitution model misspecifications that result in tree compression/tree extension artifacts, which may explain some discordance between previous divergence estimates based on different sequence types. Comparisons of fully calibrated and nominally calibrated trees support a correlation between body mass and apparent dating error. Overall, our results are consistent with (but do not require) a Paleogene radiation for most major clades of crown birds.

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.