Transcriptional regulation by the orphan nuclear receptor ERRgamma

The nuclear receptor (NR) superfamily is comprised of receptors for small lipopfilic ligands such as steroid hormones, thyroid hormone, retinoids, and vitamin D. NRs are ligand-inducible transcription factors capable of both activating and repressing their target gene expression. They control a wide range of biological functions connected to growth, development, and homeostasis. In addition to the ligand-regulated receptors, the family includes a large group of receptors whose physiological ligands are unknown. These receptors are referred to as orphan NRs. Estrogen-related receptor gamma (ERRgamma) belongs to the ERR subfamily of orphan NRs together with the related ERRalpha and ERRbeta. ERRs share amino acid sequence homology with the classical estrogen receptors (ERs) but they are unable to bind natural estrogenic ligands. ERRgamma is expressed in several embryonic and adult tissues but its biological role is still largely unknown. ERRgamma activates reporter gene expression in transfected cells independently of added hormones implying that ERRgamma harbors constitutive activity. However, the intrinsic activity of ERRgamma can be inhibited by synthetic compounds such as the selective estrogen receptor modulator 4-hydroxytamoxifen (4-OHT). Ligands of NRs can act as agonists that activate transcription, as antagonists that prevent activation of transcription, or as inverse agonists that antagonize the constitutive transcriptional activity of receptor. Most of the synthetic ERRgamma ligands act as inverse agonists but recently, a synthetic ERRgamma agonist GSK4716 was identified. This demonstrates that it is possible to design and identify agonists for ERRgamma. Prior to this thesis work, the structural and functional characteristics of ERRgamma were largely unknown. The aim of this study was to define the functional requirements for ERRgamma-mediated transcriptional regulation and to examine the cross-talk between ERRgamma and other NRs. Due to the fact that natural physiological ligands of ERRgamma are unknown, another aim of this study was to seek new natural compounds that may affect transcriptional activity of ERRgamma. Plant-derived phytoestrogens have previously been shown to act as ligands for ERs and ERRalpha, and therefore the effects of these compounds were also studied on ERRgamma-mediated transcriptional regulation. This work demonstrated that ERRgamma-mediated transcriptional regulation was dependent on DNA-binding, dimerization and activation function-2. Heterodimerization with ERRalpha inhibited the transcriptional activity of ERRgamma. In addition to 4-OHT, another anti-estrogen, 4-hydroxytoremifene (4-OHtor), was identified as an inverse agonist of ERRgamma. Interestingly, ERRgamma activated transcription in the presence of 4-OHT and 4-OHtor on activator protein-1 binding sites. ERRgamma was found to interact with another orphan NR Nurr1 by repressing the ability of Nurr1 to activate transcription of the osteopontin gene. Transcriptional activity of ERRgamma was shown to be stimulated by the phytoestrogen equol. Structural model analysis and mutational experiments indicated that equol was able to bind to the ligand binding domain of ERRgamma. The growth inhibitory effect of ERRgamma on prostate cancer cells was found to be enhanced by equol. In summary, this study demonstrates that despite the absence of an endogenous physiological ligand, the activity of ERRgamma can be modulated in other ways such as dimerization with related receptors or by cross-talk with other transcription factors as well as by binding some synthetic or natural compounds.

Distribution and adhesion-promoting activity of alpha4 and alpha5 chain laminins in human endothelia and carcinomas

Basement membranes are specialized sheets of extracellular matrix found in contact with epithelia, endothelia, and certain isolated cells. They support tissue architecture and regulate cell behaviour. Laminins are among the main constituents of basement membranes. Due to differences between laminin isoforms, laminins confer structural and functional diversity to basement membranes. The first aim of this study was to gain insights into the potential functions of the then least characterized laminins, alpha4 chain laminins, by evaluating their distribution in human tissues. We thus created a monoclonal antibody specific for laminin alpha4 chain. By immunohistochemistry, alpha4 chain laminins were primarily localized to basement membranes of blood vessel endothelia, skeletal, heart, and smooth muscle cells, nerves, and adipocytes. In addition, alpha4 chain laminins were found in the region of certain epithelial basement membranes in the epidermis, salivary gland, pancreas, esophagus, stomach, intestine, and kidney. Because of the consistent presence of alpha4 chain laminins in endothelial basement membranes of blood vessels, we evaluated the potential roles of endothelial laminins in blood vessels, lymphatic vessels, and carcinomas. Human endothelial cells produced alpha4 and alpha5 chain laminins. In quantitative and morphological adhesion assays, human endothelial cells barely adhered to alpha4 chain-containing laminin-411. The weak interaction of endothelial cells with laminin-411 appeared to be mediated by alpha6beta1 integrin. The alpha5 chain-containing laminin-511 promoted endothelial cell adhesion better than laminin-411, but it did not promote the formation of cell-extracellular matrix adhesion complexes. The adhesion of endothelial cells to laminin-511 appeared to be mediated by Lutheran glycoprotein together with beta1 and alphavbeta3 integrins. The results suggest that these laminins may induce a migratory phenotype in endothelial cells. In lymphatic capillaries, endothelial basement membranes showed immunoreactivity for laminin alpha4, beta1, beta2, and gamma1 chains, type IV and XVIII collagens, and nidogen-1. Considering the assumed inability of alpha4 chain laminins to polymerize and to promote basement membrane assembly, the findings may in part explain the incomplete basement membrane formation in these vessels. Lymphatic capillaries of ovarian carcinomas showed immunoreactivity also for laminin alpha5 chain and its receptor Lutheran glycoprotein, emphasizing a difference between normal and ovarian carcinoma lymphatic capillaries. In renal cell carcinomas, immunoreactivity for laminin alpha4 chain was found in stroma and basement membranes of blood vessels. In most tumours, immunoreactivity for laminin alpha4 chain was also observed in the basement membrane region of tumour cell islets. Renal carcinoma cells produced alpha4 chain laminins. Laminin-411 did not promote adhesion of renal carcinoma cells, but inhibited their adhesion to fibronectin. Renal carcinoma cells migrated more on laminin-411 than on fibronectin. The results suggest that alpha4 chain laminins have a counteradhesive function, and may thus have a role in detachment and invasion of renal carcinoma cells.

Milk casein-derived tripeptides : A special focus on blood pressure and vascular function

Increased consumption of low-fat milk products is inversely associated with the risk of hypertension. The beneficial effect of milk on blood pressure is attributed to high calcium and potassium content but also to specific peptide sequences, which are cleaved from milk protein during gastrointestinal digestion, fermentation of milk with proteolytic starter cultures or enzymatic hydrolysis. Milk products fermented with Lactobacillus helveticus contain casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro), which have been shown to possess antihypertensive effects in humans and in experimental animals. The aim of the present series of studies was to investigate the effects of tripeptides Ile-Pro-Pro and Val-Pro-Pro or fermented milk products containing them on vascular function and blood pressure and to elucidate the mechanisms behind them by using different experimental models of hypertension. Another aim was to characterize the acute effects of tripeptides on blood pressure and arterial stiffness in mildly hypertensive humans. Ile-Pro-Pro and Val-Pro-Pro or fermented milk products containing them attenuated the development of hypertension in two experimental models of hypertension, spontaneously hypertensive rat (SHR) and type 2 diabetic Goto-Kakizaki (GK) rat fed with high-salt diet. Significant differences in systolic blood pressure (SBP) were seen after 8 weeks treatment with tripeptide-containing products compared to control product. Plant sterols did not enhance this effect. Two differently produced tripeptide powders produced a similar attenuating effect on SBP in SHR. In mildly hypertensive subjects, a single administration of tripeptide- and plant sterol-containing fermented milk product decreased both SBP and diastolic blood pressure (DBP) over a period of 8 hours. Protective effect of tripeptides Ile-Pro-Pro and Val-Pro-Pro and fermented milk products containing them on vascular function was demonstrated in in vitro studies and long-term experimental studies. The effect was shown to be endothelium-dependent and possibly involving endothelium-derived hyperpolarizing factor (EDHF). In the clinical study, single administration of tripeptide-containing fermented milk product did not affect measures of arterial stiffness. Long-term treatment with fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro inhibited angiotensin-converting enzyme (ACE) and decreased aldosterone levels thus showing beneficial effects on the renin-angiotensin system (RAS) in SHR and GK. No changes in the components of RAS were observed by the single administration of the same product in mildly hypertensive subjects. Increased levels of cGMP, NOx and citrulline suggest increased nitric oxide (NO) production by the tripeptides. Taken together, Ile-Pro-Pro and Val-Pro-Pro -containing products attenuate the development of hypertension after long-term treatment in experimental models of hypertension and possess an acute antihypertensive effect in mildly hypertensive subjects. In addition, these tripeptides show endothelium-mediated beneficial effects on vascular function. Attenuation of blood pressure increase by the tripeptides in experimental animals involves RAS, but its role in the antihypertensive effect in humans remains to be elucidated.

Associations among Emdogain®, human oral carcinoma cells and oral proteolytic enzymes

The Enamel matrix derivative Emdogain® (EMD) is a commercially available tissue extract preparation of porcine enamel origin. Studies have shown EMD to be clinically useful in promoting periodontal regeneration. EMD has been widely used in periodontal therapy for over ten years, but the mechanism of its action and the exact composition are not completely clear. EMD is predominantly amelogenin (>90%). However, unlike amelogenin, EMD has a number of growth factor-like effects and it has been shown to enhance the proliferation, migration and other cellular functions of periodontal ligament fibroblasts and osteoblasts. In contrast, the effects of EMD on epithelial cell lines and in particular on oral malignant cells have not been adequately studied. In addition, EMD has effects on the production of cytokines by several oral cell lines and the product is in constant interaction with different oral enzymes. Regardless of the various unknown properties of EMD, it is said to be clinically safe in regenerative procedures, also in medically compromised patients. The aim of the study was to examine whether gingival crevicular fluid (GCF), which contains several different proteolysis enzymes, could degrade EMD and alter its biological functions. In addition, the objective was to study the effects of EMD on carcinogenesis-related factors, in particular MMPs, using in vitro and in vivo models. This study also aimed to contribute to the understanding of the composition of EMD. GCF was capable of degrading EMD, depending on the periodontal status, with markedly more degradation in all states of periodontal disease compared to healthy controls. EMD was observed to stimulate the migration of periodontal ligament fibroblasts (PLF), whereas EMD together with GCF could not stimulate this proliferation. In addition, recombinant amelogenin, the main component of EMD, decreased the migration of PLFs. A comparison of changes induced by EMD and TGF-β1 in the gene profiles of carcinoma cells showed TGF-β1 to regulate a greater number of genes than EMD. However, both of the study reagents enhanced the expression of MMP-10 and MMP-9. Furthermore, EMD was found to induce several factors closely related to carcinogenesis on gene, protein, cell and in vivo levels. EMD enhanced the production of MMP-2, MMP-9 and MMP-10 proteins by cultured carcinoma cells. In addition, EMD stimulated the migration and in vitro wound closure of carcinoma cells. EMD was also capable of promoting metastasis formation in mice. In conclusion, the diseased GCF, containing various proteases, causes degradation of EMD and decreased proliferation of PLFs. Thus, this in vitro study suggests that the regenerative effect of EMD may decrease due to proteases present in periodontal tissues during the inflammation and healing of the tissues in vivo. Furthermore, EMD was observed to enhance several carcinoma-related factors and in particular the production of MMPs by benign and malignant cell lines. These findings suggest that the clinical safety of EMD with regard to dysplastic mucosal lesions should be further investigated.

Young Men s Sexual Behaviour in Finland and Estonia : Opportunities for prevention of sexually transmitted infections

Background: The incidence of sexually transmitted infections (STIs) in most EU states has gradually increased and the rate of newly diagnosed HIV cases has doubled since 1999. STIs differ in their clinical features, prognosis and transmission dynamics, though they do share a common factor in their mode of transmission −that is, human behaviour. The evolvement of STI epidemiology involves a joint action of biological, epidemiological and societal factors. Of the more immediate factors, besides timely diagnosis and appropriate treatment, STI incidence is influenced by population patterns of sexual risk behaviour, particularly the number of sexual partners and the frequency of unprotected intercourse. Assessment of sexual behaviour, its sociodemographic determinants and time-trends are important in understanding the distribution and dynamic of STI epidemiology. Additionally, in the light of the basic structural determinants, such as increased level of migration, changes in gender dynamics and impacts from globalization, with its increasing alignment of values and beliefs, can reveal future challenges related to STI epidemiology. STI case surveillance together with surveillance on sexual behaviour can guide the identification of preventive strategies, assess their effectiveness and predict emerging trends. The objective of this study was to provide base line data on sexual risk behaviour, self-reported STIs and their patterns by sociodemographic factors as well as associations of sexual risk behaviour with substance use among young men in Finland and Estonia. In Finland national population based data on adult men s sexual behaviour is limited. The findings are discussed in the context of STI epidemiology as well as their possible implications for public health policies and prevention strategies. Materials and Methods: Data from three different cross-sectional population-based surveys conducted in Finland and Estonia, during 1998 2005, were used. Sexual behaviour- and health-related questions were incorporated in two surveys in Finland; the Health 2000, a large scale general health survey, focussed on young adults, and the Military health behavioural survey on military conscripts participating in the mandatory military training. Through research collaboration with Estonia, similar questions to the Finnish surveys were introduced to the second Estonian HIV/AIDS survey, which was targeted at young adults. All surveys applied mail-returned, anonymous, self-administered questionnaires with multiple choice formatted answers. Results: In Finland, differences in sexual behaviour between young men and women were minor. An age-stratified analysis revealed that the sex-related difference observed in the youngest age group (18 19 years) levelled off in the age group 20 24 and almost disappeared among those aged 25 29. Marital status was the most important sociodemographic correlate for sexual behaviour for both sexes, singles reporting higher numbers of lifetime-partners and condom use. This effect was stronger for women than for men. However, of those who had sex with casual partners, 15% were married or co-habiting, with no difference between male and female respondents. According to the Military health behavioural survey, young men s sexual risk behaviour in Finland did not markedly change over a period of time between 1998 and 2005. Approximately 30−40% of young men had had multiple sex partners (more than five) in their lifetime, over 20% reported having had multiple sex partners (at least three) over the past year and 50% did not use a condom in their last sexual intercourse. Some 10% of men reported accumulation of risk factors, i.e. having had both, multiple sex partners and not used a condom in their last intercourse, over the past year of the survey. When differences and similarities were viewed within Finland and Estonia, a clear sociodemographic patterning of sexual risk behaviour and self-reported STIs was found in Finland, but a somewhat less consistent trend in Estonia. Generally, both, alcohol and drug use were strong correlates for sexual risk behaviour and self-reported STIs in Finland and Estonia, having a greater effect on engagement with multiple sex partners rather than unprotected intercourse or self-reported STIs. In Finland alcohol use, relative to drug use, was a stronger predictor of sexual risk behaviour and self-reported STIs, while in Estonia drug use predicted sexual risk behaviour and self-reported STIs stronger than alcohol use. Conclusions: The study results point to the importance for prevention of sexual risk behaviour, particularly strategies that integrate sexual risk with alcohol and drug use risks. The results point to the need to focus further research on sexual behaviour and STIs among young people; on tracking trends among general population as well as applying in-depth research to identify and learn from vulnerable and high-risk population groups for STIs who are exposed to a combination of risk factors.

Predictors of disability retirement: From early intentions to retirement

The strong tendency of elderly employees to retire early and the simultaneous aging of the population have been major topics of policy and scientific debate. A key concern has been the financing of future pension schemes and possible labour shortage, especially in social and health services within the public sector. The aging of the population is inevitable, but efforts can be made to prevent or postpone early exit from the labour force, e.g., by identifying and intervening in the factors that contribute to the process of early retirement due to disability. The associations of intentions to retire early, poor mental health and different psychosocial factors with the process of disability retirement are still poorly understood. The purpose of this study was to investigate the associations of intentions to retire early, poor mental health, work and family related psychosocial factors and experiences of earlier life stages with the process of disability retirement. The data were derived from the Helsinki Health Study (HHS, N=8960) and the Health and Social Support Study (HeSSup, N=25 901). The Helsinki Health Study is an ongoing employee cohort study among middle-aged women and men. The Health and Social Support Study is an ongoing longitudinal study of a working-age sample representative of the Finnish population. The analyses were restricted to respondents 40 years of age or older. Age and gender adjusted prevalence and incidence rates were calculated. Associations were studied by using logistic, multinomial and Cox regression. Strong intentions to retire early were common among employees. Poor mental health, unfavourable working conditions and work-to-family conflicts were clearly associated with increased intentions to retire early. Strong intentions to retire early predicted disability retirement. Risk of disability retirement increased in a dose-response manner with increasing number of childhood adversities. Poor mental and somatic health, life dissatisfaction, heavy alcohol consumption, current smoking, obesity and low socioeconomic status were also predictors of disability retirement. The impact of poor mental health and adverse experiences from earlier life stages, work and family related psychosocial factors, e.g., work-family interface, the subjective experience of well-being and health related risk behaviours on the process of disability retirement should be recognised. Preventive measures against disability retirement should be launched before subjective experience of ill health, work disability and strong intentions to retire early emerge.

Sopimusohjaus ohjausmenettelynä sairaanhoitopiirin ja terveyskeskusten yksiköissä ja niiden lääkärien työssä

This study concerns the implementation of steering by contracting in health care units and in the work of the doctors employed by them. The study analyses how contracting as a process is being implemented in hospital district units, health centres and in the work of their doctors, as well as how these units carry out their operations and patient care within the restrictions set by the contracts. Based on interviews with doctors, the study analyses the realisation of operations within the units from the doctors perspective and through their work. The key result of the study is that the steering impact of contracting was not felt at the level of practical work. The contracting was implemented by assigning the related tasks to management only. The management implemented the contract by managing their resources rather than by intervening in doctors activities or the content of their tasks. The steering did not extend to improving practical care processes. This allowed the unchanged continuation of core operations in an autonomous manner and in part, protected from the impacts of contracting. In health centres, the contract concluded was viewed as merely steering the operations of the hospital district and its implementation did not receive the support of the centres. The fact that primary health care and specialised health care constitute separate contracting parties had adverse effects on the contract s implementation and the integration of care. A theoretical review unveiled several reasons for the failure of steering by contracting to alter operations within units. These included the perception steering by contracting as a weak change incentive. The doctors shunned the introduction of an economic logic and ideology into health care and viewed steering by contracting as a hindrance to delivering care to patients and a disturbance to their work and patient relationships. Contracting caused tensions between representatives of the financial administration and health care professionals. It also caused internal tensions, while it had varying impacts on different specialities, including the introduction of varying potential to influence contracts. Most factors preventing the realisation of the steering objective could have been ameliorated through positive leadership. There is a need to bridge the gap between financial steering and patient work. Key measures include encouraging the commitment of middle management, supporting leadership expertise and identifying the right methods of contributing to a mutual understanding between the cultures of financing, administration and health care. Criticism of the purchasers expertise and the view that undersized orders are due to the purchaser s financial difficulties underlines the importance of the purchaser s size. Overly detailed, product-based contracts seemed to place the focus on the quantities and costs of services rather than health impacts and efficiency of operations. Bundling contracts into larger service packages would encourage the enhancement of operations. Steering by contracting represents unexploited potential: it could function as a forum for integrated regional planning of services, and the prioritisation and integration of care, and offer an opportunity and an incentive for developing core operations.

Trust, participation and health among ageing people : A cross-sectional cohort study of men and women born in 1926-30, 1936-40, and 1946-50 in the Lahti region, southern Finland

The purpose of the present study was to explore the associations between good self-rated health and economic and social factors in different regions among ageing people in the Päijät-Häme region in southern Finland. The data of this study were collected in 2002 as part of the research and development project Ikihyvä 2002 2012 (Good Ageing in Lahti region GOAL project). The baseline data set consisted of 2,815 participants born in 1926 30, 1936 40, and 1946 50. The response rate was 66 %. According to the previous studies, trust in other people and social participation as the main aspects of social capital are associated with self-rated health. In addition, socioeconomic position (SEP) and self-rated health are associated, but all SEP indicators do not have identical associations with health. However, there is a lack of knowledge of the health associations and regional differences with these factors, especially among ageing people. Regarding these questions, the present study gives new information. According to the results of this study, self-perceived adequacy of income was significantly associated with good self-rated health, especially in the urban areas. Similar associations were found in the rural areas, though education was also considered an important factor. Adequacy of income was an even stronger predictor of good health than the actual income. Women had better self-rated health than men only in the urban areas. The youngest respondents had quite equally better self-rated health than the others. Social participation and access to help when needed were associated with good self-rated health, especially in the urban area and the sparsely populated rural areas. The result was comparable in the rural population centres. The correlation of trust with self-rated health was significant in the urban area. High social capital was associated with good self-rated health in the urban area. The association was quite similar in the other areas, though it was statistically insignificant. High social capital consisted of co-existent high social participation and high trust. The association of traditionalism (low participation and high trust) with self-rated health was also substantial in the urban area. The associations of self-rated health with low social capital (low participation and low trust) and the miniaturisation of community (high participation and low trust) were less significant. From the forms of single participation, going to art exhibitions, theatre, movies, and concerts among women, and studying and self-development among men were positively related to self-rated health. Unexpectedly, among women, active participation in religious events and voluntary work was negatively associated with self-rated health. This may indicate a coping method with ill-health. As a whole, only minor variations in self-rated health were found between the areas. However, the significance of the factors associated with self-rated health varied according to the areas. Economic factors, especially self-perceived adequacy of income was strongly associated with good self-rated health. Also when adjusting for economic and several other background factors social factors (particularly high social capital, social participation, and access to help when needed) were associated with self-rated health. Thus, economic and social factors have a significant relation with the health of the ageing, and improving these factors may have favourable effects on health among ageing people.

Obesity, Smoking and Dieting

Lihavuus ja ylipaino ovat viime vuosikymmeninä yleistyneet; jo yli puolet länsimaiden väestöstä on ylipainoisia ja viidennes lihavia. Varsinkin nuorilla ylipainon lisääntyminen on ollut nopeaa. Ylipaino, erityisesti yhdistettynä vyötärölihavuuteen, sekä tupakointi lisäävät sairastavuutta sydän- ja verisuonisairauksiin, metabolisiin sairauksiin, kuten diabetekseen, sekä moniin syöpiin. Lihavuus ja tupakointi ovatkin kehittyneiden maiden tärkeimpiä ehkäistävissä olevia kuolinsyitä. Samanaikaisesti ylipainon kanssa laihduttaminen ja jopa terveydelle haitalliset laihdutusmenetelmät, kuten tupakointi painonhallintakeinona on tullut yhä yleisemmäksi. Nopeaan painonpudotukseen tähtäävällä laihduttamisella on usein terveydelle haitallisia seurauksia kuten painon nousu yli alkuperäisen painon ja kehon rasvajakauman muuttuminen epäterveellisemmäksi. Kolme neljännestä merkittävästi laihduttaneista kertoo painon nousseen takaisin. Tupakoinnin ja toistuvan laihduttamisen vaikutukset ylipainon ja lihavuuden kehittymiselle kytkeytyvät toisiinsa. Tässä väitöskirjatyössä tutkittiin toistuvan laihduttamisen ja tupakoinnin vaikutusta kehon painoon ja lisäksi tupakoinnin vaikutusta vyötärölihavuuden kehittymiseen. Työn toisena tavoitteena oli tutkia, kuinka voimakkaasti tupakointi ja toistuva laihduttaminen liittyvät toisiinsa suomalaisilla ja onko tämä yhteys erilainen eri ikäryhmissä ja sukupuolilla. Työ perustuu kolmeen laajaan kyselyaineistoon: Nuorten Kaksosten Terveystutkimuksen (englanniksi FinnTwin16) aineistossa on seurattu 1975-79 syntyneitä kaksosia 16, 17, 18 ja 24 vuoden ikäisinä (N=5563). Suomen kaksoskohortin aineisto (N= 12 793) on kerätty vuonna 1990 samaa sukupuolta olevilta, vuosina 1930-57 syntyneiltä kaksosilta. Entisten huippu-urheilijoiden (N=1838) ja heille kaltaistettujen verrokkien (N=834) seurantatutkimuksessa tiedot on kerätty vuosina 1985, 1995 ja 2001. Pituus, paino ja tupakointi on kysytty kaikissa kyselyissä. Kaksoset vastasivat laihdutuskäyttäytymistä koskeviin kysymyksiin. Urheilijoiden laihdutuskäyttäytyminen pääteltiin lajin perusteella, sillä toistuvan laihduttamisen tiedetään olevan yleistä painoluokissa urheilevilla urheilijoilla (esim.painijat, nyrkkeilijät). Nuoruusiän tupakointi ennusti vyötärölihavuutta molemmilla sukupuolilla ja lisäksi ylipainoisuutta naisilla. Toistuva laihduttaminen oli yhteydessä myöhempään painonnousuun ja lihavuuteen miehillä. Lisäksi toistuvan laihduttamisen ja tupakoinnin todettiin liittyvän toisiinsa nuorilla aikuisilla. Vanhemmissa ikäluokissa miehet, jotka tupakoivat, laihduttivat harvemmin kuin tupakoimattomat. Lihavuuteen ja vyötärölihavuuteen liittyvän oheissairastavuuden ennaltaehkäisyssä tupakoinnin ja toistuvan laihduttamisen vähentäminen saattavat olla aiemmin luultua tehokkaampia keinoja.

Effect of waiting time on health outcomes and service utilization : A prospective randomized study on patients admitted to hospital for hip or knee replacement

Although the principle of equal access to medically justified treatment has been promoted by official health policies in many Western health care systems, practices do not completely meet policy targets. Waiting times for elective surgery vary between patient groups and regions, and growing problems in the availability of services threaten equal access to treatment. Waiting times have come to the attention of decision-makers, and several policy initiatives have been introduced to ensure the availability of care within a reasonable time. In Finland, for example, the treatment guarantee came into force in 2005. However, no consensus exists on optimal waiting time for different patient groups. The purpose of this multi-centre randomized controlled trial was to analyse health-related quality of life, pain and physical function in total hip or knee replacement patients during the waiting time and to evaluate whether the waiting time is associated with patients health outcomes at admission. This study also assessed whether the length of waiting time is associated with social and health services utilization in patients awaiting total hip or knee replacement. In addition, patients health-related quality of life was compared with that of the general population. Consecutive patients with a need for a primary total hip or knee replacement due to osteoarthritis were placed on the waiting list between August 2002 and November 2003. Patients were randomly assigned to a short waiting time (maximum 3 months) or a non-fixed waiting time (waiting time not fixed in advance, instead the patient followed the hospitals routine practice). Patients health-related quality of life was measured upon being placed on the waiting list and again at hospital admission using the generic 15D instrument. Pain and physical function were evaluated using the self-report Harris Hip Score for hip patients and a scale modified from the Knee Society Clinical Rating System for knee patients. Utilization measures were the use of home health care, rehabilitation and social services, physician visits and inpatient care. Health and social services use was low in both waiting time groups. The most common services used while waiting were rehabilitation services and informal care, including unpaid care provided by relatives, neighbours and volunteers. Although patients suffered from clear restrictions in usual activities and physical functioning, they seemed primarily to lean on informal care and personal networks instead of professional care. While longer waiting time did not result in poorer health-related quality of life at admission and use of services during the waiting time was similar to that at the time of placement on the list, there is likely to be higher costs of waiting by people who wait longer simply because they are using services for a longer period. In economic terms, this would represent a negative impact of waiting. Only a few reports have been published of the health-related quality of life of patients awaiting total hip or knee replacement. These findings demonstrate that, in addition to physical dimensions of health, patients suffered from restrictions in psychological well-being such as depression, distress and reduced vitality. This raises the question of how to support patients who suffer from psychological distress during the waiting time and how to develop strategies to improve patients initiatives to reduce symptoms and the burden of waiting. Key words: waiting time, total hip replacement, total knee replacement, health-related quality of life, randomized controlled trial, outcome assessment, social service, utilization of health services

Musculoskeletal disorders and psychosocial factors at work : Effects of a participatory ergonomics intervention in a cluster randomized controlled trial

This study examined the efficacy of a participatory ergonomics intervention in preventing musculoskeletal disorders (MSDs) and changing unsatisfactory psychosocial working conditions among municipal kitchen workers. The occurrence of multiple-site musculoskeletal pain (MSP) and associations between MSP and psychosocial factors at work over time were studied secondarily. A cluster randomized controlled trial was conducted during 2002-2005 in 119 municipal kitchens with 504 workers. The kitchens were randomized to an intervention (n = 59) and control (n = 60) group. The intervention lasted 11 to 14 months. The workers identified strenuous work tasks and sought solutions for decreasing physical and mental workload. The main outcomes were the occurrence of and trouble caused by musculoskeletal pain in seven anatomical sites, local musculoskeletal fatigue after work, and musculoskeletal sick leaves. Psychosocial factors at work (job control, skill discretion, co-worker relationships, supervisor support, mental strenuousness of work, hurry, job satisfaction) and mental stress were studied as intermediate outcomes of the intervention. Questionnaire data were collected at three months intervals during the intervention and the one-year post-intervention follow-up. Response rates varied between 92 % and 99 %. In total, 402 ergonomic changes were implemented. In the control group, 80 changes were spontaneously implemented within normal activity. The intervention did not reduce perceived physical workload and no systematic differences in any health outcomes were found between the intervention and control groups during the intervention or during the one-year follow-up. The results suggest that the intervention as studied in the present trial was not more effective in reducing perceived physical workload or preventing MSDs compared with no such intervention. Little previous evidence of the effectiveness of ergonomics interventions in preventing MSDs exists. The effects on psychosocial factors at work were adverse, especially in the two of the participating cities where re-organization of foodservices timed simultaneously with the intervention. If organizational reforms at workplace are expected to occur, the execution of other workplace interventions at the same time should be avoided. The co-occurrence of musculoskeletal pain at several sites is observed to be more common than pain at single anatomical sites. However, the risk factors of MSP are largely unknown. This study showed that at baseline, 73 % of the women reported pain in at least two, 36 % in four or more, and 10 % in six to seven sites. The seven pain symptoms occurred in over 80 different combinations. When co-occurrence of pain was studied in three larger anatomical areas (neck/low back, upper limbs, lower limbs), concurrent pain in all three areas was the most common combination (36 %). The 3-month prevalence of MSP (≥ 3 of seven sites) varied between 50 % and 61 % during the two-year follow-up period. Psychosocial factors at work and mental stress were strong predictors for MSP over time and, vice versa, MSP predicted psychosocial factors at work and mental stress. The reciprocality of the relationships implies either two mutually dependent processes in time, or some shared common underlying factor(s).

Mammographic mass-screening and future breast cancer burden in Finland

A population-based early detection program for breast cancer has been in progress in Finland since 1987. According to regulations during the study period 1987-2001, free of charge mammography screening was offered every second year to women aged 50-59 years. Recently, the screening service was decided to be extended to age group 50-69. However, the scope of the program is still frequently discussed in public and information about potential impacts of mass-screening practice changes on future breast cancer burden is required. The aim of this doctoral thesis is to present methodologies for taking into account the mass-screening invitation information in breast cancer burden predictions, and to present alternative breast cancer incidence and mortality predictions up to 2012 based on scenarios of the future screening policy. The focus of this work is not on assessing the absolute efficacy but the effectiveness of mass-screening, and, by utilizing the data on invitations, on showing the estimated impacts of changes in an existing screening program on the short-term predictions. The breast cancer mortality predictions are calculated using a model that combines incidence, cause-specific and other cause survival on individual level. The screening invitation data are incorporated into modeling of breast cancer incidence and survival by dividing the program into separate components (first and subsequent rounds and years within them, breaks, and post screening period) and defining a variable that gives the component of the screening program. The incidence is modeled using a Poisson regression approach and the breast cancer survival by applying a parametric mixture cure model, where the patient population is allowed to be a combination of cured and uncured patients. The patients risk to die from other causes than breast cancer is allowed to differ from that of a corresponding general population group and to depend on age and follow-up time. As a result, the effects of separate components of the screening program on incidence, proportion of cured and the survival of the uncured are quantified. According to the predictions, the impacts of policy changes, like extending the program from age group 50-59 to 50-69, are clearly visible on incidence while the effects on mortality in age group 40-74 are minor. Extending the screening service would increase the incidence of localized breast cancers but decrease the rates of non-localized breast cancer. There were no major differences between mortality predictions yielded by alternative future scenarios of the screening policy: Any policy change would have at the most a 3.0% reduction on overall breast cancer mortality compared to continuing the current practice in the near future.

Multiple socioeconomic circumstances and health : associations and explanations among Finnish and British public sector employees

Socioeconomic health inequalities have been widely documented, with a lower social position being associated with poorer physical and general health and higher mortality. For mental health the results have been more varied. However, the mechanisms by which the various dimensions of socioeconomic circumstances are associated with different domains of health are not yet fully understood. This is related to a lack of studies tackling the interrelations and pathways between multiple dimensions of socioeconomic circumstances and domains of health. In particular, evidence from comparative studies of populations from different national contexts that consider the complexity of the causes of socioeconomic health inequalities is needed. The aim of this study was to examine the associations of multiple socioeconomic circumstances with physical and mental health, more specifically physical functioning and common mental disorders. This was done in a comparative setting of two cohorts of white-collar public sector employees, one from Finland and one from Britain. The study also sought to find explanations for the observed associations between economic difficulties and health by analysing the contribution of health behaviours, living arrangements and work-family conflicts. The survey data were derived from the Finnish Helsinki Health Study baseline surveys in 2000-2002 among the City of Helsinki employees aged 40-60 years, and from the fifth phase of the London-based Whitehall II study (1997-9) which is a prospective study of civil servants aged 35-55 years at the time of recruitment. The data collection in the two countries was harmonised to safeguard maximal comparability. Physical functioning was measured with the Short Form (SF-36) physical component summary and common mental disorders with the General Health Questionnaire (GHQ-12). Socioeconomic circumstances were parental education, childhood economic difficulties, own education, occupational class, household income, housing tenure, and current economic difficulties. Further explanatory factors were health behaviours, living arrangements and work-family conflicts. The main statistical method used was logistic regression analysis. Analyses were conducted separately for the two sexes and two cohorts. Childhood and current economic difficulties were associated with poorer physical functioning and common mental disorders generally in both cohorts and sexes. Conventional dimensions of socioeconomic circumstances i.e. education, occupational class and income were associated with physical functioning and mediated each other’s effects, but in different ways in the two cohorts: education was more important in Helsinki and occupational class in London. The associations of economic difficulties with health were partly explained by work-family conflicts and other socioeconomic circumstances in both cohorts and sexes. In conclusion, this study on two country-specific cohorts confirms that different dimensions of socioeconomic circumstances are related but not interchangeable. They are also somewhat differently associated with physical and mental domains of health. In addition to conventionally measured dimensions of past and present socioeconomic circumstances, economic difficulties should be taken into account in studies and attempts to reduce health inequalities. Further explanatory factors, particularly conflicts between work and family, should also be considered when aiming to reduce inequalities and maintain the health of employees.

Palladin, a novel microfilament protein

Palladin is a novel actin microfilament associated protein, which together with myotilin and myopalladin forms a novel cytoskeletal IgC2 domain protein family. Whereas the expression of myotilin and myopalladin is limited mainly to striated muscle, palladin is widely expressed in both epithelial and mesenchymal tissues, including heart and the nervous system. Palladin has a complex genetic structure and it is expressed as several different sized and structured splice variants, which also display differences in their expression pattern and interactions. In muscle cells, all the family members localize to the sarcomeric Z-disc, and in non-muscle cells palladin also localizes to the stress-fiber-dense regions, lamellipodia, podosomes and focal adhesions. A common feature of this protein family is the binding to α-actinin, but other interactions are mostly unique to each member. Palladin has been shown to interact with several proteins, including VASP, profilin, Eps8, LASP-1 and LPP. Its domain structure, lack of enzymatic activity and multiple interactions define it as a molecular scaffolding protein, which links together proteins with different functional modalities into large complexes. Palladin has an important role in cytoskeletal regulation, particularly in stress fiber formation and stabilization. This assumption is supported by several experimental results. First, over-expression of palladin in non-muscle cells results in rapid reorganization of the actin cytoskeleton and formation of thick actin bundles. Second, the knock-down of palladin with anti-sense and siRNA techniques or knock-out by genetic methods leads to defective stress fiber formation. Furthermore, palladin is usually up-regulated in situations requiring a highly organized cytoskeleton, such as differentiation of dendritic cells, trophoblasts and myofibroblasts, and activation of astrocytes during glial scar formation. The protein family members have also direct disease linkages; myotilin missense mutations are the cause of LGMD1A and myofibrillar myopathy. Palladin mutations and polymorphisms, on the other hand, have been linked to hereditary pancreatic cancer and myocardial infarction, respectively. In this study we set out to characterize human palladin. We identified several palladin isoforms, studied their tissue distribution and sub-cellular localization. Four novel interaction partners were identified; ezrin, ArgBP2, SPIN90 and Src-kinase.The previously identified interaction between palladin and α-actinin was also characterized in detail. All the identified new binding partners are actin cytoskeleton associated proteins; ezrin links the plasma membrane to the cytoskeleton, ArgBP2 and SPIN90 localize, among other structures, to the lamellipodia and in cardiomyocytes to the Z-disc. Src is a transforming tyrosine kinase, which besides its role in oncogenesis has also important cytoskeletal associations. We also studied palladin in myofibroblasts, which are specialized cells involved in diverse physiological and pathological processes, such as wound healing and tissue fibrosis. We demonstrated that palladin is up-regulated during the differentiation of myofibroblasts in an isoform specific manner, and that this up-regulation is induced by TGF-β via activation of both the SMAD and MAPK signalling cascades. In summary, the results presented here describe the initial characterization of human palladin and offer a basis for further studies.

VEGF-C and angiopoietins in lymphangiogenesis

Angiogenesis and lymphangiogenesis occur during development as the result of tightly coordinated signalling programs to generate two hierarchically organised vascular systems. All tissues and organs are dependent on a functional blood vasculature for oxygen and nutrients, whereas the lymphatic vasculature functions to collect excess tissue fluid, passing it through lymph nodes for immune surveillance, and returning it to the blood circulation. Effectors that control developmental angiogenesis and lymphangiogenesis are also involved in pathological settings, and therefore potential targets for therapy. Vascular endothelial growth factor (VEGF) and angiopoietin (Ang) growth factors, signalling through endothelial VEGFR and Tie receptors, have been established as key regulators of angiogenic and lymphangiogenic processes in development and disease. In this study, we aimed to obtain a clearer understanding of the vascular effects of stimulation by VEGF-C, Ang1 and Ang2, all known to be involved in lymphangiogenesis. In cell culture models, we found that both intrinsic and microenvironmental regulatory mechanisms are involved in the regulation of endothelial cell phenotypes, and distinct responses to VEGF signalling are induced by specific receptor pathways in different endothelial cell types. Surprisingly, we also found that Ang1 induces sprouting lymphangiogenesis in vivo by a VEGFR-3 dependent mechanism, establishing Ang1 as a novel lymphangiogenic factor. Using inducible transgenic mouse models, we found that VEGF-C-induced lymphatic hyperplasia persisted independently of the growth factor, indicating that short pro-lymphangiogenic therapy could lead to lasting improvements in tissue oedema. While VEGF-C had blood vessel effects in embryos, no angiogenic side effects were observed in adult tissues. Furthermore, inducible transgenic expression of Ang2 during embryonic development confirmed Ang2 as an important regulator of lymphatic remodelling and mural cell contacts. The unexpected similarity of the lymphatic maturation defects caused by excess Ang2 to those observed in Ang2 deficient mice demonstrated that correct doses of Ang2 are crucial for the control of lymphatic development. Unlike Ang1, Ang2 did not induce lymphatic sprouting. Although Ang1 has been shown to be able to substitute for Ang2 during developmental lymphangiogenesis, their lymphatic effects are not identical. These findings further our understanding of the basic mechanisms of angiogenesis and lymphangiogenesis, important for the future development of targeted therapies for vascular diseases such as cancer, inflammation, lymphoedema and ischemia. VEGF-C and Ang1 especially emerged as promising candidates for pro-lymphangiogenic therapy.