Trust and Safe Choices: Coping with health-related risks in food consumption in St. Petersburg

This dissertation considers the problem of trust in the context of food consumption. The research perspectives refer to institutional conditions for consumer trust, personal practices of food consumption, and strategies consumers employ for controlling the safety of their food. The main concern of the study is to investigate consumer trust as an adequate response to food risks, i.e. a strategy helping the consumer to make safe choices in an uncertain food situation. "Risky" perspective serves as a frame of reference for understanding and explaining trust relations. The original aim of the study was to reveal the meanings applied to the concepts of trust, safety and risks in the perspective of market choices, the assessments of food risks and the ways of handling them. Supplementary research tasks presumed descriptions of institutional conditions for consumer trust, including descriptions of the food market, and the presentation of food consumption patterns in St. Petersburg. The main empirical material is based on qualitative interviews with consumers and interviews and group discussions with professional experts (market actors, representatives of inspection bodies and consumer organizations). Secondary material is used for describing institutional conditions for consumer trust and the market situation. The results suggest that the idea of consumer trust is associated with the reputation of suppliers, stable quality and taste of their products, and reliable food information. Being a subjectively constructed state connected to the act of acceptance, consumer trust results in positive buying decisions and stable preferences in the food market. The consumers' strategies that aim at safe food choices refer to repetitive interactions with reliable market actors that free them from constant consideration in the marketplace. Trust in food is highly mediated by trust in institutions involved in the food system. The analysis reveals a clear pattern of disbelief in the efficiency of institutional food control. The study analyses this as a reflection of "total distrust" that appears to be a dominant mood in many contexts of modern Russia. However, the interviewees emphasize the state's decisive role in suppressing risks in the food market. Also, the findings are discussed with reference to the consumers' possibilities of personal control over food risks. Three main responses to a risky food situation are identified: the reflexive approach, the traditional approach, and the fatalistic approach.

Postglacial climate changes and vegetation responses in northern Europe

Postglacial climate changes and vegetation responses were studied using a combination of biological and physical indicators preserved in lake sediments. Low-frequency trends, high-frequency events and rapid shifts in temperature and moisture balance were probed using pollen-based quantitative temperature reconstructions and oxygen-isotopes from authigenic carbonate and aquatic cellulose, respectively. Pollen and plant macrofossils were employed to shed light on the presence and response rates of plant populations in response to climate changes, particularly focusing on common boreal and temperate tree species. Additional geochemical and isotopic tracers facilitated the interpretation of pollen- and oxygen-isotope data. The results show that the common boreal trees were present in the Baltic region (~55°N) during the Lateglacial, which contrasts with the traditional view of species refuge locations in the south-European peninsulas during the glacial/interglacial cycles. The findings of this work are in agreement with recent paleoecological and genetic evidence suggesting that scattered populations of tree species persisted at higher latitudes, and that these taxa were likely limited to boreal trees. Moreover, the results demonstrate that stepwise changes in plant communities took place in concert with major climate fluctuations of the glacial/interglacial transition. Postglacial climate trends in northern Europe were characterized by rise, maxima and fall in temperatures and related changes in moisture balance. Following the deglaciation of the Northern Hemisphere and the early Holocene reorganization of the ice-ocean-atmosphere system, the long-term temperature trends followed gradually decreasing summer insolation. The early Holocene (~11,700-8000 cal yr BP) was overall cool, moist and oceanic, although the earliest Holocene effective humidity may have been low particularly in the eastern part of northern Europe. The gradual warming trend was interrupted by a cold event ~8200 cal yr BP. The maximum temperatures, ~1.5-3.0°C above modern values, were attained ~8000-4000 cal yr BP. This mid-Holocene peak warmth was coupled with low lake levels, low effective humidity and summertime drought. The late Holocene (~4000 cal yr BP-present) was characterized by gradually decreasing temperatures, higher lake levels and higher effective humidity. Moreover, the gradual trends of the late Holocene were probably superimposed by higher-frequency variability. The spatial variability of the Holocene temperature and moisture balance patterns were tentatively attributed to the differing heat capacities of continents and oceans, changes in atmospheric circulation modes and position of sites and subregions with respect to large water bodies and topographic barriers. The combination of physical and biological proxy archives is a pivotal aspect of this work, because non-climatic factors, such as postglacial migration, disturbances and competitive interactions, can influence reshuffling of vegetation and hence, pollen-based climate reconstructions. The oxygen-isotope records and other physical proxies presented in this work manifest that postglacial climate changes were the main driver of the establishment and expansion of temperate and boreal tree populations, and hence, large-scale and long-term vegetation patterns were in dynamic equilibrium with climate. A notable exception to this pattern may be the postglacial invasion of Norway spruce and the related suppression of mid-Holocene temperate forest. This salient step in north-European vegetation history, the development of the modern boreal ecosystem, cannot be unambiguously explained by current evidence of postglacial climate changes. The results of this work highlight that plant populations, including long-lived trees, may be able to respond strikingly rapidly to changes in climate. Moreover, interannual and seasonal variation and extreme events can exert an important influence on vegetation reshuffling. Importantly, the studies imply that the presence of diffuse refuge populations or local stands among the prevailing vegetation may have provided the means for extraordinarily rapid vegetation responses. Hence, if scattered populations are not provided and tree populations are to migrate long distances, their capacity to keep up with predicted rates of future climate change may be lower than previously thought.

Regulation of Kinin receptor Expression in Heart Failure with a Focus on Vascular Endothelium

Accumulating evidence show that kinins, notably bradykinin (BK) and kallidin, have cardioprotective effects. To these include reduction of left ventricular hypertrophy (LVH) and progression of heart failure. The effects are mediated through two G protein-coupled receptors- bradykinin type-2 receptor (BK-2R) and bradykinin type -1 receptor (BK-1R). The widely accepted cardioprotective effects of BK-receptors relate to triggering the production and release of vasodilating nitric oxide (NO) by endothelial cells. They also exert anti-proliferative effects on fibroblasts and anti-hypertrophic effects on myocytes, and thus may play an essential role in the cardioprotective response to myocardial injury. The role for BK-1Rs in HF is based on experimental animal models, where the receptors have been linked to cardioprotective- but also to cardiotoxic -effects. The BK-1Rs are induced under inflammatory and ischemic conditions, shown in animal models; no previous reports, concerning BK-1Rs in human heart failure, have been presented. The expression of BK-2Rs is down-regulated in human end-stage heart failure. Present results showed that, in these patients, the BK-1Rs were up-regulated, suggesting that also BK-1Rs are involved in the pathogenesis of human heart failure. The receptors were localized mainly in the endothelium of intramyocardial coronary vessels, and correlated with the increased TNF-α expression in the myocardial coronary vessels. Moreover, in cultured endothelial cells, TNF-α was a potent trigger of BK-1Rs. These results suggest that cytokines may be responsible for the up-regulation of BK-1Rs in human heart failure. A linear relationship between BK-2R mRNA and protein expression in normal and failing human left ventricles implies that the BK-2Rs are regulated on the transcriptional level, at least in human myocardium. The expression of BK-2Rs correlated positively with age in normal and dilated hearts (IDC). The results suggest that human hearts adapts to age-related changes, by up-regulating the expression of cardioprotective BK-2Rs. Also, in the BK-2R promoter polymorphism -58 T/C, the C-allele was accumulated in cardiomyopathy patients which may partially explain the reduced number of BK-2Rs. Statins reduce the level of plasma cholesterol, but also exert several non-cholesterol-dependent effects. These effects were studied in human coronary arterial endothelial cells (hCAEC) and incubation with lovastatin induced both BK-1 and BK-2Rs in a time and concentration-dependent way. The induced BK-2Rs were functionally active, thus NO production and cGMP signaling was increased. Induction was abrogated by mevalonate, a direct HMG-CoA metabolite. Lovastatin is known to inhibit Rho activation, and by a selective RhoA kinase inhibitor (Y27632), a similar induction of BK-2R expression as with lovastatin. Interestingly a COX-2-inhibitor (NS398) inhibited this lovastatin-induction of BK-2Rs, suggesting that COX-2 inhibitors may affect the endothelial BK-2Rs, in a negative fashion. Hypoxia is a common denominator in HF but also in other cardiovascular diseases. An induction of BK-2Rs in mild hypoxic conditions was shown in cultured hCAECs, which was abolished by a specific BK-2R inhibitor Icatibant. These receptors were functionally active, thus BK increased and Icatibant inhibited the production of NO. In rat myocardium the expression of BK-2R was increased in the endothelium of vessels, forming at the border zone, between the scar tissue and the healthy myocardium. Moreover, in in vitro wound-healing assay, endothelial cells were cultured under hypoxic conditions and BK significantly increased the migration of these cells and as Icatibant inhibited it. These results show, that mild hypoxia triggers a temporal expression of functionally active BK-2Rs in human and rat endothelial cells, supporting a role for BK-2Rs, in hypoxia induced angiogenesis. Our and previous results show, that BK-Rs have an impact on the cardiovascular diseases. In humans, at the end stage of heart failure, the BK-2Rs are down-regulated and BK-1Rs induced. Whether the up-regulation of BK-1Rs, is a compensatory mechanism against the down-regulation of BK-2Rs, or merely reflects the end point of heart failure, remains to bee seen. In a clinical point of view, the up-regulation of BK-2Rs, under hypoxic conditions or statin treatment, suggests that, the induction of BK-2Rs is protective in cardiovascular pathologies and those treatments activating BK-2Rs, might give additional tools in treating heart failure.

Determinants of vascular cognitive impairment : White matter lesions, brain atrophy and their neuropsychological correlates

The concept of vascular cognitive impairment (VCI) covers a wide spectrum of cognitive dysfunctions related to cerebrovascular disease. Among the pathophysiological determinants of VCI are cerebral stroke, white matter lesions and brain atrophy, which are known to be important risk factors for dementia. However, the specific mechanisms behind the brain abnormalities and cognitive decline are still poorly understood. The present study investigated the neuropsychological correlates of particular magnetic resonance imaging (MRI) findings, namely, medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH), general cortical atrophy and corpus callosum (CC) atrophy in subjects with cerebrovascular disease. Furthermore, the cognitive profile of subcortical ischaemic vascular disease (SIVD) was examined. This study was conducted as part of two large multidisciplinary study projects, the Helsinki Stroke Aging Memory (SAM) Study and the multinational Leukoaraiosis and Disability (LADIS) Study. The SAM cohort consisted of 486 patients, between 55 and 85 years old, with ischaemic stroke from the Helsinki University Hospital, Helsinki, Finland. The LADIS Study included a mixed sample of subjects (n=639) with age-related WMH, between 65 and 84 years old, gathered from 11 centres around Europe. Both studies included comprehensive clinical and neuropsychological assessments and detailed brain MRI. The relationships between the MRI findings and the neuropsychological test performance were analysed by controlling for relevant confounding factors such as age, education and other coexisting brain lesions. The results revealed that in elderly patients with ischaemic stroke, moderate to severe MTA was specifically related to impairment of memory and visuospatial functions, but mild MTA had no clinical relevance. Instead, WMH were primarily associated with executive deficits and mental slowing. These deficits mediated the relationship between WMH and other, secondary cognitive deficits. Cognitive decline was best predicted by the overall degree of WMH, whereas the independent contribution of regional WMH measures was low. Executive deficits were the most prominent cognitive characteristic in SIVD. Compared to other stroke patients, the patients with SIVD also presented more severe memory deficits, which were related to MTA. The cognitive decline in SIVD occurred independently of depressive symptoms and, relative to healthy control subjects, it was substantial in severity. In stroke patients, general cortical atrophy also turned out to be a strong predictor of cognitive decline in a wide range of cognitive domains. Moreover, in elderly subjects with WMH, overall CC atrophy was related to reduction in mental speed, while anterior CC atrophy was independently associated with frontal lobe-mediated executive functions and attention. The present study provides cross-sectional evidence for the involvement of WMH, MTA, general cortical atrophy and CC atrophy in VCI. The results suggest that there are multifaceted pathophysiological mechanisms behind VCI in the elderly, including both vascular ischaemic lesions and neurodegenerative changes. The different pathological changes are highly interrelated processes and together they may produce cumulative effects on cognitive decline.

Living arrangements and health

In line with major demographic changes in other Northern European and North American countries and Australia, being nonmarried is becoming increasingly common in Finland, and the proportion of cohabiters and of persons living alone has grown in recent decades. Official marital status no longer reflects an individual s living arrangement, as single, divorced and widowed persons may live alone, with a partner, with children, with parents, with siblings, or with unrelated persons. Thus, more than official marital status, living arrangements may be a stronger discriminator of one s social bonds and health. The general purpose of this study was to deepen our current understanding of the magnitude, trends, and determinants of ill health by living arrangements in the Finnish working-age population. Distinct measures of different dimensions of poor health, as well as an array of associated factors, provided a comprehensive picture of health differences by living arrangements and helped to assess the role of other factors in the interpretation of these differences . Mortality analyses were based on Finnish census records at the end of 1995 linked with cause-of-death registers for 1996 2000. The data included all persons aged 30 and over. Morbidity analyses were based on two comparable cross-sectional studies conducted twenty years apart (the Mini-Finland Survey in 1978 80 and the Health 2000 Survey in 2000 01). Both surveys were based on nationally representative samples of Finns aged 30 and over, and benefited from high participation rates. With the exception of mortality analyses, this study focused on health differences among the working-age population (mortality in age groups 30-64 and 65 and over, self-rated health and mental health in the age group 30-64, and unhealthy alcohol use in the age group 30-54). Compared with all nonmarried groups, married men and women exhibited the best health in terms of mortality, self-rated health, mental health and unhealthy alcohol use. Cohabiters did not differ from married persons in terms of self-rated health or mental health, but did exhibit excess unhealthy alcohol use and high mortality, particularly from alcohol-related causes. Compared with the married, persons living alone or with someone other than a partner exhibited elevated mortality as well as excess poor mental health and unhealthy alcohol use. By all measures of health, men and women living alone tended to be in the worst position. Over the past twenty years, SRH had improved least among single men and women and widowed women, and most among cohabiting women. The association between living arrangements and health has many possible explanations. The health-related selection theory suggests that healthy people are more likely to enter and maintain a marriage or a consensual union than those who are unhealthy (direct selection) or that a variety of health-damaging behavioural and social factors increase the likelihood of ill health and the probability of remaining without a partner or becoming separated from one s partner (indirect selection). According to the social causation theory, marriage or cohabitation has a health-promoting effect, whereas living alone or with others than a partner has a detrimental effect on health. In this study, the role of other factors that are mainly assumed to reflect selection, appeared to be rather modest. Social support, which reflects social causation, contributed only modestly to differences in unhealthy alcohol use by living arrangements, but had a larger effect on differences in poor mental health. Socioeconomic factors and health-related behaviour, which reflect both selection and causation, appeared to play a more important role in the excess poor health of cohabiters and of persons living alone or with someone other than a partner, than of married persons. Living arrangements were strongly connected to various dimensions of ill health. In particular, alcohol consumption appeared to be of great importance in the association between living arrangements and health. To the extent that the proportion of nonmarried persons continues to grow and their health does not improve at the same rate as that of married persons, the challenges that currently nonmarried persons pose to public health will likely increase.

Perspectives on prescribing in nursing homes in Helsinki

Prescribing for older patients is challenging. The prevalence of diseases increases with advancing age and causes extensive drug use. Impairments in cognitive, sensory, social and physical functioning, multimorbidity and comorbidities, as well as age-related changes in pharmacokinetics and pharmacodynamics all add to the complexity of prescribing. This study is a cross-sectional assessment of all long-term residents aged ≥ 65 years in all nursing homes in Helsinki, Finland. The residents’ health status was assessed and data on their demographic factors, health and medications were collected from their medical records in February 2003. This study assesses some essential issues in prescribing for older people: psychotropic drugs (Paper I), laxatives (Paper II), vitamin D and calcium supplements (Paper III), potentially inappropriate drugs for older adults (PIDs) and drug-drug interactions (DDIs)(Paper IV), as well as prescribing in public and private nursing homes. A resident was classified as a medication user if his or her medication record indicated a regular sequence for its dosage. Others were classified as non-users. Mini Nutritional Assessment (MNA) was used to assess residents’ nutritional status, Beers 2003 criteria to assess the use of PIDs, and the Swedish, Finnish, INteraction X-referencing database (SFINX) to evaluate their exposure to DDIs. Of all nursing home residents in Helsinki, 82% (n=1987) participated in studies I, II, and IV and 87% (n=2114) participated in the study III. The residents’ mean age was 84 years, 81% were female, and 70% were diagnosed with dementia. The mean number of drugs was 7.9 per resident; 40% of the residents used ≥ 9 drugs per day, and were thus exposed to polypharmacy. Eighty percent of the residents received psychotropics; 43% received antipsychotics, and 45% used antidepressants. Anxiolytics were prescribed to 26%, and hypnotics to 28% of the residents. Of those residents diagnosed with dementia, 11% received antidementia drugs. Fifty five percent of the residents used laxatives regularly. In multivariate analysis, those factors associated with regular laxative use were advanced age, immobility, poor nutritional status, chewing problems, Parkinson’s disease, and a high number of drugs. Eating snacks between meals was associated with lower risk for laxative use. Of all participants, 33% received vitamin D supplementation, 28% received calcium supplementation, and 20% received both vitamin D and calcium. The dosage of vitamin D was rather low: 21% received vitamin D 400 IU (10 µg) or more, and only 4% received 800 IU (20 µg) or more. In multivariate analysis, residents who received vitamin D supplementation enjoyed better nutritional status, ate snacks between meals, suffered no constipation, and received regular weight monitoring. Those residents receiving PIDs (34% of all residents) more often used psychotropic medication and were more often exposed to polypharmacy than residents receiving no PIDs. Residents receiving PIDs were less often diagnosed with dementia than were residents receiving no PIDs. The three most prevalent PIDs were short-acting benzodiazepine in greater dosages than recommended, hydroxyzine, and nitrofurantoin. These three drugs accounted for nearly 77% of all PID use. Of all residents, less than 5% were susceptible to a clinically significant DDI. The most common DDIs were related to the use of potassium-sparing diuretics, carbamazepine, and codeine. Residents exposed to potential DDIs were younger, had more often suffered a previous stroke, more often used psychotropics, and were more often exposed to PIDs and polypharmacy than were residents not exposed to DDIs. Residents in private nursing homes were less often exposed to polypharmacy than were residents in public nursing homes. Long-term residents in nursing homes in Helsinki use, on average, nearly eight drugs daily. The use of psychotropic drugs in our study was notably more common than in international studies. The prevalence of laxatives equaled other prior international studies. Regardless of the known benefit and recommendation of vitamin D supplementation for elderly residing mostly indoors, the proportion of nursing home residents receiving vitamin D and calcium was surprisingly low. The use of PIDs was common among nursing home residents. PIDs increased the likelihood of DDIs. However, DDIs did not seem a major concern among the nursing home population. Monitoring PIDs and potential drug interactions could improve the quality of prescribing.

Defining Adequate Vitamin D Intake : Cross-sectional and Intervention Studies

D-vitamiini ylläpitää normaalia luun kasvua ja uudistumista koko elämän ajan. Suomessa, kuten monissa muissakin länsimaissa, väestön D-vitamiinitilanne on riittämätön – talvisin osalla jopa puutteellinen. Tässä väitöskirjassa on tutkittu, lisääkö D-vitamiini luumassan kertymistä kasvuiässä, ja ylläpitäkö D-vitamiini luuston tasapainoista aineenvaihduntaa aikuisiällä. Nämä vaikutukset saattavat ehkäisi osteoporoosin kehittymistä eri ikäkausina. Väitöskirjatyössä tutkittiin erisuuruisten D-vitamiinilisäysten vaikutuksia kolmessa eri ikäryhmässä, jotka olivat 11-12 -vuotiaat tytöt (N=228), 21-49 -vuotiaat miehet (N=54) ja 65-85 -vuotiaat naiset (N=52). Tutkittavat satunnaistettiin ryhmiin, jotka nauttivat joko lumevalmistetta tai 5-20 µg D3-vitamiinia vitamiinilisänä. Tutkimukset olivat kaksoissokkoutettuja. Tutkimuksen aikana tutkittavilta otettiin paastoveri- ja virtsanäytteitä. Lisäksi he täyttivät tutkimuslomakkeen taustatietojen kartoittamiseksi sekä frekvenssikyselylomakkeen kalsiumin ja D-vitamiinin saannin selvittämiseksi. Tyttöjen luunmineraalitiheys (BMD) mitattiin DXA–laitteella ja miesten volumetrinen luuntiheys pQCT-menetelmällä. Näytteistä määritettiin mm. seerumin 25-hydroksi-D-vitamiinin (=S-25-OHD), lisäkilpirauhashormonin (=S-PTH) ja luun aineenvaihduntaa kuvaavien merkkiaineiden pitoisuuksia. Murrosikäisten tyttöjen poikkileikkaustutkimuksessa S-25-OHD- ja luun muodostusmerkkiaineen pitoisuudet vaihtelivat kuukausien välillä; suurimmat pitoisuudet mitattiin syyskuussa ja pienimmät maaliskuussa, mikä kuvastaa vuodenaikaisvaihtelua. Vastaava vaihtelu havaittiin lannerangan ja reisiluun BMD:ssä. D-vitamiinilisäyksellä oli myönteinen vaikutus tyttöjen luumassan lisääntymiseen. Suurin D-vitamiinilisä (10 µg/vrk) lisäsi luumassaa 17.2% enemmän reisiluussa ja 12.5% enemmän lannerangassa verrattuna lumevalmistetta nauttivien tyttöjen vastaaviin tuloksiin, mutta tulos riippui hoitomyöntyvyydestä. D-vitamiinin vaikutus luustoon välittyi vähentyneen luun hajotuksen kautta. Tutkimustuloksiin perustuen riittävä D-vitamiinin saanti murrosikäisille tytöille on 15 µg/vrk. D-vitamiinilisän vaikutus 65-85 -vuotiaiden naisten S-25-OHD-pitoisuuteen vakioitui kuudessa viikossa annoksen ollessa 5-20 µg/vrk. Näillä D-vitamiiniannoksilla ei saavutettu tavoiteltavaa S-25-OHD-pitoisuutta, joka on 80 nmol/l. Arvioimme, että 60 nmol/l -pitoisuuden, jota esiintyy kesäisin tämän ikäryhmän suomalaisilla, tämän ikäryhmän naiset saavuttaisivat 24 µg:n päivittäisellä D-vitamiinin saannilla. Terveillä miehillä havaittiin vuodenaikaisvaihtelu S-25-OHD- ja S-PTH-pitoisuudessa sekä luun hajotusta kuvaavassa merkkiainepitoisuudessa. Toisaalta vaihtelua ei havaittu radiuksen volumetrisessä luuntiheydessä eikä luun muodostusmerkkiaineen pitoisuudessa. Vuodenaikaisvaihtelu estettiin 17 µg:n päivittäisellä D-vitamiinin saannilla, mutta tämän ei havaittu vaikuttavan radiuksen luuntiheyteen kuusi kuukautta kestävän tutkimuksen aikana. Yhteenvetona todetaan, että D-vitamiinin saanti on edelleenkin riittämätöntä tutkimusten kohderyhmillä. Tämä näkyy S-25-OHD- ja PTH-pitoisuuden sekä luunaineenvaihduntaa kuvaavien merkkiaineiden vuodenaikaisvaihteluna, mikä on haitallista luuston hyvinvoinnille. D-vitamiinin saantia tulisi lisätä, jotta vähintäänkin riittävä D-vitamiinitilanne (S-25-OHD>50 nmol/l) tai mahdollisesti jopa tavoiteltava D-vitaminitilanne (S-25-OHD≥80 nmol/l) saavutettaisiin. Jotta D-vitamiinin saannin lisääminen olisi kaikissa ikäryhmissä mahdollista, on suunniteltava nykyistä enemmän D-vitamiinilla täydennettyjä elintarvikkeita.

GATA Transcription Factors in Tissue Homeostasis and Pathology of the Gastrointestinal Tract and Liver

Mammalian gastrointestinal tract and liver are self-renewing organs that are able to sustain themselves due to stem cells present in their tissues. In constant, inflammation-related epithelial damage, vigorous activation of stem cells may lead to their uncontrolled proliferation, and further, to cancer. GATA-4, GATA-5, and GATA-6 regulate cell proliferation and differentiation in many mammalian organs. Lack of GATA-4 or GATA-6 leads to defective endodermal development and cell differentiation. GATA-4 and GATA-5 are considered the ones with tumor suppressive functions, whereas GATA-6 is more related to tumor promotion. In the digestive system their roles in inflammation and tumor-related molecular pathways remain unclear. In this study, we examined the GATA-related molecular pathways involved in normal tissue organization and renewal and in inflammation-related epithelial repair in the gastrointestinal tract and liver. The overall purpose of this study was to elucidate the relation of GATA factors to gastrointestinal and hepatic disease pathology and to evaluate their possible clinical significance in tumor biology. The results indicated distinct expression patterns for GATA-4, GATA-5, and GATA-6 in the human and murine gastrointestinal tract and liver, and their involvement in the regulation of intestine-specific genes. GATA-5 was confined to the intestines of suckling mice, suggesting an association with postnatal enzymatic changes. GATA-4 was upregulated in bowel inflammation concomitantly with TGF-β signaling. In gastrointestinal tumors, GATA-4 was restricted to benign neoplasias of the stomach, while GATA-6 was detected especially at the invasive edges of malignant tumors throughout the gut. In the liver, GATA-4 was upregulated in pediatric tumors along with erythropoietin (Epo), which was detected also in the sera of tumor patients. Furthermore, GATA-4 was enhanced in areas of vigorous hepatic regeneration in patients with tyrosinemia type I. These results suggest a central role for GATA-4 in pediatric tumor biology of the liver. To conclude, GATA-4, GATA-5, and GATA-6 are associated with normal gastrointestinal and hepatic development and regeneration. The appearance of GATA-4 along with TGF-β-signaling in the inflammatory bowel suggests a protective role in the response to inflammation-related epithelial destruction. However, in extremely malignant pediatric liver tumors, GATA-4 function is unlikely to be tumor-suppressing, probably due to the nature of the very primitive multipotent tumor cells. GATA-4, along with its possible downstream factor Epo, could be utilized as novel hepatic tumor markers to supplement the present diagnostics. They could also serve a function in future biological therapies for aggressive pediatric tumors.

Human herpesvirus-6 infection in liver transplantation

Rejection and infections are the two most common complications after liver transplantation. Human herpesvirus-6 (HHV-6) belongs to the betaherpesviruses, together with its close relatives cytomegalovirus (CMV) and human herpesvirus-7 (HHV-7). The impact of CMV in liver transplantation is well characterized, but the roles of the other two betaherpesviruses have been acknowledged only recently. Although, HHV-6 reactivation after transplantation is usually asymptomatic, the virus may infect the liver transplant, cause an intragraft lymphocyte dominated inflammatory reaction and graft dysfunction. HHV-6 is also suggested to be associated with liver allograft rejection but the mechanisms are unclear. The aim of this study was to investigate the intragraft immunological processes associated with HHV-6, the involvement of HHV-6 in acute liver failure (ALF) and the hepatic HHV-6 infection of the same patients after transplantation. In addition, the occurrence of HHV-6 and HHV-7 was investigated in liver transplant patients with symptomatic CMV infection. HHV-6 infection of the liver graft was associated with portal lymphocyte infiltration and with a significant increase of adhesion molecules (ICAM-1 and VCAM-1) and the number of cells expressing their ligand molecules (LFA-1, VLA-4) and class II antigens. HHV-6 infection was associated with significant immunological changes, but the immune response was limited to lymphocyte infiltration and the adhesion molecule level. However, one third of these patients developed chronic rejection during the follow-up. Of the patients with ALF of unknown origin, most patients demonstrated HHV-6 antigens in the liver, whereas the opposite was seen in ALF patients with a known disease. After transplantation, HHV-6 recurrence was found in the liver transplant in half of these patients with pre-transplant HHV-6 infection of the liver, whereas no post-transplant HHV-6 infection of the liver was seen in patients without pre-transplant HHV-6. Our studies further demonstrated that both HHV-6 and HHV-7 antigenemia often appeared in association with CMV disease in liver transplant patients. The time-related occurrence of the viruses differed, as HHV-6 appeared early after transplantation and regularly preceded CMV whereas HHV-7 often appeared concurrently with CMV. In conclusion, these results indicate that all three betaherpesviruses are common after liver transplantation, often associated with each other. The immunological events caused by HHV-6 in the liver transplant may be involved in, or trigger mechanisms of allograft rejection. In addition, HHV-6 could be one of the causes of ALF, and pre-transplant HHV-6 infection in ALF patients is a risk factor for post-transplant HHV-6 infection of the graft. These results strongly support the clinical significance of HHV-6 in liver transplantation. Even though the reactivation is usually asymptomatic, in some individuals HHV-6 infection may lead to severe manifestations, such as liver failure or in transplant patients, graft dysfunction and rejection.

Hospital-related fears and coping strategies in 4-6-year-old children

There is only little information available on the 4-6-year-old child s hospital-related fears, and on the coping with such fears, as expressed by the children themselves. However, previous data collected from parents and hospital personnel indicate that hospitalization is an anxiety-producing experience for young children. The purpose of this study was to describe the experience of hospital-related fears and the experience of coping with hospital-related fears of 4-6-year-old children. The aim of this study was to form a descriptive model of the subjective experience of hospital-related fears and coping strategies of 4-6-year old children. The data were collected by interviewing 4-6-year-old children from a hospital and kindergarten settings in Finland from 2004 to 2006. Ninety children were interviewed in order to describe the hospital-related fear and the experience of fear, and 89 to describe their coping with the fear and the experience of coping. The children were chosen through purposive sampling. The data were gathered by semi-structured interview, supported by pictures. The data about hospital-related fears and on strategies for coping with hospital-related fears were reviewed by qualitative and quantitative methods. The experience of hospital-related fears and coping with these fears were analyzed using Colaizzi s Method of Phenomenological Analysis. The results revealed that more than 90 % of the children said they were afraid of at least one thing in hospital. Most of the fears could be categorized as nursing interventions, fears of being a patient, and fears caused by the developmental stage of the child. Children interviewed in the hospital expressed substantially more fears than children interviewed in kindergarten. Children s meanings of hospital-related fears were placed into four main clusters: 1) insecurity, 2) injury, 3) helplessness, 4) and rejection. The results also showed that children have plenty of coping strategies, to deal with their fears, especially such strategies in which the children themselves play an active role. Most often mentioned coping strategies were 1) the presence of parents and other family members, 2) the help of the personnel, 3) positive images and humour, 4) play, and 5) the child s own safety toy. The children interviewed in the hospital mentioned statistically significantly more often play, positive imagination and humour as their coping strategy than children interviewed in kindergarten. The meaning of coping with hospital fears consisted of six clusters: pleasure, security, care, understanding the meaning of the situation participating, and protecting oneself. Being admitted to a hospital is an event which may increase the fears of a 4-6-year-old child. Children who have personal experience of being admitted to a hospital describe more fears than healthy children in kindergarten. For young children, hospital-related fear can be such a distressing experience that it reflects on their feelings of security and their behaviour. Children can sometimes find it difficult to admit their fear. Children need the help of adults to express their hospital-related fears, the objects of the fears, and to cope with the fears. Personnel should be aware of children s fears and support them in the use of coping strategies. In addition to the experiences of security and care, pre-school-aged children need active coping strategies that they can use themselves, regardless of the presence of the parents or nurses. Most of all, children need the possibility to play and experience pleasure. Children can also be taught coping strategies which give them an active, positive role.

Cow’s milk related gastrointestinal symptoms in adults

The purpose of this study was to evaluate subjective food-related gastrointestinal symptoms and their relation to cow’s milk by determining the genotype of adult-type hypolactasia, measuring antibodies against milk protein, and screening the most common cause for secondary hypolactasia, namely coeliac disease. The whole study group comprised 1900 adults who gave a blood sample for the study when they attended a health care centre laboratory for various reasons. Of these 1885 (99%) completed a questionnaire on food-related gastrointestinal symptoms. Study No. I evaluated the prevalence of adult-type hypolactasia and its correlation to self-reported milk induced gastrointestinal symptoms. The testing for hypolactasia was done by determination of the C/T-13910 genotypes of the study subjects. The results show that patients with the C/C-13910 genotype associated with adult type hypolactasia consume less milk than those with C/T-13910 and T/T-13910 genotypes. Study No. II evaluated the prevalence and clinical characteristics of undiagnosed coeliac disease in the whole study population with transglutaminase and endomysium antibodies and their correlation with gastrointestinal symptoms. The prevalence of coeliac disease was 2 %, which is surprisingly high. Serum transglutaminase and endomysium antibodies are valuable tools for recognising an undiagnosed coeliac disease in outpatient clinics. In the study No. III the evaluation of milk protein IgE related hypersensitivity was carried out by stratifying all 756 study subjects with milk related problems and randomly choosing 100 age and sex matched controls with no such symptoms from the rest of the original study group. In the study No. IV 400 serum samples were randomly selected for analyzing milk protein related IgA and IgG antibodies and their correlation to milk related GI-symptoms. The measurement of milk protein IgA, IgE or IgG (studies No. III and IV) did not correlate clearly to milk induced symptoms and gave no clinically significant information; hence their measurement is not encouraged in outpatient clinics. In conclusion, adult type hypolactasia is often considered the reason for gastrointestinal symptoms in adults and determination of the C/T-13910 genotypes is a practical way of diagnosing adult type hypolactasia in an outpatient setting. Undiagnosed coeliac disease, should be actively screened and diagnosed in order to apply a gluten free diet and avoid the GI-symptoms and nutritional deficiencies. Cow’s milk hypersensitivity in the adult population is difficult to diagnose since the mechanism in which it is mediated is still unclear. Measuring of cow’s milk protein specific antibodies IgE, IgA or IgG do not correlate with subjective milk-related GI-symptoms.

Detection and progression of chronic allograft nephropathy : A study based on protocol biopsies

Background. Kidney transplantation (KTX) is considered to be the best treatment of terminal uremia. Despite improvements in short-term graft survival, a considerable number of kidney allografts are lost due to the premature death of patients with a functional kidney and to chronic allograft nephropathy (CAN). Aim. To investigate the risk factors involved in the progression of CAN and to analyze diagnostic methods for this entity. Materials and methods. Altogether, 153 implant and 364 protocol biopsies obtained between June 1996 and April 2008 were analyzed. The biopsies were classified according to Banff ’97 and chronic allograft damage index (CADI). Immunohistochemistry for TGF-β1 was performed in 49 biopsies. Kidney function was evaluated by creatinine and/or cystatin C measurement and by various estimates of glomerular filtration rate (GFR). Demographic data of the donors and recipients were recorded after 2 years’ follow-up. Results. Most of the 3-month biopsies (73%) were nearly normal. The mean CADI score in the 6-month biopsies decreased significantly after 2001. Diastolic hypertension correlated with ΔCADI. Serum creatinine concentration at hospital discharge and glomerulosclerosis were risk factors for ΔCADI. High total and LDL cholesterol, low HDL and hypertension correlated with chronic histological changes. The mean age of the donors increased from 41 -52 years. Older donors were more often women who had died from an underlying disease. The prevalence of delayed graft function increased over the years, while acute rejections (AR) decreased significantly over the years. Sub-clinical AR was observed in 4% and it did not affect long-term allograft function or CADI. Recipients´ drug treatment was modified along the Studies, being mycophenolate mophetil, tacrolimus, statins and blockers of the renine-angiotensin-system more frequently prescribed after 2001. Patients with a higher ΔCADI had lower GFR during follow-up. CADI over 2 was best predicted by creatinine, although with modest sensitivity and specificity. Neither cystatin C nor other estimates of GFR were superior to creatinine for CADI prediction. Cyclosporine A toxicity was seldom seen. Low cyclosporin A concentration after 2 h correlated with TGF- β1 expression in interstitial inflammatory cells, and this predicted worse graft function. Conclusions. The progression of CAN has been affected by two major factors: the donors’ characteristics and the recipients’ hypertension. The increased prevalence of DGF might be a consequence of the acceptance of older donors who had died from an underlying disease. Implant biopsies proved to be of prognostic value, and they are essential for comparison with subsequent biopsies. The progression of histological damage was associated with hypertension and dyslipidemia. The augmented expression of TGF-β1 in inflammatory cells is unclear, but it may be related to low immunosuppression. Serum creatinine is the most suitable tool for monitoring kidney allograft function on every-day basis. However, protocol biopsies at 6 and 12 months predicted late kidney allograft dysfunction and affected the clinical management of the patients. Protocol biopsies are thus a suitable surrogate to be used in clinical trials and for monitoring kidney allografts.

Cyclosporine population pharmacokinetics in pediatric renal transplant recipients

Cyclosporine is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics. To improve cyclosporine dose individualization in children, we used population pharmacokinetic modeling to study the effects of developmental, clinical, and genetic factors on cyclosporine pharmacokinetics in altogether 176 subjects (age range: 0.36–20.2 years) before and up to 16 years after renal transplantation. Pre-transplantation test doses of cyclosporine were given intravenously (3 mg/kg) and orally (10 mg/kg), on separate occasions, followed by blood sampling for 24 hours (n=175). After transplantation, in a total of 137 patients, cyclosporine concentration was quantified at trough, two hours post-dose, or with dose-interval curves. One-hundred-four of the studied patients were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. Pharmacokinetic modeling was performed with the nonlinear mixed effects modeling computer program, NONMEM. A 3-compartment population pharmacokinetic model with first order absorption without lag-time was used to describe the data. The most important covariate affecting systemic clearance and distribution volume was allometrically scaled body weight i.e. body weight**3/4 for clearance and absolute body weight for volume of distribution. The clearance adjusted by absolute body weight declined with age and pre-pubertal children (< 8 years) had an approximately 25% higher clearance/body weight (L/h/kg) than did older children. Adjustment of clearance for allometric body weight removed its relationship to age after the first year of life. This finding is consistent with a gradual reduction in relative liver size towards adult values, and a relatively constant CYP3A content in the liver from about 6–12 months of age to adulthood. The other significant covariates affecting cyclosporine clearance and volume of distribution were hematocrit, plasma cholesterol, and serum creatinine, explaining up to 20%–30% of inter-individual differences before transplantation. After transplantation, their predictive role was smaller, as the variations in hematocrit, plasma cholesterol, and serum creatinine were also smaller. Before transplantation, no clinical or demographic covariates were found to affect oral bioavailability, and no systematic age-related changes in oral bioavailability were observed. After transplantation, older children receiving cyclosporine twice daily as the gelatine capsule microemulsion formulation had an about 1.25–1.3 times higher bioavailability than did the younger children receiving the liquid microemulsion formulation thrice daily. Moreover, cyclosporine oral bioavailability increased over 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1–1.5 years. The largest cyclosporine doses were administered in the first 3–6 months after transplantation, and thereafter the single doses of cyclosporine were often smaller than 3 mg/kg. Thus, the results suggest that cyclosporine displays dose-dependent, saturable pre-systemic metabolism even at low single doses, whereas complete saturation of CYP3A4 and MDR1 (P-glycoprotein) renders cyclosporine pharmacokinetics dose-linear at higher doses. No significant associations were found between genetic polymorphisms and cyclosporine pharmacokinetics before transplantation in the whole population for which genetic data was available (n=104). However, in children older than eight years (n=22), heterozygous and homozygous carriers of the ABCB1 c.2677T or c.1236T alleles had an about 1.3 times or 1.6 times higher oral bioavailability, respectively, than did non-carriers. After transplantation, none of the ABCB1 SNPs or any other SNPs were found to be associated with cyclosporine clearance or oral bioavailability in the whole population, in the patients older than eight years, or in the patients younger than eight years. In the whole population, in those patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055C haplotype, however, the bioavailability of cyclosporine was about one tenth lower, per allele, than in non-carriers. This effect was significant also in a subgroup of patients older than eight years. Furthermore, in patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055T haplotype, the bioavailability was almost one fifth higher, per allele, than in non-carriers. It may be possible to improve individualization of cyclosporine dosing in children by accounting for the effects of developmental factors (body weight, liver size), time after transplantation, and cyclosporine dosing frequency/formulation. Further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.

Soy supplementation and role of equol production capability in postmenopausal women using tibolone: effects on cardiovascular risk markers

Tibolone, a synthetic steroid, is effective in the treatment of postmenopausal symptoms. Its cardiovascular safety profile has been questioned, because tibolone reduces the levels of high-density lipoprotein (HDL) cholesterol. Soy-derived isoflavones may offer health benefits, particularly as regards lipids and also other cardiovascular disease (CVD) risk factors. The soy-isoflavone metabolite equol is thought to be the key as regards soy-related beneficial effects. We studied the effects of soy supplementation on various CVD risk factors in postmenopausal monkeys and postmenopausal women using tibolone. In addition, the impact of equol production capability was studied. A total of 18 monkeys received casein/lactalbumin (C/L) (placebo), tibolone, soy (a woman s equivalent dose of 138 mg of isoflavones), or soy with tibolone in a randomized order for 14 weeks periods, and there was a 4-week washout (C/L) in between treatments. Postmenopausal women using tibolone (N=110) were screened by means of a one-week soy challenge to find 20 women with equol production capability (4-fold elevation from baseline equol level) and 20 control women, and treated in a randomized cross-over trial with a soy powder (52 g of soy protein containing 112 mg of isoflavones) or placebo for 8 weeks. Before and after the treatments lipids and lipoproteins were assessed in both monkeys and women. In addition, blood pressure, arterial stiffness, endothelial function, sex steroids, sex hormone-binding globulin (SHBG), and vascular inflammation markers were assessed. A 14% increase in plasma low-density lipoprotein (LDL) + very low-density lipoprotein (VLDL) cholesterol was observed in tibolone-treated monkeys vs. placebo. Soy treatment resulted in a 18% decrease in LDL+VLDL cholesterol, and concomitant supplementation with tibolone did not negate the LDL+VLDL cholesterol-lowering effect of soy. A 30% increase in HDL cholesterol was observed in monkeys fed with soy, whereas HDL cholesterol levels were reduced (48%) after tibolone. Interestingly, Soy+Tibolone diet conserved HDL cholesterol levels. Tibolone alone increased the total cholesterol (TC):HDL cholesterol ratio, whereas it was reduced by Soy or Soy+Tibolone. In postmenopausal women using tibolone, reductions in the levels of total cholesterol and LDL cholesterol were seen after soy supplementation compared with placebo, but there was no effect on HDL cholesterol, blood pressure, arterial stiffness or endothelial function. Soy supplementation decreased the levels of estrone in equol producers, and those of testosterone in the entire study population. No changes were seen in the levels of androstenedione, dehydroepiandrosterone sulfate, or SHBG. The levels of vascular cell adhesion molecule-1 increased, and platelet-selectin decreased after soy treatment, whereas C-reactive protein and intercellular adhesion molecule-1 remained unchanged. At baseline and unrelated to soy treatment, equol producers had lower systolic, diastolic and mean arterial pressures, less arterial stiffness and better endothelial function than non-producers. To conclude, soy supplementation reversed the tibolone-induced fall in HDL cholesterol in postmenopausal monkeys, but this effect was not seen in women taking tibolone. Equol production capability was associated with beneficial cardiovascular changes and thus, this characteristic may offer cardiovascular benefits, at least in women using tibolone.

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.