Interaction of alcohol and smoking in the pathogenesis of upper digestive tract cancers - possible chemoprevention with cysteine

Background: Alcohol consumption and smoking are the main causes of upper digestive tract cancers. These risk factors account for over 75% of all cases in developed countries. Epidemiological studies have shown that alcohol and tobacco interact in a multiplicative way to the cancer risk, but the pathogenetic mechanism behind this is poorly understood. Strong experimental and human genetic linkage data suggest that acetaldehyde is one of the major factors behind the carcinogenic effect. In the digestive tract, acetaldehyde is mainly formed by microbial metabolism of ethanol. Acetaldehyde is also a major constituent of tobacco smoke. Thus, acetaldehyde from both of these sources may have an interacting carcinogenic effect in the human upper digestive tract. Aims: The first aim of this thesis was to investigate acetaldehyde production and exposure in the human mouth resulting from alcohol ingestion and tobacco smoking in vivo. Secondly, specific L-cysteine products were prepared to examine their efficacy in the binding of salivary acetaldehyde in order to reduce the exposure of the upper digestive tract to acetaldehyde. Methods: Acetaldehyde levels in saliva were measured from human volunteers during alcohol metabolism, during tobacco smoking and during the combined use of alcohol and tobacco. The ability of L-cysteine to eliminate acetaldehyde during alcohol metabolism and tobacco smoking was also investigated with specifically developed tablets. Also the acetaldehyde production of Escherichia coli - an important member of the human microbiota - was measured in different conditions prevailing in the digestive tract. Results and conclusions: These studies established that smokers have significantly increased acetaldehyde exposure during ethanol consumption even when not actively smoking. Acetaldehyde exposure was dramatically further increased during active tobacco smoking. Thus, the elevated aerodigestive tract cancer risk observed in smokers and drinkers may be the result of the increased acetaldehyde exposure. Acetaldehyde produced in the oral cavity during ethanol challenge was significantly decreased by a buccal L-cysteine -releasing tablet. Also smoking-derived acetaldehyde could be totally removed by using a tablet containing L-cysteine. In conclusion, this thesis confirms the essential role of acetaldehyde in the pathogenesis of alcohol- and smoking-induced cancers. This thesis presents a novel experimental approach to decrease the local acetaldehyde exposure of the upper digestive tract with L-cysteine, with the eventual goal of reducting the prevalence of upper digestive tract cancers.

Stalking and violence victimization among Finnish university students

This study examined the nature and lifetime prevalence of two types of victimization among Finnish university students: stalking and violence victimization (i.e. general violence). This study was a cross-sectional study using two different datasets of Finnish university students. The stalking data was collected via an electronic questionnaire and the violence victimization data was collected via a postal questionnaire. There were 615 participants in the stalking study (I-III) and 905 participants in the violence victimization study. The thesis consists of four studies. The aims regarding the stalking substudies (Studies I-III) were to examine the lifetime prevalence of stalking among university students and to analyze how stalking is related to victim and stalker characteristics and certain central variables of stalking (victim-stalker relationship, stalking episodes, stalking duration). Specifically, the aim was to identify factors that are associated with stalking violence and to factors contributing to the stalking duration. Furthermore, the aim was also to investigate how university students cope with stalking and whether coping is related to victim and stalker background characteristics and to certain other core variables (victim-stalker relationship, stalking episodes, stalking duration, prior victimization, and stalking violence). The aims for the violence victimization substudy (Study IV) were to examine the prevalence of violence victimization, i.e. general violence (minor and serious physical violence and threats) and how violence victimization is associated with victim/abuser characteristics, symptomology, and the use of student health care services. The present study shows that both stalking and violence victimization (i.e. general violence) are markedly prevalent among Finnish university students. The lifetime prevalence rate for stalking was 48.5% and 46.5% for violence victimization. When the lifetime prevalence rate was restricted to violent stalking and physical violence only, the prevalence decreased to 22% and 42% respectively. The students reported exposure to multiple forms of stalking and violence victimization, demonstrating the diversity of victimization among university students. Stalking victimization was found to be more prevalent among female students, while violence victimization was found to be more prevalent among male students. Most of the victims of stalking knew their stalkers, while the offender in general violence was typically a stranger. Stalking victimization often included violence and continued for a lengthy period. The victim-stalking relationship and stalking behaviors were found to be associated with stalking violence and stalking duration. Based on three identified stalking dimensions (violence, surveillance, contact seeking), the present study found five distinct victim subgroups (classes). Along with the victim-stalker relationship, the victim subgroups emerged as important factors contributing to the stalking duration. Victims of violent stalking did not differ greatly from victims of non-violent stalking in their use of behavioral coping tactics, while exposure to violent stalking had an effect on the use of coping strategies. The victim-offender relationship was also associated to a set of symptoms regarding violence victimization. Furthermore, violence victimization had a significant main effect on specific symptoms (mental health symptoms, alcohol consumption, symptom index), while gender had a significant main effect on most symptoms, yet no interaction effect was found. The present results also show that victims of violence are overrepresented among frequent health care users. The present findings add to the literature on the prevalence and nature of stalking and violence victimization among Finnish university students. Moreover, the present findings stress the importance of violence prevention and intervention in student health care, and may be used as a guideline for policy makers, as well as health care and law enforcement professionals dealing with youth violence prevention.

Fatigued driving : prevalence, risk factors and groups, and the law

Fatigue and sleepiness are major causes of road traffic accidents. However, precise data is often lacking because a validated and reliable device for detecting the level of sleepiness (cf. the breathalyzer for alcohol levels) does not exist, nor does criteria for the unambiguous detection of fatigue/sleepiness as a contributing factor in accident causation. Therefore, identification of risk factors and groups might not always be easy. Furthermore, it is extremely difficult to incorporate fatigue in operationalized terms into either traffic or criminal law. The main aims of this thesis were to estimate the prevalence of fatigue problems while driving among the Finnish driving population, to explore how VALT multidisciplinary investigation teams, Finnish police, and courts recognize (and prosecute) fatigue in traffic, to identify risk factors and groups, and finally to explore the application of the Finnish Road Traffic Act (RTA), which explicitly forbids driving while tired in Article 63. Several different sources of data were used: a computerized database and the original folders of multidisciplinary teams investigating fatal accidents (VALT), the driver records database (AKE), prosecutor and court decisions, a survey of young male military conscripts, and a survey of a representative sample of the Finnish active driving population. The results show that 8-15% of fatal accidents during 1991-2001 were fatigue related, that every fifth Finnish driver has fallen asleep while driving at some point during his/her driving career, and that the Finnish police and courts punish on average one driver per day on the basis of fatigued driving (based on the data from the years 2004-2005). The main finding regarding risk factors and risk groups is that during the summer months, especially in the afternoon, the risk of falling asleep while driving is increased. Furthermore, the results indicate that those with a higher risk of falling asleep while driving are men in general, but especially young male drivers including military conscripts and the elderly during the afternoon hours and the summer in particular; professional drivers breaking the rules about duty and rest hours; and drivers with a tendency to fall asleep easily. A time-of-day pattern of sleep-related incidents was repeatedly found. It was found that VALT teams can be considered relatively reliable when assessing the role of fatigue and sleepiness in accident causation; thus, similar experts might be valuable in the court process as expert witnesses when fatigue or sleepiness are suspected to have a role in an accident’s origins. However, the application of Article 63 of the RTA that forbids, among other things, fatigued driving will continue to be an issue that deserves further attention. This should be done in the context of a needed attitude change towards driving while in a state of extreme tiredness (e.g., after being awake for more than 24 hours), which produces performance deterioration comparable to illegal intoxication (BAC around 0.1%). Regarding the well-known interactive effect of increased sleepiness and even small alcohol levels, the relatively high proportion (up to 14.5%) of Finnish drivers owning and using a breathalyzer raises some concern. This concern exists because these drivers are obviously more focused on not breaking the “magic” line of 0.05% BAC than being concerned about driving impairment, which might be much worse than they realize because of the interactive effects of increased sleepiness and even low alcohol consumption. In conclusion, there is no doubt that fatigue and sleepiness problems while driving are common among the Finnish driving population. While we wait for the invention of reliable devices for fatigue/sleepiness detection, we should invest more effort in raising public awareness about the dangerousness of fatigued driving and educate drivers about how to recognize and deal with fatigue and sleepiness when they ultimately occur.

Impulsivity, health-related behaviour and disease : A prospective study

In clinical settings impulsivity refers to a symptom of psychiatric disorder, but nonclinically oriented research treats impulsivity as a personality and temperament dimension. This prospective study examined whether impulsivity predicts adverse health-related behaviour and increased risk of health problems in a large, nonclinical sample of 5433 subjects working in 12 Finnish hospitals. The data were collected using two questionnaire surveys at a 2-year interval. After controlling for alcohol use at baseline, higher impulsivity predicted increased alcohol consumption at follow-up in both genders (p < .01) and was associated with increased likelihood of becoming a heavy drinker or taking up smoking (p < .05). Impulsivity also predicted an increased number of cigarettes smoked per day in the follow-up among women (p < .001), but not among men, although adjustment for the number of cigarettes smoked at baseline attenuated these associations (p = .08 for women). In men, higher impulsivity was associated with shorter sleep duration and waking up several times per night independent of baseline characteristics (p < .01), whereas in women, higher impulsivity predicted difficulty in falling asleep and waking up feeling tired after the usual amount of sleep (p < .05). In women, these associations became nonsignificant after adjustment for pre-existing somatic and psychiatric diseases. Finally, higher impulsivity was associated with an increased 2-year incidence of physician-diagnosed peptic ulcer disease (adjusted odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.21 - 4.82) and onset of depression (OR = 1.95, 95% CI = 1.28 - 2.97) after adjustment for a variety of baseline covariates. In conclusion, this study shows that in a nonclinical population, impulsivity appears to be a risk factor for various unhealthy behaviour and health problems.

Cloningerin psykobiologisen teorian temperamenttipiirteiden yhteys alkoholinkäyttöön nuorilla aikuisilla

The temperamental traits of Cloninger’s personality theory (novelty seeking, harm avoidance, reward dependence and persistence) reflect independent systems of central nervous system deciding responses toward new, rewarding and aversive stimuli. Thus, certain temperamental traits and their combinations may predispose to heavy drinking and alcohol dependence. Hence, the aim of the present study was to investigate associations between temperamental traits and the amount of alcohol consumption, frequency of heavy drinking and the maximum number of drinks per occasion. In this study, we investigated also whether these associations are only confounded by between-family differences in genetic and environmental factors. Furthermore the associations between temperamental trait combinations that reflect Cloninger's typology of alcoholism and alcohol use were studied. The subjects (n=401) in the current study were a group of FinnTwin16 study participators, Finnish twins born in 1974-79. Temperament was measured with TCI-R (Temperament and Character Inventory-Revised) a self-report form. The amount of alcohol consumption was asked by Semi-structured interview (Semi-Structured Assessment of Genetics of Alcoholism = SSAGA). The frequency of heavy drinking and maximum number of drinks per occasion were asked by mail form. In accordance with previous studies, novelty seeking had a positive relationship with the amount of alcohol consumption, frequency of heavy drinking and the maximum number of drinks per occasion in both genders. In this study, the association was proven independent of between-family differences in genetic and environmental factors that are associated to both novelty seeking and alcohol use. Surprisingly, reward dependence was negatively related to the maximum number of drinks per occasion in both genders. Persistence had a weak positive relationship with maximum number of drinks per occasion in men. The temperamental trait combinations that reflect Cloninger's typology of alcoholism did not differ from the other combinations in regard to alcohol use as hypothesized. The results confirm the previous finding about the relationship between novelty seeking and alcohol use. Support for Cloninger's typology of alcoholism in regard to combinations of temperamental trait was not achieved in this study.

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.

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.

Helicobacter pylori in Vammala, Finland: seroepidemiological studies and a population-based ‘screen-and-treat’ programme

Helicobacter pylorin (helikobakteeri) tartunta saadaan yleensä lapsena ja tauti jää tavallisesti pysyväksi ilman täsmähoitoa. Onnistunut hoito parantaa pysyvästi helikobakteerista aiheutuvan mahan haavataudin ja näyttää ehkäisevän mahalaukun pahanlaatuisten muutosten kehittymistä. Aloitimme Vammalassa terveyskeskuksessa toteutetun kansainvälisesti ainutlaatuisen väestöpohjaisen helikobakteeritulehduksen seulonta- ja hoito-ohjelman pilottitutkimuksella 1994. 1996 kaikki 15-40-vuotiaat ja 1997-2000 15- ja 45-vuotiaat vammalalaiset kutsuttiin verinäyteseulontaan. Yhteensä 4626 henkilöä (75% kutsutuista) osallistui seulontaan. Vasta-ainepositiivisille tarjottiin helikobakteeritulehduksen lopettava lääkekuuri. Toiminnan seurauksena helikobakteeritulehduksen esiintyvyyden laskettiin vähentyneen 12%:sta 4%:iin 15-40-vuotiaiden ikäryhmässä. Tutkimme myös helikobakteerivasta-ainepositiivisten ja -negatiivisten eroja sekä helikobakteeritulehduksen riskitekijöitä kyselytutkimuksella. Lapsuudenkodin asumisahtauden, äidin matalan koulutusasteen, tupakoinnin, alkoholinkäytön, huonojen asunto-olojen ja ylävatsavaivoista johtuvien sairauslomien todettiin liittyvän helikobakteeritulehdukseen monimuuttuja-analyysissa. Tutkimme seulontaohjelmassa käyttämiemme IgG- ja IgA-luokan helikobakteeri-vasta-ainetestien luotettavuutta eri ikäryhmissä ottaen huomioon atrofisen gastriitin esiintyvyyden. 561 kliinisin perustein gastroskopoidun potilaan aineistossa IgG-testi osoittautui erittäin herkäksi kaikissa ikäryhmissä (99%). Tarkkuus oli myös vanhemmissa ikäryhmissä hyvä (97-93%), kun atrofista gastriittia sairastavat suljettiin pois. IgA- ja CagA-helikobakteerivasta-aineiden on todettu liittyvän lisääntyneeseen mahahaava- ja mahasyöpäriskiin. Analysoimme 560 henkilön pariseeruminäytteet, jotka oli otettu kahden vuosikymmenen välein, ja totesimme, että IgA-vasta-aineiden esiintyvyyden lisääntyyminen iän myötä johtuu paitsi syntymäajankohdasta ja uusista infektioista myös IgA-vasta-ainetasojen kohoamisesta helikobakteeritulehduksen aikana. Selvitimme myös CagA-vasta-ainetasojen muuttumista analysoimalla seeruminäytteet, jotka oli otettu kahden vuosikymmenen välein. Totesimme, että samanaikaisesti kun helikobakteerin esiintyvyys väestössä on alentunut, erityisesti CagA-positiiviset infektiot ovat vähentyneet. Tutkimuksemme osoittaa, että Suomessa terveyskeskuksen yhteydessä voidaan toteuttaa näin laajamittainen seulonta- ja hoito-ohjelma, johon suomalaiset osallistuvat aktiivisesti. Nähtäväksi jää, kuinka paljon ohjelma kykeni vähentämään helikobakteeritulehdukseen liittyviä myöhäisseuraamuksia.

Glutamatergic Modulation of Cue-Induced Drug-Seeking Behavior in the Rat

The characteristics of drug addiction include compulsive drug use despite negative consequences and re-occurring relapses, returns to drug use after a period of abstinence. Therefore, relapse prevention is one of the major challenges for the treatment of drug addiction. There are three main factors capable of inducing craving for drugs and triggering relapse long after cessation of drug use and dissipation of physical withdrawal signs: stress, re-exposure to the drug, and environmental stimuli (cues) that have been previously associated with drug use. The neurotransmitters dopamine and glutamate have been implicated in the modulation of drug-seeking behavior. The aim of this project was to examine the role of glutamatergic neurotransmission in relapse triggered by conditioned drug-associated stimuli. The focus was on clarifying whether relapse to drug seeking can be attenuated by blockade of glutamate receptors. In addition, as the nucleus accumbens has been proposed to participate in the modulation of drug-seeking behavior, the effects of glutamate receptor blockade in this brain structure on cue-induced relapse were investigated. The studies employed animals models in which rats were trained to press a lever in a test cage to obtain alcohol or intravenous cocaine. Drug availability was paired with distinct olfactory, auditory, or visual stimuli. This phase was followed by extinction training, during which lever presses did not result in the presentation of the drug or the drug-associated stimuli. Extinction training led to a gradual decrease in the number of lever presses during test sessions. Relapse was triggered by presenting the rats with the drug-associated stimuli in the absence of alcohol or cocaine. The drug-associated stimuli were alone capable of inducing resumption of lever pressing and maintaining this behavior during repeated testing. The number of lever presses during a session represented the intensity of drug-seeking and relapse behavior. The results suggest that glutamatergic neurotransmission is involved in the modulation of drug-seeking behavior. Both alcohol and cocaine relapse were attenuated by systemic pretreatment with glutamate receptor antagonists. However, differences were found in the ability of ionotropic AMPA/kainate and NMDA receptor antagonists to regulate drug-seeking behavior. The AMPA/kainate antagonists CNQX and NBQX, and L-701,324, an antagonist with affinity for the glycine site of the NMDA receptor, attenuated cue-induced drug seeking, whereas the competitive NMDA antagonist CGP39551 and the NMDA channel blocker MK-801 were without effect. MPEP, an antagonist at metabotropic mGlu5 glutamate receptors, also decreased drug seeking, but its administration was found to lead to conditioned suppression of behavior during subsequent treatment sessions, suggesting that MPEP may have undesirable side effects. The mGluR2/3 agonist LY379268 and the mGluR8 agonist (S)-3,4-DCPG decreased both cue-induced relapse to alcohol drinking and alcohol consumption. Control experiments showed however that administration of the agonists was accompanied by motor suppression limiting their usefulness. Administration of the AMPA/kainate antagonist CNQX, the NMDA antagonist D-AP5, and the mGluR5 antagonist MPEP into the nucleus accumbens resulted also in a decrease in drug-seeking behavior, suggesting that the nucleus accumbens is at least one of the anatomical sites regulating drug seeking and mediating the effects of glutamate receptor antagonists on this behavior.

Placental abruption : Studies on incidence, risk factors and potential predictive biomarkers

Placental abruption, one of the most significant causes of perinatal mortality and maternal morbidity, occurs in 0.5-1% of pregnancies. Its etiology is unknown, but defective trophoblastic invasion of the spiral arteries and consequent poor vascularization may play a role. The aim of this study was to define the prepregnancy risk factors of placental abruption, to define the risk factors during the index pregnancy, and to describe the clinical presentation of placental abruption. We also wanted to find a biochemical marker for predicting placental abruption early in pregnancy. Among women delivering at the University Hospital of Helsinki in 1997-2001 (n=46,742), 198 women with placental abruption and 396 control women were identified. The overall incidence of placental abruption was 0.42%. The prepregnancy risk factors were smoking (OR 1.7; 95% CI 1.1, 2.7), uterine malformation (OR 8.1; 1.7, 40), previous cesarean section (OR 1.7; 1.1, 2.8), and history of placental abruption (OR 4.5; 1.1, 18). The risk factors during the index pregnancy were maternal (adjusted OR 1.8; 95% CI 1.1, 2.9) and paternal smoking (2.2; 1.3, 3.6), use of alcohol (2.2; 1.1, 4.4), placenta previa (5.7; 1.4, 23.1), preeclampsia (2.7; 1.3, 5.6) and chorioamnionitis (3.3; 1.0, 10.0). Vaginal bleeding (70%), abdominal pain (51%), bloody amniotic fluid (50%) and fetal heart rate abnormalities (69%) were the most common clinical manifestations of placental abruption. Retroplacental blood clot was seen by ultrasound in 15% of the cases. Neither bleeding nor pain was present in 19% of the cases. Overall, 59% went into preterm labor (OR 12.9; 95% CI 8.3, 19.8), and 91% were delivered by cesarean section (34.7; 20.0, 60.1). Of the newborns, 25% were growth restricted. The perinatal mortality rate was 9.2% (OR 10.1; 95% CI 3.4, 30.1). We then tested selected biochemical markers for prediction of placental abruption. The median of the maternal serum alpha-fetoprotein (MSAFP) multiples of median (MoM) (1.21) was significantly higher in the abruption group (n=57) than in the control group (n=108) (1.07) (p=0.004) at 15-16 gestational weeks. In multivariate analysis, elevated MSAFP remained as an independent risk factor for placental abruption, adjusting for parity ≥ 3, smoking, previous placental abruption, preeclampsia, bleeding in II or III trimester, and placenta previa. MSAFP ≥ 1.5 MoM had a sensitivity of 29% and a false positive rate of 10%. The levels of the maternal serum free beta human chorionic gonadotrophin MoM did not differ between the cases and the controls. None of the angiogenic factors (soluble endoglin, soluble fms-like tyrosine kinase 1, or placental growth factor) showed any difference between the cases (n=42) and the controls (n=50) in the second trimester. The levels of C-reactive protein (CRP) showed no difference between the cases (n=181) and the controls (n=261) (median 2.35 mg/l [interquartile range {IQR} 1.09-5.93] versus 2.28 mg/l [IQR 0.92-5.01], not significant) when tested in the first trimester (mean 10.4 gestational weeks). Chlamydia pneumoniae specific immunoglobulin G (IgG) and immunoglobulin A (IgA) as well as C. trachomatis specific IgG, IgA and chlamydial heat-shock protein 60 antibody rates were similar between the groups. In conclusion, although univariate analysis identified many prepregnancy risk factors for placental abruption, only smoking, uterine malformation, previous cesarean section and history of placental abruption remained significant by multivariate analysis. During the index pregnancy maternal alcohol consumption and smoking and smoking by the partner turned out to be the major independent risk factors for placental abruption. Smoking by both partners multiplied the risk. The liberal use of ultrasound examination contributed little to the management of women with placental abruption. Although second-trimester MSAFP levels were higher in women with subsequent placental abruption, clinical usefulness of this test is limited due to low sensitivity and high false positive rate. Similarly, angiogenic factors in early second trimester, or CRP levels, or chlamydial antibodies in the first trimester failed to predict placental abruption.

The Impact of Lifestyle and Cardiovascular Risk Factors in Midlife on the Health-Related Quality of Life among Old Men

Prevention of cardiovascular diseases is known to postpone death, but in an aging society it is important to ensure that those who live longer are neither disabled nor suffering an inferior quality of life. It is essential both from the point of view of the aging individual as well as that of society that any individual should enjoy a good physical, mental and social quality of life during these additional years. The studies presented in this thesis investigated the impact of modifiable risk factors, all of which affect cardiovascular health in the long term, on mortality and health-related quality of life (HRQoL). The data is based on the all male cohort of the Helsinki Businessmen Study. This cohort, originally of 3.490 men born between 1919 and 1934 has been followed since the 1960s. The socioeconomic status of the participants is similar, since all the men were working in leading positions. Extensive baseline examinations were conducted among 2.375 of the men in 1974 when their mean age was 48 and at this time the health, medication and cardiovascular risk factors of the participants were observed. In 2000, at the mean age of 73, the HRQoL of the survivors of the original cohort was examined using the RAND-36 mailed questionnaire (n=1.864). RAND-36, along with the equivalent SF-36, is the world s most widely used means of assessing generic health. The response rate was generally over 90%. Mortality was retrieved from national registers in 2000 and 2002. For the six substudies of this thesis, the impact of four different modifiable cardiovascular risk factors (weight gain, cholesterol, alcohol and smoking) on the HRQoL in old age was studied both independently and in combination. The follow-up time for these studies varies from 26 up to 39 years. Mortality is reported separately or included in the RAND-36 scores for HRQoL. Elevated levels of all the risk factors examined among the participants in midlife led to a diminished life expectancy. Among survivors, lower weight gain in midlife was associated with better HRQoL, both physically and mentally. Higher levels of serum cholesterol in middle age indicated both an earlier mortality and a decline in the physical component of HRQoL in a dose-response manner during the 39-year follow-up. Mortality was significantly higher in the highest baseline category of reported mean alcohol consumption (≥ 5 drinks/day), but fairly comparable in abstainers and moderate drinkers during the 29-year follow-up. When HRQoL in old age was accounted for mortality, the men with the highest alcohol consumption in midlife clearly had poorer physical and mental health in old age, but the HRQoL of abstainers and those who drank alcohol in moderation were comparatively similar. The amount of cigarette smoking in midlife was shown to have had a dose-response effect on both mortality and HRQoL in old age during the 26 year follow-up. The men smoking over 20 cigarettes daily in middle age lost about 10 years of their life-expectancy. Meanwhile, the physical functioning of surviving heavy smokers in old age was similar to men 10 years older in the general population. The impact of clustered cardiovascular risk factors was examined by comparing two subcohorts of men who were healthy in 1974, but with different baseline risk factor status. The men with low risk had a 50 % lower mortality during the 29-years follow-up. Their RAND-36 scores for the physical quality of life in old age were significantly better, and the 2002 questionnaire examining psychological well-being indicated also significantly better mental health among the low-risk group. The results indicate that different risk factor levels in midlife have a meaningful impact on life-expectancy and the quality of these extra years. Leading a healthy lifestyle improves both survival and the quality of life.

Predictors of violent reconvictions and mortality among impulsive alcoholic violent offenders: A prospective study

Acts of violence lays a great burden on humankind. The negative effects of violence could be relieved by accurate prediction of violent recidivism. However, prediction of violence has been considered an inexact science hampered by scare knowledge of its causes. The study at hand examines risk factors of violent reconvictions and mortality among 242 Finnish male violent offenders exhibiting severe alcoholism and severe externalizing personality disorders. The violent offenders were recruited during a court-ordered 2-month inpatient mental status examination between 1990—1998. Controls were 1210 individuals matched by sex-, age-, and place of birth. After a 9-year non-incarcerated follow-up criminal register and mortality data were obtained from national registers. Risk analyses were applied to estimate odds and relative risk for recidivism and mortality. Risk variables that were included in the analyses were antisocial personality disorder (ASPD), borderline personality disorder (BPD), a comorbidity of ASPD and BPD, childhood adversities, alcohol consumption, age, and monoamine oxidase A (MAOA) genotype. In addition to risk analyses, temperament dimensions (Tridimensional Personality Questionnaire [TPQ]) were assessed. The prevalence of recidivistic acts of violence (32%) and mortality (16%) was high among the offenders. Severe personality disorders and childhood adversities increased the risk for recidivism and mortality both among offenders (OR 2.0–10.4) and in comparison between offenders and controls (RR 4.3–53.0). Offenders having BPD and a history of childhood maltreatment emerged as a group with a particularly poor prognosis. MAOA altered the effects of alcohol consumption and ageing. Alcohol consumption (+2.3%) and age (–7.3%) showed significant effects on the risk for violent reconvictions among the high activity MAOA (MAOA-H) offenders, but not among the low activity MAOA (MAOA-L) offenders. The offenders featured temperament dimensions of high novelty seeking, high harm avoidance, and low reward dependence matching Cloninger’s definition of explosive personality. The fact that the risk for recidivistic acts of violence and mortality accumulated into clearly defined subgroups supports future efforts to provide for evidence based violence prevention and risk assessments among violent offenders.

Adipose tissue inflammation, liver fat and insulin resistance in humans

BACKGROUND: Obesity is closely associated with insulin resistance, which is a pathophysiologic condition contributing to the important co-morbidities of obesity, such as the metabolic syndrome and type 2 diabetes mellitus. In obese subjects, adipose tissue is characterized by inflammation (macrophage infiltration, increased expression insulin resistance genes and decreased expression of insulin sensitivity genes). Increased liver fat, without excessive alcohol consumption, is defined as non-alcoholic fatty liver disease (NAFLD) and also associated with obesity and insulin resistance. It is unknown whether and how insulin resistance is associated with altered expression of adipocytokines (adipose tissue-derived signaling molecules), and whether adipose tissue inflammation and NAFLD coexist independent of obesity. Genetic factors could explain variation in liver fat independent of obesity but the heritability of NAFLD is unknown. AIMS: To determine whether acute regulation of adipocytokine expression by insulin in adipose tissue is altered in obesity. To investigate the relationship between adipose tissue inflammation and liver fat content independent of obesity. To assess the heritability of serum alanine aminotransferase (ALT) activity, a surrogate marker of liver fat. METHODS: 55 healthy normal-weight and obese volunteers were recruited. Subcutaneous adipose tissue biopsies were obtained for measurement of gene expression before and during 6 hours of euglycemic hyperinsulinemia. Liver fat content was measured by proton magnetic resonance spectroscopy, and adipose tissue inflammation was assessed by gene expression, immunohistochemistry and lipidomics analysis. Genetic factors contributing to serum ALT activity were determined in 313 twins by statistical heritability modeling. RESULTS: During insulin infusion the expression of insulin sensitivity genes remains unchanged, while the expression of insulin resistance genes increases in obese/insulin-resistant subjects compared to insulin-sensitive subjects. Adipose tissue inflammation is associated with liver fat content independent of obesity. Adipose tissue of subjects with high liver fat content is characterized infiltrated macrophages and increased expression of inflammatory genes, as well as by increased concentrations of ceramides compared to equally obese subjects with normal liver fat. A significant heritability for serum ALT activity was verified. CONCLUSIONS: Effects of insulin infusion on adipose tissue gene expression in obese/insulin-resistant subjects are not only characterized by hyporesponse of insulin sensitivity genes but also by hyperresponse of insulin resistance and inflammatory genes. This suggests that in obesity, the impaired insulin action contributes or self-perpetuates alterations in adipocytokine expression in adipose tissue. Adipose tissue inflammation is increased in subjects with high liver fat compared to equally obese subjects with normal liver fat content. Concentrations of ceramides, the putative mediators of insulin resistance, are increased in adipose tissue in subjects with high liver fat. Genetic factors contribute significantly to variation in serum ALT activity, a surrogate marker of liver fat. These data imply that adipose tissue inflammation and increased liver fat content are closely interrelated, and determine insulin resistance even independent of obesity.

Helicobacter pylori: resistance and treatment results in Finland

Background: Helicobacter pylori infection is usually acquired in early childhood and is rarely resolved spontaneously. Eradication therapy is currently recommended virtually to all patients. While the first and second therapies are prescribed without knowing the antibiotic resistance of the bacteria, it is important to know the primary resistance in the population. Aim: This study evaluates the primary resistance of H. pylori among patients in primary health care throughout Finland, the efficacy of three eradication regimens, the symptomatic response to successful therapy, and the effect of smoking on gastric histology and humoral response in H. pylori-positive patients. Patients and methods: A total of 23 endoscopy referral centres located throughout Finland recruited 342 adult patients with positive rapid urease test results, who were referred to upper gastrointestinal endoscopy from primary health care. Gastric histology, H. pylori resistance and H. pylori serology were evaluated. The patients were randomized to receive a seven-day regimen, comprising 1) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and metronidazole 400 mg t.d. (LAM), 2) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and clarithromycin 500 mg b.d. (LAC) or 3) ranitidine bismuth citrate 400 mg b.d., metronidazole 400 mg t.d. and tetracycline 500 mg q.d. (RMT). The eradication results were assessed, using the 13C-urea breath test 4 weeks after therapy. The patients completed a symptom questionnaire before and a year after the therapy. Results: Primary resistance of H. pylori to metronidazole was 48% among women and 25% among men. In women, metronidazole resistance correlated with previous use of antibiotics for gynaecologic infections and alcohol consumption. Resistance rate to clarithromycin was only 2%. Intention-to-treat cure rates of LAM, LAC, and RMT were 78%, 91% and 81%. While in metronidazole-sensitive cases the cure rates with LAM, LAC and RMT were similar, in metronidazole resistance LAM and RMT were inferior to LAC (53%, 67% and 84%). Previous antibiotic therapies reduced the efficacy of LAC, to the level of RMT. Dyspeptic symptoms in the Gastrointestinal Symptoms Rating Scale (GSRS) were decreased by 30.5%. In logistic regression analysis, duodenal ulcer, gastric antral neutrophilic inflammation and age from 50 to 59 years independently predicted greater decrease in dyspeptic symptoms. In the gastric body, smokers had milder inflammation and less atrophy and in the antrum denser H. pylori load. Smokers also had lower IgG antibody titres against H. pylori and a smaller proportional decrease in antibodies after successful eradication. Smoking tripled the risk of duodenal ulcers. Conclusions: in Finland H. pylori resistance to clarithromycin is low, but metronidazole resistance among women is high making metronidazole-based therapies unfavourable. Thus, LAC is the best choice for first-line eradication therapy. The effect of eradication on dyspeptic symptoms was only modest. Smoking slows the progression of atrophy in the gastric body.

Prognostic markers in head and neck carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Well-known risk factors include tobacco smoking and alcohol consumption. Overall survival has improved, but is still low especially in developing countries. One reason for this is the often advanced stage of the disease at the time of diagnosis, but also lack of reliable prognostic tools to enable individualized patient treatment to improve outcome. To date, the TNM classification still serves as the best disease evaluation criterion, although it does not take into account the molecular basis of the tumor. The need for surrogate molecular markers for more accurate disease prediction has increased research interests in this field. We investigated the prevalence, physical status, and viral load of human papillomavirus (HPV) in HNSCC to determine the impact of HPV on head and neck carcinogenesis. The prevalence and genotyping of HPV were assessed with an SPF10 PCR microtiter plate-based hybridization assay (DEIA), followed by a line probe-based genotyping assay. More than half of the patients had HPV DNA in their tumor specimens. Oncogenic HPV-16 was the most common type, and coinfections with other oncogenic and benign associated types also existed. HPV-16 viral load was unevenly distributed among different tumor sites; the tonsils harbored significantly greater amounts of virus than other sites. Episomal location of HPV-16 was associated with large tumors, and both integrated and mixed forms of viral DNA were detected. In this series, we could not show that the presence of HPV DNA correlated with survival. In addition, we investigated the prevalence and genotype of HPV in laryngeal carcinoma patients in a prospective Nordic multicenter study based on fresh-frozen laryngeal tumor samples to determine whether the tumors were HPV-associated. These patients were also examined and interviewed at diagnosis for known risk factors, such as tobacco smoking and alcohol consumption, and for several other habituations to elucidate their effects on patient survival. HPV analysis was performed with the same protocols as in the first study. Only 4% of the specimens harbored HPV DNA. Heavy drinking was associated with poor survival. Heavy drinking patients were also younger than nonheavy drinkers and had a more advanced stage of disease at diagnosis. Heavy drinkers had worse oral hygiene than nonheavy drinkers; however, poor oral hygiene did not have prognostic significance. History of chronic laryngitis, gastroesophageal reflux disease, and orogenital sex contacts were rare in this series. To clarify why vocal cord carcinomas seldom metastasize, we determined tumor lymph vessel (LVD) and blood vessel (BVD) densities in HNSCC patients. We used a novel lymphatic vessel endothelial marker (LYVE-1 antibody) to locate the lymphatic vessels in HNSCC samples and CD31 to detect the blood microvessels. We found carcinomas of the vocal cords to harbor less lymphatic and blood microvessels than carcinomas arising from sites other than vocal cords. The lymphatic and blood microvessel densities did not correlate with tumor size. High BVD was strongly correlated with high LVD. Neither BVD nor LVD showed any association with survival in our series. The immune system plays an important role in tumorigenesis, as neoplastic cells have to escape the cytotoxic lymphocytes in order to survive. Several candidate HLA class II alleles have been reported to be prognostic in cervical carcinomas, an epithelial malignancy resembling HNSCC. These alleles may have an impact on head and neck carcinomas as well. We determined HLA-DRB1* and -DQB1* alleles in HNSCC patients. Healthy organ donors served as controls. The Inno-LiPA reverse dot-blot kit was used to identify alleles in patient samples. No single haplotype was found to be predictive of either the risk for head and neck cancer, or the clinical course of the disease. However, alleles observed to be prognostic in cervical carcinomas showed a similar tendency in our series. DRB1*03 was associated with node-negative disease at diagnosis. DRB1*08 and DRB1*13 were associated with early-stage disease; DRB1*04 had a lower risk for tumor relapse; and DQB1*03 and DQB1*0502 were more frequent in controls than in patients. However, these associations reached only borderline significance in our HNSCC patients.