Male eating disorders and related traits : Genetic epidemiological study in Finnish twins

The aim of this study was to deepen the understanding of eating disorders, body image dissatisfaction and related traits in males by examining the epidemiology and genetic epidemiology of these conditions in representative population-based twin samples. The sample of Study I included adolescent twins from FinnTwin12 cohorts born 1983 87 and assessed by a questionnaire at ages 14 y (N=2070 boys, N=2062 girls) and 17 y (N=1857 boys, N=1984 girls). Samples of Studies II-V consisted of young adult twins born 1974-79 from FinnTwin16 cohorts (Study II N=1245 men, Study III N=724 men, Study IV N=2122 men, Study V N=2426 women and N=1962 men), who were assessed by a questionnaire at the age 22-28 y. In addition, 49 men and 526 women were assessed by a diagnostic interview. The overall response rates for both twin cohorts in all studies were 80-90%. In boys, mainly genetic factors (82%, 95% confidence interval [CI] 72-92) explained the covariation of self-esteem between the ages 14 y and 17 y, whereas in girls, environmental factors (69%, 95% CI 43-93) were the largest contributors. Of young men, 30% experienced high muscle dissatisfaction, while 12% used or had used muscle building supplements and/or anabolic steroids on a regular basis. Muscle dissatisfaction exhibited a robust association with the indicators of mental distress and a genetic component (42%, 95% CI 23-59) for its liability in this population was found. The variation of muscle-building substance use was primarily explained by the environmental factors. The incidence rate of anorexia nervosa in males for the age of 10-24 y was 15.7 (95% CI 6.6-37.8) per 100 000 person-years, and its lifetime prevalence by the young adulthood was 0.24% (95% CI 0.03-0.44). All detected probands with anorexia nervosa had recovered from eating disorders, but suffered from substantial psychiatric comorbidity, which manifested also in their co-twins. Additionally, male co-twins of the probands displayed significant dissatisfaction with body musculature, a male-specific feature of body dysmorphic disorder. All probands were from twin pairs discordant for eating disorders. Of the five male probands with anorexia nervosa, only one was from an opposite-sex twin pair. Among women from the opposite-sex pairs, the prevalence of DSM-IV or broad anorexia nervosa was no significantly different compared to that of the women from monozygotic pairs or from dizygotic same-sex pairs. The prevalence of DSM-IV or broad bulimia nervosa did not differ in opposite- versus same-sex female twin individuals either. In both sexes, the overall profile of indicators on eating disorders was rather similar between individuals from opposite-sex and same-sex pairs. In adolescence, development of self-esteem was differently regulated in boys compared to girls: this finding may have far-reaching implications on the etiology of sex discrepancy of internalizing and externalizing disorders. In young men, muscle dissatisfaction and muscle building supplement/steroid use were relatively common. Muscle dissatisfaction was associated with marked psychological distress such as symptoms of depression and disordered eating. Both genetic and environmental factors explained muscle dissatisfaction in the population, but environmental factors appeared to best explain the use of muscle-building substances. In this study, anorexia nervosa in boys and young men from the general population was more common, transient and accompanied by more substantial co-morbidity than previously thought. Co-twins of the probands with anorexia nervosa displayed significant psychopathology such as male specific symptoms of body dysmorphic disorder, but none of them had had an eating disorder: taken together, these traits are suggestive for an endophenotype of anorexia nervosa in males. Little evidence was found on that the risk for anorexia nervosa, bulimia nervosa, disordered eating or body dissatisfaction were associated with twin zygosity. Thus, it is unlikely that in utero femininization, masculinization or postnatal socialization according to the sex of the co-twin have a major influence on the later development of eating disorders or related traits.

Memory disorders in acute encephalitis : A neuropsychological study

Acute encephalitis is an inflammation of the brain, mostly caused by viral infection. A variety of cognitive symptoms may persist after the acute stage, and neuropsychological assessment is crucial in evaluation of the outcome. The most commonly reported sequelae are memory deficits. The main aims of this study were to investigate the types of memory impairment in various encephalitides, the frequency of global amnesia following encephalitis, and the changes in the deficits during follow-up. Between 1 January 1985 and 31 December 1994, 77 adult patients under the age of 75 with acute encephalitis but without alcohol abuse, or coexisting or previous neurological diseases were consecutively referred for neuropsychological examination at the Department of Neurology, Helsinki University Central Hospital. The aetiology was established in 44/77 (57%) patients; 17 had Herpes simplex virus encephalitis (HSVE). Transient amnesia (TENA) at the acute stage of the disease was found in 70% of patients. Furthermore, similarly to brain trauma, TENA was found to indicate cognitive outcome. The frequency of persisting global amnesia syndrome with both anterograde and retrograde amnesia in all encephalitic patients was 6%. One patient had isolated retrograde amnesia, which is very rare. In HSVE the frequency of global amnesia was 12.5%, which is lower than expected. As a group, HSVE patients were not found to have a homogeneous pattern of amnesia, instead subgroups among all encephalitic patients were observed: some patients had impaired semantic memory, some had difficulty predominantly with executive functions and some suffered from an increased forgetting rate. Herpes zoster encephalitis was found to result in mild memory impairment only, and the qualitative features indicated a subcortical dysfunction. On the whole, the cognitive deficits were predominantly found to diminish during follow-up. Progressive deterioration was often associated with intractable epilepsy. The frequency of dementia was 12.5%. In conclusion, the neuropsychological outcome, especially in HSVE, was more favourable than has previously been reported, possibly due to early acyclovir medication. Memory disorders after encephalitis should not be considered uniform, and the need for neuropsychological rehabilitation should be considered case-by-case

Genetic Heterogeneity in Autism Spectrum Disorders in a Population Isolate

Positional cloning has enabled hypothesis-free, genome-wide scans for genetic factors contributing to disorders or traits. Traditionally linkage analysis has been used to identify regions of interest, followed by meticulous fine mapping and candidate gene screening using association methods and finally sequencing of regions of interest. More recently, genome-wide association analysis has enabled a more direct approach to identify specific genetic variants explaining a part of the variance of the phenotype of interest. Autism spectrum disorders (ASDs) are a group of childhood onset neuropsychiatric disorders with shared core symptoms but varying severity. Although a strong genetic component has been established in ASDs, genetic susceptibility factors have largely eluded characterization. Here, we have utilized modern molecular genetic methods combined with the advantages provided by the special population structure in Finland to identify genetic risk factors for ASDs. The results of this study show that numerous genetic risk factors exist for ASDs even within a population isolate. Stratification based on clinical phenotype resulted in encouraging results, as previously identified linkage to 3p14-p24 was replicated in an independent family set of families with Asperger syndrome, but no other ASDs. Fine-mapping of the previously identified linkage peak for ASDs at 3q25-q27 revealed association between autism and a subunit of the 5-hydroxytryptamine receptor 3C (HTR3C). We also used dense, genome-wide single nucleotide polymorphism (SNP) data to characterize the population structure of Finns. We observed significant population substructure which correlates with the known history of multiple consecutive bottle-necks experienced by the Finnish population. We used this information to ascertain a genetically homogenous subset of autism families to identify possible rare, enriched risk variants using genome-wide SNP data. No rare enriched genetic risk factors were identified in this dataset, although a subset of families could be genealogically linked to form two extended pedigrees. The lack of founder mutations in this isolated population suggests that the majority of genetic risk factors are rare, de novo mutations unique to individual nuclear families. The results of this study are consistent with others in the field. The underlying genetic architecture for this group of disorders appears highly heterogeneous, with common variants accounting for only a subset of genetic risk. The majority of identified risk factors have turned out to be exceedingly rare, and only explain a subset of the genetic risk in the general population in spite of their high penetrance within individual families. The results of this study, together with other results obtained in this field, indicate that family specific linkage, homozygosity mapping and resequencing efforts are needed to identify these rare genetic risk factors.

Assessment of neuroleptic-induced movement disorders in a naturalistic schizophrenia population

The prevalence and assessment of neuroleptic-induced movement disorders (NIMDs) in a naturalistic schizophrenia population that uses conventional neuroleptics were studied. We recruited 99 chronic schizophrenic institutionalized adult patients from a state nursing home in central Estonia. The total prevalence of NIMDs according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) was 61.6%, and 22.2% had more than one NIMD. We explored the reliability and validity of different instruments for measuring these disorders. First, we compared DSM-IV with the established observer rating scales of Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS) (for neuroleptic-induced parkinsonism, NIP) and Abnormal Involuntary Movement Scale (AIMS) (for tardive dyskinesia), all three of which have been used for diagnosing NIMD. We found a good overlap of cases for neuroleptic-induced akathisia (NIA) and tardive dyskinesia (TD) but somewhat poorer overlap for NIP, for which we suggest raising the commonly used threshold value of 0.3 to 0.65. Second, we compared the established observer rating scales with an objective motor measurement, namely controlled rest lower limb activity measured by actometry. Actometry supported the validity of BARS and SAS, but it could not be used alone in this naturalistic population with several co-existing NIMDs. It could not differentiate the disorders from each other. Quantitative actometry may be useful in measuring changes in NIA and NIP severity, in situations where the diagnosis has been made using another method. Third, after the relative failure of quantitative actometry to show diagnostic power in a naturalistic population, we explored descriptive ways of analysing actometric data, and demonstrated diagnostic power pooled NIA and pseudoakathisia (PsA) in our population. A subjective question concerning movement problems was able to discriminate NIA patients from all other subjects. Answers to this question were not selective for other NIMDs. Chronic schizophrenia populations are common worldwide, NIMD affected two-thirds of our study population. Prevention, diagnosis and treatment of NIMDs warrant more attention, especially in countries where typical antipsychotics are frequently used. Our study supported the validity and reliability of DSM-IV diagnostic criteria for NIMD in comparison with established rating scales and actometry. SAS can be used with minor modifications for screening purposes. Controlled rest lower limb actometry was not diagnostically specific in our naturalistic population with several co-morbid NIMDs, but it may be sensitive in measuring changes in NIMDs.

Recognition, comorbidity, and outcome of DSM-IV bipolar I and II disorders in psychiatric care

This study is part of an ongoing collaborative bipolar research project, the Jorvi Bipolar Study (JoBS). The JoBS is run by the Department of Mental Health and Alcohol Research of the National Public Health Institute, Helsinki, and the Department of Psychiatry, Jorvi Hospital, Helsinki University Central Hospital (HUCH), Espoo, Finland. It is a prospective, naturalistic cohort study of secondary level care psychiatric in- and outpatients with a new episode of bipolar disorder (BD). The second report also included 269 major depressive disorder (MDD) patients from the Vantaa Depression Study (VDS). The VDS was carried out in collaboration with the Department of Psychiatry of the Peijas Medical Care District. Using the Mood Disorder Questionnaire (MDQ), all in- and outpatients at the Department of Psychiatry at Jorvi Hospital who currently had a possible new phase of DSM-IV BD were sought. Altogether, 1630 psychiatric patients were screened, and 490 were interviewed using a semistructured interview (SCID-I/P). The patients included in the cohort (n=191) had at intake a current phase of BD. The patients were evaluated at intake and at 6- and 18-month interviews. Based on this study, BD is poorly recognized even in psychiatric settings. Of the BD patients with acute worsening of illness, 39% had never been correctly diagnosed. The classic presentations of BD with hospitalizations, manic episodes, and psychotic symptoms lead clinicians to correct diagnosis of BD I in psychiatric care. Time of follow-up elapsed in psychiatric care, but none of the clinical features, seemed to explain correct diagnosis of BD II, suggesting reliance on cross- sectional presentation of illness. Even though BD II was clearly less often correctly diagnosed than BD I, few other differences between the two types of BD were detected. BD I and II patients appeared to differ little in terms of clinical picture or comorbidity, and the prevalence of psychiatric comorbidity was strongly related to the current illness phase in both types. At the same time, the difference in outcome was clear. BD II patients spent about 40% more time depressed than BD I patients. Patterns of psychiatric comorbidity of BD and MDD differed somewhat qualitatively. Overall, MDD patients were likely to have more anxiety disorders and cluster A personality disorders, and bipolar patients to have more cluster B personality disorders. The adverse consequences of missing or delayed diagnosis are potentially serious. Thus, these findings strongly support the value of screening for BD in psychiatric settings, especially among the major depressive patients. Nevertheless, the diagnosis must be based on a clinical interview and follow-up of mood. Comorbidity, present in 59% of bipolar patients in a current phase, needs concomitant evaluation, follow-up, and treatment. To improve outcome in BD, treatment of bipolar depression is a major challenge for clinicians.

Depressive Disorders in Primary Health Care

The Vantaa Primary Care Depression Study (PC-VDS) is a naturalistic and prospective cohort study concerning primary care patients with depressive disorders. It forms a collaborative research project between the Department of Mental and Alcohol Research of the National Public Health Institute, and the Primary Health Care Organization of the City of Vantaa. The aim is to obtain a comprehensive view on clinically significant depression in primary care, and to compare depressive patients in primary care and in secondary level psychiatric care in terms of clinical characteristics. Consecutive patients (N=1111) in three primary care health centres were screened for depression with the PRIME-MD, and positive cases interviewed by telephone. Cases with current depressive symptoms were diagnosed face-to-face with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I/P). A cohort of 137 patients with unipolar depressive disorders, comprising all patients with at least two depressive symptoms and clinically significant distress or disability, was recruited. The Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II), medical records, rating scales, interview and a retrospective life-chart were used to obtain comprehensive cross-sectional and retrospective longitudinal information. For investigation of suicidal behaviour the Scale for Suicidal Ideation (SSI), patient records and the interview were used. The methodology was designed to be comparable to The Vantaa Depression Study (VDS) conducted in secondary level psychiatric care. Comparison of major depressive disorder (MDD) patients aged 20-59 from primary care in PC-VDS (N=79) was conducted with new psychiatric outpatients (N =223) and inpatients (N =46) in VDS. The PC-VDS cohort was prospectively followed up at 3, 6 and 18 months. Altogether 123 patients (90%) completed the follow-up. Duration of the index episode and the timing of relapses or recurrences were examined using a life-chart. The retrospective investigation revealed current MDD in most (66%), and lifetime MDD in nearly all (90%) cases of clinically significant depressive syndromes. Two thirds of the “subsyndromal” cases had a history of major depressive episode (MDE), although they were currently either in partial remission or a potential prodromal phase. Recurrences and chronicity were common. The picture of depression was complicated by Axis I co-morbidity in 59%, Axis II in 52% and chronic Axis III disorders in 47%; only 12% had no co-morbidity. Within their lifetimes, one third (37%) had seriously considered suicide, and one sixth (17%) had attempted it. Suicidal behaviour clustered in patients with moderate to severe MDD, co-morbidity with personality disorders, and a history of treatment in psychiatric care. The majority had received treatment for depression, but suicidal ideation had mostly remained unrecognised. The comparison of patients with MDD in primary care to those in psychiatric care revealed that the majority of suicidal or psychotic patients were receiving psychiatric treatment, and the patients with the most severe symptoms and functional limitations were hospitalized. In other clinical aspects, patients with MDD in primary care were surprisingly similar to psychiatric outpatients. Mental health contacts earlier in the current MDE were common among primary care patients. The 18-month prospective investigation with a life-chart methodology verified the chronic and recurrent nature of depression in primary care. Only one-quarter of patients with MDD achieved and maintained full remission during the follow-up, while another quarter failed to remit at all. The remaining patients suffered either from residual symptoms or recurrences. While severity of depression was the strongest predictor of recovery, presence of co-morbid substance use disorders, chronic medical illness and cluster C personality disorders all contributed to an adverse outcome. In clinical decision making, beside severity of depression and co-morbidity, history of previous MDD should not be ignored by primary care doctors while depression there is usually severe enough to indicate at least follow-up, and concerning those with residual symptoms, evaluation of their current treatment. Moreover, recognition of suicidal behaviour among depressed patients should also be improved. In order to improve outcome of depression in primary care, the often chronic and recurrent nature of depression should be taken into account in organizing the care. According to literature management programs of a chronic disease, with enhancement of the role of case managers and greater integration of primary and specialist care, have been successful. Optimum ways of allocating resources between treatment providers as well as within health centres should be found.

Vascular dilatory function and cardiovascular risk factors in women with a history of pre-eclampsia

Women with a history of pre-eclampsia have an increased risk of cardiovascular disease in later life. The mechanisms which mediate this heightened risk are poorly understood; it was long believed that pre-eclampsia was a separate disease without any connection to other pathologies. The present study was undertaken to investigate the cardiovascular risk milieu, vascular dilatory function and cardiovascular risk factors, in women with pre-eclampsia, 5 6 years after index pregnancy. The aim was to understand better the cardiovascular risks associated with pre-eclampsia and add tools to the evaluation of cardiovascular risk in women. --- The study involved 30 women with previous severe pre-eclampsia and 21 controls. The 2-day study protocol included venous occlusion plethysmography and pulse wave analysis for assessment of vascular dilatory function and central pulse wave reflection, respectively, office and ambulatory blood pressure measurements, assessment of insulin sensitivity, using a minimal model technique, and tests regarding renal function, lipid metabolism, sympathetic activity and inflammation. Vasodilatory function was impaired in women with a history of pre-eclampsia; this was seen in both endothelium-dependent and endothelium-independent vasodilatation. Proteinuria during pre-eclampsia did not predict changes in vasodilatation, and renal function was similar in the two groups. Insulin sensitivity was related to vasodilatation and features of metabolic syndrome, but only in the patient group, despite similar insulin sensitivity in the control group. Arterial pressure was higher in the patient group than in the controls and correlated with endothelin-1 levels in the patient group, whilst the overall difference between the groups was diminished in 24 hour arterial pressure measurements. Additionally, women with previous pre-eclampsia were characterized by increased sympathetic activity. Impaired vasodilatory function at the vascular smooth muscle level seems to characterize clinically healthy women with a history of pre-eclampsia. These vascular changes and the features of metabolic syndrome may be related to the increased risk of cardiovascular disease. Furthermore, increased blood pressure in combination with enhanced sympathetic activity may be additive as regards this risk. These women should be informed about their potential cardiovascular risk profile and the possibilities to minimize it via their own actions. Medical cardiovascular risk assessment in women should include obstetric history.

Health-Related Quality of Life and Mental Disorders in Finland

Quality of life (QoL) and Health-related quality of life (HRQoL) are becoming one of the key outcomes of health care due to increased respect for the subjective valuations and well-being of patients and an increasing part of the ageing population living with chronic, non-fatal conditions. Preference-based HRQoL measures enable estimation of health utility, which can be useful for rational rationing, evidence-based medicine and health policy. This study aimed to compare the individual severity and public health burden of major chronic conditions in Finland, including and focusing on reliably diagnosed psychiatric conditions. The study is based on the Health 2000 survey, a representative general population survey of 8028 Finns aged 30 and over. Depressive, anxiety and alcohol use disorders were diagnosed with the Composite International Diagnostic Interview (M-CIDI). HRQoL was measured with the 15D and the EQ-5D, with 83% response rate. This study found that people with psychiatric disorders had the lowest 15D HRQoL scores at all ages, in comparison to other main groups of chronic conditions. Considering 29 individual conditions, three of the four most severe (on 15D) were psychiatric disorders; the most severe was Parkinson s disease. Of the psychiatric disorders, chronic conditions that have sometimes been considered relatively mild - dysthymia, agoraphobia, generalized anxiety disorder and social phobia - were found to be the most severe. This was explained both by the severity of the impact of these disorders on mental health domains of HRQoL, and also by the fact that decreases were widespread on most dimensions of HRQoL. Considering the public health burden of conditions, musculoskeletal disorders were associated with the largest burden, followed by psychiatric disorders. Psychiatric disorders were associated with the largest burden at younger ages. Of individual conditions, the largest burden found was for depressive disorders, followed by urinary incontinence and arthrosis of the hip and knee. The public health burden increased greatly with age, so the ageing of the Finnish population will mean that the disease burden caused by chronic conditions will increase by a quarter up to year 2040, if morbidity patterns do not change. Investigating alcohol consumption and HRQoL revealed that although abstainers had poorer HRQoL than moderate drinkers, this was mainly due to many abstainers being former drinkers and having the poorest HRQoL. Moderate drinkers did not have significantly better HRQoL than abstainers who were not former drinkers. Psychiatric disorders are associated with a large part of the non-fatal disease burden in Finland. In particular anxiety disorders appear to be more severe and have a larger public health burden than previously thought.

Cognitive Functioning in Alcohol and Other Substance Use Disorders in Young Adulthood : A Genetic Epidemiological Study

Alcohol and other substance use disorders (SUDs) result in great costs and suffering for individuals and families and constitute a notable public health burden. A multitude of factors, ranging from biological to societal, are associated with elevated risk of SUDs, but at the level of individuals, one of the best predictors is a family history of SUDs. Genetically informative twin and family studies have consistently indicated this familial risk to be mainly genetic. In addition, behavioral and temperamental factors such as early initiation of substance use and aggressiveness are associated with the development of SUDs. These familial, behavioral and temperamental risk factors often co-occur, but their relative importance is not well known. People with SUDs have also been found to differ from healthy controls in various domains of cognitive functioning, with poorer verbal ability being among the most consistent findings. However, representative population-based samples have rarely been used in neuropsychological studies of SUDs. In addition, both SUDs and cognitive abilities are influenced by genetic factors, but whether the co-variation of these traits might be partly explained by overlapping genetic influences has not been studied. Problematic substance use also often co-occurs with low educational level, but it is not known whether these outcomes share part of their underlying genetic influences. In addition, educational level may moderate the genetic etiology of alcohol problems, but gene-environment interactions between these phenomena have also not been widely studied. The incidence of SUDs peaks in young adulthood rendering epidemiological studies in this age group informative. This thesis investigated cognitive functioning and other correlates of SUDs in young adulthood in two representative population-based samples of young Finnish adults, one of which consisted of monozygotic and dizygotic twin pairs enabling genetically informative analyses. Using data from the population-based Mental Health in Early Adulthood in Finland (MEAF) study (n=605), the lifetime prevalence of DSM-IV any substance dependence or abuse among persons aged 21—35 years was found to be approximately 14%, with a majority of the diagnoses being alcohol use disorders. Several correlates representing the domains of behavioral and affective factors, parental factors, early initiation of substance use, and educational factors were individually associated with SUDs. The associations between behavioral and affective factors (attention or behavior problems at school, aggression, anxiousness) and SUDs were found to be largely independent of factors from other domains, whereas daily smoking and low education were still associated with SUDs after adjustment for behavioral and affective factors. Using a wide array of neuropsychological tests in the MEAF sample and in a subsample (n=602) of the population-based FinnTwin16 (FT16) study, consistent evidence of poorer verbal cognitive ability related to SUDs was found. In addition, participants with SUDs performed worse than those without disorders in a task assessing psychomotor processing speed in the MEAF sample, whereas no evidence of more specific cognitive deficits was found in either sample. Biometrical structural equation models of the twin data suggested that both alcohol problems and verbal ability had moderate heritabilities (0.54—0.72), and that their covariation could be explained by correlated genetic influences (genetic correlations -0.20 to -0.31). The relationship between educational level and alcohol problems, studied in the full epidemiological FT16 sample (n=4,858), was found to reflect both genetic correlation and gene-environment interaction. The co-occurrence of low education and alcohol problems was influenced by overlapping genetic factors. In addition, higher educational level was associated with increased relative importance of genetic influences on alcohol problems, whereas environmental influences played a more important role in young adults with lower education. In conclusion, SUDs, especially alcohol abuse and dependence, are common among young Finnish adults. Behavioral and affective factors are robustly related to SUDs independently of many other factors, and compared to healthy peers, young adults who have had SUDs during their life exhibit significantly poorer verbal cognitive ability, and possibly less efficient psychomotor processing. Genetic differences between individuals explain a notable proportion of individual differences in risk of alcohol dependence, verbal ability, and educational level, and the co-occurrence of alcohol problems with poorer verbal cognition and low education is influenced by shared genetic backgrounds. Finally, various environmental factors related to educational level in young adulthood moderate the relative importance of genetic factors influencing the risk of alcohol problems, possibly reflecting differences in social control mechanisms related to educational level.

Uterine cervix nitric oxide and human papillomavirus infection in women

Most women acquire genital high risk human papillomavirus (HPV) infection during their lifetime, but seldom the infection persists and leads to cervical cancer. However, currently it is not possible to identify the women who will develop HPV mediated cervical cancer and this often results to large scale follow-up and overtreatment of the likely spontaneously regressing infection. Thus, it is important to obtain more information on the course of HPV and find markers that could help to identify HPV infected women in risk for progression of cervical lesions and ultimately cancer. Nitric oxide is a free radical gas that takes part both in immune responses and carcinogenesis. Nitric oxide is produced also by cervical cells and therefore, it is possible that cervical nitric oxide could affect also HPV infection. In the present study, including 801 women from the University of Helsinki between years of 2006 and 2011, association between HPV and cervical nitric oxide was evaluated. The levels of nitric oxide were measured as its metabolites nitrate and nitirite (NOx) by spectrophotometry and the expression of nitric oxide producing enzymes endothelial and inducible synthases (eNOS, iNOS) by Western blotting. Women infected with HPV had two-times higher cervical fluid NOx levels compared with non-infected ones. The expression levels of both eNOS and iNOS were higher in HPV-infected women compared with non-infected. Another sexually transmitted disease Chlamydia trachomatis that is an independent risk factor for cervical cancer was also accompanied with elevated NOx levels, whereas vaginal infections, bacterial vaginosis and candida, did not have any effect on NOx levels. The meaning of the elevated HPV related cervical nitric oxide was evaluated in a 12 months follow-up study. It was revealed that high baseline cervical fluid NOx levels favored HPV persistence with OR 4.1. However, low sensitivity (33%) and high false negative rate (67%) restrict the clinical use of the current NOx test. This study indicated that nitric oxide favors HPV persistence and thus it seems to be one of the cofactor associated with a risk of carcinogenesis.

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

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

Cognitive Functioning in Young Adults with Depression, Anxiety Disorders, or Burnout Symptoms : Findings from a Population-based Sample

Background. Evidence of cognitive dysfunction in depressive and anxiety disorders is growing. However, the neuropsychological profile of young adults has received only little systematic investigation, although depressive and anxiety disorders are major public health problems for this age group. Available studies have typically failed to account for psychiatric comorbidity, and samples derived from population-based settings have also seldom been investigated. Burnout-related cognitive functioning has previously been investigated in only few studies, again all using clinical samples and wide age groups. Aims. Based on the information gained by conducting a comprehensive review, studies on cognitive impairment in depressive and anxiety disorders among young adults are rare. The present study examined cognitive functioning in young adults with a history of unipolar depressive or anxiety disorders in comparison to healthy peers, and associations of current burnout symptoms with cognitive functioning, in a population-based setting. The aim was also to determine whether cognitive deficits vary as a function of different disorder characteristics, such as severity, psychiatric comorbidity, age at onset, or the treatments received. Methods. Verbal and visual short-term memory, verbal long-term memory and learning, attention, psychomotor processing speed, verbal intelligence, and executive functioning were measured in a population-based sample of 21-35 year olds. Performance was compared firstly between participants with pure non-psychotic depression (n=68) and healthy peers (n=70), secondly between pure (n=69) and comorbid depression (n=57), and thirdly between participants with anxiety disorders (n=76) and healthy peers (n=71). The diagnostic procedure was based on the SCID interview. Fourthly, the associations of current burnout symptoms, measured with the Maslach Burnout Inventory General Survey, and neuropsychological test performance were investigated among working young adults (n=225). Results. Young adults with depressive or anxiety disorders, with or without psychiatric comorbidity, were not found to have major cognitive impairments when compared to healthy peers. Only mildly compromised verbal learning was found among depressed participants. Pure and comorbid depression groups did not differ in cognitive functioning, either. Among depressed participants, those who had received treatment showed more impaired verbal memory and executive functioning, and earlier onset corresponded with more impaired executive functioning. In anxiety disorders, psychotropic medication and low psychosocial functioning were associated with deficits in executive functioning, psychomotor processing speed, and visual short-term memory. Current burnout symptoms were associated with better performance in verbal working memory and verbal intelligence. However, lower examiner-rated social and occupational functioning was associated with problems in verbal attention, memory, and learning. Conclusions. Depression, anxiety disorders, or burnout symptoms may not be associated with major cognitive deficits among young adults derived from the general population. Even psychiatric comorbidity may not aggravate cognitive functioning in depressive or anxiety disorders among these young adults. However, treatment-seeking in depression was found to be associated with cognitive deficits, suggesting that these deficits relate to increased distress. Additionally, early-onset depression, found to be associated with executive dysfunction, may represent a more severe form of the disorder. In anxiety disorders, those with low symptom-related psychosocial functioning may have cognitive impairment. An association with self-reported burnout symptoms and cognitive deficits was not detected, but individuals with low social and occupational functioning may have impaired cognition.