Migraine Comorbidities : A Clinical and Molecular Genetic Study

Migraine is a highly prevalent disease, and despite several important breakthroughs there are still a many questions unanswered in the clinical, genetic and pathophysiological aspects of migraine research. Migraine has been linked to several other diseases such as epilepsy and stroke, but there are still unsolved issues concerning the true nature of these associations. Three genes predisposing to hemiplegic migraine and several loci associated to migraine have been identified, but so far no genes responsible for common forms of migraine have been recognized. Triptans have provided an important step in migraine treatment, but their usefulness in rare forms of migraine have been controversial. The Finnish Migraine Gene Project (FMGP) includes more than 1600 families and 7500 individuals. We evaluated comorbidity from 1000 consecutive subjects in the FMGP. To search for novel loci, we performed a genome-wide linkage scan in 36 families with high prevalences of migraine with visual aura. We collected 76 subjects from the FMGP who suffer from hemiplegic migraine and have used triptans. Finally, to study possible links between stroke and migraine we evaluated the prevalence of migraine in subjects with cervical artery dissection (CAD) and healthy controls. Migraine was associated with increased prevalence of allergy, hypotension and psychiatric diseases. Additionally, men suffering from migraine with aura had increased prevalence of epilepsy and stroke. Further evidence of association between migraine and epilepsy was found in our linkage study. The parametric two-point linkage analysis showed significant evidence of linkage between migraine aura and a locus on 9q21-q22. Interestingly, the same locus has been associated with occipitotemporal epilepsy. CAD seems to be a migraine risk factor, and therefore a link between stroke and migraine. Notably, CAD seems to alleviate migraine activity further indicating the association between these two conditions. Despite the contraindications of triptans, it seems that they are safe and effective in the abortive treatment of hemiplegic migraine.

Questions to Artificial Nature: A Philosophical Study of Interdisciplinary Models and their Functions in Scientific Practice

This thesis presents an interdisciplinary analysis of how models and simulations function in the production of scientific knowledge. The work is informed by three scholarly traditions: studies on models and simulations in philosophy of science, so-called micro-sociological laboratory studies within science and technology studies, and cultural-historical activity theory. Methodologically, I adopt a naturalist epistemology and combine philosophical analysis with a qualitative, empirical case study of infectious-disease modelling. This study has a dual perspective throughout the analysis: it specifies the modelling practices and examines the models as objects of research. The research questions addressed in this study are: 1) How are models constructed and what functions do they have in the production of scientific knowledge? 2) What is interdisciplinarity in model construction? 3) How do models become a general research tool and why is this process problematic? The core argument is that the mediating models as investigative instruments (cf. Morgan and Morrison 1999) take questions as a starting point, and hence their construction is intentionally guided. This argument applies the interrogative model of inquiry (e.g., Sintonen 2005; Hintikka 1981), which conceives of all knowledge acquisition as process of seeking answers to questions. The first question addresses simulation models as Artificial Nature, which is manipulated in order to answer questions that initiated the model building. This account develops further the "epistemology of simulation" (cf. Winsberg 2003) by showing the interrelatedness of researchers and their objects in the process of modelling. The second question clarifies why interdisciplinary research collaboration is demanding and difficult to maintain. The nature of the impediments to disciplinary interaction are examined by introducing the idea of object-oriented interdisciplinarity, which provides an analytical framework to study the changes in the degree of interdisciplinarity, the tools and research practices developed to support the collaboration, and the mode of collaboration in relation to the historically mutable object of research. As my interest is in the models as interdisciplinary objects, the third research problem seeks to answer my question of how we might characterise these objects, what is typical for them, and what kind of changes happen in the process of modelling. Here I examine the tension between specified, question-oriented models and more general models, and suggest that the specified models form a group of their own. I call these Tailor-made models, in opposition to the process of building a simulation platform that aims at generalisability and utility for health-policy. This tension also underlines the challenge of applying research results (or methods and tools) to discuss and solve problems in decision-making processes.

Soveltuvuuskokeella täydennetty opiskelijavalinta : Seurantatutkimus eräiden sosiaali- ja terveysalan teknisluonteisten koulutusohjelmien (apuvälinetekniikka, hammastekniikka ja optometria) opiskelijavalinnan toteuttamisesta

Aptitude-based student selection: A study concerning the admission processes of some technically oriented healthcare degree programmes in Finland (Orthotics and Prosthetics, Dental Technology and Optometry). The data studied consisted of conveniencesamples of preadmission information and the results of the admission processes of three technically oriented healthcare degree programmes (Orthotics and Prosthetics, Dental Technology and Optometry) in Finland during the years 1977-1986 and 2003. The number of the subjects tested and interviewed in the first samples was 191, 615 and 606, and in the second 67, 64 and 89, respectively. The questions of the six studies were: I. How were different kinds of preadmission data related to each other? II. Which were the major determinants of the admission decisions? III. Did the graduated students and those who dropped out differ from each other? IV. Was it possible to predict how well students would perform in the programmes? V. How was the student selection executed in the year 2003? VI. Should clinical vs. statistical prediction or both be used? (Some remarks are presented on Meehl's argument: "Always, we might as well face it, the shadow of the statistician hovers in the background; always the actuary will have the final word.") The main results of the study were as follows: Ability tests, dexterity tests and judgements of personality traits (communication skills, initiative, stress tolerance and motivation) provided unique, non-redundant information about the applicants. Available demographic variables did not bias the judgements of personality traits. In all three programme settings, four-factor solutions (personality, reasoning, gender-technical and age-vocational with factor scores) could be extracted by the Maximum Likelihood method with graphical Varimax rotation. The personality factor dominated the final aptitude judgements and very strongly affected the selection decisions. There were no clear differences between graduated students and those who had dropped out in regard to the four factors. In addition, the factor scores did not predict how well the students performed in the programmes. Meehl's argument on the uncertainty of clinical prediction was supported by the results, which on the other hand did not provide any relevant data for rules on statistical prediction. No clear arguments for or against the aptitude-based student selection was presented. However, the structure of the aptitude measures and their impact on the admission process are now better known. The concept of "personal aptitude" is not necessarily included in the values and preferences of those in charge of organizing the schooling. Thus, obviously the most well-founded and cost-effective way to execute student selection is to rely on e.g. the grade point averages of the matriculation examination and/or written entrance exams. This procedure, according to the present study, would result in a student group which has a quite different makeup (60%) from the group selected on the basis of aptitude tests. For the recruiting organizations, instead, "personal aptitude" may be a matter of great importance. The employers, of course, decide on personnel selection. The psychologists, if consulted, are responsible for the proper use of psychological measures.

The Freudian unconscious in the context of the cognitive orientation

For decades psychoanalysis was the discipline studying the unconscious, and other branches of study lacked competence to take a stand on the issues concerning the unconscious. From 1980s onwards intense study of the unconscious has been taken place in the scope of cognitive orientation. Thus, nowadays it is talked about both pyschoanalytic and cognitive unconscious. The aim of this thesis is to integrate psychoanalytic and cognitive views. When the "Freudian" conception of the unconscious is considered, there are four entangled issues: 1) what is the unconscious like, 2) how does the unconsciuos give rise to psychic disorders 3) why and how certain contents are missing from consciousness (repression of contents), 4) the emergence of those contents (becoming conscious of the repressed). The conventional psychoanalytic answer to the first question - and "the cornerstone of psychoanalysis" - is "the unconscious is mental". The issues 2)-4) depend radically on the answer given to the 1): "psychoanalytic" conceptualizations on them rest on the "cornerstone". That ground was challended in study I: it was argued that it has never been clear what does it mean that the unconscious is mental. Thus, it was stated that in the current state of art psychoanalysis should drop out the ephitet "mental" before the term unconscious. That claim creates a pressure to reappraise the convential "psychoanalytic" answers to the other questions, and that reappraisal was the aim of studies II and III. In study II the question 2) is approached in terms of implicit knowledge. Study III focuses on mechanisms, which determine which contents appear in the scope of consciousness, and also cause missing of contents from there (the questions 3) and 4)). In the core of study III there are distinctions concerning the processess occuring in the levels of the brain, consciousness, self-consciousness, and narrative self-consciousness. Studies I-III set "psychoanalytic" topics in the frames of cognitive view. The picture emerging from those studies is not especially useful for a clinican (psychotherapist). Studies IV and V focused that issue. Study IV is a rather serious critique toward neuropsychoanalysis. In it it was claimed that repressive functions of conscious states are in the core of clinical psychoanalysis, and functions in general cannot be reduced to neurophysiological terminology. Thus, the limits of neuropsychoanalysis are more strict than it has been realized: crucial clinical issues remain outside its scope. In study V it was focused on the confusing state of things that although unconscious fantasies do not exist, the idea on them has been an important conceptual tool for clinicans. When put in a larger context, the aim of study V is similar to that of study IV: to determine the relation between psychotherapists' and neuroscientists' terminologies. Studies III, IV and V apply the philosopher Daniel Dennett's model on different levels of explanation.

Onnistuneen ikääntymisen ymmärrystä rakentamassa : Fysioterapeuttiopiskelijoiden oppiminen kestävää kehitystä edistävän kasvatuksen kehyksessä

The purpose of the present study was to investigate the possibilities and interconnec-tions that exist concerning the relationship between the University of Applied Sci-ences and the Learning by Developing action model (LbD), on the one hand, and education for sustainable development and high-quality learning as a part of profes-sional competence development on the other. The research and learning environment was the Coping at Home research project and its Caring TV project, which provided the context of the Physiotherapy for Elderly People professional study unit. The re-searcher was a teacher and an evaluator of her own students learning. The aims of the study were to monitor and evaluate learning at the individual and group level using tools of high-quality learning − improved concept maps − related to understanding the projects core concept of successful ageing. Conceptions were evaluated through aspects of sustainable development and a conceptual basis of physiotherapy. As edu-cational research this was a multi-method case study design experiment. The three research questions were as follows. 1. What kind of individual conceptions and conceptual structures do students build concerning the concept of successful ageing? How many and what kind of concepts and propositions do they have a) before the study unit, b) after the study unit, c) after the social-knowledge building? 2. What kind of social-knowledge building exists? a) What kind of social learn-ing process exists? b) What kind of socially created concepts, propositions and conceptual structures do the students possess after the project? c) What kind of meaning does the social-knowledge building have at an individual level? 3. How do physiotherapy competences develop according to the results of the first and second research questions? The subjects were 22 female, third-year Bachelor of Physiotherapy students in Laurea University of Applied Sciences in Finland. Individual learning was evaluated in 12 of the 22 students. The data was collected as a part of the learning exercises of the Physiotherapy for Elderly People study unit, with improved concept maps both at individual and group levels. The students were divided into two social-knowledge building groups: the first group had 15 members and second 7 members. Each group created a group-level concept map on the theme of successful ageing. These face-to-face interactions were recorded with CMapTools and videotaped. The data consists of both individually produced concept maps and group-produced concept maps of the two groups and the videotaped material of these processes. The data analysis was carried out at the intersection of various research traditions. Individually produced data was analysed based on content analysis. Group-produced data was analysed based on content analysis and dialogue analysis. The data was also analysed by simple statistical analysis. In the individually produced improved concept maps the students conceptions were comprehensive, and the first concept maps were found to have many concepts unrelated to each other. The conceptual structures were between spoke structures and chain structures. Only a few professional concepts were evident. In the second indi-vidual improved concept maps the conception was more professional than earlier, particulary from the functional point of view. The conceptual structures mostly re-sembled spoke structures. After the second individual concept mapping social map-ping interventions were made in the two groups. After this, multidisciplinary concrete links were established between all concepts in almost all individual concept maps, and the interconnectedness of the concepts in different subject areas was thus understood. The conceptual structures were mainly net structures. The concepts in these individual concept maps were also found to be more professional and concrete than in the previ-ous concept maps of these subjects. In addition, the wider context dependency of the concepts was recognized in many individual concept maps. This implies a conceptual framework for specialists. The social-knowledge building was similar to a social learning process. Both socio-cultural processes and cognitive processes were found to develop students conceptual awareness and the ability to engage in intentional learning. In the knowl-edge-building process two aspects were found: knowledge creation and pedagogical action. The discussion during the concept-mapping process was similar to a shared thinking process. In visualising the process with CMapTools, students easily comple-mented each others thoughts and words, as if mutually telepathic . Synthesizing, supporting, asking and answering, peer teaching and counselling, tutoring, evaluating and arguing took place, and students were very active, self-directed and creative. It took hundreds of conversations before a common understanding could be found. The use of concept mapping in particular was very effective. The concepts in these group-produced concept maps were found to be professional, and values of sustainable development were observed. The results show the importance of developing the contents and objectives of the European Qualification Framework as well as education for sustainable development, especially in terms of the need for knowledge creation, global responsibility and systemic, holistic and critical thinking in order to develop clinical practice. Keywords: education for sustainable development, learning, knowledge building, improved concept map, conceptual structure, competence, successful ageing

Stem Cell Markers in Cancer: Do They Have Clinical Significance?

In cancer, a subpopulation of malignant cells expresses markers of normal stem cells. These cells have the potential of initiating tumor growth and therefore also tumor recurrence. Thus, these cells are called cancer stem cells. A myriad of markers have been applied to identify these cells, but no single marker can be found exclusively in cancer stem cells. In many types of cancer, clinical recurrence and tumor progression are the main causes of mortality, despite intense oncological treatment. It has been proposed that the presence of cancer stem cells causes this resistance to therapy. The scope of this thesis is to investigate the role of stem cell markers and genes in the clinical setting. Especially, the aim was to elucidate the clinical significance of stem cell markers as novel prognostic and diagnostic tools in cancer. Tumor biopsy material from central nervous system tumors (oligodendroglioma, astrocytoma and glioblatoma), neural crest derived tumors (pheochromocytomas) and oral carcinoma was screened for stem cell markers. Initially, 15 stem cell markers were screened in a test series of gliomas. The markers applied for expanded tumor analyses (in 305 cases of glioma, 42 cases of pheochromocytoma, and 73 cases of oral carcinoma) were BMI-1, Snail, p16, mdm2, and c-Myc. Data on marker expression was compared with clinical and pathological parameters. In gliomas, BMI-1 expression was found in nearly all tumors analyzed, but the frequency of BMI-1 expressing cells was highly variable, ranging from 1 to 100%. In oligodendroglioma, BMI-1 expression was identified as a prognostic marker independent of tumor grade and clinical parameters. In pheochromocytoma, Snail expression was shown to distinguish between the metastatic and non-metastatic forms of the tumor. Snail expression was seen only in metastatic tumors, whereas non-metastatic tumors did not commonly express Snail. Finally, in oral carcinoma, BMI-1 expression was seen in roughly 80% of tumors, and Snail expression was high or very high in all cases. The lack of BMI-1 expression was associated with early relapse in oral carcinoma.

Blood pressure lowering effects of Lactobacillus helveticus fermented milk containing bioactive peptides Ile-Pro-Pro and Val-Pro-Pro; mechanistic, kinetic and clinical studies

The purpose of the present study was to evaluate the effects of Lactobacillus helveticus fermented milk (peptide milk) containing the casein-derived tripeptides Isoleucyl-prolyl-proline (Ile-Pro-Pro) and Valyl-prolyl-proline (Val-Pro-Pro) on blood pressure and vascular function in hypertensive subjects. The peptide milk lowered systolic and diastolic blood pressure in long-term use in hypertensive subjects when blood pressure was measured by using 24-hour ambulatory blood pressure measurement (ABPM). The blood pressure lowering effect was seen with the dose of 50 mg of tripeptides, and a tendency for lowering blood pressure was also observed when the dose was 5 mg. No adverse effects compared to the placebo group were reported or detected in laboratory analysis. The effect of the peptide milk on arterial stiffness was shown using two different methods, the ambulatory arterial stiffness index (AASI) and pulse wave analysis (PWA). According to the AASI, arterial stiffness was significantly reduced in the peptide milk group compared to the baseline level, but the difference was not significant compared to the placebo group. PWA showed that the peptide milk reduced arterial stiffness significantly compared to the placebo group. Endothelium-independent relaxation (nitroglycerin) and endothelium-dependent relaxation (salbutamol) did not differ between the groups. The blood pressure lowering mechanisms of the tripeptides and the kinetics of Ile-Pro-Pro were investigated using spontaneously hypertensive rats (SHR) and Sprague-Dawley rats. Previous studies have suggested that the blood pressure lowering effect of the tripeptides Ile-Pro-Pro and Val-Pro-Pro is based on angiotensin-converting enzyme inhibition, but the present findings did not agree with these previous studies. It was shown in SHR that calcium, potassium and magnesium may also have an important role in attenuating the development of hypertension as part of the peptide milk effect. In addition, the present study suggests indirectly that improved endothelial nitric oxide release capacity is not the mechanism by which peptide milk mediates its favourable circulatory effects. The kinetics of Ile-Pro-Pro were studied using adult Sprague-Dawley rats. The results showed that orally administered Ile-Pro-Pro is absorbed at least partly intact from the gastrointestinal tract. Radiolabelled Ile-Pro-Pro was distributed in different tissues and considerable radioactivity levels were found in tissues related to the renin-angiotensin system (RAS), adrenals, aorta and kidneys. Ile-Pro-Pro does not bind to plasma proteins, and therefore it is possible that its blood pressure lowering effect is mediated by free Ile-Pro-Pro. In conclusion, consumption of the peptide milk lowers blood pressure and reduces arterial stiffness in hypertensive subjects. Ile-Pro-Pro can be absorbed partly intact from the gastrointestinal tract and might accumulate in tissues related to the RAS. The precise blood pressure lowering mechanism of peptide milk remains to be studied.

The influence of HIV infection to the periodontium; a clinical, microbiological, and enzymological study

The main targets of human immunodeficiency virus (HIV) are CD4 receptors of CD4+ lymphocytes and many other cells such as monocytes/macrophages, megakaryocytes, peripheral blood dendritic cells, follicular dendritic cells (DC), epidermal Langerhans cells, and astrocytes. Infection and killing of CD4+ lymphocytes or false reaction of the body to HIV infection and the spontaneous apoptosis of CD4+ lymphocytes decrease CD4+ lymphocyte counts leading to immunosuppression, further disease progression, and appearance of opportunistic infections and malignancies. Oral manifestations are considered to be among the first signs of HIV infection. Enhanced degradation of extracellular matrix and basement membrane components in oral diseases including periodontitis is caused by Zn-dependent enzymes called matrix metalloproteinases (MMPs). The levels and degrees of activation of MMP-1, -2, -3, -7, -8, -9, -25, -26, tissue inhibitors of MMPs (TIMP)-1 and -2, and myeloperoxidase (MPO) and collagenolytic/gelatinolytic activities, and also Ig A, -G, and -M, total protein, and albumin levels in a two-year follow-up were studied from salivary samples. The expression of MMP-7, -8, -9, -25, and -26 immunoreactivities in gingival tissue specimens were studied. Healthy HIV-negative subjects served as controls. All studied clinical periodontal parameters and microbiological evaluation of the periodontopathogens showed that periodontal health of the HIV-positive patients was moderately decreased in comparison to the healthy controls. The levels of Candida in the periodontal pockets and salivary MPO increased with the severity of HIV infection. Immunoreactivities and levels of MMPs and TIMPs, and MMP activities (collagenase, gelatinase) were enhanced in the HIV-positive patient salivary samples relative to the healthy controls regardless of the phase of HIV infection. However, these parameters did not reflect periodontal status in a similar way as in the generally healthy periodontitis patients. Salivary total protein, albumin, IgA, -G, and -M levels were significantly higher in all phases of HIV infection compared to the controls, and salivary total protein, IgG and IgM levels remained higher after two years follow-up, partly correlating with the disease progression and which may reflect the leakage of serum components into the mouth and thus a decreased mucosal barrier. Salivary analyses of MMPs and TIMPs with immunohistochemical analyses showed that HIV infection could predispose to periodontal destruction when compared with healthy controls or the body s defence reactions associated with HIV infection may have been reflected or mediated by MMPs.

Temporomandibular disorders and related psychosocial factors in non-patients : A survey and a clinical follow-up study based on the RDC/TMD

Temporomandibular disorders (TMD) and psychosocial factors reportedly associate. The underlying factors remain partially obscure, however, and further studies are required to clarify the relationships. The aims of this study were thus to assess in a non-patient working population the prevalence of TMD and related symptoms, and to clinically diagnose and follow the natural courses of TMD over a one-year period. In addition, possible comorbidity of temporomandibular and/or neck muscle pain and perceived stress and their impact on work performance were investigated, as well as how various psychosocial aspects relate to TMD. A questionnaire was mailed to all 30- to 55-year-old employees of the Finnish Broadcasting Company Ltd. whose employment in the Helsinki area had lasted at least five years (n = 1784). Of the 1339 subjects, who returned the questionnaire, 241 were examined according to the RDC/TMD and standard neck muscle palpation methods. Clinical signs of temporomandibular and/or neck muscle pain were found in 118 subjects. One-year follow-up TMD examinations were conducted on 211 subjects. The prevalence of frequent painless TMJ-related symptoms was 10%, orofacial pain 7%, neck pain 38%, and headache 15%. TMD diagnoses were: myofascial pain (13%), disc displacements (16%), and arthralgia, osteoarthritis, osteoarthrosis (4%). Chronic myofascial pain was present in 7% and chronic disc displacement with reduction in 11% of the subjects. Symptoms were significantly associated with almost all the studied psychosocial symptoms. Reduced work performance was significantly positively associated with continuous pain, severity of pain, and health stress perception, and according to logistic regression, somatization with the probability of having chronic myofascial pain. It could be concluded based on the results of this study among a non-patient working population that TMD and related symptoms are common and associated with psychosocial factors. Moreover, myofascial pain and disc displacement with reduction are the most common diagnoses of TMD. In addition, self-reported health related stress, and continuous pain in temporomandibular and/or neck muscles are associated with reduced work performance, and somatization is significantly associated with chronic myofascial pain.

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

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

Molecular and clinical characteristics of tricarboxylic acid cycle-associated tumors

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare, dominantly inherited tumor predisposition syndrome characterized by benign cutaneous and uterine (ULM) leiomyomas, and sometimes renal cell cancer (RCC). A few cases of uterine leiomyosarcoma (ULMS) have also been reported. Mutations in a nuclear gene encoding fumarate hydratase (FH), an enzyme of the mitochondrial tricarboxylic acid cycle (TCA cycle), underlie HLRCC. As a recessive condition, germline mutations in FH predispose to a neurological defect, FH deficiency (FHD). Hereditary paragangliomatosis (HPGL) is a dominant disorder associated with paragangliomas and pheochromocytomas. Inherited mutations in three genes encoding subunits of succinate dehydrogenase (SDH), also a TCA cycle enzyme, predispose to HPGL. Both FH and SDH seem to act as tumor suppressors. One of the consequences of the TCA cycle defect is abnormal activation of HIF1 pathway ( pseudohypoxia ) in the HLRCC and HPGL tumors. HIF1 drives transcription of genes encoding e.g. angiogenetic factors which can facilitate tumor growth. Recently hypoxia/HIF1 has been suggested to be one of the causes of genetic instability as well. One of the aims of this study was to broaden the clinical definers of HLRCC. To determine the cancer risk and to identify possible novel tumor types associated with FH mutations eight Finnish HLRCC/FHD families were extensively evaluated. The extension of the pedigrees and the Finnish Cancer Registry based tumor search yielded genealogical and cancer data of altogether 868 individuals. The standardized incidence ratio-based comparison of HLRCC/FHD family members with general Finnish population revealed 6.5-fold risk for RCC. Moreover, risk for ULMS was highly increased. However, according to the recent and more stringent diagnosis criteria of ULMS many of the HLRCC uterine tumors previously considered malignant are at present diagnosed as atypical or proliferative ULMs (with a low risk of recurrence). Thus, the formation of ULMS (as presently defined) in HLRCC appears to be uncommon. Though increased incidence was not observed, interestingly the genetic analyses suggested possible association of breast and bladder cancer with loss of FH. Moreover, cancer cases were exceptionally detected in an FHD family. Another clinical finding was the conventional (clear cell) type RCC of a young Spanish HLRCC patient. Conventional RCC is distinct from the types previously observed in this syndrome but according to these results, FH mutation may underlie some of young conventional cancer cases. Secondly, the molecular pathway from defective TCA cycle to tumor formation was intended to clarify. Since HLRCC and HPGL tumors display abnormally activated HIF1, the hypothesis on the link between HIF1/hypoxia and genetic instability was of interest to study in HLRCC and HPGL tumor material. HIF1α (a subunit of HIF1) stabilization was confirmed in the majority of the specimens. However, no repression of MSH2, a protein of DNA mismatch repair system, or microsatellite instability (MSI), an indicator of genetic instability, was observed. Accordingly, increased instability seems not to play a role in the tumorigenesis of pseudohypoxic TCA cycle-deficient tumors. Additionally, to study the putative alternative functions of FH, a recently identified alternative FH transcript (FHv) was characterized. FHv was found to contain instead of exon 1, an alternative exon 1b. Differential subcellular distribution, lack of FH enzyme activity, low mRNA expression compared to FH, and induction by cellular stress suggest FHv to have a role distinct from FH, for example in apoptosis or survival. However, the physiological significance of FHv requires further elucidation.