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  • Kallio, Elisa (Helsingin yliopisto, 2014)
    Periodontitis is characterized by an inflammatory response to bacterial infection in the supporting tissues of the teeth. The disease manifests with gingival swelling and bleeding, increased periodontal pocket depth, and alveolar bone loss. Intact bacteria or bacterial products, including lipopolysaccharide (LPS), may enter the bloodstream through inflamed periodontal tissue or via saliva. Bacterial dissemination, further potentiated by gastrointestinal microbiota, may result in endotoxemia and low-grade inflammation. The general aim of this thesis research was to investigate whether LPS links periodontitis with cardiometabolic disorders. The following topics were studied: genetic factors associated with the susceptibility to periodontitis, the systemic effects of endotoxemia induced by periodontitis and cardiometabolic disorders, as well as the influence of periodontal treatment on plasma LPS activity and lipoprotein composition. A study of genetic polymorphisms of the human major histocompatibility complex region demonstrated that a haplotype comprising six SNPs of the BAT1, NFKBIL1, and LTA genes was associated with the risk of having periodontitis. The risk haplotype showed an association with bleeding on probing, probing pocket depth ≥6 mm, and severe periodontitis, and the result was replicated in two different study populations with concordance. In addition, the serum lymphotoxin-α (LTA) concentration was associated with LTA SNPs of the risk haplotype in homozygous patients, and LTA was expressed in the inflamed periodontal tissue. The systemic effects of the periodontitis-derived endotoxemia were investigated before and after periodontal treatment. In the serum of periodontitis patients, LPS was associated with the proatherogenic very low-density lipoprotein intermediate-density lipoprotein (VLDL-IDL) fraction. Although local healing of the periodontium was successful, the systemic inflammation status of the patients failed to improve after periodontal treatment, reflecting the complexity and persistence of the disease. There were no significant changes in plasma LPS activity or its distribution among lipoprotein classes after periodontal treatment. However, the VLDL of patients with severe periodontitis induced higher expression of proinflammatory cytokines in macrophages when compared with VLDL derived from patients with moderate periodontitis. In addition, VLDL isolated from patients with severe periodontitis with suppuration contained more LPS and induced higher cholesterol uptake in macrophages. The effect of nutrient intake on the association of serum LPS activity with cardiometabolic disorders was examined in a population-based cohort. Endotoxemia was strongly associated with prevalent obesity, metabolic syndrome (MetS), diabetes, and coronary heart disease (CHD). In addition, high serum LPS activity was associated with an increased risk of future CHD events. Even though energy intake was correlated with LPS activity in lean, healthy subjects, the general associations were independent of energy or macronutrient intake. The results indicate that genetic variation in the MHC class III region may be important in periodontitis susceptibility. Endotoxemia and low-grade inflammation originating from periodontitis may induce the proatherogenic properties of VLDL particles via macrophage activation and foam cell formation, thereby promoting atherogenesis. The association of obesity, MetS, diabetes, and CHD with endotoxemia supports the significance of bacterial infections and the immune response in the etiology of cardiometabolic disorders. In conclusion, the findings highlight the close relationship between genetics, the immune response, and lipid metabolism, promoting the role of LPS as a link between periodontitis and cardiometabolic disorders.
  • Mutanen, Annika (Helsingin yliopisto, 2014)
    Intestinal failure (IF) is characterized by the reduced capacity of the intestine to digest and absorb nutrients and fluids required for the maintenance of energy, fluid, electrolyte, and micronutrient balance, as well as normal growth and development in children. Patients with IF are at risk for multiple potentially life-threatening complications, including IF-associated liver disease (IFALD). In this thesis, studies on the incidence of long-term parenteral nutrition (PN) and IFALD, risk factors of IFALD, including parenteral plant sterols, and liver histology were performed to determine the long-term effects of pediatric onset IF on liver function and histology. During PN, serum plant sterol levels were significantly increased in neonates and children with IF compared to healthy controls. In neonates with IFALD, serum plant sterols ratios to cholesterol, especially stigmasterol, were increased compared with healthy controls, neonates without IFALD, and children on PN. After weaning off PN, IFALD, defined by liver biochemistry, persisted in 25% of neonates with 4.2- and 2.2-times higher serum stigmasterol and cholestanol ratios to cholesterol compared with neonates without IFALD. Abnormal liver histology was found in 94% of IF patients on PN and 77% of patients weaned off PN. During PN, liver histology was weighted with cholestasis and portal inflammation. After weaning off PN, cholestasis resolved, but significant fibrosis and steatosis persisted. Fibrosis stage was associated with remaining small bowel length, duration of PN, and number of septic episodes. In a multivariate analysis, age-adjusted small bowel length, portal inflammation, and absence of ileocaecal valve were predictive for fibrosis stage. Fibroblast growth factor 21 (FGF21), a hormone which is shown to regulate glucose and lipid metabolism and relate to liver steatosis in other conditions, concentration was markedly higher in IF patients with steatosis compared to those without steatosis. Liver steatosis was coupled with progression of fibrosis and reflected by serum FGF21. Based on our results, serum plant sterol levels are high and reflect their distribution in PN lipid emulsions during PN. In neonates, IFALD is frequent and associates with markedly increased serum plant sterols compared to healthy neonatal controls and children on PN with more mature liver function. After weaning off PN, serum stigmasterol and cholestanol remain high in neonates with persistent IFALD. Liver histology is characterized by cholestasis, portal inflammation, liver fibrosis and steatosis in IF patients on PN. After weaning off PN, portal inflammation diminishes and cholestasis resolves, but fibrosis and steatosis persists. In addition to duration of PN, extensive small intestinal resection and loss of ileocaecal valve as well as septic episodes are major risk factors of histological liver fibrosis. Increased serum FGF21 levels reflect the presence and the degree of liver steatosis in patients with pediatric onset IF.
  • Kotronen, Anna (Helsingin yliopisto, 2008)
    Introduction: The epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). However, not all obese subjects develop these metabolic abnormalities. Hepatic fat accumulation is related to hepatic insulin resistance, which in turn leads to hyperglycemia, hypertriglyceridemia, and a low HDL cholesterol con-centration. The present studies aimed to investigate 1) how intrahepatic as compared to intramyocellular fat is related to insulin resistance in these tissues and to the metabolic syndrome (Study I); 2) the amount of liver fat in subjects with and without the metabolic syndrome, and which clinically available markers best reflect liver fat content (Study II); 3) the effect of liver fat on insulin clearance (Study III); 4) whether type 2 diabetic patients have more liver fat than age-, gender-, and BMI-matched non-diabetic subjects (Study IV); 5) how type 2 diabetic patients using exceptionally high doses of insulin respond to addition of a PPARγ agonist (Study V). Subjects and methods: The study groups consisted of 45 (Study I), 271 (Study II), and 80 (Study III) non-diabetic subjects, and of 70 type 2 diabetic patients and 70 matched control subjects (Study IV). In Study V, a total of 14 poorly controlled type 2 diabetic patients treated with high doses of insulin were studied before and after rosiglitazone treatment (8 mg/day) for 8 months. In all studies, liver fat content was measured by proton magnetic resonance spectroscopy, and sub-cutaneous and intra-abdominal fat content by MRI. In addition, circulating markers of insulin resistance and serum liver enzyme concentrations were determined. Hepatic (i.v. insulin infusion rate 0.3 mU/kg∙min combined with [3-3H]glucose, Studies I, III, and V) and muscle (1.0 mU/kg min, Study I) insulin sensitivities were measured by the euglycemic hyperinsulinemic clamp technique. Results: Fat accumulation in the liver rather than in skeletal muscle was associated with features of insulin resistance, i.e. increased fasting serum (fS) triglycerides and decreased fS-HDL cholesterol, and with hyperinsulinemia and low adiponectin concentrations (Study I). Liver fat content was 4-fold higher in subjects with as compared to those without the metabolic syndrome, independent of age, gender, and BMI. FS-C-peptide was the best correlate of liver fat (Study II). Increased liver fat was associated with both impaired insulin clearance and hepatic insulin resistance independent of age, gender, and BMI (Study III). Type 2 diabetic patients had 80% more liver fat than age-, weight-, and gender-matched non-diabetic subjects. At any given liver fat content, S-ALT underestimated liver fat in the type 2 diabetic patients as compared to the non-diabetic subjects (Study IV). In Study V, hepatic insulin sensitivity increased and glycemic control improved significantly during rosiglitazone treatment. This was associated with lowering of liver fat (on the average by 46%) and insulin requirements (40%). Conclusions: Liver fat is increased both in the metabolic syndrome and type 2 diabetes independent of age, gender, and BMI. A fatty liver is associated with both hepatic insulin resistance and impaired insulin clearance. Rosi-glitazone may be particularly effective in type 2 diabetic patients who are poorly controlled despite using high insulin doses.
  • Joutsenniemi, Kaisla (Helsingin yliopisto, 2007)
    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.
  • Pimenoff, Ville (Helsingin yliopisto, 2008)
    The major aim of this thesis was to examine the origins and distribution of uniparental and autosomal genetic variation among the Finno-Ugric-speaking human populations living in Boreal and Arctic regions of North Eurasia. In more detail, I aimed to disentangle the underlying molecular and population genetic factors which have produced the patterns of uniparental and autosomal genetic diversity in these populations. Among Finno-Ugrics the genetic amalgamation and clinal distribution of West and East Eurasian gene pools were observed within uniparental markers. This admixture indicates that North Eurasia was colonized through Central Asia/ South Siberia by human groups already carrying both West and East Eurasian lineages. The complex combination of founder effects, gene flow and genetic drift underlying the genetic diversity of the Finno-Ugric- speaking populations were emphasized by low haplotype diversity within and among uniparental and biparental markers. A high prevalence of lactase persistence allele among the North Eurasian Finno- Ugric agriculturalist populations was also shown indicating a local adaptation to subsistence change with lactose rich diet. Moreover, the haplotype background of lactase persistence allele among the Finno- Ugric-speakers strongly suggested that the lactase persistence T-13910 mutation was introduced independently more than once to the North Eurasian gene pool. A significant difference in genetic diversity, haplotype structure and LD distribution within the cytochrome P450 CYP2C and CYP2D regions revealed the unique gene pool of the Finno-Ugric Saami created mainly by population genetic processes compared to other Europeans and sub-Saharan Mandenka population. From all studied populations the Saami showed also significantly the highest allele frequency of a CYP2C19 gene mutation causing variable drug reactions. The diversity patterns observed within CYP2C and CYP2D regions emphasize the strong effect of demographic history shaping genetic diversity and LD especially among such small and constant size populations as the Finno-Ugric-speaking Saami. Moreover, the increased LD in Saami due to genetic drift and/or admixture was shown to offer an advantage for further attempts to identify alleles associated to common complex pharmacogenetic traits.
  • Katajisto, Pekka (Helsingin yliopisto, 2008)
    Peutz-Jeghers syndrome (PJS) is a condition characterized by gastrointestinal polyposis and increased risk of cancer. At the onset of this study, mutations in the LKB1 serine/threonine kinase had been identified in approximately half of the studied PJS patients, indicating that LKB1 is a tumor suppressor underlying at least a subset of PJS cases. Mice with targeted heterozygous deletion of Lkb1 develop gastrointestinal polyps remarkably similar to PJS polyps corroborating the tumor suppressor function of LKB1/Lkb1. Most importantly, the polyps in Lkb1+/– mouse contain a notable stromal compartment with a core of smooth muscle cells that is the defining characteristic of a PJS polyp. In addition, the PJS and mouse polyps frequently exhibit elevated cyclooxygenase-2 (COX-2), a feature also noted in other gastrointestinal polyposis syndromes. Despite the aforementioned characterizations, the molecular mechanism driving PJS polyp development has not been identified. As only a subset of PJS patients have been reported to harbor LKB1 mutations, mutations in other loci might represent an alternative cause of PJS. To characterize the genetic background of PJS, mutation analysis of three genes encoding LKB1 interacting proteins, BRG1, STRADα, and MO25α, was performed in PJS patients without identified LKB1 mutations. No disease causing mutations were detected in these genes. The exclusion of the studied candidate genes with these criteria, and the concurrent increase in frequency of detected LKB1 mutations does not support involvement of other loci in PJS. As COX-2 inhibition has been effective in suppression of familial adenomatous polyposis, the elevation of COX-2 in PJS polyps suggested that COX-2 inhibition could decrease PJS polyposis. This was investigated by genetic and pharmacological interventions that targeted COX-2 in the Lkb1+/– mice. In comparison to PJS modeling Lkb1+/– mice, the polyp burden in the Lkb1+/– mice with either mono- or biallelic deletion of COX-2 was dramatically reduced. Furthermore, a selective COX-2 inhibitor celecoxib efficiently suppressed the tumor burden in Lkb1+/– mice. COX-2 inhibition reduced particularly the incidence of the large (>5mm) polyps whereas the number of smaller polyps was unaffected, suggesting that COX-2 expression is not required for polyp initiation but contributes significantly to tumor growth. These results prompted a pilot clinical trial with PJS patients receiving 200mg of celecoxib twice a day for 6 months. A subset of PJS patients (2/6) responded favorably to the celecoxib treatment, and a significant reduction in polyposis severity was also noted when the polyp grading data of all patients were combined. Together the data establish the polyposis promoting role of COX-2 in Peutz-Jeghers polyposis, and suggest that COX-2 inhibition is efficient in suppression of PJS polyposis. Polyp development is commonly thought to result from mutations in epithelial cells. However, the characteristic stroma of PJS polyps together with the suggestion that polyps can retain a functional copy of Lkb1 raised the possibility of non-epithelial origin of tumorigenesis in PJS. To investigate this possibility, murine Lkb1 was deleted tissue specifically in smooth muscle cells. Both monoallelic and biallelic deletions resulted in the development of gastrointestinal polyps indistinguishable from PJS polyps. Moreover, multiplicity of tumors in the smooth muscle specific biallelic deletion was only moderately (1.8-fold) higher than in the monoallelic deletion, demonstrating that Lkb1 LOH in stromal cells is not required for polyp development. The Lkb1 deficient mesenchymal cells produced less TGFß, and p-Smad2 staining was reduced in epithelial cells adjacent to Lkb1 deleted mesenchyme. These results identified impaired TGFß signaling from mesenchyme to epithelium as a possible mechanism for polyp development. Consistently, the epithelial proliferation in tumors coincided with the reduced p-Smad2 staining and with Lkb1 deficiency of the adjacent stroma. The TGFß signaling defect was importantly also noted in polyps from PJS patients, supporting the role of stroma as a major contributor to PJS polyposis by generation of a permissive microenvironment for epithelial expansion. The results of this thesis contribute to the notion that LKB1 is the only PJS gene substantiating the findings from the Lkb1 heterozygous mouse model of PJS. From the viewpoint of therapy development, the results provide proof of principle for the efficacy of COX-2 chemoprevention in PJS. Furthermore, the discovery of the stromal-derived mechanism of LKB1 tumor suppression forms a basis for the development of novel therapeutic interventions targeting mesenchymal signaling in PJS polyposis and possibly other cancers with loss of LKB1.
  • Siponen, Elina (Helsingin yliopisto, 2013)
    Local and regional recurrences in breast cancer and Paget´s disease of the breast The aim of the present study was to evaluate the incidence and risk factors of local and regional recurrences after surgical treatment of invasive breast cancer treated with modern adjuvant therapies. Another interest was to determine the outcome of surgical treatment in patients with Paget´s disease of the breast, with a special emphasis on sentinel node biopsy and magnetic resonance imaging. The study population consisted of 1297 patients with pT1 invasive breast cancer treated with breast-conserving therapy, 755 patients with invasive cancer treated with mastectomy and 1180 patients with invasive cancer and axillary lymph node dissection treated at the Breast Surgery Unit of Helsinki University Central Hospital between the years 2000 and 2005. Also included were 58 patients with Paget´s disease of the breast treated between 1995 and 2006 at the same unit. Medical files were retrospectively reviewed and analysed. After breast conservation, the 5-year local recurrence rate was 2.1% in patients with pT1 tumours. Local recurrences were located in the quadrant of the prior breast resection in 63% cases. The most significant risk factor for local recurrence after breast conservation was omission of radiotherapy. After mastectomy, the 7-year local recurrence rate was 2.9%. In the multivariate model, no independent risk factors emerged for local recurrence. Calculated from the date of detection of the recurrence, the 5-year breast-cancer specific survival was 77.5% and overall survival 59.2% in patients with isolated local recurrence. After axillary lymph node dissection, the 7-year axillary recurrence rate was 0.7% and supraclavicular recurrence rate 1.3%. No risk factors for axillary recurrence were identified. A vast majority, 86% of patients with supraclavicular recurrence and 50% of patients with axillary recurrence, had concomitant distant recurrences. Altogether 56 patients with Paget´s disease of the breast (97%) had underlying invasive or in situ carcinoma in the ipsilateral breast. Multifocal or multicentric invasive or in situ carcinoma was detected in 40% of patients with Paget´s disease. The overall mastectomy rate was 76%. Local and regional recurrences are rare after breast cancer surgery and modern multidisciplinary treatment, at least during a short follow-up. Paget´s disease is rather frequently associated with peripheral or multicentric cancer. Sentinel node biopsy is recommended in patients with Paget´s disease with invasive cancer or in case of mastectomy. Magnetic resonance imaging may be helpful in patients with Paget´s disease with negative findings in conventional imaging.
  • Åberg, Fredrik (Helsingin yliopisto, 2010)
    With transplant rejection rendered a minor concern and survival rates after liver transplantation (LT) steadily improving, long-term complications are attracting more attention. Current immunosuppressive therapies, together with other factors, are accompanied by considerable long-term toxicity, which clinically manifests as renal dysfunction, high risk for cardiovascular disease, and cancer. This thesis investigates the incidence, causes, and risk factors for such renal dysfunction, cardiovascular risk, and cancer after LT. Long-term effects of LT are further addressed by surveying the quality of life and employment status of LT recipients. The consecutive patients included had undergone LT at Helsinki University Hospital from 1982 onwards. Data regarding renal function – creatinine and estimated glomerular filtration rate (GFR) – were recorded before and repeatedly after LT in 396 patients. The presence of hypertension, dyslipidemia, diabetes, impaired fasting glucose, and overweight/obesity before and 5 years after LT was determined among 77 patients transplanted for acute liver failure. The entire cohort of LT patients (540 patients), including both children and adults, was linked with the Finnish Cancer Registry, and numbers of cancers observed were compared to site-specific expected numbers based on national cancer incidence rates stratified by age, gender, and calendar time. Health-related quality of life (HRQoL), measured by the 15D instrument, and employment status were surveyed among all adult patients alive in 2007 (401 patients). The response rate was 89%. Posttransplant cardiovascular risk factor prevalence and HRQoL were compared with that in the age- and gender-matched Finnish general population. The cumulative risk for chronic kidney disease increased from 10% at 5 years to 16% at 10 years following LT. GFR up to 10 years after LT could be predicted by the GFR at 1 year. In patients transplanted for chronic liver disease, a moderate correlation of pretransplant GFR with later GFR was also evident, whereas in acute liver failure patients after LT, even severe pretransplant renal dysfunction often recovered. By 5 years after LT, 71% of acute liver failure patients were receiving antihypertensive medications, 61% were exhibiting dyslipidemia, 10% were diabetic, 32% were overweight, and 13% obese. Compared with the general population, only hypertension displayed a significantly elevated prevalence among patients – 2.7-fold – whereas patients exhibited 30% less dyslipidemia and 71% less impaired fasting glucose. The cumulative incidence of cancer was 5% at 5 years and 13% at 10. Compared with the general population, patients were subject to a 2.6-fold cancer risk, with non-melanoma skin cancer (standardized incidence ratio, SIR, 38.5) and non-Hodgkin lymphoma (SIR 13.9) being the predominant malignancies. Non-Hodgkin lymphoma was associated with male gender, young age, and the immediate posttransplant period, whereas old age and antibody induction therapy raised skin-cancer risk. HRQoL deviated clinically unimportantly from the values in the general population, but significant deficits among patients were evident in some physical domains. HRQoL did not seem to decrease with longer follow-up. Although 87% of patients reported improved working capacity, data on return to working life showed marked age-dependency: Among patients aged less than 40 at LT, 70 to 80% returned to work, among those aged 40 to 50, 55%, and among those above 50, 15% to 28%. The most common cause for unemployment was early retirement before LT. Those patients employed exhibited better HRQoL than those unemployed. In conclusion, although renal impairment, hypertension, and cancer are evidently common after LT and increase with time, patients’ quality of life remains comparable with that of the general population.
  • Hiukka, Anne (Helsingin yliopisto, 2009)
    Background and aims. Diabetic dyslipidemia is a highly atherogenic triad of increased triglycerides, decreased HDL cholesterol, and small dense LDL. Fibrates have a beneficial effect on diabetic dyslipidemia, and they have reduced cardiovascular events in randomized trials. Fenofibrate has reduced albuminuria and markers of low-grade inflammation and endothelial dysfunction. The present studies were undertaken to characterize the alterations of VLDL and LDL subclasses and to investigate the binding of LDL to arterial wall in type 2 diabetes. Further purpose was to elucidate the effects of fenofibrate on several lipoprotein subclasses, augmentation index (AIx), carotid intima-media thickness (IMT), and renal function. Subjects. 239 type 2 diabetic subjects were recruited among participants of the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study at the Helsinki centre. The patients were randomized to fenofibrate (200mg/d) or placebo for 5 years. Additionally, a healthy control group (N = 93) was recruited. Results. VLDL1 triglycerides increased in similar proportion to total triglycerides in type 2 diabetic patients and control subjects. Despite the increase in total apoCIII levels, VLDL apoCIII was decreased in diabetic patients. Enrichment of LDL with apoCIII induced a small increase in binding of LDL to arterial wall proteoglycan. Intrinsic characteristics of diabetic LDL, rather than levels of apoCIII, were responsible for increased proteoglycan binding of diabetic LDL with high apoCIII. Fenofibrate reduced triglycerides, increased LDL size, and shifted HDL subclasses towards smaller particles with no change in levels of HDL cholesterol. High levels of homocysteine were associated with lower increase of HDL cholesterol and apoA-I during fenofibrate treatment. Long-term fenofibrate treatment did not improve IMT, AIx, inflammation, or endothelial function. Fenofibrate decreased creatinine clearance and estimated glomerular filtration rate. No effect on albuminuria was seen with fenofibrate. Instead, Cystatin C was increased during fenofibrate treatment. Conclusions. 1) Elevation of VLDL 1 triglycerides was the major determinant of plasma triglyceride concentration in control subjects and type 2 diabetic patients. 2) LDL with high apoCIII showed multiple atherogenic properties, that were only partially mediated by apoCIII per se in type 2 diabetes 3) Fenofibrate demonstrated no effect on surrogate markers of atherosclerosis. 4) Fenofibrate had no effect on albuminuria and the observed decrease in markers of renal function could complicate the clinical surveillance of the patients. 5) Fenofibrate can be used to treat severe hypertriglyceridemia or in combination therapy with statins, but not to increase HDL levels.
  • Holma, Irina (Helsingin yliopisto, 2013)
    Major depressive disorder (MDD) is a commonly occurring and burdensome disorder and one of the most important mental disorders in terms of public health impact. By the year 2030 MDD is predicted to be the leading cause of functional disability and the major disease or injury burden followed by ischemic heart disease and road traffic accidents (WHO, 2004). Depression is not only highly prevalent but also often a chronic, recurrent and comorbid illness often co-occurring with anxiety, personality, substance use disorders, and smoking. Effective MDD treatments have been available for decades. However, only a realized treatment is useful for patients. This study investigated (1) the 5-year prevalence, duration and predictors of maintenance pharmacological treatment of MDD, (2) temporal patterns of pharmacological and psychosocial treatment attitudes and adherence, (3) predictors of a granted disability pension, and (4) long-term associations and covariation of smoking behavior and MDD with comorbid alcohol use disorder as a potential confounding factor. The investigated cohort consisted of psychiatric out- and inpatients (N=269) of the Vantaa Depression Study (VDS), a regionally representative, prospective and naturalistic follow-up study. Just over a half of patients with recurrent depression received maintenance pharmacotherapy, and below a fifth of the time indicated; this was predicted by a good adherence to pharmacotherapy in the acute phase. Most patients reported positive attitudes towards treatment, and good adherence. Employment predicted positive attitude and larger social network good adherence to pharmacotherapy. Cluster B personality disorder symptoms predicted a negative attitude and poor adherence, while cluster C symptoms predicted a positive attitude and living alone good adherence to psychosocial treatment. One-fifth were granted a disability pension within 5 years, which was predicted by higher age, introversion, subjective inability to work, larger proportion of time spent depressed, comorbid somatic disorders, and lack of vocational education. A third of MDD patients smoked regularly throughout the follow-up. Smoking patients differed from non-smoking patients with regard to several clinical characteristics (particularly alcohol use disorders) and personality factors (personality disorders and neuroticism), which may markedly confound research on the impact of smoking.
  • Tainio, Juuso (Helsingin yliopisto, 2015)
    Renal transplantation (RTx) has become an established treatment modality for end-stage renal disease in children. Along with the improvements in pre- and post-transplant care, the patient and graft outcomes have improved significantly during the past two decades. This attracts more attention to avoiding secondary complications and long-term side effects of the post-RTx immunosuppressive medication. Several risk factors cast a shadow over patients normal physical and mental development, but detailed reports on long-term outcome after pediatric RTx are scarce. This thesis was designed to investigate pubertal development and subsequent male fertility and semen quality with special emphasis on the effects of immunosuppressive medication on reproductive function. The study also aimed to analyze the prevalence of metabolic syndrome and its components in pediatric RTx patients and the association of these parameters with the long-term graft function. The onset of pubertal development occurred at the mean age of 12.7 years in boys with 22% considered delayed. In girls, however, no delayed development occurred, with the age at onset of puberty and menarche averaging 10.7 years and 12.5 years, respectively. Pubertal growth continued relatively long resulting in average final height of -1.7 height standard deviation score in boys and -1.2 in girls. The reproductive hormone levels were normal in a great majority of the patients. In young adult males who had received RTx in childhood, the free testosterone levels were lower and luteinizing hormone levels were higher in comparison with age-matched healthy controls. The RTx patients had also smaller testicular volumes and total sperm counts than the controls. Only a quarter of the RTx men who provided a semen sample had normospermia. Patients with a history of cyclophosphamide therapy had the worst outcome. Metabolic data were collected at several time points during a 13-year follow-up post-RTx. Hypertriglyceridemia associated with a worse kidney graft function at 1.5 and 5 years post-RTx, and it predicted the subsequent rate of kidney function decrease after 1.5 years post-RTx. Beyond the first postoperative year, other metabolic risk factors associated modestly with the long-term kidney graft function in pediatric RTx patients. The ambulatory BP monitoring data were retrospectively analyzed 5 to 10 years post-transplantation. The BP profiles were similar between renal, heart, and liver transplant groups. Hypertension was common especially at nighttime and the nocturnal BP dipping was often blunted. The use of antihypertensive medication did not notably change the ambulatory BP profile in RTx recipients. The BP variables correlated poorly with the metabolic parameters or kidney graft function.
  • Wedenoja, Satu (Helsingin yliopisto, 2007)
    The rare autosomal recessive disease congenital chloride diarrhea (CLD) is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene on chromosome 7q22.3-31.1. SLC26A3 encodes for an apical epithelial chloride-bicarbonate exchanger, the intestinal loss of which leads to profuse chloride-rich diarrhea, and a tendency to hypochloremic and hypokalemic metabolic alkalosis. Although untreated CLD is usually lethal in early infancy, the development of salt substitution therapy with NaCl and KCl in the late 1960s made the disease treatable. While the salt substitution allows normal childhood growth and development in CLD, data on long-term outcome have remained unclarified. One of the world s highest incidences of CLD 1:30 000 to 1:40 000 occurs in Finland, and CLD is part of the Finnish disease heritage. We utilized a unique sample of Finnish patients to characterize the long-term outcome of CLD. Another purpose of this study was to search for novel manifestations of CLD based on the extraintestinal expression of the SLC26A3 gene. This study on a sample of 36 patients (ages 10-38) shows that the long-term outcome of treated CLD is favorable. In untreated or poorly treated cases, however, chronic contraction and metabolic imbalance may lead to renal injury and even to renal transplantation. Our results demonstrate a low-level expression of SLC26A3 in the human kidney. Although SLC26A3 may play a minor role in homeostasis, post-transplant recurrence of renal changes shows the unlikelihood of direct transporter modulation in the pathogenesis of CLD-related renal injury. Options to resolve the diarrheal symptoms of CLD have been limited. Unfortunately, our pilot trial indicated the inefficacy of oral butyrate as well. This study reveals novel manifestations of CLD. These include an increased risk for hyperuricemia, inguinal hernias, and probably for intestinal inflammation. The most notable finding of this study is CLD-associated male subfertility. This involves a low concentration of poorly motile spermatozoa with abnormal morphology, high seminal plasma chloride with a low pH, and a tendency to form spermatoceles. That SLC26A3 immunoexpression appeared at multiple sites of the male reproductive tract in part together with the main interacting proteins cystic fibrosis transmembrane conductance regulator (CFTR) and sodium-hydrogen exchanger 3 (NHE3) suggests novel sites for the cooperation of these proteins. As evidence of the cooperation, defects occurring in any of these transporters are associated with reduced male fertility. Together with a finding of high sweat chloride in CLD, this study provides novel data on extraintestinal actions of the SLC26A3 gene both in the male reproductive tract and in the sweat gland. These results provide the basis for future studies regarding the role of SLC26A3 in different tissues, especially in the male reproductive tract. Fortunately, normal spermatogenesis in CLD is likely to make artificial reproductive technologies to treat infertility and even make unassisted reproduction possible.
  • Riihimäki, Kirsi (Helsingin yliopisto, 2014)
    This study is the first naturalistic prospective long-term follow-up with a life-chart among primary care patients with depressive disorders. Patients with lifetime MDD spent 34% of follow-up time in MDEs, 24% in partial and only 42% in full remission. Nine in ten achieved at least partial and two-thirds full remission. Baseline severity of depression and substance use comorbidity predicted time spent in MDEs: a rise in Hamilton Rating Scale for Depression (HAMD) score of ten at baseline predicted 14 months and comorbid substance use disorder 25 months more time in MDEs. One-half of those who achieved partial remission and one-third of those who reached full remission were having at least one recurrence. The recurrences were predicted by personality disorders. The time from remission to recurrence was predicted by generalized anxiety disorder and somatoform disorder. One-tenth of patients attempted suicide one to three times. The incidence rate varied robustly depending on the level of depression, being 0 per 1000 patient-years during full remission, 5.8 during partial remission and 107 during MDEs. Functional and work ability were strongly associated with duration and severity of depression. Patients who belonged to the labour force spent one-third of the follow-up off work due to depression; two-thirds were granted sick leave, and one-tenth a disability pension due to depression. Longer duration of depression, comorbid disorders and having received social assistance predicted dropping out from work. A quarter of patients suffered from concurrent borderline personality disorder (BPD). Comorbid anxiety and substance use disorders were common among them. Concurrent BPD increased the severity and duration of depression, suicidal behaviour, unemployment and economic difficulties. This study revealed often slow and incomplete recovery and a common recurrent course, which needs to be taken into account when developing services. The use of measurement scales is warranted when planning and monitoring treatment. Comorbidity, concurrent substance use disorder, anxiety disorders, somatoform disorder and BPD all need to be taken into account in clinical practice guidelines. Duration of depression appears most decisive for suicide attempts among primary care patients with depression. Efforts should focus on the continuity of care.
  • Holma, Mikael (Helsingin yliopisto, 2010)
    Much of what we know regarding the long-term course and outcome of major depressive disorder (MDD) is based on studies of mostly inpatient tertiary level cohorts and samples predating the era of the current antidepressants and the use of maintenance therapies. In addition, there is a lack of studies investigating the comprehensive significance of comorbid axis I and II disorders on the outcome of MDD. The present study forms a part of the Vantaa Depression Study (VDS), a regionally representative prospective and naturalistic cohort study of 269 secondary-level care psychiatric out- and inpatients (aged 20-59) with a new episode of DSM-IV MDD, and followed-up up to five years (n=182) with a life-chart and semistructured interviews. The aim was to investigate the long-term outcome of MDD and risk factors for poor recovery, recurrences, suicidal attempts and diagnostic switch to bipolar disorder, and the association of a family history of different psychiatric disorders on the outcome. The effects of comorbid disorders together with various other predictors from different domains on the outcome were comprehensively investigated. According to this study, the long-term outcome of MDD appears to be more variable when its outcome is investigated among modern, community-treated, secondary-care outpatients compared to previous mostly inpatient studies. MDD was also highly recurrent in these settings, but the recurrent episodes seemed shorter, and the outcome was unlikely to be uniformly chronic. Higher severity of MDD predicted significantly the number of recurrences and longer time spent ill. In addition, longer episode duration, comorbid dysthymic disorder, cluster C personality disorders and social phobia predicted a worse outcome. The incidence rate of suicide attempts varied robustly de¬pending on the level of depression, being 21-fold during major depressive episodes (MDEs), and 4-fold during partial remission compared to periods of full remission. Although a history of previous attempts and poor social support also indicated risk, time spent depressed was the central factor determining overall long-term risk. Switch to bipolar disorder occurred mainly to type II, earlier to type I, and more gradually over time to type II. Higher severity of MDD, comorbid social phobia, obsessive compulsive disorder, and cluster B personality disorder features predicted the diagnostic switch. The majority of patients were also likely to have positive family histories not exclusively of mood, but also of other mental disorders. Having a positive family history of severe mental disorders was likely to be clinically associated with a significantly more adverse outcome.
  • Tiippana-Kinnunen, Tarja (Helsingin yliopisto, 2014)
    This 15-year follow-up focused on radiographic outcome, functional capacity, work disability and comorbidity in 86 patients (age 18-65 years), with early (≤ 12 months of disease duration) rheumatoid arthritis (RA) collected in 1986-1989 in Helsinki area and treated with early initiated DMARD therapy. The outcome was determined in relation to DMARD continuity, early disease activity, early radiographic remission (ERR) and baseline comorbidity. Of the 70 patients evaluated at 15-year examination, 50 (71%) needed continuous DMARD therapy (group A). In 20 patients (29%) DMARDs were discontinued due to clinical remission. Of these disease flared up and DMARDs were reintroduced in 9 patients (45%, group B) and 11 (55%) remained in remission (group C). The 15-year outcome was most favourable in group C: 64% of patients being in remission, according to American Collage of Rheumatology criteria, compared with 0% in B and 6% in A. Final functional capacity [mean Health Assessment Questionnaire (HAQ)] was 0.24 in C, 0.38 in B and 0.60 in A and radiographic outcome assessed with mean Larsen score (LS) 12, 25 and 54, respectively. As conclusion, patients whose DMARDs are discontinued due to remission, should be followed up closely for a flare-up of the disease. For those whose disease flares up, DMARDs should be reintroduced immediately. The 15-year LS of 69 patients determined in relation to ERR [an increase of LS ≤ 1 Larsen unit (LU) between two sequential sets of small joint radiographs during the first 2 years]. Mean 15-year LS of the small joints (14) and LS of the large joints (0.8) were lower in patients with sustained ERR (both year 1 and year 2), compared with 33 and 1.9 in patients with temporary ERR (either year 1 or year 2) or with 67 and 6.3 in patients with radiographic progression ≥ 2 LU during both first years. Considering these findings, radiographic remission should be a treatment goal in RA and early progression in small joints should be taken as a warning sign for later damage of large joints. Of 80 patients with adequate data, 20% had at least one comorbid condition at baseline and 60 % had comorbidities at the 15-year visit or at time od death, most commonly hypertension (30%), cardiovascular diseases (14%), malignancies (11%) or osteoporosis (11%). Elderly patients with baseline comorbidity showed higher disease activity both during first year of RA and at endpoint than younger patients without comorbidities. Of the 86 patients, 42 (49%) retired due to work disability (WD) during 15 years or before death, most of these due to RA. The Kaplan-Meier estimated cumulative RA-related WD was less frequent in patients with low disease activity during first 12 months (3% at year 5, 10% at year 10 and 22% at year 15) than in those with moderate or high disease activity (28%, 55% and 64%, respectively). The results of this study showed that most patients with RA need continuous DMARD treatment and emphasize the importance of targeting to clinical remission and to radiographic remission in early phase of the disease for the long-term outcome in RA.
  • Pelttari, Hanna (Helsingin yliopisto, 2012)
    The goal of initial therapy in differentiated thyroid cancer (DTC) is to minimize disease related mortality and morbidity by surgically removing the primary tumour and all metastasized tumour tissue. A second goal is to minimize risk of recurrence and metastatic spread by facilitating post-operative radio-iodine ablation (RRA), permitting accurate long-term surveillance. Recurrences are relatively common even in patient population at low-risk for cancer-specific death, occurring in 10-40% of cases. The treatment and follow-up schemes have varied between centres and there is ongoing debate about appropriate methods for primary therapy and surveillance. With the increasing incidence of DTC, the need for new factors prognostic of disease recurrence is growing; most of the prognostic systems have been validated with cancer-specific death as outcome. We designed an observational retrospective study to assess the outcome of a large cohort of patients with low-risk thyroid carcinoma and with a uniform primary therapy. All patients belong to TNM stage I or II and were considered disease-free after initial therapy. We evaluated the safety and efficacy of a surveillance paradigm, comprising yearly thyroglobulin (TG) measurements on L-T4 therapy and neck ultrasonography (US) every second year, with an increase in TG to a detectable level being an indication for further investigations. We examined the health-related quality of life (HRQoL) of the patient cohort after long-term follow-up using a validated multidimensional method (15D®). We studied factors correlating with disease recurrence, including patient demographics, tumour characteristics and parameters with primary therapy, in 495 low-risk patients treated at Helsinki University Central Hospital over a 15-year period. Post-operative and post-ablative TG concentrations, age, tumour size, local infiltration and nodal metastasis at primary surgery, number of neck US, fine-needle aspiration biopsies (FNABs) and operations performed, presence of BRAF mutation in papillary tumour tissue, disease recurrences and cancer-specific deaths were evaluated. The majority of patients had total thyroidectomy and radio-active iodine remnant ablation as initial treatment. The median follow-up was 16 (range 10 24) years. Fifty-one patients (10.3%) experienced disease recurrence during follow-up. A combination of neck US and high TG revealed most recurrences. In multiple logistic regression analysis, post-ablative measurable TG concentrations (odds ratio (OR) 3.72, confidence interval (CI) 1.71 8.05, P = 0.0009) and presence of local infiltration on primary surgery (OR 2.66, CI 1.03 6.90, P = 0.04) were the only independent predictors of recurrence. BRAF V600E mutation is common (prevalence 67%) in this low-risk papillary thyroid cancer patient group but does not predict recurrence after long-term follow-up after initial treatment with total thyroidectomy (TTE) and RRA. HRQoL was preserved in DTC patients compared to a large age- and gender-standardized sample of the general Finnish population (n = 6001). After long-term follow-up, overall HRQoL is comparable with that of the general population. DTC patients demonstrate an age-related decline in HRQoL, similar to that seen in the population in general. We conclude that post-ablative TG concentration is a strong predictor of disease recurrence in DTC. Although longer follow-up is needed, monitoring low-risk differentiated thyroid carcinoma patients with neck US and TG measured on L-T4 appears safe and effective.The same principles have now been adapted also by many international centres.