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  • Hytinantti, Timo Kalevi (Helsingin yliopisto, 2001)
  • Linnankivi, Tarja (Helsingin yliopisto, 2006)
    Within the last 15 years, several new leukoencephalopathies have been recognized. However, more than half of children with cerebral white matter abnormalities still have no specific diagnosis. Our aim was to classify unknown leukoencephalopathies and to identify new diseases among them. During the study, three subgroups of patients were delineated and examined further. First, we evaluated 38 patients with unknown leukoencephalopathy. Brain MRI findings were grouped into seven categories according to the predominant location of the abnormalities. The largest subgroups were myelination abnormalities (n=20) and periventricular white matter abnormalities (n=12). Six patients had uniform MRI findings with signal abnormalities in hemispheric white matter and in selective brain stem and spinal cord tracts. Magnetic resonance spectroscopy (MRS) showed elevated lactate and decreased N-acetylaspartate in the abnormal white matter. The patients presented with ataxia, tremor, distal spasticity, and signs of dorsal column dysfunction. This phenotype - leukoencephalopathy with brain stem and spinal cord involvement and elevated white matter lactate (LBSL) - was first published elsewhere in 2003. A new finding was development of a mild axonal neuropathy. The etiopathogenesis of this disease is unknown, but elevated white matter lactate in MRS suggests a mitochondrial disorder. Secondly, we studied 22 patients with 18q deletions. Clinical and MRI findings were correlated with molecularly defined size of the deletion. All patients with deletions between markers D18S469 and D18S1141 (n=18) had abnormal myelination in brain MRI, while four patients with interstitial deletions sparing that region, had normal myelination pattern. Haploinsufficiency of myelin basic protein is suggested to be responsible for this dysmyelination. Congenital aural atresia/stenosis was found in 50% of the cases and was associated with deletions between markers D18S812 (at 18q22.3) and D18S1141 (at q23). Last part of the study comprised 13 patients with leukoencephalopathy and extensive cerebral calcifications. They showed a spectrum of findings, including progressive cerebral cysts, retinal telangiectasias and angiomas, intrauterine growth retardation, skeletal and hematologic abnormalities, and severe intestinal bleeding, which overlap with features of the previously reported patients with "Coats plus" syndrome and "leukoencephalopathy with calcifications and cysts", suggesting that these disorders are related. All autopsied patients had similar neuropathologic findings showing calcifying obliterative microangiopathy. Our patients may represent an autosomally recessively inherited disorder because there were affected siblings and patients of both sexes. We have started genealogic and molecular genetic studies of this disorder.
  • Põder, Pentti (Helsingin yliopisto, 2006)
    Levosimendan is a drug developed for the treatment of heart failure. Its mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-sensitive potassium channels. The combination of positive inotropy with possible anti-ischaemic effects via potassium channel opening may offer benefits in comparison with currently available intravenous inotropes, which are contraindicated in patients with ongoing myocardial ischaemia. The active levosimendan metabolite OR-1896 significantly prolongs the duration of the haemodynamic effects of levosimendan. The aims of the present study were to investigate: 1) the clinical effects and safety of intravenous and oral levosimendan and 2) the pharmacodynamics and pharmacokinetics of intravenous and oral levosimendan and its metabolites in patients with ischaemic heart disease. Levosimendan was administered intravenously or orally in four studies to 557 patients with ischaemic heart disease with or without concomitant heart failure. One study included patients with acute myocardial infarction, while the other three studies included stable ischaemic patients. Non-invasive haemodynamic measurements were used in all studies, and blood samples for pharmacokinetics were drawn in three studies. Safety was followed by ECG recordings, adverse event inquiries and laboratory assessments. Intravenous levosimendan, administered as a 6-hour infusion did not cause clinically significant hypotension or ischaemia in comparison with placebo and reduced worsening heart failure and short- and long-term mortality. Increase in incidence of hypotension and ischaemia was seen only with the highest dose (0.4 µg/kg/min). Both intravenous and oral levosimendan possessed a moderate positive inotropic effect. Vasodilatory effect was more pronounced with intravenous levosimendan. A chronotropic effect was seen in all studies; however, it was not accompanied by any increase in arrhythmic events. The formation of levosimendan metabolites after oral dosing increased linearly with the daily dose of the parent drug, leading to increased inotropic and chronotropic response. Levosimendan was well tolerated in all studies. In conclusion, levosimendan was safe and effective in the treatment of patients with acute or chronic ischaemia. The risk-benefit ratio of intravenous levosimendan is favourable up to the dose of 0.2 µg/kg/min. The daily dose of oral levosimendan in patients with ischaemic heart failure should not exceed 4 mg due to an increase in chronotropic response.
  • Kaheinen, Petri (2009)
    Acute heart failure syndrome represents a prominent and growing health problem all around the world. Ideally, medical treatment for patients admitted to hospital because of this syndrome, in addition to alleviating the acute symptoms, should also prevent myocardial damage, modulate neurohumoral and inflammatory activation, and preserve or even improve renal function. Levosimendan is a cardiac enhancer having both inotropic and vasodilatory effects. It is approved for the short-term treatment of acutely decompensated chronic heart failure, but it has been shown to have beneficial clinical effects also in ischemic heart disease and septic shock as well as in perioperative cardiac support. In the present study, the mechanisms of action of levosimendan were studied in isolated guinea-pig heart preparations: Langendorff-perfused heart, papillary muscle and permeabilized cardiomyocytes as well as in purified phosphodiesterase isoenzyme preparations. Levosimendan was shown to be a potent inotropic agent in isolated Langendorff-perfused heart and right ventricle papillary muscle. In permeabilized cardiomyocytes, it was demonstrated to be a potent calcium sensitizer in contrast to its enantiomer, dextrosimendan. It was additionally shown to be a very selective phosphodiesterase (PDE) type-3 inhibitor, the selectivity factor for PDE3 over PDE4 being 10000 for levosimendan. Irrespective of this very selective PDE3 inhibitory property in purified enzyme preparations, the inotropic effect of levosimendan was demonstrated to be mediated mainly through calcium sensitization in the isolated heart as well as the papillary muscle preparations at clinically relevant concentrations. In the isolated Lagendorff-perfused heart, glibenclamide antagonized the levosimendan-induced increase in coronary flow (CF). Therefore, the main vasodilatory mechanism in coronary veins is believed to be the opening of the ATP-sensitive potassium (KATP) channels. In the paced hearts, CF did not increase in parallel with oxygen consumption (MVO2), thus indicating that levosimendan had a direct vasodilatory effect on coronary veins. The pharmacology of levosimendan was clearly different from that of milrinone, which induced an increase in CF in parallel with MVO2. In conclusion, levosimendan was demonstrated to increase cardiac contractility by binding to cardiac troponin C and sensitizing the myofilament contractile proteins to calcium, and further to induce coronary vasodilatation by opening KATP channels in vascular smooth muscle. In addition, the efficiency of the cardiac contraction was shown to be more advantageous when the heart was perfused with levosimendan in comparison to milrinone perfusion.
  • Patja, Kristiina (Helsingin yliopisto, 2001)
  • Vainio, Saara (Helsingin yliopisto, 2006)
  • Tolonen, Nina (Helsingin yliopisto, 2015)
    Background: Cardiovascular disease is the most common cause of death in patients with type 1 diabetes, and the premature mortality rates are especially high in patients with diabetic nephropathy. Diabetic retinopathy is the leading cause of vision loss among the working-age population in industrialized countries. Early identification and aggressive treatment of risk factors are crucial to reduce the incidence of diabetic complications. Aims: To examine the relationships between lipid profiles and diabetic nephropathy, diabetic retinopathy, and incident coronary artery disease (CAD) events in a large nationwide cohort of patients with type 1 diabetes. Subjects and methods: These studies are part of the ongoing Finnish Diabetic Nephropathy Study (FinnDiane). Studies I (N=2927) and III (N=1465) have a cross-sectional design. At follow-up, renal status was verified by a review of all available medical files (Study II, N=2304), and data on CAD events were retrieved from the Finnish Hospital Discharge Register and the Causes of Death Register (Study IV, N=3520). Results: The recommended lipid concentrations of current treatment guidelines were poorly met, especially regarding the target for LDL cholesterol. Triglycerides and apolipoprotein (Apo) B were independent predictors of progression to micro- and macroalbuminuria, and total cholesterol was an independent predictor of progression to end-stage renal disease. HDL and HDL2 cholesterol were independently associated with proliferative diabetic retinopathy (PDR). In patients with PDR, the correlations between albumin excretion rate (AER) and lipid variables were strong. However, in patients without retinopathy no significant correlations were observed. In multivariate models, ApoB, triglycerides, non-HDL cholesterol, ApoB/ApoA-I ratio, and triglyceride/HDL cholesterol ratio were the strongest lipid predictors of an incident CAD event. Conclusions: Lipid abnormalities were associated with an increased risk of all three diabetic complications studied, i.e. diabetic nephropathy, retinopathy, and incident CAD events. Triglycerides and ApoB were independently associated with AER and estimated glomerular filtration rate (eGFR) and predicted the progression to micro- and macroalbuminuria as well as incident CAD events. Far lower concentrations of triglycerides than the currently recommended cut-off level (less than 1.7 mmol/l) increased the risk of progression of renal disease. Total and LDL cholesterol were poor predictors of an incident CAD event in patients with normal AER, in patients with HbA1c below the median (8.3%, 67mmol/l) of the cohort, and in women, in whom the ratios of atherogenic and anti-atherogenic lipoproteins and lipids performed better. Current treatment recommendations may need to be revised to reflect residual CAD risk in patients with type 1 diabetes.
  • 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.