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  • Lyytinen, Heli (Helsingin yliopisto, 2009)
    Since national differences exist in genes, environment, diet and life habits and also in the use of postmenopausal hormone therapy (HT), the associations between different hormone therapies and the risk for breast cancer were studied among Finnish postmenopausal women. All Finnish women over 50 years of age who used HT were identified from the national medical reimbursement register, established in 1994, and followed up for breast cancer incidence (n= 8,382 cases) until 2005 with the aid of the Finnish Cancer Registry. The risk for breast cancer in HT users was compared to that in the general female population of the same age. Among women using oral or transdermal estradiol alone (ET) (n = 110,984) during the study period 1994-2002 the standardized incidence ratio (SIR) for breast cancer in users for < 5 years was 0.93 (95% confidence interval (CI) 0.80–1.04), and in users for ≥ 5 years 1.44 (1.29–1.59). This therapy was associated with similar rises in ductal and lobular types of breast cancer. Both localized stage (1.45; 1.26–1.66) and cancers spread to regional nodes (1.35; 1.09–1.65) were associated with the use of systemic ET. Oral estriol or vaginal estrogens were not accompanied with a risk for breast cancer. The use of estrogen-progestagen therapy (EPT) in the study period 1994-2005 (n= 221,551) was accompanied with an increased incidence of breast cancer (1.31;1.20-1.42) among women using oral or transdermal EPT for 3-5 years, and the incidence increased along with the increasing duration of exposure (≥10 years, 2.07;1.84-2.30). Continuous EPT entailed a significantly higher (2.44; 2.17-2.72) breast cancer incidence compared to sequential EPT (1.78; 1.64-1.90) after 5 years of use. The use of norethisterone acetate (NETA) as a supplement to estradiol was accompanied with a higher incidence of breast cancer after 5 years of use (2.03; 1.88-2.18) than that of medroxyprogesterone acetate (MPA) (1.64; 1.49-1.79). The SIR for the lobular type of breast cancer was increased within 3 years of EPT exposure (1.35; 1.18-1.53), and the incidence of the lobular type of breast cancer (2.93; 2.33-3.64) was significantly higher than that of the ductal type (1.92; 1.67-2.18) after 10 years of exposure. To control for some confounding factors, two case control studies were performed. All Finnish women between the ages of 50-62 in 1995-2007 and diagnosed with a first invasive breast cancer (n= 9,956) were identified from the Finnish Cancer Registry, and 3 controls of similar age (n=29,868) without breast cancer were retrieved from the Finnish national population registry. Subjects were linked to the medical reimbursement register for defining the HT use. The use of ET was not associated with an increased risk for breast cancer (1.00; 0.92-1.08). Neither was progestagen-only therapy used less than 3 years. However, the use of tibolone was associated with an elevated risk for breast cancer (1.39; 1.07-1.81). The case-control study confirmed the results of EPT regarding sequential vs. continuous use of progestagen, including progestagen released continuously by an intrauterine device; the increased risk was seen already within 3 years of use (1.65;1.32-2.07). The dose of NETA was not a determinant as regards the breast cancer risk. Both systemic ET, and EPT are associated with an elevation in the risk for breast cancer. These risks resemble to a large extent those seen in several other countries. The use of an intrauterine system alone or as a complement to systemic estradiol is also associated with a breast cancer risk. These data emphasize the need for detailed information to women who are considering starting the use of HT.
  • Domanskyi, Andrii (Helsingin yliopisto, 2007)
    Androgen receptor (AR) is necessary for normal male phenotype development and essential for spermatogenesis. AR is a classical steroid receptor mediating actions of male sex steroids testosterone and 5-alpha-dihydrotestosterone. Numerous coregulators interact with the receptor and regulate AR activity on target genes. This study deals with the characterization of androgen receptor-interacting protein 4 (ARIP4). ARIP4 binds DNA, interacts with AR in vitro and in cultured yeast and mammalian cells, and modulates AR-dependent transactivation. ARIP4 is an active DNA-dependent ATPase, and this enzymatic activity is essential for the ability of ARIP4 to modulate AR function. On the basis of sequence homology in its ATPase domain, ARIP4 belongs to the SNF2 family of proteins involved in chromatin remodeling, DNA repair, and homologous recombination. Similar to its closest homologs ATRX and Rad54, ARIP4 does not seem to be a classical chromatin remodeling protein in that it does not appear to form large protein complexes in vivo or remodel mononucleosomes in vitro. However, ARIP4 is able to generate superhelical torsion on linear DNA fragments. ARIP4 is covalently modified by SUMO-1, and mutation of six potential SUMO attachment sites abolishes the ability of ARIP4 to bind DNA, hydrolyze ATP, and activate AR function. ARIP4 expression starts in early embryonic development. In mouse embryo ARIP4 is present mainly in the neural tube and limb buds. In adult mouse tissues ARIP4 expression is virtually ubiquitous. In mouse testis ARIP4 is expressed in the nuclei of Sertoli cells in a stage-dependent manner. ARIP4 is also present in the nuclei of Leydig cells, spermatogonia, pachytene and diplotene spermatocytes. Testicular expression pattern of ARIP4 does not differ significantly in wild-type, FSHRKO, and LuRKO mice. In the testis of hpg mice, ARIP4 is found mainly in interstitial cells and has very low, if any, expression in Sertoli and germ cells. Heterozygous Arip4+/ mice are fertile and appear normal; however, they are haploinsufficient with regard to androgen action in Sertoli cells. In contrast, Arip4 / embryos are not viable. They have significantly reduced body size at E9.5 and die by E11.5. Compared to wild-type littermates, Arip4 / embryos possess a higher percentage of apoptotic cells at E9.5 and E10.5. Fibroblasts derived from Arip4 / embryos cease growing after 2-3 passages and exhibit a significantly increased apoptosis and decreased proliferation rate than cells from wild-type embryos. Our findings demonstrate that ARIP4 plays an essential role in mouse embryonic development. In addition, testicular expression and AR coregulatory activity of ARIP4 suggest a role of ARIP4-AR interaction in the somatic cells of the testis.
  • Kang , Zhigang (Helsingin yliopisto, 2006)
    Androgens control a variety of developmental processes that create the male phenotype and are important for maintaining male fertility and normal functions of tissues and organs that are not directly involved in procreation. Androgen receptor (AR) that mediates the biological actions of androgens is a member of the nuclear receptor superfamily of ligand-inducible transcription factors. Although AR was cloned over 15 years ago, the mechanisms by which it regulates gene expression are not well understood. A growing body of in vitro experimental evidence suggests that a complex network of proteins is involved in the androgen-dependent transcriptional regulation. However, the process of AR-dependent transcriptional regulation under physiological conditions is largely elusive. In the present study, a series of experiments were performed, including quantitative chromatin immunoprecipitation (ChIP) assays, to investigate AR-mediated transcription process using living prostate cancer cells. Our results show that the loading of AR and recruitment of coactivators and RNA polymerase II (Pol II) to both the promoter and enhancer of AR target genes are a transient and cyclic event that in addition to hyperacetylation, also involves dynamic changes in methylation, phosphorylation of core histone H3 in androgen-treated LNCaP cells. The dynamics of testosterone (T)-induced loading of AR onto the proximal promoters of the genes clearly differed from that loaded onto the distal enhancers. Significantly, more holo-AR was loaded onto the enhancers than the promoters, but the principal Pol II transcription complex was assembled on the promoters. By contrast, the pure antiandrogen bicalutamide (CDX) complexed to AR elicited occupancy of the PSA promoter, but was unable to load onto the PSA enhancer and was incapable of recruiting Pol II, coactivators and following changes of covalent histone modifications. The partial antagonist cyproterone acetate (CPA) and mifepristone (RU486) were capable of promoting AR loading onto both the PSA promoter and enhancer at a comparable efficiency with androgen in LNCaP cells expressing mutant AR. However, CPA- and RU486-bound AR not only recruited Pol II and coactivator p300 and GRIP1 onto the promoter and enhancer, but also recruited the corepressor NCoR onto the promoter as efficiently as CDX. In addition, we demonstrate that both proteasome and protein kinases are implicated in AR-mediated transcription. Even though proteasome inhibitor MG132 and protein kinase inhibitor DRB (5, 6-Dichlorobenzimidazole riboside) can block ligand-dependent accumulation of PSA mRNA with same efficiency, their use results in different molecular profiles in terms of the formation of AR-mediated transcriptional complex. Collectively, these results indicate that transcriptional activation by AR is a complicated process, which includes transient loading of holo-AR and recruitment of Pol II and coregulators accompanied by a cascade of distinct covalent histone modifications; This process involves both the promoter and enhancer elements, as well as other general components of the cell machineries e.g. proteasome and protein kinase; The pure antiandrogen CDX and the partial antagonist CPA and RU486 exhibit clearly different profiles in terms of their ability to induce the formation of AR-dependent transcriptional complexes and the histone modifications associated with the target genes in human prostate cancer cells. Finally, by using quantitative RT-PCR to compare the expression of sixteen AR co-regulators in prostate cancer cell lines, xenografts, and clinical prostate cancer specimens we suggest that AR co-regulators protein inhibitor of activated STAT1 (PIAS1) and steroid receptor coactivator 1(SRC1) could be involved in the progression of prostate cancer.
  • Lehto, Hanna (Helsingin yliopisto, 2015)
    Objective: Aneurysms of the vertebral artery (VA) and its branch posterior inferior cerebellar artery (PICA) are rare, comprising only about 1 to 3% of all intracranial aneurysms. The series published thus far on these lesions are small. We aim to describe the special anatomical and morphological features of these aneurysms compared to aneurysms in other locations, and to describe the variety of symptoms they cause. We describe their treatment and analyze the outcome. Additionally, we describe their anatomy imaged with computed tomography angiography. Patients and methods: We reviewed retrospectively 9 709 consecutive patients with intracranial aneurysms treated in the Department of Neurosurgery at Helsinki University Central Hospital, Finland, between 1934 and 2011. The study population included 268 patients with 284 VA or PICA aneurysms or both. Follow-up data came from the Population Registry Centre (dates of death), Statistics Finland (causes of death), from written questionnaires to patients still alive, medical records of the Department of Neurosurgery, and for those deceased, medical records from all public health services. Results: Among all the aneurysm patients, 5.1% had an aneurysm in the VA or PICA. Most aneurysms, 51%, were located at the VA PICA junction. The proportion of fusiform aneurysms was 28%. Compared to patients with ruptured aneurysms at other locations, patients with a ruptured VA or PICA aneurysm were older and had a higher Fisher grade. Ruptured distal PICA aneurysms also re-bled more regularly. Compared to other ruptured aneurysms, ruptured VA and PICA aneurysms were smaller and more often fusiform. At least one VA or PICA aneurysm was treated in 209 (78%) patients. The most common technique for aneurysm occlusion was clipping, used in 107 aneurysms. Total occlusion of the aneurysm was achieved among saccular aneurysms in 90%, and among fusiform aneurysms in 61%. Within one year of aneurysm diagnosis, 26% of the patients were dead. Among those who survived a minimum one year and in whom the VA or PICA aneurysm received active treatment; those returning to an independent or their previous stage of life amounted to 92%. Conclusion: In treatment of VA and PICA aneurysms, their special anatomical and morphological features are challenge. Despite this, and often severe hemorrhage, most patients surviving the initial stage make a good recovery.
  • Laurila, Jouni (Helsingin yliopisto, 2002)
  • Leppä, Elli (Helsingin yliopisto, 2011)
    Neurons can be divided into various classes according to their location, morphology, neurochemical identity and electrical properties. They form complex interconnected networks with precise roles for each cell type. GABAergic neurons expressing the calcium-binding protein parvalbumin (Pv) are mainly interneurons, which serve a coordinating function. Pv-cells modulate the activity of principal cells with high temporal precision. Abnormalities of Pv-interneuron activity in cortical areas have been linked to neuropsychiatric illnesses such as schizophrenia. Cerebellar Purkinje cells are known to be central to motor learning. They are the sole output from the layered cerebellar cortex to deep cerebellar nuclei. There are still many open questions about the precise role of Pv-neurons and Purkinje cells, many of which could be answered if one could achieve rapid, reversible cell-type specific modulation of the activity of these neurons and observe the subsequent changes at the whole-animal level. The aim of these studies was to develop a novel method for the modulation of Pv-neurons and Purkinje cells in vivo and to use this method to investigate the significance of inhibition in these neuronal types with a variety of behavioral experiments in addition to tissue autoradiography, electrophysiology and immunohistochemistry. The GABA(A) receptor γ2 subunit was ablated from Pv-neurons and Purkinje cells in four separate mouse lines. Pv-Δγ2 mice had wide-ranging behavioral alterations and increased GABA-insensitive binding indicative of an altered GABA(A) receptor composition, particularly in midbrain areas. PC-Δγ2 mice experienced little or no motor impairment despite the lack of inhibition in Purkinje cells. In Pv-Δγ2-partial rescue mice, a reversal of motor and cognitive deficits was observed in addition to restoration of the wild-type γ2F77 subunit to the reticular nucleus of thalamus and the cerebellar molecular layer. In PC-Δγ2-swap mice, zolpidem sensitivity was restored to Purkinje cells and the administration of systemic zolpidem evoked a transient motor impairment. On the basis of these results, it is concluded that this new method of cell-type specific modulation is a feasible way to modulate the activity of selected neuronal types. The importance of Purkinje cells to motor control supports previous studies, and the crucial involvement of Pv-neurons in a range of behavioral modalities is confirmed.
  • Uhlenius, Nina (Helsingin yliopisto, 2002)
  • von Schantz-Fant, Carina (Helsingin yliopisto, 2009)
    Neuronal ceroid lipofuscinoses (NCLs) are a family of inherited pediatric neurodegenerative disorders, leading to retinal degeneration, death of selective neuronal populations and accumulation of autofluorscent ceroid-lipopigments. The clinical manifestations are generally similar in all forms. The Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCLFin) is a form of NCL, especially enriched in the Finnish population. The aim of this thesis was to analyse the brain pathology of vLINCLFin utilising the novel Cln5-/- mouse model. Gene expression profiling of the brains of already symptomatic Cln5-/- mice revealed that inflammation, neurodegeneration and defects in myelinization are the major characteristics of the later stages of the disease. Histological characterization of the brain pathology confirmed that the thalamocortical system is affected in Cln5-/- mice, similarly to the other NCL mouse models. However, whereas the brain pathology in all other analyzed NCL mice initiate in the thalamus and spread only months later to the cortex, we observed that the sequence of events is uniquely reversed in Cln5-/- mice; beginning in the cortex and spreading to the thalamus only months later. We could also show that even though neurodegeneration is inititated in the cortex, reactive gliosis and loss of myelin are evident in specific nuclei of the thalamus already in the 1 month old brain. To obtain a deeper insight into the disturbed metabolic pathways, we performed gene expression profiling of presymptomatic mouse brains. We validated these findings with immunohistological analyses, and could show that cytoskeleton and myelin were affected in Cln5-/- mice. Comparison of gene expression profiling results of Cln5-/- and Cln1-/- mice, further highlighted that these two NCL models share a common defective pathway, leading to disturbances in the neuronal growth cone and cytoskeleton. Encouraged by the evidence of this defected pathway, we analyzed the molecular interactions of NCL-proteins and observed that Cln5 and Cln1/Ppt1 proteins interact with each other. Furthermore, we demonstrated that Cln5 and Cln1/Ppt1 share an interaction partner, the F1-ATP synthase, potentially linking both vLINCLFIN and INCL diseases to disturbed lipid metabolism. In addition, Cln5 was shown to interact with other NCL proteins; Cln2, Cln3, Cln6 and Cln8, implicating a central role for Cln5 in the NCL pathophysiology. This study is the first to describe the brain pathology and gene expression changes in the Cln5-/- mouse. Together the findings presented in this thesis represent novel information of the disease processes and the molecular mechanisms behind vLINCLFin and have highlighted that vLINCLFin forms a very important model to analyze the pathophysiology of NCL diseases.
  • Kyrklund, Kristiina (Helsingin yliopisto, 2016)
    Aims – To perform a detailed evaluation of the bowel functional outcomes of anorectal malformations (ARMs) after standardized treatment and systematic follow-up in relation to matched controls. To study the bowel habits of a large cohort of individuals from the general population to obtain a baseline for comparison to patients. Methods – A single-institution, cross-sectional study of all patients treated between 1983-2006 for anterior anus (AA, conservative or anal dilatations), perineal fistula (PF) males (anoplasty and/or dilatations) vestibular fistula (VF) or PF females (anterior sagittal anorectoplasty - ASARP) rectourethral fistula (RUF; posterior sagittal anorectoplasty – PSARP). Patients with significant cognitive impairment, total sacral agenesis/caudal regression syndrome, Currarino syndrome, or meningomyelocele were excluded. Participants answered a detailed questionnaire on bowel function by post. Parents of children <16 years assisted in responses. Case details were obtained from records. Patients were matched by age and gender to 3 individuals from the general population who had answered identical questionnaires. Ethical approval was obtained. Results – Our study of 594 individuals from the general population identified that minor aberrations in bowel function, especially soiling prevail in healthy individuals in an age-dependent manner. A total of 159 patients (72%; median age 12.5 (4-29) years) participated in the study on outcomes for ARMs (79 females: 45 AA and 34 VF/PF and 80 males: 46 PF/low ARM and 34 RUF males (35% bulbar, 53% prostatic, 12% bladder neck fistula). Fecal control in AA females and low ARM males was not significantly different from controls in the long-term (p=NS). In VF/PF in females, 68% of patients attained a functional outcome comparable to controls and 85% were socially continent (vs 100% of controls; p<0.001) Among RUF males, 76% of patients were social continent (vs 95% of controls; p<0.002). Despite some improvement in symptoms with increasing age, both soiling and fecal accidents among patients with VF/PF (65% and 24% respectively) and RUF (59% and 37% respectively) remained significantly higher than in controls in the long-term (18-26% for soiling and 4-6% for fecal accidents; p≤0.006 vs patients).The median BFS, the proportion with voluntary bowel movements and total continence decreased with increasing level of fistula in RUF. Constipation was an important sequel in all types of ARMs, affecting 31-44% of patients vs 2-13% of controls (p≤0.003 vs patients). Social restrictions affected a 15-36% of patients with severe ARMs (vs ≤5% of controls; p≤0.01). Conclusions - Our results support the appropriateness of sagittal repair methods for the treatment of VF/PF in females and RUF, and minor perineal procedures for mild ARMs. Patients with mild ARMs can generally be expected to develop bowel functional outcomes comparable to matched peers. In females with VF/PF and males with RUF, problems with fecal control persist at higher levels than controls into adulthood. However, the majority can be expected to achieve social continence with appropriate aftercare and effective management of constipation.
  • Jansson, Kim (Helsingin yliopisto, 2007)
    Anterior cruciate ligament (ACL) tear is a common sports injury of the knee. Arthroscopic reconstruction using autogenous graft material is widely used for patients with ACL instability. The grafts most commonly used are the patellar and the hamstring tendons, by various fixation techniques. Although clinical evaluation and conventional radiography are routinely used in follow-up after ACL surgery, magnetic resonance imaging (MRI) plays an important role in the diagnosis of complications after ACL surgery. The aim of this thesis was to study the clinical outcome of patellar and hamstring tendon ACL reconstruction techniques. In addition, the postoperative appearance of the ACL graft was evaluated using several MRI sequences. Of the 175 patients who underwent an arthroscopically assisted ACL reconstruction, 99 patients were randomized into patellar tendon (n=51) or hamstring tendon (n=48) groups. In addition, 62 patients with hamstring graft ACL reconstruction were randomized into either cross-pin (n=31) or interference screw (n=31) fixation groups. Follow-up evaluation determined knee laxity, isokinetic muscle performance and several knee scores. Lateral and anteroposterior view radiographs were obtained. Several MRI sequences were obtained with a 1.5-T imager. The appearance and enhancement pattern of the graft and periligamentous tissue, and the location of bone tunnels were evaluated. After MRI, arthroscopy was performed on 14 symptomatic knees. The results revealed no significant differences in the 2-year outcome between the groups. In the hamstring tendon group, the average femoral and tibial bone tunnel diameter increased during 2 years follow-up by 33% and 23%, respectively. In the asymptomatic knees, the graft showed homogeneous and low signal intensity with periligamentous streaks of intermediate signal intensity on T2-weighted MR images. In the symptomatic knees, arthroscopy revealed 12 abnormal grafts and two meniscal tears, each with an intact graft. Among 3 lax grafts visible on arthroscopy, MRI showed an intact graft and improper bone tunnel placement. For diagnosing graft failure, all MRI findings combined gave a specificity of 90% and a sensitivity of 81%. In conclusion, all techniques appeared to improve patients' performance, and were therefore considered as good choices for ACL reconstruction. In follow-up, MRI permits direct evaluation of the ACL graft, the bone tunnels, and additional disorders of the knee. Bone tunnel enlargement and periligamentous tissue showing contrast enhancement were non-specific MRI findings that did not signify ACL deficiency. With an intact graft and optimal femoral bone tunnel placement, graft deficiency is unlikely, and the MRI examination should be carefully scrutinized for possible other causes for the patients symptoms.
  • Song, Xin (Helsingin yliopisto, 2015)
    Background and aims: Obesity has become the sixth most important risk factor contributing to the overall burden of a variety of diseases worldwide. The association of anthropometric measures of obesity with mortality from various causes and incidence of cancers of various sites has been investigated, but it remains controversial. The aims of this study were to: 1) evaluate the epidemiological nature of the association of anthropometric measures of obesity with mortality from various causes, and to detect a potential threshold in this association; 2) study the epidemiological nature of the association between body mass index and incidence of cancer of different sites, and to detect a potential threshold in the association; 3) compare the strengths of different anthropometric measures of obesity in relation to cardiovascular disease (CVD) mortality; 4) assess the risk of CVD mortality in relation to obesity and sex in the general population, and also separately for those with or without diabetes at baseline. Study population and Methods: This study was based on data subsets of the Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study and the National FINRISK study, including 72 947 European men and 62 798 women (I), 26 636 Finnish men and 28 089 women (II), 24 686 European men and 21 965 women (III/IV), and 23 629 European men and 21 965 women (V) aged 24 years or above at baseline. Hazard ratios (HRs) corresponding to categorical or continuous body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) or waist-to-stature ratio (WSR), a body shape index (ABSI) and waist-to-hip-to-height ratio (WHHR) were estimated by the Cox proportional hazards model adjusting for several potential confounding factors measured at baseline. The non-parametric smooth functions of several anthropometric measures of obesity were fitted to health outcomes in order to explore the potential curvilinear relationship using the spline regression model, with a threshold detected by a piecewise regression model (II/III). HR per standard deviation increment of each anthropometric measure of obesity in relation to CVD mortality was compared using the paired homogeneity test (IV). Results: BMI, WC and WHtR had a U- or J-shaped relationship with all-cause mortality (I/III), whereas WHR, ABSI and WHHR had a linear positive relationship with all-cause mortality (III). BMI had a J-shaped relationship with CVD mortality (I/III), whereas anthropometric measures of abdominal obesity (WC, WHR, WHtR and ABSI) had a linear positive relationship with CVD mortality (III). BMI had a U-shaped relationship with cancer mortality in both men and women but disappeared among non-smokers, which showed no association (I). BMI had a linear positive association with incidence of cancers of the colon, liver, kidney, bladder and all sites combined in men, and of cancers of the stomach, colon, gallbladder and ovary in women, an inverse association with incidence of cancers of the lung in men and the lung and breast in women, and a J-shaped association with incidence of all cancers combined in women (II). A one-standard-deviation increase in all obesity indicators were significantly associated with a more than 19% increase of CVD mortality risk in both men and women, and the prediction for CVD mortality was stronger with anthropometric measures of abdominal obesity than that with BMI and ABSI, and most strongly with the WHtR/WSR (IV). Men had higher CVD mortality rates and higher HRs across BMI categories, and categories of abdominal obesity than women (V). The sex difference in CVD mortality was slightly smaller in obese than in non-obese individuals; the negative interactions were statistically significant between sex and WC (p =0.02), and sex and WHtR (p =0.01). None of the interaction terms was significant when the analyses were carried out among non-diabetic or diabetic individuals separately (V). Conclusions: This study confirmed the deleterious effect of obesity on mortality from various causes and incidence of cancers of certain sites. The prediction for CVD mortality with anthropometric measures of abdominal obesity was stronger than that with BMI, which may imply a more important role of fat distribution than fat accumulation and suggest that an effective obesity prevention strategy should emphasize the importance of abdominal obesity. Men had higher CVD mortality than women across all categories of anthropometric measures of obesity, which further supports the view of higher intra-abdominal fat accumulation in men than in women, even in non-obese individuals. Obesity seems slightly to diminish the female advantage in CVD mortality, irrespective of diabetes status. This may indicate that women may gradually lose their cardiovascular advantage when they are obese, probably due to a more pronounced clustering of CVD risk factors among obese women.
  • Nyamdorj, Regzedmaa (Helsingin yliopisto, 2010)
    Clinical trials have shown that weight reduction with lifestyles can delay or prevent diabetes and reduce blood pressure. An appropriate definition of obesity using anthropometric measures is useful in predicting diabetes and hypertension at the population level. However, there is debate on which of the measures of obesity is best or most strongly associated with diabetes and hypertension and on what are the optimal cut-off values for body mass index (BMI) and waist circumference (WC) in this regard. The aims of the study were 1) to compare the strength of the association for undiagnosed or newly diagnosed diabetes (or hypertension) with anthropometric measures of obesity in people of Asian origin, 2) to detect ethnic differences in the association of undiagnosed diabetes with obesity, 3) to identify ethnic- and sex-specific change point values of BMI and WC for changes in the prevalence of diabetes and 4) to evaluate the ethnic-specific WC cutoff values proposed by the International Diabetes Federation (IDF) in 2005 for central obesity. The study population comprised 28 435 men and 35 198 women, ≥ 25 years of age, from 39 cohorts participating in the DECODA and DECODE studies, including 5 Asian Indian (n = 13 537), 3 Mauritian Indian (n = 4505) and Mauritian Creole (n = 1075), 8 Chinese (n =10 801), 1 Filipino (n = 3841), 7 Japanese (n = 7934), 1 Mongolian (n = 1991), and 14 European (n = 20 979) studies. The prevalence of diabetes, hypertension and central obesity was estimated, using descriptive statistics, and the differences were determined with the χ2 test. The odds ratios (ORs) or  coefficients (from the logistic model) and hazard ratios (HRs, from the Cox model to interval censored data) for BMI, WC, waist-to-hip ratio (WHR), and waist-to-stature ratio (WSR) were estimated for diabetes and hypertension. The differences between BMI and WC, WHR or WSR were compared, applying paired homogeneity tests (Wald statistics with 1 df). Hierarchical three-level Bayesian change point analysis, adjusting for age, was applied to identify the most likely cut-off/change point values for BMI and WC in association with previously undiagnosed diabetes. The ORs for diabetes in men (women) with BMI, WC, WHR and WSR were 1.52 (1.59), 1.54 (1.70), 1.53 (1.50) and 1.62 (1.70), respectively and the corresponding ORs for hypertension were 1.68 (1.55), 1.66 (1.51), 1.45 (1.28) and 1.63 (1.50). For diabetes the OR for BMI did not differ from that for WC or WHR, but was lower than that for WSR (p = 0.001) in men while in women the ORs were higher for WC and WSR than for BMI (both p < 0.05). Hypertension was more strongly associated with BMI than with WHR in men (p < 0.001) and most strongly with BMI than with WHR (p < 0.001), WSR (p < 0.01) and WC (p < 0.05) in women. The HRs for incidence of diabetes and hypertension did not differ between BMI and the other three central obesity measures in Mauritian Indians and Mauritian Creoles during follow-ups of 5, 6 and 11 years. The prevalence of diabetes was highest in Asian Indians, lowest in Europeans and intermediate in others, given the same BMI or WC category. The  coefficients for diabetes in BMI (kg/m2) were (men/women): 0.34/0.28, 0.41/0.43, 0.42/0.61, 0.36/0.59 and 0.33/0.49 for Asian Indian, Chinese, Japanese, Mauritian Indian and European (overall homogeneity test: p > 0.05 in men and p < 0.001 in women). Similar results were obtained in WC (cm). Asian Indian women had lower  coefficients than women of other ethnicities. The change points for BMI were 29.5, 25.6, 24.0, 24.0 and 21.5 in men and 29.4, 25.2, 24.9, 25.3 and 22.5 (kg/m2) in women of European, Chinese, Mauritian Indian, Japanese, and Asian Indian descent. The change points for WC were 100, 85, 79 and 82 cm in men and 91, 82, 82 and 76 cm in women of European, Chinese, Mauritian Indian, and Asian Indian. The prevalence of central obesity using the 2005 IDF definition was higher in Japanese men but lower in Japanese women than in their Asian counterparts. The prevalence of central obesity was 52 times higher in Japanese men but 0.8 times lower in Japanese women compared to the National Cholesterol Education Programme definition. The findings suggest that both BMI and WC predicted diabetes and hypertension equally well in all ethnic groups. At the same BMI or WC level, the prevalence of diabetes was highest in Asian Indians, lowest in Europeans and intermediate in others. Ethnic- and sex-specific change points of BMI and WC should be considered in setting diagnostic criteria for obesity to detect undiagnosed or newly diagnosed diabetes.
  • Mattsson, Johanna (Helsingin yliopisto, 2014)
    Prostate-specific antigen (PSA) is a very useful biomarker for prostate cancer. The PSA concentration in circulation increases due to leakage of PSA from cancerous tissue. Normally PSA, a serine protease with chymotrypsin-like enzymatic activity, is secreted into seminal fluid by the epithelial cells of the prostate. The major physiological function of PSA in seminal fluid is to digest semenogelins, which leads to liquefaction of the seminal clot. Several other functions have also been suggested for PSA, some of which are associated with cancer. PSA exerts antiangiogenic activity, but PSA may also promote tumor growth and metastatic dissemination. The aim of the research presented in this thesis was to characterize the antiangiogenic and proteolytic activities of PSA. One of the main goals was to elucidate whether the enzymatic activity of PSA is a requirement for its antiangiogenic activity. The antiangiogenic activity of PSA was studied using an in vitro angiogenesis model based on tube formation of human umbilical vein endothelial cells (HUVEC). In this model only enzymatically active PSA was able to inhibit angiogenesis. Peptides that stimulate the proteolytic activity of PSA enhanced the antiangiogenic activity, while small molecule compounds that inhibit PSA abolished this activity. DNA microarray study showed that PSA-induced changes in the gene expression of HUVECs were small during tube formation, and it was not clear whether these changes were primary or secondary to the antiangiogenic activity of PSA. The results of this thesis suggest that the antiangiogenic activity of PSA is mediated by a proteolytic product generated by PSA. The proteolytic activity of PSA was studied using several peptide and protein substrates. Semenogelins are the major physiological substrates of PSA and they were shown to be degraded much more rapidly than any other protein substrate studied. Nidogen-1, a component of the basement membrane, was identified as a novel substrate for PSA by mass spectrometry. However, the cleavage of nidogen-1 did not explain the antiangiogenic activity of PSA, since either its fragments or full-length form did not affect HUVEC tube formation. Contrary to a previous report, we showed that the antiangiogenic activity of PSA was not mediated by angiostatin-like fragments generated by the cleavage of plasminogen. The results of this thesis established that the proteolytic activity is necessary for the antiangiogenic activity of PSA and that the antiangiogenic activity can be enhanced by PSA-stimulating peptides and abolished by PSA-inhibitors. The comparison of the efficiency of PSA to cleave different protein substrates and the identification of nidogen-1 as one of these substrates provided new information about the biological role of PSA. The typically slow growth of most prostate cancers may be caused by the antiangiogenic activity of PSA, as there are high concentrations of active PSA present in prostatic tissue. Therefore, peptides that stimulate the antiangiogenic activity of PSA and reduce tumor angiogenesis could be used to control prostate cancer growth.
  • Kreutzman, Anna (Helsingin yliopisto, 2012)
    Tyrosine kinase inhibitors (TKIs), such as imatinib (Glivec®) and dasatinib (Sprycel®), have dramatically improved the outcome of chronic myeloid leukemia (CML) patients. Besides inhibiting the actual on-target BCR-ABL1 kinase in leukemic cells, TKIs also inhibit several off-target kinases, which may affect healthy cells. Dasatinib has a particularly wide kinase-inhibition profile and inhibits kinases important in immune effector cells, such as SRC-kinases. Opposite to immunosuppressive in vitro effects, dasatinib induces an oligoclonal expansion of large granular lymphocytes (LGLs) in the blood in vivo, which has been associated with improved therapy responses. The purpose of this PhD thesis was to uncover the cellular and molecular mechanisms of dasatinib-related LGL lymphocytosis. Unlike healthy controls, clonal lymphocytes were detected in the majority of CML patients at diagnosis. During dasatinib therapy these clones expanded, eventually leading to absolute lymphocytosis. Hypothetically, the lymphocyte clones detected at diagnosis are unresponsive (anergic) anti-leukemic clones, which recover, reactivate and expand during dasatinib therapy. In concord, the expanded CD8+ T cells and NK cells had a late differentiated phenotype of long-lived T-cells. The long-term dasatinib treatment also differentiated CD4+ T cells into cytotoxic LGLs. These unique CD4-LGLs secreted increased amounts of IFN-gamma indicating a sensitized role in eliminating leukemic cells. Dasatinib therapy also enhanced the cytotoxicity of NK cells. Immunomodulatory effects of IFN-α treatment in CML patients were also studied. Previous work have shown that a small proportion of IFN-α treated patients can permanently discontinue therapy without relapse. This curative property of IFN-α could be caused by an immune mediated mechanism and as a proof of this, we noticed that patients who had responded very well to treatment, had an increased number of CD8+ T cells and unique clonal γ/δ T cells. Intriguingly, patients who were able to stop the treatment also had significantly higher numbers of NK cells. Taken together, the results in this PhD project provide a proof of a unique, previously unrecognized dual mode of action of TKI-treatment: direct cytotoxic effects are accompanied with the activation of immune system which is potentially relevant for the long-term control of CML. These findings can be utilized in developing novel immunotargeting therapies of leukemia and other cancers.
  • Rummukainen, Maija-Liisa (Helsingin yliopisto, 2013)
    Background and aims. The rapidly growing ageing population results in a demand for new types of housing that may face the same challenges as nursing homes (NHs) do today. Elderly persons are at particular risk for healthcare-associated infections, since few long-term care facilities (LTCFs) have in-house expertise in infection control or in infectious diseases. This may lead to inappropriate prescription of antimicrobials and promote development of multidrug-resistant bacteria. The movement of residents between LTCFs and acute-care hospitals facilitates the spread of resistant bacteria. The aim of the present study was to determine the use of antimicrobials and prevalence of infections in LTCFs in Finland. An additional aim was to evaluate the feasibility of different methods in assessing antibiotic use and prevalence of infections in LTCFs. Methods. A team comprising an infectious disease consultant, an infection control nurse, and a geriatrician visited all 123 LTCFs for elderly persons in the Central Finland Healthcare District during 2004 2005. The site visits consisted of a structured interview concerning patients, ongoing systemic antimicrobial use, diagnostic practices for urinary tract infection (UTI), and monthly amount in liters of alcohol-based hand rubs used and in patient-days. Following the visits, regional guidelines for prudent use of antimicrobials in LTCFs were published and the use of antimicrobials was followed up by an annual questionnaire during 2006-2008. All residents present in nine voluntary NHs for ≥ 24 hours (n = 5,791) and receiving systemic antimicrobials on the day of the survey were included in the study. Data on antibiotics and their indications (prophylaxis or treatment, type of infection) were collected in April and November 2009 and May-September 2010. All residents for whom a Minimum Data Set (MDS) form (n = 12,784) was completed in 753 LTCFs using a Resident Assessment Instrument (RAI) in April and September 2011 were included. Results. The proportions of patients receiving antimicrobials in surveys varied between 10% and 19%. Most of the antimicrobials were used for UTI prophylaxis (42-69%) and treatment (13-25%). The proportion of patients on UTI prophylaxis decreased in the Central Finland Healthcare District from 13% to 6% and in eight NHs from 12% to 6%. The most common antimicrobial used was methenamine (36-44%), followed by trimetoprim (14-31%), cephalexin (6-9%), and pivmecillinam (6-11%). In Central Finland Healthcare District LTCFs, the total amount of alcohol-based hand rub used increased by 70%, from the mean (SD) of 7.3 (5.1) L/1000 patient-days on the baseline visit in 2005 to 12.4 (14.9) L in 2008. In LTCFs using RAI, the risk factors for antimicrobial prescription included female sex, age < 85 years, urinary catheter, urinary incontinence, confusion, restriction to bed, pressure ulcers, diarrhea, and hospital stay during the previous 90 days. Conclusions. Antimicrobial use was common in Finnish LTCFs and most were used for UTI prophylaxis and treatment. The decrease in antimicrobial usage during the surveys suggests that LTCFs may benefit from antimicrobial stewardship interventions focused on UTI. The multidisciplinary team succeeded in promoting hand hygiene in LTCFs, which was sustained over the 3-year follow-up. RAI with MDS data also constitutes a feasible tool for collecting data on antibiotic use and infections in LTCFs.
  • Järvinen, Kristiina (Helsingin yliopisto, 2001)