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  • Natah, Sirajedin Sabri (Helsingin yliopisto, 2001)
  • Ilmarinen, Taru (Helsingin yliopisto, 2013)
    Some manifestations of human papillomavirus (HPV) infection are indolent and self-limiting, while others cause considerable morbidity. In recurrent respiratory papillomatosis (RRP), low-risk HPV types within the respiratory tract cause wart-like lesions, typically on vocal folds. The most common symptom is hoarseness, but stridor may also occur due to airway obstruction. In a minority of patients, the disease becomes aggressive and may undergo malignant transformation. Medical records were reviewed from all patients (n=32) treated for juvenile-onset recurrent respiratory papillomatosis (JORRP) between 1975 and 1994 at Helsinki University Hospital. Eighteen patients participated in a study assessing the effect of JORRP on adult voice quality and health-related quality of life (HRQOL). Compared to age- and gender-matched controls with similar smoking habits, the quality of voice in these adult patients with a history of JORRP was significantly lower in both acoustic and perceptual analyses. Significant differences emerged neither in HRQOL, nor in subjective voice-related handicap. Despite the viral etiology, treatment of RRP is based on surgery. Patients with frequently relapsing or otherwise aggressive disease may benefit from adjuvant medical therapies, such as local injections of cidofovir. Cidofovir is an antiviral medicine officially indicated for intravenous treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). Its intravenous administration has caused nephrotoxic side-effects and neutropenia. Animal studies have raised suspicions of its carcinogenicity. According to its manufacturer, patients treated either by off-label indications, or by an unapproved route of administration (intraocular or topical) have developed severe side-effects. An international multicenter study collected data from 635 RRP patients, 275 of which were treated with cidofovir. Mean follow-up after the first cidofovir injection was 3.3 years. Differences in incidence of upper respiratory tract and tracheal malignancies were non-significant between patients treated with and without cidofovir. After local administration of cidofovir, no clinical evidence emerged for nephrotoxicity or neutropenia. Between 1975 and 2011, a total of 324 RRP patients underwent treatment at Helsinki University Hospital for laryngeal papillomas (LPs). Nine patients (2.8%) developed laryngeal squamous cell carcinoma (SCC). Expression of toll-like receptors (TLRs) 2, 4, and 9 were analyzed in laryngeal tissue specimens from these patients by immunohistochemistry (IHC). Controls were 9 RRP patients without malignant transformation, 23 patients clinically presenting with chronic laryngitis, and 19 laryngeal SCC patients without pre-existing RRP. Compared to specimens from those with chronic laryngitis and laryngeal SCC, expression of cytoplasmic TLR4 and TLR9 was significantly lower in LPs. Nuclear TLR4 staining was significantly lower in LPs undergoing transformation into laryngeal SCC, than in LPs without malignant conversion. In laryngeal SCCs, high cytoplasmic staining for TLR4 was associated with higher grade and advanced T stage. HPV infections are spread through direct contact from skin or mucosa during sexual contact, and from mother to child during labor. Five RRP patients and five patients with genital warts participated with six physicians and twelve nurses in a study investigating transmission of HPV from patients to the oral mucosa and surgical gloves and masks of health care personnel during carbon dioxide (CO2) laser treatment. HPV deoxyribonucleic acid (DNA) was detected by polymerase chain reaction (PCR) on the surgical gloves, but not on the surgical masks or oral mucosa of health care personnel. Provided that protection is sufficient during CO2 laser treatment, the risk for HPV transmission to health care personnel seems low.
  • Laitinen, Arja (Helsingin yliopisto, 2009)
    The purpose of this study was to estimate the prevalence and distribution of reduced visual acuity, major chronic eye diseases, and subsequent need for eye care services in the Finnish adult population comprising persons aged 30 years and older. In addition, we analyzed the effect of decreased vision on functioning and need for assistance using the World Health Organization’s (WHO) International Classification of Functioning, Disability, and Health (ICF) as a framework. The study was based on the Health 2000 health examination survey, a nationally representative population-based comprehensive survey of health and functional capacity carried out in 2000 to 2001 in Finland. The study sample representing the Finnish population aged 30 years and older was drawn by a two-stage stratified cluster sampling. The Health 2000 survey included a home interview and a comprehensive health examination conducted at a nearby screening center. If the invited participants did not attend, an abridged examination was conducted at home or in an institution. Based on our finding in participants, the great majority (96%) of Finnish adults had at least moderate visual acuity (VA ≥ 0.5) with current refraction correction, if any. However, in the age group 75–84 years the prevalence decreased to 81%, and after 85 years to 46%. In the population aged 30 years and older, the prevalence of habitual visual impairment (VA ≤ 0.25) was 1.6%, and 0.5% were blind (VA < 0.1). The prevalence of visual impairment increased significantly with age (p < 0.001), and after the age of 65 years the increase was sharp. Visual impairment was equally common for both sexes (OR 1.20, 95% CI 0.82 – 1.74). Based on self-reported and/or register-based data, the estimated total prevalences of cataract, glaucoma, age-related maculopathy (ARM), and diabetic retinopathy (DR) in the study population were 10%, 5%, 4%, and 1%, respectively. The prevalence of all of these chronic eye diseases increased with age (p < 0.001). Cataract and glaucoma were more common in women than in men (OR 1.55, 95% CI 1.26 – 1.91 and OR 1.57, 95% CI 1.24 – 1.98, respectively). The most prevalent eye diseases in people with visual impairment (VA ≤ 0.25) were ARM (37%), unoperated cataract (27%), glaucoma (22%), and DR (7%). One-half (58%) of visually impaired people had had a vision examination during the past five years, and 79% had received some vision rehabilitation services, mainly in the form of spectacles (70%). Only one-third (31%) had received formal low vision rehabilitation (i.e., fitting of low vision aids, receiving patient education, training for orientation and mobility, training for activities of daily living (ADL), or consultation with a social worker). People with low vision (VA 0.1 – 0.25) were less likely to have received formal low vision rehabilitation, magnifying glasses, or other low vision aids than blind people (VA < 0.1). Furthermore, low cognitive capacity and living in an institution were associated with limited use of vision rehabilitation services. Of the visually impaired living in the community, 71% reported a need for assistance and 24% had an unmet need for assistance in everyday activities. Prevalence of ADL, instrumental activities of daily living (IADL), and mobility increased with decreasing VA (p < 0.001). Visually impaired persons (VA ≤ 0.25) were four times more likely to have ADL disabilities than those with good VA (VA ≥ 0.8) after adjustment for sociodemographic and behavioral factors and chronic conditions (OR 4.36, 95% CI 2.44 – 7.78). Limitations in IADL and measured mobility were five times as likely (OR 4.82, 95% CI 2.38 – 9.76 and OR 5.37, 95% CI 2.44 – 7.78, respectively) and self-reported mobility limitations were three times as likely (OR 3.07, 95% CI 1.67 – 9.63) as in persons with good VA. The high prevalence of age-related eye diseases and subsequent visual impairment in the fastest growing segment of the population will result in a substantial increase in the demand for eye care services in the future. Many of the visually impaired, especially older persons with decreased cognitive capacity or living in an institution, have not had a recent vision examination and lack adequate low vision rehabilitation. This highlights the need for regular evaluation of visual function in the elderly and an active dissemination of information about rehabilitation services. Decreased VA is strongly associated with functional limitations, and even a slight decrease in VA was found to be associated with limited functioning. Thus, continuous efforts are needed to identify and treat eye diseases to maintain patients’ quality of life and to alleviate the social and economic burden of serious eye diseases.
  • Vuori-Heikkilä, Elisa (Helsingin yliopisto, 2010)
    In anisometropia, the two eyes have unequal refractive power. Anisometropia is a risk factor for amblyopia. The visual deficiencies are thought to be irreversible after the first decade of life. There is, however, accumulating evidence that neural plasticity exists also in adult brains. The aim of this study was to investigate functional outcome of excimer laser refractive surgery in adult anisometropic and visually impaired patients. Additional goal was to examine changes in the primary visual cortex (V1) using multifocal functional magnetic resonance imaging (mffMRI) after laser refractive surgery. Study I comprised of 57 anisometropic patients (anisometropia of ≥3.25 diopters) and 174 isometropic myopic subjects formed the control group. A significant improvement in best-spectacle-corrected visual acuity (BSCVA) among myopic control subjects was evident 3 months postoperatively. The improvement in BSCVA was significantly slower for anisometropic patients and the improvement appeared to persist to the end of the follow-up (24 months). In study II we found that refractive surgery may be also successfully used for iathrogenic anisometropia. In Study III we evaluated mildly visually impaired adult patients after refractive surgery. There was a statistically significant improvement in BSCVA among visually impaired patients and the difference in the mean BSCVA between visually impaired patients and isometropic myopic control subjects diminished during follow-up. Study IV was a prospective follow-up trial examining the changes in the primary visual cortex after refractive surgery. Two anisometropic patients and two isometropic myopic patients were examined with a 61-region mffMRI before refractive surgery and at three, six, nine and twelve months postoperatively. In this study, a dramatic decrease in the number of active voxels in the fovea was found among anisometropic patients. The results presented in this thesis revealed that refractive surgery may be successfully used for the treatment of anisometropic adults with both congenital and iatrogenic anisometropia and for mildly visually impaired adults. The findings in conclusion strengthen our hypothesis of plastic changes in the visual cortex of adult anisometropic and mildly visually impaired patients after refractive surgery.
  • Maille, Kukka (Helsingin yliopisto, 2012)
    Inflammatory bowel diseases (IBD) and cancers of the gastrointestinal (GI) tract cause considerable morbidity and mortality. In order to enhance the diagnostics and therapeutic measures, the biology of these diseases needs to be better understood. Cellular targets and biomarkers are needed to identify subgroups of patients that are likely to respond to the treatments. This study concentrates on a novel potential biomarker. Its significance for the biology of the normal GI tract, the IBDs, the cancers of the GI tract and neuroendocrine tumors (NET) is studied. IBD cDNA expression libraries were screened to detect potential diagnostic, prognostic or predictive markers and/or targets for therapeutic intervention. A previously unknown gene, later named Reg IV, was identified. The gene was selected for characterization because of its restricted expression pattern and its upregulated expression in IBDs and in colorectal cancer (CRC). DNA cloning techniques, Western, Southern, and Northern blot techniques, cell culture, gene transfection, in situ hybridization, immunohistochemistry, and immunofluorescence were used to characterize Reg IV. Reg IV protein is a 17 kD secreted C-type lectin that belongs to the Reg protein family of known mitogens and/or antiapoptotic factors. It is physiologically expressed in enteroendocrine cells (EEC) and in proliferating goblet cells. It is expressed to a lesser extent in pancreas, stomach, prostate and testes. In EECs, it is co-expressed with serotonin and substance P, and partially co-expressed with somatostatin, ghrelin, PYY, GLP-1, GLP-2, and secretin. Interestingly, co-expression with somatostatin and ghrelin occurs only in colon and appendix, but not in the small intestine, which suggests different functions for EECs of the small intestine and colon. Reg IV protein expression was upregulated in the intestinal epithelium during inflammation and regeneration, i.e. in goblet cells of intestinal metaplasia, in proliferating margins of stomach ulcers, and in IBDs, so it can be considered a marker of reactive , proliferating goblet cells. Reg IV expression was upregulated in many mucinous and neuroendocrine tumors (NET). Strong expression was noted in mucinous cystadenoma of the appendix and pseudomyxoma peritonei. Reg IV expression in these tumors coincided partially with CDX2, MUC2, MUC5AC, and MUC6, but no regulatory correlation was found. Reg IV was also upregulated in NETs of small intestine, appendix, colon, lung, parathyroid, skin, and, more rarely, of pancreas. Co-expression with the intestinal transcription factor Hath1 was studied in normal gut epithelium and in the NETs, but no regulatory correlation was found. In ileal NET, a spatial correlation in with CD138, c-met, bFGF and HGF was found, supporting the existing data on the role of Reg IV in EGFR signaling and cell proliferation. Reg IV was thus found to be a novel member of the Reg protein family, an intestinal protein, and a putative mitogen. The regulation of its expression and its exact mechanisms of action still remain to be elucidated. Based on its expression pattern, Reg IV might have a role in maintaining the integrity of the epithelial lining of the GI tract, in the proliferation of goblet cells, and in the development of certain types of GI cancer, i.e., CRC, PMP and NETs. Further investigation is needed to confirm its value as a therapeutic target and/or prognostic or predictive biomarker.
  • Parviainen, Helka (Helsingin yliopisto, 2011)
    Transcription factors play a key role in tumor development, in which dysfunction of genes regulating tissue growth and differentiation is a central phenomenon. The GATA family of transcription factors consists of six members that bind to a consensus DNA sequence (A/T)GATA(A/G) in gene promoters and enhancers. The two GATA factors expressed in the adrenal cortex are GATA-4 and GATA-6. In both mice and humans, GATA-4 can be detected only during the fetal period, whereas GATA-6 expression is abundant both throughout development and in the adult. It is already established that GATA factors are important in both normal development and tumorigenesis of several endocrine organs, and expression of GATA-4 and GATA-6 is detected in adrenocortical tumors. The aim of this study was to elucidate the function of these factors in adrenocortical tumor growth. In embryonal development, the adrenocortical cells arise and differentiate from a common pool with gonadal steroidogenic cells, the urogenital ridge. As the adult adrenal cortex undergoes constant renewal, it is hypothesized that undifferentiated adrenocortical progenitor cells reside adjacent to the adrenal capsule and give rise to daughter cells that differentiate and migrate centripetally. A diverse array of hormones controls the differentiation, growth and survival of steroidogenic cells in the adrenal gland and the gonads. Factors such as luteinizing hormone and inhibins, traditionally associated with gonadal steroidogenic cells, can also influence the function of adrenocortical cells in physiological and pathophysiological states. Certain inbred strains of mice develop subcapsular adrenocortical tumors in response to gonadectomy. In this study, we found that these tumors express GATA-4, normally absent from the adult adrenal cortex, while GATA-6 expression is downregulated. Gonadal markers such as luteinizing hormone receptor, anti-Müllerian hormone and P450c17 are also expressed in the neoplastic cells, and the tumors produce gonadal hormones. The tumor cells have lost the expression of melanocortin-2 receptor and the CYP enzymes necessary for the synthesis of corticosterone and aldosterone. By way of xenograft studies utilizing NU/J nude mice, we confirmed that chronic gonadotropin elevation is sufficient to induce adrenocortical tumorigenesis in susceptible inbred strains. Collectively, these studies suggest that subcapsular adrenocortical progenitor cells can, under certain conditions, adopt a gonadal fate. We studied the molecular mechanisms involved in gene regulation in endocrine cells in order to elucidate the role of GATA factors in endocrine tissues. Ovarian granulosa cells express both GATA-4 and GATA-6, and the TGF-β signaling pathway is active in these cells. Inhibin-α is both a target gene for, and an atypical or antagonistic member of the TGF-β growth factor superfamily. In this study, we show that GATA-4 is required for TGF-β-mediated inhibin-α promoter activation in granulosa cells, and that GATA-4 physically interacts with Smad3, a TGF-β downstream protein. Apart from the regulation of steroidogenesis and other events in normal tissues, TGF-β signaling is implicated in tumors of multiple organs, including the adrenal cortex. Another signaling pathway found often to be aberrantly active in adrenocortical tumors is the Wnt pathway. As both of these pathways regulate the expression of inhibin-α, a transcriptional target for GATA-4 and GATA-6, we wanted to investigate whether GATA factors are associated with the components of these signaling cascades in human adrenocortical tumors. We found that the expression of Wnt co-receptors LRP5 and LRP6, Smad3, GATA-6 and SF-1 was diminished in adrenocortical carcinomas with poor outcome. All of these factors drive inhibin-α expression, and their expression in adrenocortical tumors correlated with that of inhibin-α. The results support a tumor suppressor role previously suggested for inhibin-α in the mouse adrenal cortex, and offer putative pathways associated with adrenocortical tumor aggressiveness. Unraveling the role of GATA factors and associated molecules in human and mouse adrenocortical tumors could ultimately contribute to the development of diagnostic tools and future therapies for these diseases.
  • Pietarinen-Runtti, Petra (Helsingin yliopisto, 2000)
  • Myllärniemi, Marjukka (Helsingin yliopisto, 1999)
  • Erkkilä, Krista (Helsingin yliopisto, 2002)
  • Liesmaa, Inka (Helsingin yliopisto, 2010)
    Accumulating evidence show that kinins, notably bradykinin (BK) and kallidin, have cardioprotective effects. To these include reduction of left ventricular hypertrophy (LVH) and progression of heart failure. The effects are mediated through two G protein-coupled receptors- bradykinin type-2 receptor (BK-2R) and bradykinin type -1 receptor (BK-1R). The widely accepted cardioprotective effects of BK-receptors relate to triggering the production and release of vasodilating nitric oxide (NO) by endothelial cells. They also exert anti-proliferative effects on fibroblasts and anti-hypertrophic effects on myocytes, and thus may play an essential role in the cardioprotective response to myocardial injury. The role for BK-1Rs in HF is based on experimental animal models, where the receptors have been linked to cardioprotective- but also to cardiotoxic -effects. The BK-1Rs are induced under inflammatory and ischemic conditions, shown in animal models; no previous reports, concerning BK-1Rs in human heart failure, have been presented. The expression of BK-2Rs is down-regulated in human end-stage heart failure. Present results showed that, in these patients, the BK-1Rs were up-regulated, suggesting that also BK-1Rs are involved in the pathogenesis of human heart failure. The receptors were localized mainly in the endothelium of intramyocardial coronary vessels, and correlated with the increased TNF-α expression in the myocardial coronary vessels. Moreover, in cultured endothelial cells, TNF-α was a potent trigger of BK-1Rs. These results suggest that cytokines may be responsible for the up-regulation of BK-1Rs in human heart failure. A linear relationship between BK-2R mRNA and protein expression in normal and failing human left ventricles implies that the BK-2Rs are regulated on the transcriptional level, at least in human myocardium. The expression of BK-2Rs correlated positively with age in normal and dilated hearts (IDC). The results suggest that human hearts adapts to age-related changes, by up-regulating the expression of cardioprotective BK-2Rs. Also, in the BK-2R promoter polymorphism -58 T/C, the C-allele was accumulated in cardiomyopathy patients which may partially explain the reduced number of BK-2Rs. Statins reduce the level of plasma cholesterol, but also exert several non-cholesterol-dependent effects. These effects were studied in human coronary arterial endothelial cells (hCAEC) and incubation with lovastatin induced both BK-1 and BK-2Rs in a time and concentration-dependent way. The induced BK-2Rs were functionally active, thus NO production and cGMP signaling was increased. Induction was abrogated by mevalonate, a direct HMG-CoA metabolite. Lovastatin is known to inhibit Rho activation, and by a selective RhoA kinase inhibitor (Y27632), a similar induction of BK-2R expression as with lovastatin. Interestingly a COX-2-inhibitor (NS398) inhibited this lovastatin-induction of BK-2Rs, suggesting that COX-2 inhibitors may affect the endothelial BK-2Rs, in a negative fashion. Hypoxia is a common denominator in HF but also in other cardiovascular diseases. An induction of BK-2Rs in mild hypoxic conditions was shown in cultured hCAECs, which was abolished by a specific BK-2R inhibitor Icatibant. These receptors were functionally active, thus BK increased and Icatibant inhibited the production of NO. In rat myocardium the expression of BK-2R was increased in the endothelium of vessels, forming at the border zone, between the scar tissue and the healthy myocardium. Moreover, in in vitro wound-healing assay, endothelial cells were cultured under hypoxic conditions and BK significantly increased the migration of these cells and as Icatibant inhibited it. These results show, that mild hypoxia triggers a temporal expression of functionally active BK-2Rs in human and rat endothelial cells, supporting a role for BK-2Rs, in hypoxia induced angiogenesis. Our and previous results show, that BK-Rs have an impact on the cardiovascular diseases. In humans, at the end stage of heart failure, the BK-2Rs are down-regulated and BK-1Rs induced. Whether the up-regulation of BK-1Rs, is a compensatory mechanism against the down-regulation of BK-2Rs, or merely reflects the end point of heart failure, remains to bee seen. In a clinical point of view, the up-regulation of BK-2Rs, under hypoxic conditions or statin treatment, suggests that, the induction of BK-2Rs is protective in cardiovascular pathologies and those treatments activating BK-2Rs, might give additional tools in treating heart failure.
  • Suomalainen, Laura (Helsingin yliopisto, 2004)
  • Pihlajoki, Marjut (Helsingin yliopisto, 2014)
    The main steroidogenic organs, adrenal cortex and ovary, arise from a common pool of progenitors in the developing embryo. Similar signaling pathways regulate the differentiation, growth, and survival of cells in these tissues. Proper development of the adrenal cortex and ovary requires precise spatiotemporal control of gene expression and apoptosis; disruption of these processes may lead to congenital disorders or malignant transformation. Earlier in vitro studies demonstrated that transcription factor GATA6 regulates the expression of multiple steroidogenic genes in the adrenal cortex. To show that GATA6 is a crucial regulator of adrenocortical development and function in vivo, we generated a mouse model in which Gata6 is conditionally deleted in steroidogenic cells. These mice exhibited a complex adrenal phenotype that includes cortical thinning, blunted aldosterone production, lack of an X-zone, impaired apoptosis, and subcapsular cell hyperplasia. These results offer genetic proof that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells. Ovarian granulosa cell tumors (GCTs), the most common sex-cord stromal tumors in women, are thought to be caused by aberrant granulosa cell apoptosis during folliculogenesis. A somatic missense mutation in transcription factor FOXL2 (402C→G) is present in vast majority of human GCTs. FOXL2 plays a key role in the development and function of normal granulosa cells. Wild type (wt) FOXL2 induces GCT cell apoptosis, while mutated FOXL2 is less effective. To clarify the molecular pathogenesis of GCTs, we investigated the impact of FOXL2 and two other factors implicated in granulosa cell function, GATA4 and SMAD3, on gene expression and cell viability in GCTs. We found that these factors physically interact and that GATA4 and SMAD3 synergistically induce CCND2 promoter transactivation, which is reduced by both wt and mutated FOXL2. Finally, we demonstrated that GATA4 and SMAD3 protect GCT cells from wt FOXL2 induced apoptosis without affecting the apoptosis induced by mutated FOXL2. These findings suggest that mutated FOXL2 disrupts the balance between growth and apoptosis in granulosa cells, leading to malignant transformation. The treatment of recurrent or metastatic GCTs is challenging, and biologically targeted treatment modalities are needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) activates the extrinsic apoptotic pathway. Interestingly, TRAIL is able to induce apoptosis in malignant cells without affecting normal cells. Vascular endothelial growth factor (VEGF) is the key regulator of both physiological and pathological angiogenesis. Cancer cells often express VEGF receptor, and an autocrine VEGF/VEGFR signaling loop exists in several types of cancer cells. We found that GCT cells express functional TRAIL and VEGF receptors, and that treatment with TRAIL and the VEGF-binding antibody (bevacizumab) induce GCT cell apoptosis. These findings establish a preclinical basis for targeting these two pathways in the GCT treatment.
  • Myöhänen, Heli (Helsingin yliopisto, 2003)
  • Martelin, Eeva (Helsingin yliopisto, 2004)