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  • Kantojärvi, Katri (Helsingin yliopisto, 2013)
  • Vanhanen, Markku (Helsingin yliopisto, 2001)
  • Vaajanen, Anu (Helsingin yliopisto, 2009)
    Glaucoma is a multifactorial long-term ocular neuropathy associated with progressive loss of the visual field, retinal nerve fiber structural abnormalities and optic disc changes. Like arterial hypertension it is usually a symptomless disease, but if left untreated leads to visual disability and eventual blindness. All therapies currently used aim to lower intraocular pressure (IOP) in order to minimize cell death. Drugs with new mechanisms of action could protect glaucomatous eyes against blindness. Renin-angiotensin system (RAS) is known to regulate systemic blood pressure and compounds acting on it are in wide clinical use in the treatment of hypertension and heart failure but not yet in ophthalmological use. There are only few previous studies concerning intraocular RAS, though evidence is accumulating that drugs antagonizing RAS can also lower IOP, the only treatable risk factor in glaucoma. The main aim of this experimental study was to clarify the expression of the renin-angiotensin system in the eye tissues and to test its potential oculohypotensive effects and mechanisms. In addition, the possible relationship between the development of hypertension and IOP was evaluated in animal models. In conclusion, a novel angiotensin receptor type (Mas), as well as ACE2 enzyme- producing agonists for Mas, were described for the first time in the eye structures participating in the regulation of IOP. In addition, a Mas receptor agonist significantly reduced even normal IOP. The effect was abolished by a specific receptor antagonist. Intraocular, local RAS would thus to be involved in the regulation of IOP, probably even more in pathological conditions such as glaucoma though there was no unambiguous relationship between arterial and ocular hypertension. The findings suggest the potential as antiglaucomatous drugs of agents which increase ACE2 activity and the formation of angiotensin (1-7), or activate Mas receptors.
  • Louhimo, Johanna (Helsingin yliopisto, 2003)
  • Linder, Nina (Helsingin yliopisto, 2005)
  • Kalliomäki, Maija-Liisa (Helsingin yliopisto, 2003)
  • Volotinen, Marjo (Helsingin yliopisto, 2009)
    Glaucoma is a group of progressive optic neuropathies causing irreversible blindness if not diagnosed and treated in the early state of progression. Disease is often, but not always, associated with increased intraocular pressure (IOP), which is also the most important risk factor for glaucoma. Ophthlamic timolol preparations have been used for decades to lower increased intraocular pressure (IOP). Timolol is locally well tolerated but may cause e.g. cardiovascular and pulmonary adverse effects due to systemic absorption. It has been reported that approximately 80% of a topically administered eye drop is systemically absorbed. However, only limited information is available on timolol metabolism in the liver or especially in the human eye. The aim of this work was to investigate metabolism of timolol in human liver and human ocular tissues. The expression of drug metabolizing cytochrome P450 (CYP) enzymes in the human ciliary epithelial cells was studied. The metabolism of timolol and the interaction potential of timolol with other commercially available medicines were investigated in vitro using different liver preparations. The absorption of timolol to the aqueous humor from two commercially available products: 0.1% eye gel and 0.5% eye drops and the presence of timolol metabolites in the aqueous humor were investigated in a clinical trial. Timolol was confirmed to be metabolized mainly by CYP2D6 as previously suggested. Potent CYP2D6 inhibitors especially fluoxetine, paroxetine and quinidine inhibited the metabolism of timolol. The inhibition may be of clinical significance in patients using ophthalmic timolol products. CYP1A1 and CYP1B1 mRNAs were expressed in the human ciliary epithelial cells. CYP1B1 was also expressed at protein level and the expression was strongly induced by a known potent CYP1B1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The CYP1B1 induction is suggested to be mediated by aryl hydrocarbon receptor (AHR). Low levels of CYP2D6 mRNA splice variants were expressed in the human ciliary epithelial cells and very low levels of timolol metabolites were detected in the human aqueous humor. It seems that negligible amount of CYP2D6 protein is expressed in the human ocular tissues. Timolol 0.1% eye gel leads to aqueous humor concentration high enough to achieve therapeutic effect. Inter-individual variation in concentrations is low and intraocular as well as systemic safety can be increased when using this product with lower timolol concentration instead of timolol 0.5% eye drops.
  • Alakuijala, Anniina (Helsingin yliopisto, 2007)
    γ-aminobutyric acid (GABA) is the main inhibitory transmitter in the nervous system and acts via three distinct receptor classes: A, B, and C. GABAC receptors are ionotropic receptors comprising ρ subunits. In this work, we aimed to elucidate the expression of ρ subunits in the postnatal brain, the characteristics of ρ2 homo-oligomeric receptors, and the function of GABAC receptors in the hippocampus. In situ hybridization on rat brain slices showed ρ2 mRNA expression from the newborn in the superficial grey layer of the superior colliculus, from the first postnatal week in the hippocampal CA1 region and the pretectal nucleus of the optic tract, and in the adult dorsal lateral geniculate nucleus. Quantitative RT-PCR revealed expression of all three ρ subunits in the hippocampus and superior colliculus from the first postnatal day. In the hippocampus, ρ2 mRNA expression clearly dominated over ρ1 and ρ3. GABAC receptor protein expression was confirmed in the adult hippocampus, superior colliculus, and dorsal lateral geniculate nucleus by immunohistochemistry. From the selective distribution of ρ subunits, GABAC receptors may be hypothesized to be specifically involved in aspects of visual image motion processing in the rat brain. Although previous data had indicated a much higher expression level for ρ2 subunit transcripts than for ρ1 or ρ3 in the brain, previous work done on Xenopus oocytes had suggested that rat ρ2 subunits do not form functional homo-oligomeric GABAC receptors but need ρ1 or ρ3 subunits to form hetero-oligomers. Our results demonstrated, for the first time, that HEK 293 cells transfected with ρ2 cDNA displayed currents in whole-cell patch-clamp recordings. Homomeric rat ρ2 receptors had a decreased sensitivity to, but a high affinity for picrotoxin and a marked sensitivity to the GABAC receptor agonist CACA. Our results suggest that ρ2 subunits may contribute to brain function, also in areas not expressing other ρ subunits. Using extracellular electrophysiological recordings, we aimed to study the effects of the GABAC receptor agonists and antagonists on responses of the hippocampal neurons to electrical stimulation. Activation of GABAC receptors with CACA suppressed postsynaptic excitability and the GABAC receptor antagonist TPMPA inhibited the effects of CACA. Next, we aimed to display the activation of the GABAC receptors by synaptically released GABA using intracellular recordings. GABA-mediated long-lasting depolarizing responses evoked by high-frequency stimulation were prolonged by TPMPA. For weaker stimulation, the effect of TPMPA was enhanced after GABA uptake was inhibited. Our data demonstrate that GABAC receptors can be activated by endogenous synaptic transmitter release following strong stimulation or under conditions of reduced GABA uptake. The lack of GABAC receptor activation by less intensive stimulation under control conditions suggests that these receptors are extrasynaptic and activated via spillover of synaptically released GABA. Taken together with the restricted expression pattern of GABAC receptors in the brain and their distinctive pharmacological and biophysical properties, our findings supporting extrasynaptic localization of these receptors raise interesting possibilities for novel pharmacological therapies in the treatment of, for example, epilepsy and sleep disorders.
  • Weckroth, Miina (Helsingin yliopisto, 2004)
  • Renkonen, Suvi (Helsingin yliopisto, 2012)
    Background Juvenile Nasopharyngeal Angiofibroma (JNA) is a rare, benign tumour affecting adolescent males. Due to its capability to erode bone, JNA can be accompanied by life-threatening complications when growing into the cranium. The etiology of JNA is unknown, as are the factors determing the variable growth patterns of individual tumours. The treatment of choice for JNA is surgery, but high recurrence rates or persistent growth are charasteristic. Aims The aim of this study was to elucidate factors determing the variable outcomes of JNA. For this purpose the various surgical techniques used to resect JNA during the past 40 years at the Helsinki University Central Hospital (HUCH) were investigated, immunohistochemistry was performed and the gene copy number and mRNA expression data of two phenotypically different JNA tumours were combined to seek for processes putatively determining their growth pattern. Methods Retrospective clinicopathological data of all JNA patients diagnosed and treated, during the years 1970-2011, were reviewed. By immunohistochemistry, we investigated the cellular distribution and expression levels of C-KIT, C-MYC, BMI-1, GLUT-1, tenascin-C, syndecan-1, syndecan-2 and SYK in JNA samples, in order to find their possible correlations with clinicopathological factors. Comparative genomic hybridisation and gene expression analyses were performed for two phenotypically different tumour samples to investigate the possible processes leading to more aggressive growth. A gene ontology enrichment analysis for the in silico translated proteins of genes with altered gene expression status was performed to detect the categories with enrichments. Results The primary recurrence rate was 37% and correlated with the surgical approach used, transpalatal approach linked with higher risk of recurrence, vascularity of the tumour and young age of the patient. Contrary to previous reports, C-KIT was expressed in both stromal and endothelial cells of JNA samples and was more prominent in slit-like vessels. A correlation between its endothelial expression and cellular density of the tumour was found. Frequent stromal tenascin-C expression had a strong correlation with vessel density and higher tumour stage. When present, endothelial GLUT-1 expression correlated with higher tumour stage. SYK expression was found to correlate with lower tumour stage. Between the low and high stage JNA tumours studied, 1245 genes showed at least a two-fold- change in their expression. The corresponding proteins of these transcripts were enriched in different biological processes, e.g., hypoxia in the low stage tumour and signal transduction activity in the high stage tumour. Conclusions The type of surgical approach seemed crucial for the outcome. Other clinical factors affecting the recurrence rate were young age of the patient and vascular density of the tumour. In selective cases of JNA, we could thus carefully recommend the consideration of antiangiogenic treatment. Based on our finding of protein expressions, we suggest that at least C-KIT, tenascin-C, GLUT-1 and SYK might be substantial in the growth of JNA by having an effect on tumour cellularity, vessel density and the stage of the tumour. Based on our result of GLUT-1 positivity correlating with higher tumour stage, we suggest that JNAs are not likely to be vascular malformations. Although we were able to identify gene expression changes that relate to particular biological processes, the assessing of clinically relevant molecular profiles of JNA still requires further characterization. In the future, combinating molecular profiling data from several studies will be useful to better understand the molecular background of this rare tumour.
  • Tonteri, Elina (Helsingin yliopisto, 2014)
    Tick-borne encephalitis virus (TBEV) circulates mainly in the Ixodes ricinus and Ixodes persulcatus tick species, which serve both as hosts and vectors for the virus. Wild rodents are considered as bridges for non-viremic transmission between the ticks, which is the most important maintenance factor for TBEV. The fragile maintenance cycle of the virus is affected by climates and availability of biotic factors thus, TBEV is found in restricted foci. TBEV is transmitted to humans when bitten by an infected tick or when consuming contaminated milk. Infection may lead to a clinical disease, tick-borne encephalitis (TBE). In studies included in this thesis, we targeted both maintenance factors of TBEV in Finland, a country lying in the boreal region at the northernmost range endemic for the virus and surveyed the geographical distribution of all human TBE cases during years 2007-2013. In addition, we surveyed the determinants for development of TBE incidence. Apodemus flavicollis (yellow-necked mouse) has been considered as the main host species for maintenance of TBEV, at least in Central-Europe. However, in this study, the rodent species found in the studied TBEV foci in Finland were Myodes glareolus (bank vole) and Microtus agrestis (field vole). TBEV-RNA could be shown in wild rodents both in absence and presence of antibodies and was detected in wild voles in winter, several months after tick-feeding season. Furthermore, virus persisted in Myodes glareolus up to 168 days post infection also in an experimental setting. TBEV was highly neurotropic in voles both in wild and in an experimental infection study, thus we suggest, that brain is the best target organ for detecting TBEV in voles. Myodes glareolus provides an excellent and resistant model for studies on TBE - even if acute encephalitis was confirmed by histopathological examination, no significant clinical symptoms could be seen. Between years 2007-2013, 233 TBE cases were reported to the Finnish National Institute of Health and Welfare. New geographical places with confirmed patient cases are emerging in Finland. The incidence is increasing and shifting from Åland, where a national vaccination program is running, to the south-western archipelago and to mainland of Finland. In some areas, however, increase in case numbers may be due to the increased clinical alertness rather than or in addition to the changes in climate, ecological factors or human behavior as number of diagnostic samples sent to clinical laboratories did double during the study period. There are three subtypes of TBEV: European, Siberian and Far-Eastern, of which the two latter are mainly carried by I. persulcatus and the European by I.Ricinus. Both tick species and Siberian and European subtypes of TBEV have been found in Finland. In Simo, in Southern Lapland, TBEV was circulating both in Myodes glareolus and in ticks. This is so far the northernmost established TBEV focus known in the world. Furthermore the hosting tick species was found to be I.persulcatus, but unexpectedly the TBEV subtype was European. We suggest, that in the mixing zone of the two main host tick species and the virus subtypes the tick species in an area does not restrict the formation of a TBEV focus regardless of the presented virus subtype.
  • Hiltunen, Leena (Helsingin yliopisto, 2011)
    Factor V Leiden (FV Leiden) is the most common inherited thrombophilia in Caucasians increasing the risk for venous thrombosis. Its prevalence in Finland is 2-3%. FV Leiden has also been associated with several pregnancy complications. However, the importance of FV Leiden as their risk factor is unclear. The aim of the study was to assess FV Leiden as a risk factor for pregnancy complications in which prothrombotic mechanisms may play a part. Specifically, the study aimed to assess the magnitude of the risk, if any, associated with FV Leiden for pregnancy-associated venous thrombosis, pre-eclampsia, unexplained stillbirth, and preterm birth. The study was conducted as a nested case-control study within a fixed cohort of 100,000 consecutive pregnant women in Finland. The study was approved by the ethics committee of the Finnish Red Cross Blood Service and by the Ministry of Social Affairs and Health. All participants gave written informed consent. Cases and controls were identified by using national registers. The diagnoses of the 100,000 women identified from the National Register of Blood Group and Blood Group Antibodies of Pregnant Women were obtained from the National Hospital Discharge Register. Participants gave blood samples for DNA tests and filled in questionnaires. The medical records of the participants were reviewed in 49 maternity hospitals in Finland. Genotyping was performed in the Finnish Genome Center. When evaluating pregnancy-associated venous thrombosis (34 cases, 641 controls), FV Leiden was associated with 11-fold risk (OR 11.6, 95% CI 3.6-33.6). When only analyzing women with first venous thrombosis, the risk was 6-fold (OR 5.8, 95% CI 1.6-21.8). The risk was increased by common risk factors, the risk being highest in women with FV Leiden and pre-pregnancy BMI over 30 kg/m2 (75-fold), and in women with FV Leiden and age over 35 years (60-fold). When evaluating pre-eclampsia (248 cases, 679 controls), FV Leiden was associated with a trend of increased risk (OR 1.7, 95% CI 0.8-3.9), but the association was not statistically significant. When evaluating unexplained stillbirth (44 cases, 776 controls), FV Leiden was associated with over 3-fold risk (OR 3.8, 95% CI 1.2-11.6). When evaluating preterm birth (324 cases, 752 controls), FV Leiden was associated with over 2-fold risk (OR 2.4, 95% CI 1.3-4.6). FV Leiden was especially associated with late preterm birth (32-36 weeks of gestation), but not with early preterm birth (< 32 weeks of gestation). The results of this large population-based study can be generalized to Finnish women with pregnancies continuing beyond first trimester, and may be applied to Caucasian women in populations with similar prevalence of FV Leiden and high standard prenatal care.
  • Harjutsalo, Valma (Helsingin yliopisto, 2007)
    Type 1 diabetes (T1D) is a common, multifactorial disease with strong familial clustering. In Finland, the incidence of T1D among children aged 14 years or under is the highest in the world. The increase in incidence has been approximately 2.4% per year. Although most new T1D cases are sporadic the first-degree relatives are at an increased risk of developing the same disease. This study was designed to examine the familial aggregation of T1D and one of its serious complications, diabetic nephropathy (DN). More specifically the study aimed (1) to determine the concordance rates of T1D in monozygotic (MZ) and dizygotic (DZ) twins and to estimate the relative contributions of genetic and environmental factors to the variability in liability to T1D as well as to study the age at onset of diabetes in twins; (2) to obtain long-term empirical estimates of the risk of T1D among siblings of T1D patients and the factors related to this risk, especially the effect of age at onset of diabetes in the proband and the birth cohort effect; (3) to establish if DN is aggregating in a Finnish population-based cohort of families with multiple cases of T1D, and to assess its magnitude and particularly to find out whether the risk of DN in siblings is varying according to the severity of DN in the proband and/or the age at onset of T1D: (4) to assess the recurrence risk of T1D in the offspring of a Finnish population-based cohort of patients with childhood onset T1D, and to investigate potential sex-related effects in the transmission of T1D from the diabetic parents to their offspring as well as to study whether there is a temporal trend in the incidence. The study population comprised of the Finnish Young Twin Cohort (22,650 twin pairs), a population-based cohort of patients with T1D diagnosed at the age of 17 years or earlier between 1965 and 1979 (n=5,144) and all their siblings (n=10,168) and offspring (n=5,291). A polygenic, multifactorial liability model was fitted to the twin data. Kaplan-Meier analyses were used to provide the cumulative incidence for the development of T1D and DN. Cox s proportional hazards models were fitted to the data. Poisson regression analysis was used to evaluate temporal trends in incidence. Standardized incidence ratios (SIRs) between the first-degree relatives of T1D patients and background population were determined. The twin study showed that the vast majority of affected MZ twin pairs remained discordant. Pairwise concordance for T1D was 27.3% in MZ and 3.8% in DZ twins. The probandwise concordance estimates were 42.9% and 7.4%, respectively. The model with additive genetic and individual environmental effects was the best-fitting liability model to T1D, with 88% of the phenotypic variance due to genetic factors. The second paper showed that the 50-year cumulative incidence of T1D in the siblings of diabetic probands was 6.9%. A young age at diagnosis in the probands considerably increased the risk. If the proband was diagnosed at the age of 0-4, 5-9, 10-14, 15 or more, the corresponding 40-year cumulative risks were 13.2%, 7.8%, 4.7% and 3.4%. The cumulative incidence increased with increasing birth year. However, SIR among children aged 14 years or under was approximately 12 throughout the follow-up. The third paper showed that diabetic siblings of the probands with nephropathy had a 2.3 times higher risk of DN compared with siblings of probands free of nephropathy. The presence of end stage renal disease (ESRD) in the proband increases the risk three-fold for diabetic siblings. Being diagnosed with diabetes during puberty (10-14) or a few years before (5-9) increased the susceptibility for DN in the siblings. The fourth paper revealed that of the offspring of male probands, 7.8% were affected by the age of 20 compared with 5.3% of the offspring of female probands. Offspring of fathers with T1D have 1.7 times greater risk to be affected with T1D than the offspring of mothers with T1D. The excess risk in the offspring of male fathers manifested itself through the higher risk the younger the father was when diagnosed with T1D. Young age at onset of diabetes in fathers increased the risk of T1D greatly in the offspring, but no such pattern was seen in the offspring of diabetic mothers. The SIR among offspring aged 14 years or under remained fairly constant throughout the follow-up, approximately 10. The present study has provided new knowledge on T1D recurrence risk in the first-degree relatives and the risk factors modifying the risk. Twin data demonstrated high genetic liability for T1D and increased heritability. The vast majority of affected MZ twin pairs, however, remain discordant for T1D. This study confirmed the drastic impact of the young age at onset of diabetes in the probands on the increased risk of T1D in the first-degree relatives. The only exception was the absence of this pattern in the offspring of T1D mothers. Both the sibling and the offspring recurrence risk studies revealed dynamic changes in the cumulative incidence of T1D in the first-degree relatives. SIRs among the first-degree relatives of T1D patients seems to remain fairly constant. The study demonstrates that the penetrance of the susceptibility genes for T1D may be low, although strongly influenced by the environmental factors. Presence of familial aggregation of DN was confirmed for the first time in a population-based study. Although the majority of the sibling pairs with T1D were discordant for DN, its presence in one sibling doubles and presence of ESRD triples the risk of DN in the other diabetic sibling. An encouraging observation was that although the proportion of children to be diagnosed with T1D at the age of 4 or under is increasing, they seem to have a decreased risk of DN or at least delayed onset.
  • Nopola-Hemmi, Jaanamarja (Helsingin yliopisto, 2002)
  • Fagerudd, Johan (Helsingin yliopisto, 2000)
  • Kallinen, Outi (Helsingin yliopisto, 2013)
    To study fatal burns in the Helsinki Burn Center, sixteen years of data on burn deaths were collected and analyzed. These data included information obtained during pre-hospital care, clinical notes and autopsy reports. The study classified clinically missed diagnosis revealed in autopsy and paid special interest in the prevalence of adrenal hemorrhage (AH). The study was carried out in two phases. First phase included all deceased burn victims of Helsinki Burn Center from 1995 to 2005. The clinical charts and medicolegal autopsy reports with organ specific changes were retrieved and compared. The data were evaluated by a team of two plastic surgeons specialized in burn care, an intensivist, and a pathologist. Causes of death, incidence of multiple organ failure (MOF) and AH and occurrence of diagnostic discrepancies were documented and analyzed. The second phase includedburn patients with life-threatening burns in Helsinki Burn Center during 2006-2010.Pre-hospital patient records and clinical data collected during treatment were analyzed with reference to survival. The data were analyzed in groups based on the presence or absence of a physician in the pre-hospital phase. The majority of the burn victims die of untreatable burn injury (40%) or MOF (40%). Kidneys (100%) and liver (82%) were the organs most commonly affected in MOF. Lethal sepsis was never a sole cause of death, but always associated with MOF. Three MOF patients had bilateral adrenal hemorrhage. Medicolegal autopsies revealed major diagnostic discrepancies in less than 6% of patients. These diagnostic discrepancies would have altered the clinical outcome or therapy had they been known in time. The most commonly missed diagnosis was pneumonia. Patients treated by paramedics compared with patients treated by pre-hospital physicians were comparable with regard to age, gender and etiology of the injury. However, patients treated by pre-hospital physicians were more severely injured than patients treated by paramedics in terms of percentage of total body surface area (%TBSA) burned, injury severity score (ISS) and inhalation injuries. Patient s age, %TBSA and ISS are significantly associated with short- and long-term survival in burn patients. The study reveals all the causes of death of the burn patients in the study period in the Helsinki Burn Center.The usefulness of autopsies in providing valuable clinical data for the treatment of burn patients is emphasized. The study also highlights a few missed diagnoses that may occur in burn patients. The prevalence of AH was shown to be higher than previously estimated in non-surviving patients with burns. This study also reveals that the emergency medical system is able to recognize the situations and patients more likely to benefit from physician attendance.