Lääketieteellinen tiedekunta

 

Recent Submissions

  • Häkkinen, Heini (Helsingin yliopisto, 2016)
    Muissa Euroopan maissa tehtyjen tutkimusten mukaan näyttäisi siltä, että paperittomien odottajien raskauden seurantaan liittyy monia ongelmia, kuten myöhäinen hakeutuminen terveydenhuollon palveluiden piiriin. Suomessa tutkimusnäyttöä paperittomien naisten raskauden seurannan toteutumisesta ei ole. Tutkimuksemme tarkoituksena oli selvittää muun muassa, mistä paperittomat synnyttäjät ovat kotoisin, miten heidän neuvolaseurantansa toteutui ja miten synnytys eteni. Tavoitteena oli kehittää paperittomien odottajien hoitopolkua neuvolassa ja synnytyssairaalassa. Vapaaehtoisvoimin toimiva paperittomien klinikka, Global clinic, pitää kirjaa asiakkaistaan. Näiden asiakastietojen perusteella Helsingin ja Uudenmaan sairaanhoitopiirin potilastietojärjestelmistä haettiin synnytykseen liittyvät käynnit ja toteutuneet laboratoriotutkimukset. Aineiston koko jäi pieneksi, minkä vuoksi luotettavaa analyysia tuloksista ei voitu tehdä. Näyttäisi kuitenkin siltä, että myös Suomessa paperittomat odottajat hakeutuvat äitiysneuvolaan myöhemmin kuin suomalaisnaiset keskimäärin. Lisäksi paperittomilla on todennäköisesti suhteellisesti enemmän sukupuoliteitse tarttuvia tauteja. Lisää tutkimusta aiheesta kuitenkin tarvitaan.
  • Patjas, Anu (Helsingin yliopisto, 2016)
    Urinary tract infections (UTIs) are among women’s most common infections, E. coli causing most of these. The proportion of ESBL E. coli as a causative agent of UTIs has been increasing. The aim of this study is to investigate factors predisposing to ESBL E. coli caused UTIs. Data about urine samples was gathered from HUSLAB database. All patients with ESBL E. coli and a consistent amount of ESBL negative UTI patients were invited to participate in the study. Participants filled a questionnaire online. A descriptive analysis was done on all urine samples with E. coli growth. Risk factor analyses were performed on data received by questionnaire. Prevalence of ESBL was greatest in men over the age of 50. Travelling during preceding year by the patient himself or by a person living in a same household and use of antibiotics during past year were detected as risk factors for ESBL UTI.
  • Viitanen, Janne (Helsingin yliopisto, 2016)
    Objective Mitochondrial recessive ataxia syndrome (MIRAS) patients’ phenotypes vary from early onset epileptic seizures to late onset ataxia and neuropathy. We aim to find possible phenotype influencing and this study focuses on folate as a predisposing factor. Methods MIRAS Patients (n=8; 2 early-onset, 3-early-adult-onset, 3 late-onset; all carriers of W748S) were interviewed, eating habits analyzed with food diaries and patients’ folate levels analyzed. Results Early onset patients were markedly overweight at age of onset, while late-onset patients were mostly of normal weight at age of onset. Folate intake was inadequate but blood folate values were in normal range. Patients’ folate serum levels were noticeably but non-significantly lower than controls’, the levels correlated with age of onset(p<0,05). Patient erythrocyte folate levels did not differ from controls. Conclusion Weight gain and serum folate levels may be associated with an earlier age of onset. Patient folate levels are not markedly different from controls.
  • Rowland, Daniel (Helsingin yliopisto, 2016)
    Dientamoeba fragilis is an intestinal parasite that has attracted increasing interest due to its high prevalence and potential to perpetrate long-standing gastrointestinal symptoms. A number of patients have been treated at the Aurora hospital infectious diseases outpatient clinic for dientamoebiasis. Experience has shown that some patients repeatedly fail to respond to treatment. In this retrospective study, we set out to establish whether reinfection from infected family members is a cause of failed treatment. The results show that concurrent infection of multiple family members is not only common, but has a significant effect on treatment results. This suggests that contact tracing should be considered in treatment resistant cases and simultaneous medication of family members is worthwhile. Checking results both immediately and three months post-treatment is not useful. We also investigated the reliability of microscopy for the detection of D. fragilis, reinforcing the view that at least three samples are required.
  • Sunila, Iiro (Helsingin yliopisto, 2016)
    Tutkielman tavoitteena oli selvittää lapsuusiässä alkavan eli juveniilin spondylartriitin (JSpA) ominaisuuksia 16–20 vuotiailla potilailla. Tutkimustieto muodostettiin HYKS:n reumatologian siirtymävaiheen poliklinikalla 1.1.2015–31.3.2016 hoidossa olleiden lasten selkärankareuma (JAS) -diagnoosin saaneiden seitsemäntoista potilaan (n=17) sairaskertomusmerkinnöistä retrospektiivisesti. Potilaista 70,6 % oli miespuolisia. HLA- B27 genotyyppi todettiin 94,5 %:lla. Ensioireet alkoivat keskimäärin 11,6-vuotiaana. JSpA-diagnoosi asetettiin keskimäärin 13,8-vuotiaana. 88,2 %:lla selkää magneettikuvattiin, ja heistä kaikilla todettiin selkärangan tulehdusmuutoksia. Selkärangan ulkopuoliset niveloireet (70,6 %:lla) ja jänteiden tulehdukset (35,3%:lla) esiintyivät pääosin alaraajoissa. 23,5 %:lla tautikuva tulkittiin infektion laukaisemaksi reaktiiviseksi artriitiksi (ReA), jolloin oireet poikkesivat muista tapauksista käsittäen myös yläraajan niveltulehduksia (r=1,000, p=0,000) ja tulehdusoireilua useammassa nivelessä (p=0,001.) Tulehduksellinen suolistosairaus (IBD) todettiin 5,9 %:lla, mutta nivelpsoriasista (PsA) ei kenelläkään. Antireumaattista lääkitystä (DMARD) oli käytetty 94,1 %:lla. Biologisella DMARD-hoidolla (aloitettiin 52,9 %:lla) todettiin yhteys alhaisempaan kliiniseen taudin aktiivisuuteen. Vakavia lääkehaittavaikutuksia ei todettu. Tutkimuksen päätepisteessä potilaiden kokonaislääkehoitoa vähennettiin rauhallisen taudinkuvan vuoksi. 58,8 %:lla taudin voitiin katsoa olevan remissiossa. Reumakirurgiaa ei tehty kenellekään.
  • Li, Huini (Helsingin yliopisto, 2016)
    Glioblastoma Multiforme (GBM) is the most common and aggressive types of glioma in adults. Autophagy allows degradation and recycling of cellular components such as damaged proteins and dysfunctional organelles to sustain the metabolism and homeostasis of rapidly growing cells. Recent reports suggest that autophagy may promote tumor cell survival under stress condi-tions and can be an emerging target for cancer therapy. Autophagy inhibitor combined with TMZ can induce glioblastoma cell death and improve the radiotherapy efficacy. The Neuropilin-1 (NRP1) is 120 kDa-130 kDa type I integral transmembrane protein. It was originally identified as a co-receptor for the class 3 semaphorins (SEMA3) involved in axon guidance and found to interact with VEGF/VEGFR2 to promote angio-genesis. Recent studies have revealed its much broader roles on tumor progression. In various types of human cancers, NRP1 is often up-regulated and associated with aggressive clinical tumor behaviour. NRP1 overexpression is independently correlated with poor prognosis in human glioma and contributes to balance the glioblastoma cell proliferation and survival. In cancer cells, it interacts with diverse growth factor receptors including TGFR, c-Met, FGFR, EGFR as well as PDGFR to promote their signal-ling pathways in tumor cell survival, proliferation, migration and invasion. Although these functions of NRP1 mainly rely on its ectodomain, the cytoplasmic domain of NRP1 has been recently found to be essential for the internalization of NRP1-binding complex. In addition, the C-terminal SEA sequence on its cytoplasmic domain have potential to bind intracellular PDZ domain-containing molecules. Tyrosine phosphorylation of p130Cas has been identified to regulate the downstream pathways of NRP1, which is dependent on NRP1 intracellular domain. However, the downstream trafficking of NRP1 is poorly understood and its tumor-promoting function relevance remains ambiguous. The p62/Sequestosome 1, encoded by SQSTM1 gene, is an intracellular protein commonly found in inclusion bodies. It is asso-ciated with protein aggregation diseases in liver and brain. Owing to its ability to interact with multiple important cellular intermedi-ates, it works as a ‘hub’ adaptor linked to nuclear factor-kappaB (NF-κB) activation, protein aggregates formation, selective au-tophagy, adipogenesis and tumorigenesis. The p62 has a critical role on autophagy via regulating the collection and delivery of ubiquitinylated cargos to the autophagosome via its PB1, UBA and LIR domains. On the other hand, recent study has revealed a new role of p62 as a negative regulator in the autophagy regulation. High level of p62 is able to suppress the autophagy by pro-moting mTORC1 activation. This route forms a feed-forward loop for increasing level of p62 due to the reduced autophagy. Thus, p62 plays a critical role in regulation of autophagy. Here we observed that suppression of NRP1 in glioblastoma cell clearly exhibits a defected autophagy accompanied by marked accumulation of p62, the autophagic adaptor. Overexpression of NRP1 by glioblastoma cells shows enhanced autophagy flux. These data suggests the role of NRP1 in autophagy promotion. In addition, we mapped out that p62 binds to the cytoplasmic domain of NRP1 mediating its pro-autophagy effects. PB1 domain of p62 overexpression enhances the p62-positive aggregates and NRP1/p62 interaction. Taken together, our results define a novel role of NRP1 in the regulation of autophagy through its association with p62. In summary, our present results provide novel insights into the molecular basis of the emerging interplay between NRP1 and autophagy, the identification of a new cytoplasmic protein that binding to intracellular domain of NRP1 and the implications of the p62-mediated signalling loop for NRP1-promoted autophagy in GBMs. Since efforts to inhibit autophagy to improve GBM thera-py have thereby attracted great interest, our findings may provide valuable clues for future cancer therapeutic strategies.
  • Schmidt, Eeva-Kaisa; Atula, Sari; Tanskanen, Maarit; Nikoskinen, Tuuli; Notkola, Irma-Leena; Kiuru-Enari, Sari (Helsingin yliopisto, 2016)
    Background: Finnish type of hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant disorder. Until recently, there has only been little knowledge of fatal complications of the disease and its possible impact on the patients’ life span. Methods: We identified 272 deceased patients based on patient interviews and genealogical data. After collecting their death certificates we recorded the patients’ underlying and immediate causes of death (CoD) and life span and compared them to the general Finnish population. We then calculated proportional mortality ratios (PMR), standardised for age and sex, for the CoDs. Results: The underlying CoD in 20% of the patients was AGel amyloidosis (PMR=114.2; 95% CI 85.6-149.4). The frequency of fatal cancers (10%) was significantly diminished (PMR=0.47; 95% CI 0.31-0.69). Renal complications were overrepresented as the immediate CoD in female patients (PMR=2.82 95% CI 1.13-5.81). The mean life span for male patients was 73.9 years (95% CI 72.0-75.6) and 78.0 years for female patients (95% CI 76.4-79.5) compared to 72.1 and 80.1 years for the general population. Conclusions: Our results suggest that the disease increases the risk for fatal renal complications, but does not substantially shorten the life span, possibly due to the significantly lower frequency of fatal cancers.
  • malkamäki, teppo (Helsingin yliopisto, 2016)
    Background: Injuries of the extensor tendons can take place as complications of treatment in forearm fractures stabilized with flexible intramedullary nails (FIN). We do not know of any previous reports of flexor pollicis longus (FPL) entrapment in a distal radius fracture treated with FIN. Patient and Methods: A 14-year-old boy sustained a displaced fracture of distal radius and a greenstick fracture of distal ulna. Fracture of the radius was percutaneously fixed with a flexible intramedullary nail. Extension deficit of the IP joint of the thumb was recorded after nailing. Extensor pollicis longus (EPL) was explored and found intact at the time of nail removal, four months after surgery. The patient was referred to the Children’s Hospital, where entrapment of the flexor pollicis longus (FPL) at the fracture site was suspected, imaged with MRI and released surgically 13 months after the initial injury. Results: Thumb IP joint extension improved intra-operatively after the muscle release and returned to normal within a year. Conclusions: FPL entrapment at the fracture site should be remembered as a possible complication of the fracture itself, or as a complication of the percutaneous FIN of distal radius fractures.
  • Varpuluoma, Elina (Helsingin yliopisto, 2016)
    Ennenaikaisten perätilasynnytysten oikea hoitotapa on kiistelty aihe synnytyslääkäreiden keskuudessa. Satunnaistettuja tutkimuksia aiheesta on vaikea tehdä. Kohorttitutkimusten tulokset aiheesta ovat ristiriitaisia. Useissa tutkimuksissa perätilojen alatiesynnytyksiin on liittynyt suurentuneet riskit verrattuna sektioon. Kuitenkin sektioon liittyy suuremmat komplikaatioriskit äidille. Tämän tutkimuksen tarkoituksena on tuoda lisätietoa siitä, onko sektiosynnytysten ja alatiesynnytysten välillä eroja vastasyntyneiden voinnissa ennenaikaisissa perätilasynnytyksissä. Tutkimus on retrospektiivinen kohorttitutkimus, jonka aineisto koostuu vuosina 2006-2014 Naistenklinikalla ja Kätilöopiston sairaalassa hoidetuista ennenaikaisista perätilasynnytyksistä. Tiedot kerättiin potilasasiakirjoista. Tutkimuksessa vertailtiin lasten välitöntä vointia kuvaavia muuttujia sekä keskoskomplikaatioita eri synnytystaparyhmin välillä ja äidin synnytykseen liittyviä komplikaatioita ja sairaalahoidon kestoa. Tuloksena oli, että alatiesynnytys ei huomattavasti huononna vastasyntyneiden vointia, mutta sektio lisää äidin komplikaatioriskiä.
  • Urpa, Lea M (Helsingin yliopisto, 2016)
    Anxiety disorders are the most frequently reported mental health disorder in Europe and treatment outcomes for approximately 30% of patients remains poor. Development of new therapies has been hindered by the fact that neural mechanisms of anxiety disorders are poorly understood. Anxiety is known to be heritable but genetic studies have failed to identify significant gene variants, and it appears that it may not be fully explained by common genetic variation. Recent work has suggested that this ‘missing heritability’ may in part be explained by epigenetic mechanisms, which include the regulation of transposable elements (TEs). Transposable elements are mobile genetic elements that possess the capability to move their location within a genome. TEs have been found to be specifically repressed in the rodent brain following stress, and also have been found to be overexpressed in human brain tissues and animal models of several neuropsychiatric disorders including schizophrenia and post-traumatic stress disorder. Given the evidence of transposable element overexpression in human patients and animal models of psychiatric disorders, we hypothesized that rodents who underwent psychosocial stress would have differential expression of TEs corresponding to their resilience or susceptibility to anxiety-like behaviors. In this study we examined the expression of transposable elements in C57BL/6Crl and DBA/2Crl inbred mouse strains following chronic social defeat stress. We also examined the baseline levels of six inbred strains (DBA/2J, A/J, 129S/SvImJ, C3H/HeJ, C57BL/6J, and FVB/NJ) that were previously characterized for innate anxiety levels. Overall expression of transposable elements was examined with RNA sequencing, while the expression of Long Interspered Element 1 (LINE-1) family TEs was evaluated with quantitative real-time PCR. We found that following psychosocial defeat, C57BL/6 and DBA/2 animals had strain-specific differences in transposable element expression in the ventral hippocampus but not the medial prefrontal cortex. In the ventral hippocampus, C57BL/6Crl animals resilient to anxiety-like behaviors appeared to have distinctly different transposable element expression profiles compared to control and resilient C57BL/6Crl animals. Conversely, DBA/2Crl animals susceptible to anxiety-like behaviors appeared to have distinctly different transposable element expression profiles from DBA/2Crl controls. We also observed innate strain differences between C57BL/6Crl and DBA/2Crl animals in both the medial prefrontal cortex and the ventral hippocampus and some differences between the six inbred strains in LINE-1 family TE expression. Our findings of differential transposable element expression in the hippocampus following psychosocial stress fits in with the current work on TE activity in the adult brain, which indicates that TE activity in the hippocampus may contribute to adult somatic neural diversity and plasticity. We suggest that a mechanistic effect of variable TE expression may exist that contributes to an individual’s susceptibility or resilience to anxiety-like behaviors. Further work identifying de novo TE insertions at the genomic level needs to be done to identify the specific role that differential TE expression may be playing in the neural response to psychosocial stress.
  • Rantanen, Mimi (Helsingin yliopisto, 2016)
    The main purpose of this study was to participate in setting up the In situ hybridization for microRNA detection at the Department of Pharmacology. In situ hybridization (ISH) is an effective method for detection of molecules like DNA and RNA from paraffin fixed tissue sections. ISH provides information of expression and location of selected target molecules. Challenges of ISH for miRNA are the small size of the miRNAs and requirement of RNase free environment to prevent contamination. Micro-RNAs are single-stranded, noncoding, 19 to 25 nucleotides long RNAs, involved in post-transcriptional gene silencing. MiRNA-1 is known to be upregulated in ischemic heart muscle, which increases arrhythmias and apoptosis in heart. Adminstration of isoprenaline to Wistar rats induces similar conditions as acute myocardial infarction, which leads to rise in mir-1 levels. By in situ hybridization we were able to detect mir-1 from heart tissue and adjust suitable conditions for ISH.
  • Hartonen, Tuomo Samuli (Helsingin yliopisto, 2016)
    Novel experimental methods ChIP-exo and ChIP-Nexus allow studying transcription factor binding accurately in vivo. Only fraction of transcription factor binding mechanisms are yet fully understood and can be explained with simple positional weight matrix (PWM) models. Accurate knowledge of binding locations and patterns of transcription factors is key to understanding binding not explained by the current models. ChIP-exo and ChIP-Nexus experiments can also offer insights on the effects of single nucleotide polymorphism (SNP) at transcription factor binding sites on expression of the target genes. This is an important mechanism of action for disease-causing SNPs at non-coding genomic regions. In this thesis I describe a transcription factor binding site discovery software PeakXus specifically designed to leverage the increased resolution of ChIP-exo and ChIP-Nexus experiments. The key development principle of PeakXus is to make minimal number of assumptions of the data to allow discovery of novel binding patterns and mechanisms. PeakXus is tested with ChIP-Nexus and ChIP-exo experiments performed both in Homo sapiens and Drosophila melanogaster cell lines. PeakXus is shown to consistently find more peaks overlapping with a transcription factor-specific recognition sequence than published methods. As an application example I demonstrate how PeakXus can be coupled with Unique Molecular Identifiers (UMI) to measure the effect of a SNP overlapping with a transcription factor binding site on the in vivo transcription factor binding. The allele specific binding pipeline presented in this thesis takes better into account the read duplication bias and the varying coverage of the sequencing experiments than previous methods.
  • Peled, Nitai (Helsingin yliopisto, 2014)
    Impact of the PXR-activator rifampicin on whole blood drug transporter gene expression in humans Nitai Peled1, Miao Zefeng1, Tuija Tapaninen1,2, Pertti J. Neuvonen1,2 and Mikko Niemi1,2 1Department of Clinical Pharmacology, University of Helsinki, Finland 2HUSLAB, Helsinki University Central Hospital, Helsinki, Finland Rifampicin is a broad spectrum antibiotic used in the treatment of tuberculosis and staphylococcal infections. Through activation of pregnane X receptor (PXR), rifampicin induces the expression of several drug metabolizing enzymes and drug transporters. Previous studies suggest that rifampicin can induce the expression of certain drug transporters (e.g., ABCB1) in blood. Our aim was to investigate possible effects of rifampicin on drug transporter gene expression in whole blood. In a randomized crossover study, 12 healthy volunteers took 600 mg rifampicin or placebo once daily for 5 days (Tapaninen et al 2010). On the morning of day 6, a venous blood RNA sample was collected from each participant into a PaxGene® tube. The expression of 18 ABC, 24 SLC and 10 SLCO transporters was investigated using reverse transcription quantitative real-time PCR (RT-qPCR) with OpenArray® technology on a QuantStudio™ 12 K Flex Real-Time PCR system (Life Technologies, Paisley, UK). FPGS, TRAP1, DECR1 and PPIB served as reference genes. A total of 16 ABC transporters, 18 SLC transporters and 4 SLCO transporters were expressed above the quantification limit in most samples. Rifampicin had no significant effect on the expression of any transporter. However, SLC5A6 (sodium-dependent multivitamin transporter, SMVT) and ABCB4 (multidrug resistance protein 3, MDR3) expression tended to be increased by rifampicin (by 19% and 18%; P=0.066 and P=0.096, respectively). In conclusion, multiple drug transporter genes are expressed in whole blood, but rifampicin has limited effects on their expression. References: Tapaninen T, Neuvonen PJ, Niemi M. Rifampicin reduces the plasma concentrations and the renin-inhibiting effect of aliskiren. Eur J Clin Pharmacol 2010;66:497-502.
  • Duarte, Daniel Pereira (Helsingin yliopisto, 2016)
    Mitochondrion is an essential organelle capable to produce high amounts of energy from oxidative phosphorylation (OXPHOS). The organelle counts on its own set of mitoribosomes and quality control (QC) factors to efficiently translate the OXPHOS components encoded by the mitochondrial DNA. Organelle dysfunction leads to development of mitochondrial diseases, which show a wide variety of symptoms and poor prognosis. ybeY is a highly conserved gene amongst prokaryotes that acts as factor for maturation and QC of bacterial ribosome. The ybeY-homolog C21orf57 is found remarkably conserved in eukaryotes, but its role in mammalian cells is completely unknown. In this study we characterised the mouse gene C21orf57 (mYBEY) in mammalian cells. mYBEY is transcribed at low levels in mouse tissues, where nervous tissue, skeletal and cardiac muscle show relatively higher amounts of mYBEY transcript. Endogenous mYbey protein could not be detected immunoblot due to its low expression level and/or rapid protein turnover. In parallel, mYBEY was cloned and successfully expressed in mammalian cells using transient and stable expression methodologies. We discovered that mYbey is imported into mitochondria and not covalently associated with mitoribosomes. Interestingly, protein translation stress and mitoribosome decay promoted by actinonin treatment is accompanied by a decrease in mYbey protein. In addition, depletion of mYbey using iRNA promotes the accumulation of mitoribosome proteins. We hypothesise a model in which mYbey is part of a QC mechanism for mitoribosome, and possibly involved with mitoribosome turnover. Although we successfully deleted mYBEY gene in mouse embryonic fibroblasts using the CRISPR/Cas9 approach, the isolation of viable mYBEY knock-out cells was not possible due to the possible deleterious and/or suppressive effects. In conclusion, we verified for the first time that mYbey is located within mammalian mitochondria and may be involved in a possible QC mechanism as a factor recruited for mitoribosome turnover. Further studies are necessary to fully elucidate the role of mYbey in the mitochondrial context.
  • Ylävuo, Sanna (Helsingin yliopisto, 2016)
    Endometrioosissa kohdun limakalvon kaltainen kudos kasvaa kohdun ulkopuolella. Tautia sairastaa noin 10 % hedelmällisessä iässä olevista naisista. Endometrioosi on yleisin lapsettomuutta aiheuttava tauti naisilla, sillä joka toinen lapsettomuudesta kärsivä nainen sairastaa endometrioosia. Tutkimuksen aineiston muodostavat Naistentautien ja synnytysten klinikkaryhmässä HYKS:ssa vuosina 2004-2012 rektovaginaalisen endometrioosin vuoksi leikatut potilaat. Tutkimus käsittää 128 fertiili-ikäistä naista, joille on tehty suoliresektio rektovaginaalisen endometrioosin vuoksi ja kohtu on tallella. Tietoja kerättiin kotiin lähetettävän kyselytutkimuksen ja sairaskertomusten avulla. Tutkimuksen tarkoituksena oli selvittää leikkausta edeltävää ja sen jälkeistä fertiliteettiä sekä mahdollista infertiliteettiä ja sen hoitoja, sillä aiemmin endometrioosipotilaiden leikkaushoidon jälkeistä fertiliteettiä ja lapsettomuushoitoja ei ole laajemmin tutkittu Suomessa. Tulosten mukaan suoliendometrioosipotilaille tehdään paljon lapsettomuushoitoja, mutta monet tulevat endometrioosista huolimatta raskaaksi. Kuitenkin vain vähän alle puolet suoliendometrioosipotilaista tulee raskaaksi spontaanisti. Suoliresektio näyttäisi parantavan raskaaksi tulemisen mahdollisuutta naisilla, joilla on löydetty endometrioosipesäkkeitä suolesta. (133 sanaa)