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Lisääntyvä antibioottiresistenssi (AMR, antimicrobial resistance) on maailmanlaajuinen uhka ihmisen terveydelle. Vuonna 2019 arvioitiin AMR:n aiheuttamien ylimääräisten kuolemien määräksi jo 1.27 miljoona; luku ylittää malarian tai HIV-infektion vastaavat arviot. Sairaaloissa AMR ongelma johtaa pidentyneisiin hoitojaksoihin, vakavampiin infektioihin ja suurempaan kuolleisuuteen ja myös leikkaushoidossa tarvittavan profylaksian käyttö on vaarassa. On selvää, että moderni lääketiede ei toimi nykyiseen tapaan ilman antibiootteja. Moniresistentit Enterobakteerit ovat yleistyneet viime vuosina kaikkialla; korkeimman antibioottiresistenssin alueilla ne aiheuttavat jo suurimman osan esimerkiksi virtsatieinfektioista. Näiden bakteerien esiintyvyys on suurinta Etelä- ja Kaakkois-Aasiassa,Saharan eteläpuolisessa Afrikassa sekä Etelä-Amerikassa. Kehitys on hälyttävää myös Euroopassa. Merkittävänä syynä tähän on resistenssin leviäminen alueelta toiselle matkailun, kaupan ja eläinten mukana. Korkean riskin alueilla vierailevista jopa 30-90% kantaa palatessaan moniresistenttejä suolistobakteereita. Tässä työssä tutkimme 783:n Benin matkaajan ESBL-PE (extended-spectrum betalactamase producing Enterobacteriaceae) bakteerin kantajuutta ulostenäytteistä, jotka kerättiin ennen matkaa, Beninissä, heti matkalta paluun jälkeen ja säännöllisin väliajoin sen jälkeen.. Ennen matkaa ESBL-PE kantajien osuus oli 4.4% ja heti matkan jälkeen 54%. Matkan aikana ja heti paluun jälkeen kerättyjen näytteiden perusteella 80% kolonisoitui matkan aikana. Kuukauden kuluttua paluusta kerätyissä näytteissä esiintyvyys oli enää 24%. Tutkimuksessa tuli tilastollisesti merkittävä ero niiden välillä, jotka antoivat näytteen paluupäivänä tai sitä seuraavana päivänä verrattuna niihin jotka antoivat näytteen vasta kolmen päivän kuluttua (68% vs 48%). Riskitekijäanalyysin perusteella D-vitamiinin talviaikainen käyttö saattoi jopa suojata ESBL-PE kolonisaatiolta. Tutkimus osoitti, että matkailijoista merkittävä osa dekolonisoituu jo ensimmäisten päivien ja viikkojen aikana. Jatkossa tarkoituksena on selvittää, miksi jotkut kannat onnistuvat kolonisoimaan suoliston pitkäksi aikaa.

Kaposi’s sarcoma herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), was discovered following the AIDS-epidemic as the causative agent of Kaposi’s sarcoma (KS), an angiogenic endothelial tumor of the skin, and of two rare lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Infection by KSHV displays two life cycle phases; latent and lytic replication. In latency, the virus stays dormant within the host, expressing only a few genes and no viral particles are produced. Latency is the default mode of infection, however, upon appropriate induction the virus reactivates to express all of its genes and replicate viral DNA during the productive lytic replication, culminating with the release of infectious progeny particles and lysis of the host cells. Virus reactivation from latency to the lytic replication is an essential step in the KS pathogenesis. Upon KSHV infection, endothelial cells (EC) undergo reprogramming towards spindle cell, the principal proliferating cell in advanced KS lesions. The transcription factor prospero related homeobox gene Prox1 has an important role in mediating the effects of KSHV on EC reprogramming, contributing to the KS development. Prox1 is the master regulator of lymphatic endothelial cell fate, and its expression is manipulated during the KSHV infection. However, the role of Prox1 in the KSHV life cycle and lytic reactivation has not been studied. To elucidate the role of Prox1 in KSHV reactivation from latency, the effect of ectopic expression of Prox1 on the lytic gene and protein expression in both latent and reactivated KSHV-infected cells was studied. This led to a significant increase in KSHV lytic gene and protein expression, suggesting Prox1 as a positive regulator of KSHV lytic replication. Moreover, Prox1 wild-type, but not its DNA-binding deficient mutant, could significantly increase the release of infectious virions. To investigate the expression levels of Prox1 during KSHV infection, infection kinetics assay was performed, which showed an increase in the Prox1 levels during acute infection. Intriguingly, this was followed by a progressive decrease in the Prox1 levels as latency was established. In conclusion, the focus of this thesis is to investigate the role of Prox1 in KSHV reactivation, and to provide a deeper insight into the virus reactivation mechanisms that can be utilized for future therapeutic strategies against KSHV-mediated tumorigenesis of KS. Keywords: KSHV, Kaposi’s sarcoma, Prox1, virus reactivation, lytic replication

För den här avhandlingen har den operativa vården av metakarpalfrakturer undersökts. Syftet med studien har varit att kartlägga de opererade frakturernas egenskaper och beskriva patientmaterialet. Sammanlagt 95 fall av operererade metakarpalfrakturer vid Tölö och Hertonäs sjukhus från år 2012 ingår i den här undersökningen. Patientberättelser och röntgenbilder har använts som materialkälla. Information om bland annat frakturernas uppkomstmekanismer och felställningar har plockats fram. Resultaten visar att den typiska patienten som har opererats för en fraktur i metakarpalbenet var en ung man som hade skadat handen till följd av ett avsiktligt slag mot någonting. Frakturer i den femte metakarpalen var vanligast och det vanligaste frakturstället var skaftet. Gällande val av operationsteknik var operationer med plattor vanligare och de var i synnerhet överrepresenterade vid frakturer i skaftet. Det här var första gången som den här typens forskning om metakarpalfrakturer gjordes vid Tölö sjukhus.

Background: The population in many countries is becoming more diverse and heterogenic and the population of people from foreign background is growing in Finland as well. We wanted to find out how public sector dentists in Finland find this phenomenon. The aim of this study was to better understand how the foreign background of a patient affects the dentist’s work. Methods: The research was carried out as a semi-structured interview study. We interviewed 6 dentists from Helsinki municipality public dental care between December 2019 and January 2020. Each interview took approximately an hour. After the interviews were transcribed verbatim, two members of research group read individually the interviews to find emerging themes. Results: The most common problems that arose in the interviews were problems within communication and interpretation. The dentists also noticed different expressions of pain among foreign background patients compared to native Finnish patients. The periodontal diseases and importance of selfcare in treating those were also observed not to be familiar to many foreign background patients. The time a patient had lived in Finland was thought to affect the experienced difficulties and prejudice faced by the interviewed dentists. Conclusion: In this qualitative research we were already able to identify some of the common difficulties the dentists experience while treating patients from foreign background despite the small number of participants.

Objectives. Perinatal risk factors, e.g. low birth weight, can increase risk for depression. Whether perinatal risks are linked to received treatment and rehabilitation of depression and cognitive deficits in depression is largely unknown. The aim of the study was to examine the use of antidepressants, received rehabilitative psychotherapy and cognition among adults with lifetime depressive symptoms by comparing whether they differ in the perinatal risk group and in the control group. Methods. The study is part of a longitudinal birth cohort research project examining long-term ef-fects of perinatal risk factors. The present sample included 67 adults with perinatal risk factors and 20 control adults. All of the participants (n = 87) had experienced lifetime depressive symptoms. Lifetime depressive symptoms were assessed by lifetime depression and/or current depressive symptoms (DEPS ≥ 9). The use of antidepressants and received rehabilitative psychotherapy were compared between groups by χ2-tests. Cognition was assessed with several neuropsychological tests and compared between groups by t-tests. The effects of the most prevalent perinatal risk fac-tors and education on cognition was controlled by separate analyses of variance. Results and conclusions. The use of antidepressants was indicatively more prevalent in the perinatal risk group, although no statistically significant difference was observed. No difference between groups was found in received rehabilitative psychotherapy. Processing speed and visual perceptual performance was significantly poorer in the perinatal risk group compared to the control group. Low birth weight was linked to poorer cognitive performance in the perinatal risk group. Furthermore, lower level of education in the perinatal risk group explained difference in cognitive performance. The results suggest that perinatal risk factor may be linked to more prevalent use of antidepressants, which may reflect more severe lifetime depressive symptoms compared to controls. Perinatal risk factors do not seem to be linked to received rehabilitative psychotherapy and cognitive performance among adults with lifetime depressive symptoms.

Histamine is an important neurotransmitter in the central nervous system (CNS). It is involved e.g. in the sleep-wake cycle, endocrine and energy homeostasis as well as in synaptic plasticity and learning. It is produced from L-histidine by histidine decarboxylase (HDC). Almost all species have histamine in their body although the amount varies between species. Histaminergic neurons are located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus. There are four different histamine receptors in mammals and they are all metabotropic GPCR receptors. The first three (Hrh1, Hrh2 and Hrh3) are located in the brain while Hrh1 and Hrh2 along with Hrh4 that is mainly found in mast cells, are found in the periphery. Receptors have different functions e.g. Hrh1 regulates wakefulness and alertness while Hrh2 is involved in learning and memory. It is established that histaminergic neurons contain GABA-producing enzyme GAD1 and GABA itself. In the present study we aimed to evaluate GABAergic phenotype of the hypothalamic histaminergic neurons with double fluorescent in situ hybridization. Specifically, we were interested in co-existence of VGAT, which is responsible for vesicular release of GABA, and HDC mRNA. The animals used in this study were mouse and zebrafish. The percentage of mouse HDC-neurons that expressed GAD1 was 99.65% and co-expression for VGAT was also high (94.53%). This coexistence was verified also in the zebrafish model. Our data suggest that histaminergic neurons containing VGAT mRNA and are potentially able to release GABA. If GABA is released in a paracrine manner like histamine, it causes tonic inhibition that counterbalances the effects of histamine during wakefulness. The fact that VGAT mRNA was also found in zebrafish histaminergic neurons indicates that histamine-GABA system is preserved among species.

Epilepsy is one of the most common neurological diseases worldwide. Around one-fifth of people with epilepsy are diagnosed with drug-resistant epilepsy. Some of them benefit from epilepsy surgery. Before surgical treatment, the location of the epileptogenic zone (EZ) must be carefully identified to achieve a good surgical outcome. New methods for locating the EZ are constantly being developed. The aim of this study was to investigate whether long-range temporal correlations (LRTC) can be used for non-invasive localization of the EZ in patients with drug-resistant epilepsy. The study involved 10 patients with epilepsy who had previously undergone epilepsy surgery and an MRI. We used the detrended fluctuation analysis (DFA) method to quantify the LRTCs in four different frequency bands in 200 cortical regions based on the patients' individual source reconstructions. We correlated the DFA values with distances from the resection areas and cortical locations of interictal epileptiform discharges (IEDs). In addition, DFA maps were visually inspected by three clinicians to identify the most likely EZs. The study found that DFA maps were significantly correlated with distance from the location of the resection only in the patients with type II focal cortical dysplasia (FCD II) and were associated with IED sites only in the FCD II patients. In addition, visual analysis of the DFA maps showed that in the FCD patients, there was a high interobserver agreement and accuracy in defining the affected hemisphere and lobe. These findings suggest that LRTCs could provide a non-invasive method to identify EZ and facilitate the preoperative evaluation of epilepsy patients.

Antibiotic resistance of pathogenic bacteria has increased in recent years. When antibiotics do not work, alternative therapies are developed to prevent major bacterial epidemics. Phage therapy is one of the alternative possibilities to cure infections caused by antibiotic resistant bacteria. Due to the narrow host range of phages, hundreds or even thousands of phages are required to cover the various bacterial pathogens. For a reliable selection process, high-throughput rapid host range screening of phages is needed to cover the future demands. In addition, collaboration between laboratories is highly important, as the collections of phages of individual laboratories are not broad enough. Thus, the transportation of phages between laboratories is one of the key elements to provide successful phage therapy for patients. The aim of the study was to use gel-based products as protective matrix in phage host-range screening and transportation. The optimal conditions were selected to set a baseline for high-throughput rapid host range screening process, and to set up a ready-to-screen plate assay for phage transportation. In addition, the purpose of the study was to evaluate whether hydrogels could be used as a long-term storage matrix for phages and future product development. Fourteen Escherichia coli phages were used to optimize the liquid culture assay for the E.coli strains. The hydrogel based assays were conducted with two Escherichia and two Staphylococcus phages. For long-term storage, phages were mixed with different consistencies of hydrogels and stored in three different conditions for up to six months at +4oC. The transportation experiments were conducted with phages stored with optimized hydrogel consistencies. The phage viability was measured using liquid culture method. Results show that liquid culture method on microtiter plate is a convenient way to screen bacteriophages in high-throughput assay and that phages can be stored reliably in hydrogel format. When stored in microcentrifuge tubes, phage stability was shown to last for at least six months. When stored as drops on microtiter plate, the phages retained their viability for up to two months. These plates can be used as a robust means for phage transportation.

Tyypin 2 diabetes on merkittävä maailmanlaajuinen terveysriski ja sen yleisyys kasvaa jatkuvaa tahtia maailmalla. Suuri osa sairastaa diabetesta tietämättään. Diabeteksen aiheuttama systeeminen tulehdustila vaikuttaa haitallisesti ympäri kehoa. Diabeteksen ja suunterveyden yhteyttä on tutkittu paljon ja diabeteksen on osoitettu lisäävän parodontiitin, karieksen ja hammaspuutosten syntyä. Vaikutusmekanismit näiden välillä ovat kuitenkin vielä epäselvät. Tutkielman tavoitteena oli vertailla diabeetikkojen suunterveyttä muihin poikkileikkausasetelmassa. Tutkimusaineistona oli Helsingin kaupungilta kerätyt yli 29-vuotiaiden potilastiedot vuosilta 2001-2003. Suunterveyttä mitattiin hampaiden lukumäärällä, DMFS-indeksillä ja parodontologisilla toimenpiteillä. Lisäksi tarkasteluun otettiin mukaan diabeetikkojen yleisterveys sekä sosioekonominen asema. Tutkielman tulokset olivat samassa linjassa aiheesta aiemmin tehtyjen tutkimusten kanssa. Diabeetikkojen suun terveys oli selvästi huonompi muihin verrattuna ja diabetesta esiintyy enemmän alhaisemmissa sosioekonomisissa luokissa. Regressioanalyysissa diabeteksen esiintyvyyden riskiin olivat yhteydessä merkittävästi ikä, miessukupuoli, parodontiitti, korkea DMF-indeksi ja puuttuvat hampaat. Tyypin 2 diabetes on paljolti huonoista elämäntavoista johtuva sairaus, jonka vuoksi tutkielman tulosten perusteella ei voida olettaa, että näiden välillä olisi syy-yhteys. Tutkielmasta puuttui tiedot potilaiden painoindeksin, tupakoinnin, liikunnan ja ruokailutottumusten suhteen. Nämä tekijät ovat kaikki suuria diabeteksen riskitekijöitä. Tutkielma osoittaa kuitenkin selkeästi diabeetikkojen suurentuneen suunterveyden hoitotarpeen. Tyypin 2 diabetes on yhdistetty huonompaan omahoitoon ja täten olisikin tärkeää ohjeistaa diabeetikkoja suunterveyden tärkeydestä.

Syftet med studien var att undersöka sambanden mellan de diabetesassocierade autoantikropparna ICA, IAA, GADA, IA-2A och klinisk manifestation, HLA-genotyp, släktanamnes samt demografiska faktorer såsom ålder och kön hos finländska barn under 15 år med nydiagnostiserad typ 1 diabetes. Analyserna baserades på ett utdrag ur det finländska pediatriska diabetesregistret (2257 barn). Antikroppsfrekvenserna fastställdes utgående från halterna i serum. Alla barn HLA-genotypades och indelades i DR3- och DR4-positiva. Småbarnen (< 5 år) hade ofta 3-4 positiva antikroppar. Äldre barn hade färre autoantikroppar men en allvarligare metabolisk dekompensering vid diagnostillfället. Diabetisk ketoacidos var vanligare hos flickor. I gruppen med endast en positiv autoantikropp var IA-2A-barnen oftare acidotiska, i övrigt påverkade inte antikroppsprofilen den kliniska bilden. Högriskgenotypen DR4/non-DR3 var associerad med IA-2A, som verkar fungera som en markör för betacelldestruktion. Det omfattande patientmaterialet gav stöd åt tidigare rapporter om samband mellan autoantikroppar och ålder, kön samt genotyp. Den allvarligare metaboliska dekompenseringen hos äldre barn tyder på att de inte diagnostiseras lika snabbt som småbarn.