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(2023)Pandemiaksi levinnyt SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) aiheuttaa taudinkuvaltaan ja vaikeusasteeltaan vaihtelevan COVID-19 (Coronavirus disease 2019) taudin. Tutkielman tavoitteena on kuvata Helsingin ja Uudenmaan sairaanhoitopiirin (HUS) alueella keväällä 2020 positiivisen SARS-CoV-2-testituloksen saaneiden henkilöiden oirekuvaa, taudinkulkua sekä kartoittaa riskitekijöitä, jotka ennustavat vakavalle tautimuodolle sairastumista. Tutkielma on deskriptiivinen retrospektiivinen yksikeskuksinen rekisteritutkimus, joka on toteutettu osana ClinCOVID-19-tutkimusta, joka on Helsingin ja Uudenmaan sairaanhoitopiirin sekä Helsingin yliopiston yhteishanke. Aineistoon kerättiin tietoa positiivisen SARS-CoV-2-testituloksen saaneista tutkittavista potilastietojärjestelmiä (Uranus, Apotti) käyttäen. Tämän tutkielman kannalta erityisen kiinnostuksen kohteena olivat tutkittavien oirekuva ja taudinkulku, sekä riskitekijät vakavalle sairastumiselle. Sairaalahoitoa vaatineista sekä tehohoidon piiriin ajautuneista tutkittavista kerättiin tietoa hoidon kulusta sekä ilmaantuneista komplikaatioista. Aineistoa analysoitiin Excelin sekä R-ohjelmiston avulla. Tutkielman aineisto koostui 103 HUS-alueella asuvasta tutkittavasta, jotka saivat positiivisen SARS-CoV-2-testituloksen helmi-toukokuussa 2020. Tutkittavien keski-ikä oli 45,3 vuotta. Sairaalahoitoon joutui 24,3 % (n=25, keski-ikä 59.7 vuotta) kohortista. Pitkäaikaissairauksia oli kaikista tutkittavista 28.2%:lla, sairaalassa hoidetuista 80,0%:lla. Tehohoitoon joutui kaikkiaan 7,77 % (n=8), sairaalassa hoidetuista 32,0 %. Tehohoidettujen keski-ikä oli 54,7 vuotta. Potilailla, joilla oli krooninen pitkäaikaissairaus, sairaalahoidon joutumisen riski oli 3,2-kertainen (P = 0.00065). Jokainen yksittäinen pitkäaikaissairauden diagnoosi lisäsi tehohoitoon joutumisen riskiä 1,2-kertaiseksi (P = 0.00024). Yleisimmät oireet sekä sairaalahoitoisilla että kotihoitoisilla tutkittavilla olivat kuume ja yskä. Tutkielman tulokset olivat yhteneviä tutkimuskirjallisuudessa esiteltyjen COVID-19 taudin analyysien kanssa.
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(2021)Objective: The coronavirus disease COVID-19 causes neuropsychological problems to a proportion of patients having contracted the illness in the months following the illness and on a more long-term basis. Currently there is little knowledge about how the required level of care in the acute phase affects the presence of symptoms and their change over time. The objective of this study was to investigate the neuropsychological effects of COVID-19 from a patient self-reported symptoms and cognitive screening perspective. The study examines the effects of the required level of care in the acute phase and time since contracting the illness on self-reported symptoms and cognitive screening results three and six months after the acute phase. Furthermore, the aim was to illustrate the relationship between these two assessments. Methods: The data was collected within the RECOVID-20 project (Helsinki and Uusimaa Hospital District and University of Helsinki). Subjects (N = 164, of which 96 women, mean age 54.1 years) contracted COVID-19 in the spring of 2020. The data was collected from three different levels of care as required by the acute phase: intensive care unit patients, regular inpatient wards and patients who were ill at home. Self-reported symptoms were assessed with the A-B Neuropsychological Assessment Schedule and cognitive performance was measured by the Montreal Cognitive Assessment-Blind screening tool three and six months after the acute phase. Group differences and change over time was analysed using multivariate variance analyses and linear mixed models. Results and conclusions: About a third of all patients reported neuropsychological symptoms regardless of the level of care required in the acute phase both three and six months after the acute phase. Symptoms consisted mainly of fatigue, slowing and concentration problems. In the cognitive screening patients having received ICU and inpatient ward care performed worse compared to patients having been ill at home, but a statistically significant result was not detected when controlling for age. A statistically significant relationship between self-reported symptoms and cognitive performance was observed only in ICU patients at three months. Although the majority of COVID-19 patients do not have significant symptoms after the acute phase, there are patients that show preliminary signs of more chronic symptoms based on both self-reported symptoms and cognitive screening. More research is needed to investigate the causes of these symptoms.
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(2022)Objective: Preliminary evidence has shown that COVID-19-disease can be associated with memory problems, but previous research is still limited and contains many methodological issues. The aim of this research was to investigate whether COVID-19-disease associates with memory functions. Moreover, this study compared possible differences in memory functioning six months after the acute illness between COVID-19-patiences who had required intensive care (ICU), were treated in regular inpatient ward, or recovered at home. Methods: This study is part of RECOVID-20-project. It includes 164 COVID-19-patients and 48 healthy controls who participated in a comprehensive neuropsychological assessment six months after the acute illness. Assessment variables contains neuropsychological subtests which measure different aspects of memory (logical memory I & 2, word list 1 & 2, digit span and Rey-Osterrieth Complex Figure). COVID19-patiens were divided into three groups according to the required level of hospital care in acute phase of illness. The three groups were: ICU (n=71), ward (n=49) and home group (N=44). Associations between COVID-19-disease and memory functions were analyzed using covariance analysis and multivariate covariance analysis. Group differences in memory functions were assessed with MANCOVA and further with Discriminatory Analysis. Results and conclusions: No significant differences were found in any memory aspects between COVID-19- patients and healthy controls. Results are partly in conflict with previous studies which have shown that COVID-19-disease can be associated with memory problems especially in aspects of working memory, short- and long-term auditory memory and long-term visual memory. However, this study indicated that ICU and ward group with severe or critical COVID-19-disease had significantly worse overall memory performance than patients who had recovered at home. Age affected different ways of memory functioning in different groups.
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(2022)Objective: Long-term associations of the COVID-19-disease with patients’ wellbeing are not currently well known, but so far evidence of prolonging somatic and mental symptoms after the acute phase have been reported. Patients that have been treated in the ICU or normal wards have been suggested to be in elevated risk for experiencing these symptoms. How prolonging symptoms affect patient’s quality of life has not yet been thoroughly studied. The aim of this study was to investigate how the symptoms reported in three-months follow-up were associated with the quality of life at six-months follow-up of patients treated in the ICU or normal wards and those who were sick at home in six-months follow-up. COVID-19 patients were also compared with healthy controls. Associations between the length of hospital stay and quality of life in ICU and ward patients were also investigated. Methods: The data of this study were collected during the first and second waves of COVID-19 in 2020. This study is a part of the RECOVID-20 project, which is a collaboration project of Helsinki and Uusimaa Hospital District and University of Helsinki. Altogether 241 subjects (54 % women, mean age 54.5) participated in this study (54 % women, mean age 54.5), and the subjects were recruited from four groups: ICU and ward group, patients who were sick at home and healthy controls. Somatic and mental symptoms at three-months of the acute phase were assessed with a telephone survey and a questionnaire was sent to the patients’ home. In the six-months follow-up the patients’ quality of life was assessed with RAND-36 survey that was sent home. The associations of prolonging COVID-19 symptoms with quality of life were analyzed using multivariate covariance analysis (MANCOVA) and further with discriminant analysis. The relationship between the length of hospital stay and quality of life was assessed with MANCOVA. Results and conclusions: The symptoms reported in the three-months follow-up were associated with lowered quality of life in the six-months follow-up. There were no significant differences in quality of life between the patient groups. The length of hospital stay was not associated with quality of life in ICU and ward groups. These results support previous studies that have found prolonging symptoms of COVID-19 to be associated with quality of life. According to this study, all patient groups can experience clinically significant prolonging symptoms of COVID-19 alike with later association with quality of life.
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(2023)Since the beginning of the Coronavirus Disease 2019 (COVID-19) pandemic, there has been a need for developing an efficient vaccine against the SARS-CoV-2 virus and its emerging variants. In this thesis, humoral immune responses induced by either two doses of mRNA Pfizer-BioNTech (Pfizer) vaccine or one dose of adenoviral vector-based Oxford-AstraZeneca followed by a second dose of Pfizer were studied. Levels of anti-spike protein (anti-S1) IgG, IgA and IgM antibodies were measured with enzyme-linked immunosorbent assay. In addition, neutralizing antibody titers against the original Wuhan-Hu-1 strain, the Beta variant and the Delta variant were studied with a pseudovirus neutralization assay. The study used 180 serum samples from a cohort of vaccinated Finnish healthcare workers. Sera were collected from vaccinees before their first vaccination, after which vaccinees provided sequential samples at timepoints of three weeks, six weeks, three months, and six months. The results showed that both vaccination regimes produce high levels of anti-S1 IgG antibodies in vaccinees, and the antibodies persist in blood at least for six months. Anti-S1 IgA levels were lower compared to IgG levels, but were long-lasting, as 95% of vaccinees were IgA seropositive six months after the first vaccine dose in both study groups. Anti-S1 IgM levels resembled the levels of IgA, but the IgM seropositivity after six months was only 50% in the Pfizer-only group and 70% in the “mix-and-match” vaccination group. Neutralization assays demonstrated that the heterologous vaccination induces higher neutralizing antibody titers compared to the homologous vaccination. After six months, the neutralization in the homologous vaccination group was 6-fold reduced against Wuhan-Hu-1, 4-fold reduced against the Beta variant and 5-fold reduced against the Delta variant compared to the heterologous regime. The results are in line with previous findings that have proven the “mix-and-match” vaccination to be more immunogenic than the homologous prime-boost vaccination. By combining different booster COVID-19 vaccines to the primer vaccine dose, it would aid in cases of vaccine shortages and provide options to individuals that respond poorly to a specific type of vaccine.
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(2020)Ahtauttava uniapnea on maailmanlaajuisesti yleinen sairaus, jota hoidetaan ensisijaisesti nenän kautta annettavalla ylipainehengityksellä (CPAP). Hoidon onnistumista arvioidaan seuraamalla CPAP-maskin ilmavuotoja ja unenaikaisten hengityskatkosten määrää (CPAP-AHI). CPAP-maskeja joudutaan uusimaan säännöllisesti, mihin liittyy suuria kustannuksia: yksittäisen maskin hinta vaihtelee 90 ja 180 euron välillä. Maskien käyttöiästä ei ole saatavilla tutkimustietoa, ja suositukset uusintaväleistä vaihtelevat 3:sta 12 kuukauteen. Tutkielmani tarkoitus on selvittää maskien kestävyyttä potilaskäytössä, sekä arvioida eri uusintavälien taloudellisia eroja. Analysoin 4.5 miljoonaa tuntia CPAP-maskien käyttöä 1843 maskilta. Aineisto oli systemaattisesti kerätty ja edusti tyypillistä uniapneapotilasta niin ikä- kuin sukupuolijakaumaltaan. Vertasin maskien toimintaa sekä toisten maskien, että maskien itsensä toimintaan yhteensä 30 kuukauden ajalta. Analyysit tehtiin koko aineiston lisäksi jaoteltuna ryhmiin maskityypeittäin ja -valmistajittain. Maskien ilmavuotojen suuruus ja CPAP-AHI pysyivät matalina koko seurantajakson ajan. Käytetyimpien maskityyppien (nenä- ja sierainmaskien) väliset erot olivat kliinisesti merkityksettömiä, ja molempien toiminnalliset ja hoidolliset muuttujat pysyivät hyvällä tasolla 30 kuukauden ajan. Kokokasvomaskeilla sekä ilmavuodot että CPAP-AHI olivat muita maskityyppejä suurempia ja lisääntyivät aiemmin. Maskivalmistajien väliset erot olivat pieniä. Pidentämällä maskien uusintavälejä kahteen vuoteen vuotuiset säästöt voivat olla 50–88 % nykytilanteeseen nähden. Ehdotan tutkielmassani nenä- ja sierainmaskeille uusintaväleiksi kaksi vuotta. Kokokasvomaskit on hyvä uusia vuosittain. Siirtymällä ehdottamiini vaihtoväleihin saavutetaan merkittäviä säästöjä vuosittaisissa maskikuluissa ilman maskien toiminnan heikkenemistä.
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(2018)Tutkielma käsittelee karnitiinipalmitoyylitransferaasi-1A (CPT-1A) -mitokondrioentsyymin puutosta, joka on autosomaalisesti resessiivisesti periytyvä harvinainen tauti. Tauti ilmenee paastonaikaisessa metaboliassa, jolloin elimistön tulisi alkaa pilkkoa rasvahappoja energianlähteeksi. Entsyymipuutoksesta kärsivillä potilailla tämä kompensaatiomekanismi on puutteellinen. Tauti voidaan diagnosoida mittaamalla ihon fibroblastien CPT-1A-aktiivisuutta tai varmistamalla geenimutaatio. Tutkimuksen tavoitteena on kartoittaa Suomessa todettujen CPT-1A-puutosta sairastavien kasvuikäisten potilaiden tämän hetkinen neuropsykologinen ja kognitiivinen terveydentila ja tarkastella CPT-1A-puutoksen mahdollisia vaikutuksia potilaiden kehitykseen. CPT-1A-puutos on todettu Suomessa yhteensä kuudella potilaalla, joista tutkimukseen valittiin viisi kasvuikäistä potilasta. Tutkimus oli laadullinen seurantatutkimus. Aineistona käytettiin CPT-1A-puutospotilaiden sairaskertomusmerkintöjä ja tutkimustuloksia, joita kerättiin potilastietokannoista. Kaikilla suomalaisilla potilailla diagnosoitiin CPT-1A-puutos varhaislapsuudessa akuutin sairastumisen jälkeen, ja diagnoosin myötä heille aloitettiin pitkiä paastoja välttävä ruokavaliohoito, johon hoidon alkuvaiheessa kuului myös rasvarajoitus. Hoidon aloituksen jälkeen kaikki potilaat ovat olleet metabolisesti hyvässä kompensaatiossa ja he ovat olleet somaattisesti terveitä. Neuropsykologisissa tutkimuksissa potilailla todettiin kuitenkin tavallista enemmän ADHD:ta, oppimisvaikeuksia, lukemisen ja kirjoittamisen erityisvaikeutta ja toiminnanohjauksen vaikeutta. Tulos oli yhteneväinen aiheesta aikaisemmin tehtyjen tutkimustulosten kanssa. Menetelmällisesti CPT-1A-puutoksen tutkiminen tilastollisin menetelmin on vaikeaa johtuen pienestä otoskoosta ja potilasmäärästä. Jatkossa olisi mielenkiintoista vertailla vastasyntyneenä seulonnan avulla diagnosoitujen ja vasta myöhemmin todettujen tautitapausten kehitystä, jolloin alkuvaiheen metabolisen kriisin pitkäaikaisvaikutuksia olisi mahdollista kartoittaa. Seulonnalla ei kuitenkaan ole toistaiseksi löydetty uusia tautitapauksia.
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(2022)Tausta: CP-vamma on sikiön tai pikkulapsen kehittyviin aivoihin tapahtuneen aivovaurion aiheuttama liikuntavamma. CP-vamma jaotellaan spastiseen, dyskineettiseen ja ataktiseen alatyyppiin. Anatomisen sijainnin perusteella CP-vamma jaotellaan edelleen kvadriplegiseen, diplegiseen ja hemiplegiseen muotoon. Lisäksi käytössä ovat määrittämätön ja muu CP-vamma. CP-vamma on yleensä diagnosoitu noin 1–2 vuoden iässä, mutta on mahdollista jo ennen 6 kuukauden ikää. Tanskassa mediaani-ikä diagnoosin asettamiselle on 11 kuukautta. Suomessa vastaava ikä on 1,5 vuotta, mutta eri alatyypeille tätä ikää ei ole selvitetty. Tavoitteet: Tutkimuksen tavoitteena on selvittää HYKS:n lastenneurologialla diagnosoitujen CP-vammaisten lasten diagnoosi-iän mediaani. Tämä määritetään koko tutkimuspopulaatiolle sekä eri alatyypeille huomioiden myös sukupuolien väliset mahdolliset erot. Menetelmät: Aineistona käytettiin HYKS:n lastenneurologialla ajalla 1/2009–6/2018 alle 9-vuotiaana diagnosoituja potilaita. Tiedot diagnoosista ja sen ajankohdasta haettiin potilastietojärjestelmästä. Lopullinen tutkittavien määrä oli 213, joista poikia oli 122 ja tyttöjä 91. Spastisia kvadriplegisiä potilaita oli 7, spastisia diplegisiä 37, spastisia hemiplegisiä 139, dyskineettisiä 29 ja ataktisia 1. Tulokset: Mediaani-ikä diagnoosivaiheessa oli kaikille 17 kuukautta, pojille 16,5 kk ja tytöille 17 kk. Mediaani-iät alatyypeissä olivat kvadriplegialle 17, diplegialle 22, hemiplegialle 14, dyskineettiselle 19 ja ataktiselle 42 kuukautta. Alatyypillä yleisesti tarkasteltuna oli tilastollisesti merkitsevä vaikutus diagnoosi-ikään, mutta sukupuolella ei. Pohdinta: Koko tutkimuspopulaation diagnoosi-iän mediaani oli hyvin yhtenäinen aiemmin tutkitun, koko Suomen kattavan diagnoosi-iän kanssa. Näiden perusteella diagnostiikka ei kuitenkaan ole Suomessa yhtä aikaista kuin Tanskassa. Aikainen diagnoosi on etu hoitointerventioiden aloituksen suhteen, mutta Suomen ja Tanskan eroja hoitointerventioissa ei kuitenkaan tämän perusteella voi arvioida. Tärkeää diagnostiikassa on myös diagnoosin pysyvyys myöhemmällä iällä.
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(2020)Mitochondrial aminoacyl tRNA-synthetases (mt-aaRS) catalyse the charging of tRNAs with their cognate amino acids in mitochondria. Mutations in mt-aaRS cause tissue-specific mitochondrial diseases, especially affecting tissues with high energy expenditure like the nervous system, heart, and kidneys. However, disease mechanisms for the heterogeneous group of diseases have not yet been fully elucidated. Harnessing CRISPR-Cas9 genome editing in induced pluripotent stem cells (iPSC) provides an opportunity to model mt-aaRS mutations in vitro and investigate the effects of individual mutations on cellular phenotype. SARS2 encodes mitochondrial seryl tRNA-synthetase, and its c.1347 G>A mutation causes severe childhood-onset progressive spastic paresis. Here, CRISPR-Cas9 ribonucleoprotein (RNP) complex and associated donor template were used to induce homology directed repair (HDR) the genome of iPSC and knock-in the patient mutation. Guide RNAs were designed and tested for efficiency before electroporation into wild type iPSC. Clonal cell lines were made by low-density seeding and manual colony picking. The expression of pluripotency markers was measured by RT-qPCR. RT-qPCR and Western blot measured SARS2 mRNA expression and protein level respectively. The success and precision of genome editing were analysed by Sanger sequencing, comparing the performance of the different guide RNAs, and screening regions of potential off-target genome editing. Two genome-edited iPSC lines with the SARS2 c.1347 G>A mutation were successfully generated to model the patient mutation. The iPSC lines expressed pluripotency markers and contained no off-target genome editing and modelled the patient’s decrease in SARS2 protein level and mRNA expression. More evidence of differentiation ability is needed before differentiation into the affected cell type (motor neurons) and further disease modelling. The efficiency of CRISPR-Cas9 for genome editing, especially harnessing HDR in iPSC, is an area of future research.
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(2018)The capability to generate human induced pluripotent stem cells (iPSC) from somatic cells provides remarkable possibilities for regenerative medicine. However, prior to clinical applications the process of reprogramming should be optimized and carefully characterized. The purpose of this study was to get insight in reprogramming of human somatic cells to pluripotency using CRISPR-dCas9 activator system (CRISPRa). CRISPRa is a RNA guided bacterial nuclease system that has been modified for gene expression control. The study had two subprojects. The aims of the first subproject were 1) to reprogram hNESCs to pluripotency with CRISPRa in 2D culture, 2) to determine the efficacy of reprogramming and 3) to study whether CRISPRa-mediated pluripotent reprogramming pathway involves a mesendoderm-resembling intermediate state. The aim of the second subproject was to explore the possibility of CRISPRa-mediated endogenous gene activation and reprogramming to pluripotency also in 3D cell cultures. I performed the reprogramming in 2D and 3D cell cultures by using a dCas9 activator to induce different combinations of endogenous pluripotency reprogramming factors OCT4 (octamer-binding transcription factor 4), SOX2 (Sex determining region Y-box 2), NANOG, c-MYC, KLF4 (Krüppel-like factor 4) and LIN28. I analysed the results of the reprogramming at protein level, using alkaline phosphatase staining and immunocytochemistry, and at mRNA level, using qRT-PCR. The 2D reprogramming served as a proof-of-principle for reprogramming with CRISPRa. This study shows, that CRISPRa can be used to reprogram human neural stem cells to iPSC with different combinations of pluripotency reprogramming factors or by inducing a single master-regulator gene, OCT4. In addition, the reprogramming process was very efficient. I did not detect mesendodermal intermediate state in CRISPRa-mediated reprogramming to pluripotency, in contrast to published results from transgene- and small molecules-based reprogramming studies. Thus, this result suggests that the pathway leading to pluripotency differs between CRISPRa-mediated reprogramming and the two other reprogramming methods. CRISPRa can be used to initiate reprogramming also in 3D cell culture. However, in 3D cell culture the cells were not fully reprogrammed. Based on these findings, I postulate that CRISPRa serves as an alternative method for generating human iPSC. In addition, CRISPRa can be further developed into a platform for direct reprogramming of organoids for in vitro disease modelling in 3D.
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(2020)Background: Cardiovascular (CVD) risk factors and several biomarkers have been linked to phenotypic frailty but the data is inconsistent, especially in oldest-old men. Purpose: To examine the association of frailty phenotype and different clinical and laboratory parameters in a cohort of older men. Methods: The Helsinki Businessmen Study (HBS) -cohort consists of men with high socioeconomic status (born 1919-1934, original n=3490). Their health status and CVD risk factors have been followed up since the 1960s and the clinical-epidemiological, longitudinal study is still ongoing. In 2017/2018 a random subcohort of community-dwelling survivors (n=232) was assessed. A postal questionnaire was sent to the men and they were invited to a study visit including clinical and laboratory examinations. Phenotypic frailty was identified according to the Fried physical phenotype criteria (nonfrail, prefrail or frail). SPSS software was used for statistical analyses. Results: Phenotypic frailty could be assessed in surviving 130 participants. Of them, 31%, 54% and 15% were nonfrail, prefrail, frail, respectively. Median ages were 86, 87 and 87.5 years. Frailty was associated with lower levels of systolic blood pressure, peak expiratory flow (PEF), total cholesterol, HDL cholesterol, and an increase in β2 microglobulin levels. Compared to nonfrail men, β2 microglobulin was 0.5 mg/L higher in the prefrail and frail subgroups (median [IQ range] 2.50 [0.8], 3.10 [1.5], 3.0 [2.6] mg/L, p=0.024). PEF, in turn, decreased with increasing frailty status (440 [80], 410 [160], 350 [160] L/min, p=0,013). Conclusions: β2 microglobulin can be considered an interesting candidate for a biomarker of frailty. As a simple clinical measurement, PEF may be a quick and inexpensive way to assess physical frailty in older adults. Further study on these matters is encouraged.
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(2019)CRPS:n, kuten muidenkin kroonisten kipuoireyhtymien, tiedetään huonontavan elämänlaatua. CRPS-potilailla esiintyy usein psyykkisiä oireita kuten masentuneisuutta ja ahdistuneisuutta. Toisin kuin aiemmin on luultu, psyykkisten tekijöiden ei ole osoitettu olevan osallisina CRPS:n synnyssä, mutta ne saattavat kuitenkin fysiologisten mekanismien ja käyttäytymismallien kautta vaikuttaa potilaiden kokemiin oireisiin. Tässä tutkielmassa tarkasteltiin 22 CRPS tyyppi I -potilaan elämänlaatua ja sen yhteyttä masentuneisuuteen, kivun hyväksymiseen sekä kipuun liittyviin pelko- ja ahdistusreaktioihin käyttäen 15D-elämänlaatumittaria sekä BDI-II, CPAQ ja PASS 20 -kyselyitä. 15D-mittarin perusteella CRPS-potilailla on tilastollisesti merkitsevästi huonontunut elämänlaatu verrattuna terveiden vertailuryhmään (p<0,01). Vaikeammat psykiatriset oireet vaikuttavat myös olevan yhteydessä huonompaan elämänlaatuun tutkituilta osin. Tulosten perusteella CRPS-potilaiden psyykkisten tekijöiden huomioiminen hoidossa voi olla tärkeää elämänlaadun kannalta.
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(2024)Objective. Hyperglycemia and dyslipidemia are well-known risk factors for coronary artery disease (CAD) in type 1 diabetes. The impact of long-term cumulative exposure to these risk factors is less explored. We investigated the relationship between cumulative glycemic and lipid exposure and CAD in individuals with type 1 diabetes. Research Design and Methods. This longitudinal study included 3,495 adults with type 1 diabetes from the FinnDiane cohort, without end-stage kidney disease and no history of CAD or stroke at the study baseline. Total cumulative glycemic exposure (CGEtot) and cumulative hyperglycemic exposure (CGEhg), accounting only for time spent above an HbA1c of 7% (53 mmol/mol), were calculated from diabetes diagnosis. Results. During a median follow-up of 19.4 years, 534 participants had their first-ever CAD event. CGEhg (odds ratio 1.03 [95% CI 1.02-1.05], P <0.001) and cumulative exposure to LDL cholesterol, triglycerides, and non-HDL cholesterol all significantly increased the odds for incident CAD. The highest tertile of CGEhg associated with a 2-fold odds increase for incident CAD. CGEtot was not significantly associated with CAD after adjusting for cumulative lipid exposure. Conclusions. Both hyperglycemia and dyslipidemia are independently associated with CAD in type 1 diabetes. These findings emphasize the importance of reaching an HbA1c below 7% (53 mmol/mol) as well as calling on health care professionals to not settle for suboptimal glucose control, but to continue their support and encouragement towards better management of diabetes.
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(2018)In vitro studies have shown that esomeprazole, the S-isomer of omeprazole, is a metabolism dependent inhibitor (MDI) of cytochrome P450 2C19, an essential drug-metabolizing enzyme. In this study, we characterized the effects of esomeprazole in vivo on CYP2C19, 3A4, and 1A2 using pantoprazole, midazolam, and caffeine, respectively, as probe drugs. In addition, we estimated the half-life of CYP2C19 by observing its recovering activity after inhibition. In a 5-phase study 10 healthy volunteers were administered 20 mg pantoprazole, 50 mg caffeine and 0.5 mg midazolam before and 1, 25, 49 and 73 hours after a 7 day pretreatment with 80mg esomeprazole twice daily. Esomeprazole increased the (R)-pantoprazole’s exposure up to 5-fold and the significant increase lasted at least 72 hours, which suggests strong MDI of CYP2C19. Esomeprazole had a minor effect on CYP3A4 and no effect on CYP1A2. The turnover half-life of CYP2C19 was estimated to be 46 hours. This estimation will be useful in the future for in vitro-in vivo extrapolations and physiologically based pharmacokinetic modeling of CYP2C19. Concomitant use of drugs metabolized by CYP2C19 should be considered cautiously because of the clinically relevant strong and prolonged inhibition of CYP2C19 by esomeprazole. Alterations in exposures to drugs metabolized by CYP2C19 are expected after discontinuation of esomeprazole treatment for at least 3-4 days.
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(2019)Finland har världens högsta incidens för typ 1 diabetes (T1D). Incidensen har ökat mångfalt under de senaste årtiondena i Finland och i andra utvecklade länder. Bl.a. detta och sjukdomens säsongberoende natur har riktat blickarna mot säsongberoende miljö-faktorer som utlösare av sjukdomsprocessen. Denna studies syfte var att undersöka om detta säsongberoende kan påvisas också i Finland och hur den förhåller sig till kön och ålder. Studiepopulationen bestod av 0–14 åriga finländska barn som hade diagnosticerats med T1D under åren 2002–2015. Säsonganalyser gällande diagnostidpunkten gjordes med hjälp av Poissons regressionsanalys, som säsongmodifierades. Vi observerade inci-densmönstret i förhållande till debutmånad samt säsongberoendets förhållande till kön och ålder. Diabetikerbarnen jämfördes med den teoretiska populationsenliga riskgrup-pen bestående av totalt antal levande 0–14 åringar i Finland per månad. Vår studie utvisade ett starkt säsongberoende. Säsongberoendet påverkades inte av kön men verkade bli kraftigare med stigande diagnosålder. Incidensen för pojkar var högre än hos flickor. Den årliga incidenstrenden var sjunkande fr.o.m. år 2006. Intressant var också att den yngsta åldersgruppen uppvisade den klart mest sjunkande incidenstrenden bland grupperna vilket väcker frågor om rotavirusvaccinets roll gällande incidensföränd-ringen. Rotavirusvaccinet infogades i det nationella vaccinationsprogrammet år 2009. Resultaten kan generera nya insikter angående sjukdomens patogenes och etiologi.
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(2022)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.
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(2015)Successful vocabulary acquisition requires encoding of newly learned spoken words into a long-term storage. At the neural level, this means optimal establishment of novel neural connections and rapid formation of memory traces for words. In adults the rapid formation of memory traces is seen as an enhanced neural response at 50 ms after word recognition point to novel words after short exposure. To explore the rapid word memory trace formation in children with dyslexia, we recorded online neural activity using electroencephalography (EEG) and event-related potentials (ERPs) during a short (~35mins) session of passive exposure to a novel pseudo-word in school-aged dyslexic children and matched fluently reading controls. The memory trace formation for the novel word was investigated by comparing the average ERPs of trials in the early and late part of the exposure. In fluently reading children, the neural response to the unfamiliar pseudo-word at early latencies after word disambiguation point increased significantly by the end of the session, putatively indicating memory trace formation for the novel word. In contrast, the neural response at the early latencies did not show any change in the group with dyslexia between the early and late stages of the exposure, indicating impaired rapid formation of memory traces for novel words. We propose that rapid neural learning of new spoken words is impaired in dyslexic children, possibly due to deficient phonological processing, development of phonological representations and phonological short-term memory, and hinders efficient vocabulary growth.
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(2018)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
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(2021)Psychological pain is a concept, that describes pain in the mind, also know as psyache. It is a phenomenon closely related to suicidal acts (Shneidman, 1996; Baumeister, 1990, Troister and Holden 2010). Psycyhological pain is a relatively new concept and not yet that well known, atleast among general practicioners. For example in the USA 5,6% of the general population and 53% of the patients with severe mental illness are thought to suffer from psychological pain (American Psychiatric Association, 2003). Depression and hopelessness are perhaps the most well known factors in the development of suicidal ideation, atleast for people not familiar with the research literature of this field. However Troister and Holden (Troister and Holden, 2012) compared the effects of psychological pain, depression and hopelessness. The results were that out of depression, hopelessness and psychological pain psychological pain is the only variable that contributes significantly to a change in suicidal ideation. In this study the contributions of depression and hopelessness were reduced to statistically nonsignificant levels. Furthermore psycological pain has been identified as a high risk factor for suicide with a greater predictive power than depression (Olié et al., 2010; Pereira et al., 2010; Troister and Holden, 2010; Li et al., 2014; Troister et al., 2015). Neuroimaging can be used in psychiatric diagnostics and also in psychiatric research. In diagnostics neuroimaging can be used to for differentiate between psychiatric and somatic causes of a psychosis, as psychosis can arise from a psychiatric disorder or from for example a brain tumor. Neuroimaging can be used for example in the field of pain research. There is overlap between neural networks of physical and psychological pain, but it seems like these different types of pain have some unique brain areas as well (Meerwijk et al., 2013). In addition to neuroimaging one of the ways of measuring psychological pain is through questionnaires, of which there are several. Perhaps because of these overlapping neural networks of pain some of the medication used to treat physical pain seems to have a positive effect on suicidal population suffering from psychological pain. It seems like the dose needed to treat psychological pain is a lot smaller than a dose needed to treat equivalent physical pain (Yovell et al., 2016).
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(2016)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.
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