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(2024)Amyotrofinen lateraaliskleroosi (ALS) on etenevä ja parantumaton tahdonalaisten liikehermojen rappeumasairaus. Sairaus johtaa vääjäämättä tahdonalaisten lihasten surkastumiseen sekä etenevään hengitysvajaukseen. Yleisin kuolinsyy sairaudessa onkin hengitysvajaus, jota liitännäisoireineen voidaan lievittää mekaanisella, kehon ulkopuolisella hengitystuella. Mekaanista hengitystukea voidaan tarjota joko kajoamattomasti esimerkiksi maskin kautta tai kajoavasti henkitorveen tehdyn avanteen kautta. Kajoavaan hengitystukeen liittyy kuitenkin eettisiä ongelmia, sillä se voi pidentää huomattavasti potilaan elinikää vaikuttamatta itse sairauden etenemiseen, mikä mahdollistaa sairauden pahenemisen jopa täydelliseen halvaustilaan. Kajoavan hengitystukihoidon yleisyys ALS-taudin hoitomuotona vaihtelee kansainvälisesti, ja tutkielman tarkoituksena on selvittää näihin valtioiden välisiin yleisyyseroihin johtavia syitä. Tutkielma suoritettiin kirjallisuuskatsauksena keräten aineistoa PubMed, Web of Science, Cochrane ja Duodecim -tietokannoista. Aineistoon sisällytettiin ALS-potilaiden hengitystukihoidon tehokkuutta käsitteleviä tutkimuksia, kliinisiä suosituksia, eettisiä ongelmia käsitteleviä kirjoituksia sekä kajoavan hengitystukihoidon alueellista yleisyyttä käsitteleviä kirjoituksia. Tuloksena kajoamattoman hengitystukihoidon vallitsevuus ALS-potilailla on Suomessa 5 %, Yhdysvalloissa 2,1–2,6 %, Italiassa 10–32 % sekä Japanissa 29,3–36,9 %. Vallitsevuuseroja selittäviä tutkimuksia löytyi niukasti. Yhdysvalloissa ja Japanissa toteutettujen kyselytutkimusten perusteella eroavaisuuksia on niin lääkäreiden ja potilaiden kuin omaistenkin suhtautumisessa kajoavaan hengitystukihoitoon. Japanissa kyselyyn vastanneet lääkärit ja omaiset suhtautuivat positiivisemmin kajoavaan hengitystukihoitoon kuin Yhdysvalloissa vastanneet. Lisäksi eettiset ongelmat, kulttuureiden erilaiset suhtautumiset näihin ongelmiin sekä erilaiset terveydenhuoltojärjestelmät voivat osaltaan selittää vallitsevuuseroja. Suomessa ei ole kansallista ALS-taudin hoitosuositusta, minkä lisäksi muuttuva lainsäädäntö tulee vaikuttamaan hoidon toteutukseen käytännössä. Päätöksenteon tueksi tarvitaan lisää tutkimuksia kajoavaa hengitystukea saavien ALS-potilaiden elämänlaadusta sekä hoidon tuomasta elinaikahyödystä kajoamattomaan hengitystukeen verrattuna.
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(2017)Cardiovascular disease is one of the leading causes of mortality worldwide. Upon myocardial infarction, billions of cardiomyocytes are lost, a fibrotic scar forms, and the heart's contractile function is compromised. Mammalian cardiomyocytes lose most of their proliferative capacity shortly after birth. This decline in proliferative capacity is associated with a switch from glycolysis to oxidative phosphorylation, yielding more ATP, but also inevitably forming reactive oxygen species (ROS). Therefore, finding a way to extend the proliferative window seems crucial to cardiac repair. microRNAs (miRNAs) are short, single-stranded noncoding RNAs that repress gene expression after transcription by binding to their target mRNAs. SIRT1-7, mammalian homologs of the Sirt2 protein in yeast, have been implicated in the regulation of metabolic homeostasis, cell proliferation, cardiac hypertrophy, and aging. The objective of our research was to investigate the differential expression of SIRT1-7 between day 1 and day 7 neonatal mice. Since cells continue to divide until day 7, we wanted to compare the differences in sirtuin expression during the two time points. By doing so, we hoped to gain insight into ways we could regulate sirtuin protein expression by manipulating miRNA and sirtuin gene expression in diseased hearts, thereby promoting the fetal gene program and inducing cells to reenter the cell cycle. Proteins were isolated from whole cell lysates of cardiac tissue of day 1 and day 7 neonatal mice, and western blotting technique was used to analyze SIRT1-7 expression. Expression of SIRT3 and 7 was significantly higher in day 7 as opposed to day 1 in at least two of the three runs, with SIRT7 levels being higher in day 7 in all three runs. Our study provides a basis for carrying out more quantitative analysis to validate gene and protein expression and protein activity, since expression is different at the gene and protein levels and does not necessarily translate into activity.
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(2019)Liver Kinase B1 (LKB1), also known as STK11, is a well-known tumor suppressor and a metabolic regulator, mutated in Peutz-Jeghers syndrome (PJS) and other sporadic cancers. LKB1 regulates several cellular functions: metabolism, polarity, cytoskeleton organization, differentiation, and proliferation by activating 14 AMPK-related downstream substrates. In a recent study, LKB1 was found to maintain intestinal homeostasis by repressing ATOH1 with the involvement of pyruvate dehydrogenase kinase 4 (PDK4). ATOH1 is a transcription factor and master regulator of secretory lineage in the intestine. It has been reported that ATOH1 is epigenetically regulated in inner hair cells and intestinal epithelium via Polycomb repressive complex 2 (PRC2). However, the repression mechanism of ATOH1 by LKB1 is currently unknown. This study aimed to determine the molecular mechanism of ATOH1 repression by LKB1. In this study, Ls174t, a human colorectal adenocarcinoma cell line, was used to investigate ATOH1 induction by LKB1 signaling from two angles: First, involvement of LKB1 downstream substrates was investigated using shRNA mediated knockdown screen. Interestingly, silencing of either MARK4 or SIK3 alone was found to induce ATOH1 and thus mimic silencing of LKB1 unlike other LKB1 substrates including AMPK kinases. A second angle explored possible epigenetic mechanism in ATOH1 repression pathway, using dichloroacetate (DCA, a PDK4 inhibitor) and GSK126 (a PRC2 inhibitor). DCA treatment resulted in no change on the global levels of histone modifications tested. In addition, GSK126 caused the downregulation of ATOH1 in both control and LKB1 depleted condition. Thus, this study concludes that LKB1 represses ATOH1 through MARK4 and SIK3 and that global changes in the histone modifications investigated are not involved in the mechanism.
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(2023)Objectives. The five-factor model of personality is the most researched and widely accepted theory of the structure of personality. It is claimed to be a near universal even though studies of the model have overwhelmingly relied on samples from Western, educated, industrialized, rich, and democratic (WEIRD) populations and/or university or college students from non-WEIRD countries. Therefore, multiple scholars have called for studies that examine personality traits with other kinds of samples, but only relatively few studies like that have been conducted. The aims of this study were to examine whether the model is suitable to explain personality variation in elephant handlers, or mahouts, from Myanmar, and, if it is not applicable, how personality appears to manifest in the mahouts. Testing whether the model applies to this sample is highly valuable for assessing the model’s cultural variability and the claims about its near universality. Methods. The sample (n = 237) consisted of 138 mahouts and 99 of their peers, most of whom were fellow mahouts. They gave self- or observer ratings to an interviewer asking questions from the 44-item Big Five Inventory (BFI), which was translated into Burmese. Self-observer agreement and retest correlations were also calculated. The personality structure of the 138 mahouts was investigated with confirmatory and exploratory factor analysis. Results. The confirmatory factor analysis resulted in a covariance matrix of latent variables that was not positive-definite possibly because of the small sample size. The analysis method was then changed into exploratory factor analysis, and models with four, five, and six factors were com-pared in more detail. However, no clean factor structure emerged since the items measuring Open-ness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism in the BFI did not, in general, load in a clear or sensible way in any of the factor solutions. Conclusions. These results could provide support for the hypothesis that mahout personality cannot be described with the five factors. Their personality variation may instead be organized along differently composed dimensions. This study could therefore be another example of the five-factor model of being more culture-specific than (near) universal.
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(2022)Autophagy is an essential pathway that evolved to sustain cellular integrity by removing damaged and aged organelles. During this process, our cells sense, encapsulate and deliver defective cellular components to the lysosome for destruction. Over the past decade, many laboratories have demonstrated that damaged mitochondria can be selectively eliminated, during a process known as "mitophagy". Mitophagy senses, targets, and engulfs defective mitochondria for elimination via lysosomal hydrolysis. The identification of factors that promote or prevent mitophagy has high therapeutic relevance, particularly those that alter PINK1/Parkin-independent mitophagy. Recent research in the McWilliams lab uncovered a novel role for lipid metabolism in the regulation of PINK1/Parkin-independent mitophagy. Briefly, the team discovered that DGAT1-dependent lipid droplet (LD) biosynthesis occurred several hours upstream of mitochondrial clearance, with LDs accumulation upon iron chelation. LDs accumulate in a DGAT1-dependent fashion as mitochondria are eliminated. Pharmacological or genetic inhibition of DGAT1, restricts mitophagy levels in vitro and in vivo. However, the mechanism that linked defective lipid metabolism to reduced mitophagy remained mysterious. We hypothesized that defective lipid signalling may compromise lysosomal activity leading to reduced levels of mitophagy. Accordingly, my project examined the functional contribution of DGAT-dependent LD biogenesis to lysosomal homeostasis in the context of PINK1/Parkin-independent mitophagy. After first verifying the DGAT1-dependent nature of LD accumulation in human cells, I established assays to investigate lysosomal homeostasis in the context of iron chelation-induced mitophagy. Using a variety of labelling approaches, live cell imaging experiments revealed a significant displacement of endolysosomes upon DGAT1/2 inhibition, in addition to possible alterations in lysosomal dynamics. My data suggest that loss of DGAT1 activity impairs lysosomal homeostasis when iron levels are low. This likely explains the mitophagy impairments and might account for additional phenotypes of impaired cell viability upon DGAT1 inhibition. Changes in lysosomal acidity were inconclusive, indicating further timepoints may need to be analysed to detect transient impairments in hydrolysis. My results emphasize the importance of organelle crosstalk in mitophagy and the emerging role of LDs in cellular integrity. These data further highlight that targeting lipid metabolism may provide a means to sustain efficient mitochondrial turnover.
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(2023)Circadian clocks govern our bodily rhythms both in health and disease. A diurnal pattern in neuropathic pain has been demonstrated in humans, but whether analgesics used to treat it have clinically relevant circadian effects is still largely unknown. This systematic literature review aims to describe the relationship between circadian rhythms and the specific analgesics used in the treatment of neuropathic pain. Based on current neuropathic pain drug treatment recommendations, analgesics of interest were chosen as gabapentin, pregabalin, carbamazepine, oxcarbazepine, serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants, opioids, capsaicin, and lidocaine. A literature search was conducted on PubMed, Web of Science, Cinahl, and Medic electronic databases, through August 2023. Publications were screened for human clinical studies and full-text availability. Data were collected from studies conducted on chronic pain patients or healthy volunteers, that describe the use of analgesics of interest and provide data on any measurable circadian-related marker or diurnal variation in drug effects. A total of 32 studies were included. Evidence of diurnal variations were found in the pharmacokinetics of morphine and tricyclic antidepressants as well as in the analgesic effects of dihydrocodeine and tramadol. Serotonin-noradrenaline reuptake inhibitors do not seem to disturb the normal circadian patterns seen in melatonin, cortisol, or body temperature levels. In contrast, tricyclic antidepressants may affect melatonin and cortisol profiles. The diurnal pattern of neuropathic pain is preserved during gabapentin, morphine, and nortriptyline treatment. Drug-induced changes in different sleep parameters were seen in several of the analgesic groups, but the possible circadian dependence of these effects is unclear. The results of this review suggest that circadian rhythms may influence the pharmacokinetics and pharmacodynamics of analgesics. The clinical significance of these circadian effects in humans needs further investigation. A better understanding of the relationships between circadian rhythms and non-opioid analgesics can eventually lead to improved and personalized treatment strategies for neuropathic pain.
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(2014)The objective of this project was to determine whether the new Ad3-hTERT-E1A based viruses armed with immunological genes are functional and have efficacy for further research aiming at clinical experiments. The hypothesis was that they would be oncolytically as potential as earlier studied Ad3-hTERT-E1A virus in vitro and in vivo. The encouraging results from previous studies had shown the potential of serotype 3 adenoviruses (Ad3). (1, 2) Unlike the more extensively researched Ad5 and Ad5/3 viruses, the Ad3 viruses open epithelial junctions while infecting cells and use other receptors to enter cells, which might enable them to spread more easily in tumours.(3) The new viruses were compared with the E1A first in vitro (progressive TCID50, MTS) and then in vivo in a SKOV3-luc intra peritoneal tumour animal experiment with SCID mice (immunodeficient). We found that the new viruses have the same oncolytic potential as the old E1A virus both in vitro and in vivo, which confirmed the basic hypothesis. This provides a starting point for further research on the immunologically armed Ad3 viruses.
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In vitro assessment of mechanism-based CYP2C8 and CYP3A4 inhibition by six protein kinase inhibitors (2016)Several protein kinase inhibitors are known to be mechanism-based inhibitors of cytochrome P450 (CYP) enzymes, especially CYP3A4. Mechanism-based inhibition of CYP enzymes by a drug may have long lasting and serious consequences due to the irreversible nature of the inhibition. The CYP enzyme must be resynthesized before regaining functionality, affecting the concentrations of other drugs metabolized by the same CYP enzymes and potentially leading to drug-drug interactions. Six protein kinase inhibitors were tested for mechanism-based inhibition of CYP2C8 and CYP3A4 using human liver microsomes; masitinib, midostaurin, nintedanib, quizartinib, trametinib and vatalanib. Amodiaquine was used as the substrate for CYP2C8, while midazolam was the CYP3A4 substrate. None of the inhibitors tested displayed time-dependent inhibition of CYP2C8. Midostaurin and nintedanib exhibited time-dependent inhibition of CYP3A4 while masitinib, quizartinib, trametinib and vatalanib did not. Both midostaurin and nintedanib had an inhibitor concentration causing a 50% inhibition (IC50) shift of >1.5-fold with increased inhibition of CYP3A4 after preincubation with NADPH for 30 minutes when compared to no preincubation. The mechanism-based inactivation constants kinact (the maximal inactivation rate) and KI (the inhibitor concentration that supports half-maximal rate of inactivation) were determined for midostaurin and nintedanib. The kinact values were 0.053 1/min for midostaurin and 0.024 1/min for nintedanib, while the KI values were 2.65 µM for midostaurin and 16.5 µM for nintedanib. Predictions using a mechanistic static model suggested that nintedanib is unlikely to cause CYP3A4 mediated drug-drug interactions, while midostaurin was predicted to increase the exposure of CYP3A4 substrates by several times. Reversible inhibition by trametinib is unlikely to cause drug-drug interactions involving either CYP2C8 or CYP3A4 substrates. On the other hand, masitinib and vatalanib were predicted to increase the exposure of CYP2C8 and CYP3A4 substrates several fold. In conclusion, two protein kinase inhibiters were identified as mechanism-based inhibitors of CYP3A. Mechanism-based inhibition of CYP enzymes by protein kinase inhibitors has the potential to cause severe long lasting consequences and careful testing should be conducted to determine the actual clinical drug-drug interaction risk.
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(2023)Työ koostuu huolellisesti kerätyn tieteellisen aineiston pohjalta kirjoitetusta katsausartikkelista. Työn tarkoituksena on ollut kartoittaa tämänhetkisen syöpälääketestauksen menetelmiä ja niiden kehitysmahdollisuuksia sekä koota uusimpaan tieteelliseen tietoon perustuva katsausartikkeli, jonka sisältö on lukijalle informatiivistä ja loogisesti etenevää. Artikkelin pääpainona on ollut suun- ja kaulan alueen syöpien lääketestaus sekä humaaniperäinen syöpäsolujen kasvatusympäristö. Aluksi katsauksessa kartoitetaan tämän hetkisten syöpälääketutkimusten ongelmakohtia sekä tutkimusten kehittämisen tarvetta. Artikkelissa paneudutaan niihin mikrotason tekijöihin, jotka vaikuttavat in vivo -syöpäkudoksessa ja joiden puuttuminen vaikeuttaa uusien lääkeainekandidaattien tunnistamista syöpälääketutkimuksissa. Katsaus kuvaa menetelmiä, joilla in vitro -suun ja nielun alueen syöpien lääketutkimuksia voidaan kehittää paremmin mallintamaan eläviä kudoksia luotettavamman syöpäsolujen lääkehoitovasteen määrittämiseksi. Katsauksessa tutustutaan humaanikudosperäiseen syöpäsolujen kasvatusympäristöön, solun ulkoiseen matriksiin ja sitä vertaillaan nykyisin yleisesti käytössä oleviin matrikseihin ja muihin soluviljelutapoihin. Artikkelissa selvitetään humaaniperäisen matriksin onnistuneita käyttökohteita syöpälääketutkimuksissa sekä kuinka humaanikudosperäiset matriksit ovat osoittautuneet paremmin kuvaamaan syöpälääkkeiden todellista kliinisissä kokeissa todettua tehoa kuin tällä hetkellä käytössä olevat matriksit. Lopuksi on lyhyt pohdinta humaaniperäisten solunulkoisten matriksien tulevaisuudesta. Katsauksessa havaittiin humaanikudosperäisten solun ulkoisten matriksin toimivan luotettavimpana syöpäsolujen kasvatusympäristönä. Tulevaisuuden syöpälääketutkimuksessa olisi tärkeää löytää in vitro -olosuhteet, jotka parhaiten mallintaisivat myös syövän mikroympäristöä ja näin parantaisivat tulosten luotettavuutta. Katsaus voi tarjoita syöpätutkijalle keinoja syöpälääketutkimuksen kehittämiseksi.
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(2023)Head and neck cancers form the seventh most common type of cancer globally, and 90% of these cancers are classified as head and neck squamous cell carcinomas (HNSCC). The 5-year survival rate for head and neck cancers remains around 50%, indicating a need for new treatment strategies. This thesis aimed to examine the potential of BH3 mimetics A 1155463, A-1331852, and navitoclax combined with irradiation, as a treatment for HNSCC. BH3 mimetics are compounds able to bind to anti-apoptotic proteins, thereby blocking their ability to exhibit anti-apoptotic effects. A high-throughput screening method was used to characterize the synergistic effects of the BH3 mimetics with different irradiation doses on the viability of twelve HNSCC, normal (NOF) and cancer-associated fibroblastic (CAF), and HPV-16 immortalized oral dysplastic keratinocyte (ODA) cell lines. Additionally, the effects of A-1155463 and A-1331852 on apoptosis and proliferation of two HNSCC cell lines (UT SCC 40 and UT-SCC-42A), in combination with 8 Gy irradiation, were measured. Effects on invasion of UT-SCC-42A cells with the irradiation-mimetic combination were tested in a 3D spheroid model. Lastly, the effect of A 1331852 and navitoclax in combination with immunotherapy drug nivolumab on donor-derived immune cell migration and apoptosis of UT-SCC-40 was assessed with a microfluidic chip assay. All three BH3 mimetics in combination with irradiation synergistically reduced viability in six to ten HNSCC cell lines and ODA cells, but not in NOF or CAF. A-1155463 and A-1331852 induced apoptosis and reduced proliferation in both tested cell lines. The addition of irradiation to the compounds significantly increased the apoptotic ratio in both cell lines and compounds. In the spheroids, A-1331852 significantly reduced cancer cell area and length of invasion both with and without irradiation. A-1155463, unlike navitoclax, had a trend in reducing HNSCC invasion. The combination of A-1331852 with nivolumab increased the immune cell migration of one out of the three donors. These results show the synergistic and apoptosis-inducing effects of the BH3 mimetics combined with irradiation, proving them plausible candidates for HNSCC treatment. The reduction of invasion by A 1331852 suggests a role for Bcl-xL in HNSCC invasion. It is proposed to further investigate the properties of A-1331852 in in vitro cocultures and in vivo studies, with and without irradiation.
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(2021)Mitokondriotautien etiologia on vielä runsaasta tutkimuksesta huolimatta monilta osin tuntematonta. Tiedetään, että nämä taudit aiheuttavat monimuotoisia aineenvaihduntahäiriöitä kudos- ja soluspesifisti. Tämä tutkielma keskittyy yhteen näistä sairauksista ja pyrkii valottamaan folaatin vaikutusta kudosten yhden-hiilen-metaboliaan ja sen merkitystä imeväisiässä alkavaan pikkuaivo- ja selkäydinperäisen ataksian (IOSCA) etiologiassa. Aiemmat tutkimukset hiirellä ovat osoittaneet, että IOSCA-mutaatioon liittyy häiriintynyt deoksinukleotidi (dNTP) -varastojen tasapaino, mitokondrioDNA:n (mtDNA) vähenemä ja muuntunut yhden-hiilen-metabolia. Nämä yhdessä ovat mitokondriaalisen toiminnan häiriön aiheuttama stressireaktio. Tutkimuksessa käytettiin mallieläimenä hiirtä. Koeryhmiä altistettiin sekä folaatittomalle ruokavaliolle että foliinihappolisälle. Tutkimuksessa tarkasteltiin mtDNA määriä, dNTP-varastojen tasoja sekä mitokondriaalisen hengitysketjun, folaattisyklin ja transsulfuraatioreitin entsyymien ekspressiota. Kohdekudoksina olivat isoaivokuori, pikkuaivot, lihas ja maksa. IOSCA-hiirillä nähdään kudos- ja genotyyppispesifi dATP-tasojen lasku lihaksessa, jota folaatin puute pahentaa ja foliinihappolisä korjaa. Tämä osoittaa folaatilla olevan suora yhteys dATP-tasojen säätelyyn IOSCA-hiirien lihaksessa. Tutkimus antaa myös viitteitä, että metaboliset muutokset IOSCA-hiirissä ovat ikään sidottuja. IOSCA-hiirillä on 15 kk:n ja 18 kk:n iässä vasta alkava dNTP-varastojen epätasapaino, toisin kun aiemmissa vanhemmilla hiirillä tehdyissä tutkimuksissa, joissa dNTP-varastojen epätasapaino oli merkittävä. IOSCA-hiiret ovat myös kontrollia herkempiä folaatin puutteelle. Lisäksi nähdään folaatin saannin vaikuttavan merkittävästi niin folaattisykliin ja laajemmin yhden-hiilen-metaboliaan kuin myös kudosten dNTP-varastojen tasoon. (186 sanaa)
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(2020)Punasolusiirrot ovat tärkeä osa leukemiahoitoon ja kantasolusiirtoon liittyviä tukihoitoja. Runsaat punasolusiirrot altistavat rautaylimäärälle, jonka pitkäaikaisvaikutuksia kantasolusiirretyillä lapsilla on tutkittu suhteellisen vähän. Tutkimuksen tarkoituksena oli selvittää rautaylimäärän esiintyvyyttä sekä sen yhteyttä elinvaurioihin ja lapsuusiän pituuskasvuun potilailla, jotka olivat saaneet allogeenisen kantasolusiirron lapsuusiässä akuutin lymfaattisen leukemian vuoksi. Tutkimukseen osallistui 23 potilasta, jotka olivat mediaani-iältään 12.6 (vaihteluväli 7.5-21.4) vuotta. Kehon rautalastin suuruutta arvioitiin laboratoriokokeilla, sydämen ja maksan magneettikuvantamisella sekä laskemalla punasolusiirroista saadun raudan määrä. Käytimme monimuuttuja-analyysiä tutkiaksemme yhteyttä kehon rautalastin ja sydämen toiminnan, maksaentsyymitasojen, insuliiniresistenssin ja pituuskasvun välillä. Plasman ferritiini oli mediaaniarvoltaan 344 (vaihteluväli 40-3235) ng/ml ja ylitti tason 1000 ng/ml kolmella potilaalla (13%). Magneettikuvauksessa yhdellätoista potilaalla (48%) todettiin rautaylimäärä maksassa ja yhdellä potilaalla (4%) rautaylimäärä sydämessä. Sydämen magneettitutkimuksessa ejektiofraktio oli subkliinisesti alentunut kahdeksalla potilaalla (35%), mutta sydämen toiminta ei assosioitunut kehon rautalastiin. Maksaentsyymitaso korreloi punasolusiirroista saadun rautamäärän kanssa (p=0.001), mutta potilailla ei esiintynyt kohonneita maksaentsyymiarvoja tai merkkejä maksavauriosta mediaaniltaan 4.5 vuoden seurannan jälkeen. Rautalasti ei korreloinut pituuskasvun tai insuliiniresistenssin kanssa. Rautaylimäärä on yleinen akuutin leukemian vuoksi kantasoluriirretyillä lapsilla, mutta rautalastiin liittyviä elinvauriota ei esiinny nuorella iällä. Suosittelemme rautalastin arvioimista kaikille potilaille ainakin kerran kantasolusiirron jälkeisen seurannan aikana.
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(2019)Objective: Mindfulness-based programs are increasingly used with adolescents in school environment. Many preliminary studies have shown that training mindfulness can be helpful for enhancing students’ mental health and psychological well-being. The current evidence base on the effectiveness, however, is still quite narrow and most studies have been limited due to methodological weaknesses. The aim of this study was to investigate how mindfulness training impacts on adolescents’ psychological well-being in secondary school. Methods: The study is a cluster randomized controlled trial, and a part of the Finnish school-based mindfulness research project Healthy Learning Mind (N=3519). Adolescents (age: 12-15 years) either participated in a 9-week mindfulness program, a standardized relaxation program, or followed usual school curriculum. Students’ emotional and behavioural problems, and prosocial behaviour were measured at baseline, post-intervention, and after six-month follow-up, using self- and parent-rated Strengths and Difficulties Questionnaire (SDQ). Linear mixed effects modelling (LMM) was used to compare differences between groups in the change from baseline to post-intervention and follow-up in the SDQ-scales. Results: There weren’t any statistically significant differences in change in any SDQ -outcome variables between the three groups at post-intervention or follow-up. However, during mindfulness program, students’ self-rated emotional symptoms and hyperactivity problems decreased and prosocial behaviour increased. Findings in the parent-rated results paralleled these results, and students’ conduct and emotional problems and hyperactivity were significantly decreased. Conclusions: Despite positive changes in the psychological well-being of the adolescents in the mindfulness group, no differences between the groups were found. Further research is still required to identify psychological well-being benefits of mindfulness training in school environment, using multiple measurement methods and longitudinal designs.
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(2015)Background: Fluid therapy is required to maintain the perfusion to donor organs. Recent reviews on the choices of fluids have emphasized the safety of using crystalloids, as opposed to fluid therapy with colloids, which has been reported either unequivocal or potentially harmful in a number of studies on various patient populations. We aimed to analyze if the type of fluids given to donors is connected with the outcome of kidney transplantation. Methods: A total of 100 consecutive brain-dead multi-organ donors and the respective 181 kidney recipients were studied retrospectively. Data concerning donor fluid therapy, the characteristics of the donors and the recipients, and the outcome after kidney transplantation were extracted from organ retrieval and patient records. Cases with early graft function (EGF) were compared to cases with delayed graft function (DGF). Results: The donor had received both crystalloids and colloids in most cases (84 %). Fluid therapy with crystalloids alone was more common among the 40 recipients with delayed graft function (30 %) than the 103 recipients with early graft function (11 %) (P=0.005). Donor age, time on dialysis before transplantation and donor fluid therapy with crystalloids alone were independent risk factors for delayed graft function in multivariate analysis. Conclusion: Our results suggest that donor fluid therapy including colloids could be beneficial instead of harmful when compared to treatment with crystalloids alone. This finding needs to be evaluated in prospective studies.
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(2024)Abstract Background Musculoskeletal (MSK) disorders represent a remarkable burden to society and an unpleasant burden for the individual. Physical activity (PA) can prevent MSK disorders while conferring other beneficial effects on health. The present study aimed to investigate associations between device-measured PA and perceived MSK disorders among young adult men. Methods Participants’ physical behavior was measured with a hip-worn accelerometer in a sample of 422 young adult Finnish men aged 26 (SD 7) years. Incidences of three common MSK disorders (knee pain, lumbar radiating pain, and lumbago pain) during the last month were inquired by a questionnaire. Binary logistic regression was used to examine the associations between the MSK outcomes and explanatory PA variables (PA times at different intensity levels, standing, and sedentary times). Age, education, smoking, BMI, and maximal oxygen uptake were controlled for in the models. Results PA and sedentary times were not significantly associated with the incidence of perceived MSK pain during the last month, except for lumbago pain. For lumbar radiating pain, the odd ratio (OR) was 1.02 (95% CI 0.96 to 1.09), and for knee pain, the OR was 1.02 (95%CI 0.96 to 1.08). Lumbago pain was more probable if the relative time spent in light PA increased, even after adjusting for potential confounding factors, including moderate-to-vigorous physical activity. However, the OR was yet small, only 1.07 (95% CI 1.02 – 1.14). Conclusions The lack of significant and clinically meaningful associations between device-measured PA and common MSK disorders observed in by young adult men was surprising and requires further confirmation.
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(2017)Objective. Preterm birth can cause challenges for early interaction between parent and infant. Early interaction is the basis for language and cognitive development, so parents play an essential part in supporting the development of their preterm child. Very little research of early interaction has been made from the fathers' point of view. The aim of this study was to depict fathers' experiences of early interaction with their prematurely born infants and examine the effect premature birth has on fatherhood. Participants and methods. The participants were four fathers of prematurely born infants and eight fathers of full-term infants. The prematurely born children were born between 30+4–33+6 weeks of gestation and weighed between 1 400–2 900 grams at birth. At the time of the study the premature infants were between 2–7 months of corrected age. The full-term children were between 1–6 months of age at the time of the study. The method of this study was semi-structured interview. The themes were composed for this study, based on previous research on premature birth, parenthood and early interaction. A pilot interview was carried out prior to the research interviews. The research interviews were conducted in autumn 2016. A theory-based content analysis and theme identification was carried out. Results and conclusions. The fathers described feelings of stress and anxiety, but felt that most of the support available for parents of premature children was focused on the mothers. The fathers' experiences differed most with the time spent in the hospital, the perceived fragility and passivity of the child, the concern over the well-being of the mother and the strain of childcare. Similar types of play were used in both groups. The premature infants had more variation in sleep and eye-contact. The results indicate there should be more support available for the fathers of prematurely born children.
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(2022)The early life gut microbiota plays a major role in establishing neonatal immunity and child’s long-term health. However, relatively little is still known about the role of individual bacteria as most studies so far have focused on characterizing the diversity and the individual and temporal variations of the infant gut microbiome. The genus Bacteroides is of particular interest since its abundance is remarkably decreased in infants born via C-section, and relatively little is known about the genomic and phenotypic characteristics of early Bacteroides colonizers despite their anticipated role in the increased morbidity following C-section birth. This thesis aims to contribute to the isolation and characterization of Bacteroides strains from infant and mother stool samples from the Health and Early Life Microbiota (HELMi) cohort study using culture-based and metagenomic approaches. Gram-negative bacteria were isolated from stool samples of 9-week-old infants and identified by Sanger sequencing. In total, seven isolates identified as unique species of Bacteroides, isolated from infant samples or previously from mother samples in late pregnancy, were then characterized for their potential to activate innate immunity in vitro by using HEK-Blue™ hTLR2-hTLR6 reporter cells either as live cells or filtered culture media. Whole genome shotgun sequenced stool metagenomes obtained from 88 infants during the first year of life were leveraged as well. A computational pipeline able to scale to the large size of the dataset was developed to obtain metagenome assembled genomes (MAGs) from the metagenomes. MAGs obtained from Bacteroides species were further taxonomically and functionally annotated. Among the seven Bacteroides spp. isolated from HELMi mother and infant samples, the majority were able to activate the TLR2/6 receptor in vitro. The isolates varied in their potential to activate the receptor via their cell surface molecules and substances they excreted to the culture media. In addition, over 2500 MAGs could be retrieved from the infant metagenomes, of which 18 belonged to Bacteroides spp. Based on predicted open reading frames, majority of the identified proteins of these MAGs were involved in housekeeping functions. Most of predicted proteins involved in cellular metabolism were, however, related to carbohydrate metabolism, amino acid metabolism, and glycan metabolism, stressing the role of Bacteroides spp. in the gut as important and versatile carbohydrate consumers. The results indicate that the Bacteroides spp. colonizing infant gut have an immunologically and metabolically active role. Further work is needed to characterize the molecules responsible for the TLR2/6 activation as well as the nature of the downstream immune responses elicited by the isolated Bacteroides spp.
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(2022)Isoloitu silmäkuopan murtuma on yksi yleisimmistä kasvojen alueen murtumista. Se on tyypillisesti seurausta silmään ja sitä ympäröivälle alueelle kohdistuneesta tylpästä iskusta. Murtuma voidaan hoitaa leikkauksella tai ilman leikkausta. Leikkauksesta saatavan hyödyn on arvioitu olevan suurin, mikäli se suoritetaan kahden viikon kuluessa vammasta. Tästä huolimatta suuri osa leikkaushoitoon valituista potilaista leikataan yli kaksi viikkoa vammasta. Retrospektiivisen asiakirjatutkimuksen tavoitteena oli havainnoida Helsingin yliopistollisen keskussairaalan Korvaklinikalla hoidettujen isoloitujen silmäkuopan murtumien hoitoketjussa olevia viiveitä ja selvittää, miten vammaan liittyvä alkoholinkäyttö, samanaikainen silmävamma, vammamekanismi ja Korvaklinikalle lähettävä yksikkö vaikuttavat hoitoviiveisiin. Lisäksi halusimme selvittää, miksi osa potilaista leikataan yli kaksi viikkoa vammasta. Havaitsimme, että 30,2 prosenttia leikatuista potilaista leikattiin yli kaksi viikkoa vammasta. Vammaan liittyvä alkoholinkäyttö vaikutti yllättäen hieman nopeuttavan hoitopolulla etenemistä, ja samanaikainen silmävamma vaikutti hieman nopeuttavan hoitoon hakeutumista ja murtuman diagnosointia. Vammamekanismilla ei näyttänyt olevan vaikutusta hoitoviiveeseen vammasta ensimmäiseen käyntiin Korvaklinikalla. Lähete Silmäklinikalta vaikutti hieman hidastavan viivettä vammasta ensimmäiseen käyntiin Korvaklinikalla verrattuna lähetteeseen päivystyspoliklinikalta. Minkään tutkitun muuttujan ei katsottu vaarantavan tavoitetta suorittaa leikkaushoito kahden viikon kuluessa vammasta. Tavallisin syy viivästyneelle leikkaushoidolle oli leikkauksen suunnitteleminen Korvaklinikalla yli kaksi viikkoa vammasta. Tutkimuksen perusteella Korvaklinikan sisäiset tekijät ovat merkittävin interventiokohde, mikäli murtuman hoidossa halutaan vähentää yli kaksi viikkoa vamman jälkeen leikattujen potilaiden osuutta.
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(2019)Objective: Traumatic brain injury (TBI) is a major public health issue leading to long-term cognitive, emotional, and physical impairments. New, effective, multimodal and multidisciplinary rehabilitation practices are needed. Dance is a multimodal activity that engages several brain regions simultaneously and, therefore, might be ideal for enhancing complex functions. Dance also combines physical exercise and the use of music, both of which positively affect healthy and neuropathological populations. The aim of the research project was to develop a multidisciplinary dance rehabilitation method and to evaluate its feasibility and effectiveness in chronic severe TBI. The current study investigates the intervention’s effects on cognition, depressive mood, and health-related quality of life. The feasibility of the intervention is also discussed. Methods: The current study had 11 participants with severe TBI; four women and seven men, 19 – 45 years old, with an average time of 7.6 years from the acquisition of the injury. A two-group crossover design with random allocation was used. The intervention (three months, two weekly sessions) was carried out together by a dance instructor and a physiotherapist. Neuropsychological assessments were conducted at the beginning of the study (t0), and twice after that every three months (t3 and t6). Performance before and after the intervention in general cognition, frontal lobe functions, abstract reasoning, visuo-spatial reasoning, working memory, mood, health-related quality of life, and executive functions were compared with paired sample t-tests. Time and group interactions were studied by repeated measures analyses of variance. Results: Abstract reasoning, health-related quality of life, and most saliently, mood improved significantly during the intervention. Qualitative findings also indicated enhanced mood. One of the participants described being reconnected to emotions for the first time a after the acquisition of the TBI and several other participants expressed positive feelings and experiences during the intervention. Conclusions: The current study suggests that dance rehabilitation may improve mood, abstract reasoning, and quality of life in the chronic state of severe TBI. These results are tentative and more research with larger samples is needed to verify the findings.
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(2017)Kuvantamista hyödyntävässä toimenpiteessä eli toimenpideradiologiassa on kliininen tarve määrittää potilaan tukos- tai vuototaipumusta. Ultraäänitoimenpiteissä vuotoriskiä ennakoidaan protrombiiniajan (PT) ja siitä johdetun International Ration (INR) avulla. Sydänpotilailla tukosriskiä pienennetään toimenpiteen aikana annostelemalla suonen- sisäisesti hepariinia, jolloin aktivoidulla hyytymisajalla (ACT) voidaan seurata hepariinin vaikutusta. Kannettavalla vierilaitteella voidaan verianalyysit suorittaa toimenpide- huoneessa,jolloin tulosviive pienenee. Tutkielmassa verifioitiin HUS-Kuvantamisen radiologian hankkima ITC Hemochron® Signature Elite-vierilaitteen kokoverianalyysit PT, INR ja aktivoitu partielli tromboplastiiniaika (APTT) vertaamalla laitteen antamia tuloksia laboratorion veriplasmaa käyttäviin analyysituloksiin. Laitteen aktivoidun hyytymisajan (ACT LR ja ACT+) tuloksia verrattiin laboratorion antifaktori X-aktiivisuuteen (anti-FXa). Tavoitteena oli selvittää potilasaineiston avulla soveltuuko ITC Hemochron® Signature Elite-vierilaite kliiniseen käyttöön toimenpideradiologiassa. Ultraäänitoimenpiteissä potilaita oli yhteensä 20 ja sydänpotilaita oli 15. Potilaita ei valikoitu vaan kaikki näyt- teiden keräyspäivinä tammikuussa ja huhtikuussa 2015 HUS-Kuvantaminen radiolo- giassa ulträäni- tai sydäntoimenpiteissä olleet potilaat otettiin mukaan. PT-mittauksissa ero laboratorion menetelmän ja Hemochron® Signature Elite PT:n välillä oli -5,5 sekuntia (-26,3 prosenttia) ja keskinäinen riippuvuus eli korrelaatio vähäinen (R=0,02). INR- mittauksissa ero oli 0,15 (15 prosenttia) ja korrelaatio vähäinen (R=0,1). APTT-mittauk- sissa ero oli 8,4 sekuntia (33,9 prosenttia) ja korrelaatio alhainen (R=0,33). ACT LR:lle ja ACT+:lle ei määritelty eroa, koska mittausasteikko eroaa laboratorion antiFXa:n kanssa. ACT LR:lle saatii korrelaatio oli 0,49 ja ja ACT+:lle 0,35.
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