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  • Itkonen, Suvi (Helsingin yliopisto, 2015)
    Phosphorus (P) intake in Western countries exceeds the nutritional recommendations 2- to 3-fold, and the increased use of food additive phosphates (FAPs) in the food industry has augmented total P (TP) intake; an estimated 10-50% of TP intake comes from additives. However, in food composition databases, the amounts of FAPs may have not been taken into account. Difficulties in measuring true P intake occur also because bioavailability of P differs between foodstuffs; inorganic P from additives is absorbed better in the intestine than natural, organic P. The harmfulness of high P intake to kidney patients has been known for years, and dietary P restriction is used in the treatment of the disease to avoid vascular calcification, which occurs due to calcium-phosphate deposition in the vascular vessel wall. However, recently, concerns have been raised about the role of elevated serum phosphate concentrations in cardiovascular health in the general population, but data on dietary P is scarce. This thesis aims to offer new insights into the potential health risks related to high dietary P intake in Finland by providing knowledge on the bioavailability of P in foodstuffs, and on the association of high dietary P intake with cardiovascular disease risk factors in the general population. In Study I, a new method was developed for analysis of in vitro digestible P (DP), indicating bioavailable and absorbable P. DP and TP contents of certain differently processed cereals were analyzed. The calculated uncertainty of the new analysis method had little effect on the DP contents in the samples. Soured cereals contained more DP than unsoured cereals, and the long processing time increased the amounts of DP. In Study II, the DP contents of selected plant-based foodstuffs with or without FAPs were determined by the analysis method developed in Study I. The analyzed plant-based products contained varying amounts of P, but most P was not digestible, except in FAP-containing foodstuffs (cola drinks and baking powder-leavened muffins). In Study III, the associations between TP intake, P density of the diet (TP intake related to energy intake), FAP intake, and a risk factor of cardiovascular disease, carotid intima-media thickness were investigated in a middle-aged Finnish population (n=546). Linear associations among P density of the diet, FAP intake, and carotid intima-media thickness were found when all subjects were included in the analysis, and between FAP intake and carotid intima-media thickness in females (n=370). However, among males (n=176) no significant associations were found. In conclusion, results of this thesis reinforce the previous understanding about the importance of the source of P when assessing P intake in a population. The plant-based foodstuffs generally contain low amounts of DP, but the FAP-containing plant-based products have relatively higher DP contents than FAP-free products. The method developed for the analysis of DP is reliable but requires validation against an in vivo method before these results can be generalized. Albeit high dietary P intake (P density of the diet and FAP intake) was associated with a cardiovascular disease risk factor, carotid intima-media thickness, due to the cross-sectional design of the study, no causal relationships can be inferred. Thus, the potential adverse effects of highly absorbable FAPs should be further investigated both in intervention and in follow-up studies before final conclusions about the harmfulness of high P intake for the general population can be drawn. To find this out, data on use of FAPs in the food industry and updated information on P contents in foodstuffs are also needed.
  • Karp, Heini (Helsingin yliopisto, 2013)
    A high P intake is deleterious to chronic kidney disease (CKD) patients, but based on more recent data, it has also been associated with an increased risk of osteoporosis and cardiovascular diseases in the general population. In addition to several natural sources of P (especially dairy products, meats, whole grains, legumes, and eggs), the use of P additives in the food industry is common and further increases P intake. In this thesis, P contents of foods were analysed and the effects of different P sources on mineral metabolism were compared in healthy young female subjects. In Studies I and II, the objective was to measure both total phosphorus (TP) and in vitro digestible phosphorus (DP) contents of selected foods and to compare the amounts of TP and DP and the proportion of DP to TP among different foods. In DP analysis, samples were digested enzymatically in principle in the same way as in the alimentary canal before P analyses. The results suggest that the absorbability of P may differ substantially among different foods. Despite high TP content, legumes may be a relatively poor P source. In foods containing phosphate additives, the proportion of DP is high, which supports previous conclusions of the effective absorbability of P from P additives. Among foods of animal origin, the highest TP and DP contents were found in processed and hard cheeses; the lowest, in milk and cottage cheese. Studies III and IV were controlled intervention studies in healthy young women. Each subject served as her own control, and the order of the study sessions was randomized. Markers of mineral metabolism from blood and urine samples were measured. In Study III, acute effects of dietary P from three different food sources (meat, cheese and whole grains) and a phosphate supplement on calcium (Ca) and bone metabolism were investigated. Only the phosphate supplement increased serum parathyroid hormone (S-PTH) concentration compared with the control session. Relative to the control session, meat increased markers of both bone formation and bone resorption. Cheese decreased S-PTH and bone resorption. These data suggest that the metabolic response was different for different foods. The purpose of Study IV was to determine whether the effects of mono- and polyphosphate salts (MP and PP, respectively) used as additives differ on markers of Ca and P metabolism in young women. In both MP and PP sessions, serum phosphate, urinary phosphate, and S-PTH increased relative to the control session. PP decreased urinary Ca more than did MP. The results suggest that PP binds Ca in the intestine better than does MP. In the long run, increased S-PTH, caused by either an MP or PP salt, could have negative effects on bone metabolism. In summary, the studies support the previous understanding of differences in P absorbability and mineral metabolism. This is relevant regarding the diets of CKD patients, but may also have a wider relevance if the significance of high P intake in the aetiology of cardiovascular diseases and osteoporosis is confirmed.
  • Marttinen, Maija (Helsingin yliopisto, 2014)
    Plant sterols and stanols (collectively named as phytosterols) are plant-derived dietary compounds. The intake of natural phytosterols from a habitual Western diet varies between 150 to 400 mg/d. Phytosterols are added to functional foods for their serum cholesterol-lowering effect and their intake increases greatly when phytosterol enriched functional foods are consumed. Phytosterols reduce the absorption of dietary and biliary cholesterol from the intestine, leading to increased concentrations of cholesterol excreted in the feces. Increased fecal cholesterol may act as a carcinogen in the intestinal lumen. The focus of this thesis was to study the effect of plant sterols and stanols on the tumor formation in the ApcMin mouse, an experimental model of colon cancer. The ApcMin carries an inherited mutation in the Apc tumor-suppressor gene, which eventually leads to the development of adenomas in the intestine. Mice were fed a control diet or a 0.8% (w/w) plant sterol/ stanol diet. Commercial foods enriched with plant sterols or stanols were used to compose the experimental diets. The impact of phytosterol feeding on cell signaling pathways involved in intestinal tumorigenesis and the changes in sterol metabolism were studied in the intestinal mucosa of ApcMin mouse. The final part of this work assesses the intake of phytosterols from enrichment among Finnish men and women from the FINDIET 2007 Survey. Both plant sterols and plant stanols increased the number of adenomas in the small intestine of ApcMin mice. Plant stanol feeding increased the number of intestinal tumors in both genders, whereas plant sterol feeding increased the number of tumors more pronouncedly in female mice. Wnt- β-catenin and Egfr signaling were up-regulated in the intestinal mucosa of plant stanol fed ApcMin mice when compared with control mice. Plant sterol and stanol feeding increased fecal cholesterol concentration that positively associated with the number of intestinal adenomas. Significant changes in the composition of intestinal sterols were observed after plant sterol and stanol feeding. It appears that plant sterol feeding affects genders differently, and estrogen signaling may play a role in intestinal tumorigenesis in female ApcMin mice after plant sterol feeding. Overall, the mice responded in a different manner to plant sterol and plant stanol feeding in intestinal sterol handling, cell signaling, and tumor development. Finally, this thesis shows that according to the FINDIET 2007 Survey the intake of phytosterols from enrichment can go beyond the advised intake; for 20% of those using phytosterol enriched products the intake of phytosterols was more than 3 g/d. The consistency or duration of the consumption of phytosterol enriched products was not determined in this work. The results show that phytosterols at high intakes are harmful in the intestine of tumor-prone mice. Whether phytosterols from enrichment affect human intestinal health warrants for further research.
  • Huurinainen, Outi (2009)
    Microbiota inhabiting the colon fermentate carbohydrates, proteins and endogenous substrates to volatile fatty acids (VFA) and produce energy for the microbial growth. Because all species of bacteria ferment some component of the digesta and produce various VFAs, alterations in microflora may modify these fermentative end products. Thus, measuring the amount and type of VFA produced gives an instrument which reflects changes in the bacterial microbiota of the intestine. This study set out to explain the connections between diet composition and the formation of VFAs. The general hypothesis was that different food compositions cause differences in the VFA profile, and this may have systemic effect on animal health. Graeco Latin Square design study with 5 healthy Beagles was performed, feeding high protein (diet A, starch 54 g/kg, crude protein 609 g/kg), high carbohydrate (diet B, starch 438 g/kg, crude protein 194 g/kg), and a balanced commercial (diet C, starch 277 g/kg, crude protein 264 g/kg) diets for three weeks each. The diet C was used also for the baseline. VFA, fecal dry matter and fecal consistency score were assessed. All dogs had formed feces during diets B and C but diarrhea during diet A, leading to significant differences in fecal consistency score between the diets (p < 0.0001). The results indicate that alterations in diet had a large influence on the amount and quality of VFAs produced. Mixed-effect model analysis shows that the diets had a statistically significant (p<0.05) influence on all of the VFAs produced excluding butyric acid. The most significant changes from the baseline diet were seen with the high protein diet. Compared to the baseline diet, valeric acid production increased 24-fold, isobutyric acid by 79.5% and isovaleric acid by 42.4%. Production of propionic acid decreased by 43.3%, acetic acid by 25.0%, and butyric acid by 10.2%. In previous studies similar changes in VFA profile have been coupled with various intestinal diseases as well as inhibition in biotin absorption. Furthermore, this might have an influence on inflammatory response at the cellular level. Thus, changes in VFA profile may have an influence at least on the local intestinal health. The total amount of fatty acids decreased on both experimental diets. It seems that having moderate protein and carbohydate levels in the diet is a virtue and more is not necessarily better. This study provides additions to existing understanding of the relationship between diet composition and the formation of VFAs in the intestine. The findings suggest that observing the alterations in VFA levels formed in the intestine and therefore present in feces, may provide an instrument to indirectly observe changes in the bacterial microbiota of the intestine. Thus, there is a need to find the link between the changes in VFA profiles and colonic microbiota, and bacterial diversity in feces by using molecular methods. Having this greater level of understanding would lead to more robust insights into the role of intestinal microbiota in animal health, and to potential advances in the prevention and curing of related diseases. Paksusuolen mikrobit fermentoivat hiilihydraatteja, proteiineja ja sisäsyntyisiä substraatteja haihtuviksi rasvahapoiksi ja energiaksi, jota mikrobit käyttävät aineenvaihduntaansa. Tämän tutkimuksen tavoitteena oli selittää dieetin koostumuksen ja haihtuvien rasvahappojen välinen yhteys. Yleinen tutkimushypoteesi oli, että muutokset ruoan koostumuksessa aiheuttavat muutoksia myös haihtuvien rasvahappojen pitoisuuksiin, millä saattaa olla vaikutusta eläimen yleiseen terveydentilaan. Kokeellinen tutkimus (kreikkalais-latinalainen neliö) tehtiin syöttämällä viidelle terveelle Beagle-rotuiselle koiralle korkeaproteiinista (dieetti A, tärkkelys 54g/kg, raakaproteiini 609g/kg), korkeahiilihydraattista (dieetti B, tärkkelys 438g/kg, raakaproteiini 194g/kg) sekä tasapainotettua kaupallista ruokaa (dieetti C, tärkkelys 277g/kg, raakaproteiini 264g/kg) kolmen viikon ajan kutakin. C dieettiä syötettiin myös “baseline” aikana. Haihtuvat rasvahapot, ulosteen kuiva-aineen määrä sekä koostumus mitattiin. Ulosteen koostumus oli hyvä B ja C dieettien aikana, mutta dieetti A aiheutti kaikille koirille ripulin johtaen merkitseviin eroihin ulosteen koostumuksessa (p < 0.0001). Tulosten mukaan muutokset ruoan koostumuksessa vaikuttivat suuresti haihtuvien rasvahappojen määrään ja koostumukseen. Dieeteillä oli tilastollisesti merkitsevä vaikutus kaikkien muiden paitsi voihapon tuottoon. Suurimmat muutokset tavattiin korkeaproteiinisen dieetin aikana. Verrattuna lähtökohtaan valeriaanahapon tuotto muuttui 24-kertaiseksi, isovoihapon tuotto lisääntyi 79.5% ja isovaleriaanahapon 42.4%. Propionihapon tuotto sen sijaan laski 43.3%, etikkahapon 25.0% ja voihapon 10.2%. Aiemmissa tutkimuksissa vastaavanlaiset muutokset haihtuvien rasvahappojen koostumuksessa on yhdistetty useisiin eri suolistosairauksiin sekä biotiinin imeytymisen häiriintymiseen. Lisäksi tämänkaltaisilla muutoksilla saattaa olla yhteys solutasolla tapahtuvaan immuunipuolustukseen. Näin ollen havaituilla muutoksilla saattaa olla vaikutusta ainakin paikallisesti suoliston terveyteen. Haihtuvien rasvahappojen kokonaismäärä väheni molempien kokeellisten dieettien aikana. Näyttäisi siltä että kohtuus on hyve myös dieetin proteiinien ja hiilihydraattien suhteen eikä enemmän ole välttämättä parempi. Tämä tutkimus toi lisää tietoa dieetin koostumuksen ja haihtuvien rasvahappojen tuoton välisestä yhteydestä. Tulokset viittavat siihen että tutkimalla haihtuvien rasvahappojen muodostumista suolistossa määrittämällä kyseisten aineiden pitoisuus ulosteissa, voidaan epäsuorasti saada tietoa mikrobiston muutoksista suolistossa. Näin ollen lisätutkimuksia molekulaarisia menetelmiä käyttäen tarvitaan, jotta voitaisiin löytää yhteys haihtuvien rasvahappojen pitoisuuden ja suoliston mikrobien välille. Näin ymmärrettäisiin paremmin suolistomikrobiston merkitys eläimen terveydelle ja voitaisiin paremmin ennaltaehkäistä ja hoitaa suolistomikrobien epätasapainotiloihin liittyviä sairauksia.
  • Kangas, Suvi (2013)
    Background: Cancer is the leading cause of death worldwide, claiming 7.6 million lives a year. Five behavioural factors have been recognised to be responsible for 30 % of the disease burden. Among them is low fruit and vegetable consumption. Fruit and vegetable consumption has been inversely associated with cancer risk but the mechanisms behind this effect are still largely debated. Dietary antioxidants present in large quantities in plant foods have been hypothesised to contribute to this protection. Objective: The aim of this study was to investigate the relationship between dietary total antioxidant capacity (TAC) and overall cancer incidence. This was done applying a new antioxidant measurement that reflects the whole set of direct antioxidant reducers (vitamin C, alpha-tocopherol, carotenoids and flavonoids) present in diet. The average TAC intake levels of the participants were assessed and the main dietary contributors to the TAC scores were examined. Subjects: Study subjects included 67 634 middle aged French women participating in an on-going prospective cohort study called E3N. Their dietary assessment was made between June 1993 and July 1995 using a semi-quantitative food frequency questionnaire able to quantitatively and qualitatively assess the average daily intake of 208 different foods, recipes and beverages. Cancer cases were self-reported and validated against medical records. The follow up of the participants ended in May 2008. Methods: Four different total antioxidant capacity scores were created using two different TAC methods, the ferric reducing ability parameter (FRAP) and the total radical-trapping antioxidant parameter (TRAP), and including or excluding coffee from the dietary TAC calculation. Coffee exclusion was justified with the fact that it is the largest contributor to the dietary TAC intake, and because of its association with some negative lifestyle behaviours, it can act as a confounder even if adjustments are made. Statistical analyses for cancer risk according to dietary TAC intake were made using Cox proportional hazards model adjusting for energy intake without alcohol, tobacco smoking, alcohol intake, BMI, physical activity level, educational background, region of residence and family history of cancer. Results: When coffee was included in the dietary TAC scores a significant but modest increase in cancer risk was observed towards higher TAC intakes (p for trend < 0.05 for both FRAP and TRAP). On the contrary, when coffee was excluded from the TAC scores a significant although modest decrease in overall cancer risk was observed (p for trend = 0.016 for both FRAP and TRAP without coffee). In the indexes where coffee was included in the score it contributed up to 43 % and 76 % of total FRAP and TRAP scores respectively. After coffee the main contributors to dietary TAC intake were tea, wine, fruits, vegetables, fruit juice and chocolate. The mean daily intake of TAC was 20.5 mmol of FRAP and 20.2 TE of TRAP in the scores including coffee. When coffee was excluded from the scores, the mean intake levels dropped to 9.4 mmol and 4.9 TE. Conclusion: Dietary total antioxidant capacity was associated with a statistically significant but modest decrease in cancer incidence when intake of coffee, the main TAC source, was not taken into account. Coffee seems to be acting as a confounding factor since when it was included in the TAC scores, there was a small but statistically significant positive association with cancer risk. For future studies it would be crucial to standardise the TAC methods so that comparisons between studies could be made. On the other hand in vitro nature of the TAC methods should be kept in mind; a fact that challenges the interpretation of the results from the biological perspective.
  • Männistö, Satu (Helsingin yliopisto, 1999)
  • Rajakangas-Tolsa, Johanna (Helsingin yliopisto, 2008)
    The incidence of colon cancer is high in Western societies, and in Finland it is among the three most common cancer types in both females and males. Environmental factors, including diet, affect colon cancer development. During the last few years, a vast amount of new, functional foods have been introduced to the consumers. Several products are already available that are marketed as promoting intestinal health. To be able to reliably call a dietary compound a chemopreventive substance it is of fundamental importance to understand the mechanism by which it affects tumour formation and the integrity of the epithelial cells. In this thesis, three different dietary compounds were studied in an experimental model of colon cancer. Inulin is a non-digestible fibre found naturally in chicory roots, artichokes and onions, amongst others. Nowadays it is widely used as an added dietary fibre in several food products. Conjugated linoleic acid (CLA) is a conjugated form of the fatty acid linoleic acid. CLA is formed by bacterial fermentation of linoleic acid in the rumen of cows and other ruminants. Concomitantly, it can naturally be found in milk and meat of ruminants. White currant is a colourless berry low in phenolic compounds that are believed to prevent cancer formation. Contrary to what was expected, inulin and the conjugated linoleic acid isomer trans-10, cis-12, were tumour growth promoting dietary constituents when fed to Min mice. Both diets decreased the NF-kappaB levels in the mucosa, but physiological adenoma development did not affect NF-kappaB. Diet altered beta-catenin and p53 signalling in the adenomas, confirming their involvement in adenoma growth. White currant, on the other hand, was chemopreventive, despite its low contents of phenolic compounds. The chemopreventive effect was accompanied by increased p53 levels in the mucosa, and decreased beta-catenin and NF-kappaB levels in the adenoma. This could explain the reduced adenoma number and size. The results underline the importance of carefully testing new dietary compounds in different settings to reliably confirm their health benefits. In this study two compounds that are consumed and believed to add to our health proved to be cancer promotive. A berry with low phenolic contents, on the other hand, was chemopreventive.
  • Salonen, Saija (1971)
  • Dolfus, Gero (2009)
    In this thesis, I analyze how differences in redistributive tax schedules alone and together with wage differences arising from industry-specific shocks form migration incentives. I do so with the help of a theoretical model in which there are two countries that are identical except that in only one of them income is redistributed. The citizens of these two countries maximize their expected lifetime utility by investing in education and deciding on migration. Allowing for migration increases the investment in human capital by the citizens who initially live in the redistributive country and want to emigrate, while those who wish to emigrate from the country without redistribution may lower their educational effort. Moreover, migration influences the composition of the population of the redistributive country which, in turn, changes the size of the tax revenue and may reduce or increase the flat-rate benefit. Comparing the individuals' utility before and after migration is allowed reveals that integrating labor markets may result in a Pareto improvement.
  • Jansson, Julia (2008)
    Pro gradu –tutkielmani sijoittuu poliisihistorian alaan ja liittyy sekä kriminologiaan että kansainvälisiin suhteisiin. Tutkielma käsittelee terrorismin ja anarkismin vastaista poliisiyhteistyötä. Työssä analysoidaan Rooman kansainvälisen anarkismin vastaisen konferenssin (International Anti-Anarchist Conference of Rome) päätöksiä vuodelta 1898 sekä Interpolin (the International Criminal Police Organization – Interpol) päätöslauselmia vuodelta 1998. Nämä ovat työni primaarilähteet. Lisäksi tarkastelen myös muita Interpolin vuoden 1951 jälkeen tekemiä terrorismiin liittyviä päätöslauselmia. Työssäni tutkin päätöslauselmia ja vertailen niiden tapoja käsitellä ja määritellä terrorismia. Työn lähtökohta on Richard Bach Jensenin ajatus siitä, että Interpol on itse asiassa anarkismin vastaisen konferenssin seuraaja. Tämän takia päätöslauselmia on hedelmällistä verrata keskenään. Interpolin suhtautuminen terrorismiin muuttui huomattavasti vuonna 1998, minkä takia juuri tämä vuosi on valittu tutkimuksen kohteeksi. Tähän saakka Interpol oli pitänyt tärkeimpänä ohjenuoranaan peruskirjansa kolmatta artiklaa, joka kieltää organisaatiota puuttumasta poliittisiin, sotilaallisiin, uskonnollisiin tai rotuun liittyviin asioihin. Terrorismia pidettiin näihin asioihin kuuluvana. Vuoden 1998 jälkeen terrorismi kuitenkin katsottiin osaksi kansainvälistä rikollisuutta, eli asiaksi, jota vastaan Interpolin tulee taistella. Sekä Rooman anarkismin vastaisen konferenssin että Interpolin päätöslauselmissa (anarkistinen) terrorismi epäpolitisoitiin, eli määriteltiin rikolliseksi. Tutkielma pyrkii kuvaamaan sitä, miten epäpolitisointi näkyy päätöslauselmissa sekä hahmottelemaan sille mahdollisia syitä. Yhtenä epäpolitisoinnin tärkeimmistä syistä voidaan pitää anarkismin ja terrorismin poliittista luonnetta, jonka takia kansainväliselle poliisiyhteistyölle on ollut vaikea rakentaa pohjaa. Epäpolitisoinnin avulla ongelma on voitu kiertää, koska teot on erotettu niiden motiiveista. Tällä tavalla niitä on voitu käsitellä tekoina, joita jokainen maa pitää rikollisina, kuten tuhopolttoina tai murhina. Vuosina 1898 ja 1998 molemmat toimijat, sekä Rooman anarkismin vastainen konferenssi että Interpol, kohtasivat samankaltaisen uhan ja reagoivat siihen samalla tavoin. Terrorismin luonteen muutos lisäsi tarvetta tiiviimmälle kansainväliselle yhteistyölle, minkä epäpolitisointi mahdollisti. Lisäksi yhteiskunnalliset olot ja poliisin byrokratisoituminen vaikuttivat anarkismin vastaisen konferenssin ja Interpolin toimintatavan muutoksiin.
  • Yang, Ying (Helsingin yliopisto, 2014)
    Cyclin-dependent kinases (Cdks) are an evolutionary conserved group of serine/threonine protein kinases involved in critical cellular processes such as cell cycle and transcription. Cdk7 and CCRK (cell cycle related kinase; also known as Cdk20) form a separate branch together in a phylogenetic alignment of Cdks family. This study here has identified distinct cellular functions of these two kinases and does not support overlapping functions as suggested by orthologs in yeast. Cdk7 together with cyclin H and Mat1 forming the kinase subcomplex of TFIIH basal transcription factor complex is proposed to regulate RNA polymerase II (Pol II) mediated mRNA synthesis by phosphorylating the serine-5 (Ser5) residues of POL II large subunit C-terminal domain (CTD). Investigations in the genetic systems generated here allowing acute depletion of the Cdk7 subcomplex demonstrate that Cdk7 is the mammalian Ser5 phosphorylating kinase and is required for general transcription noted by analysis of newly transcribed RNAs. The analysis also reveals a requirement of Cdk7 for RNA polymerase I mediated rRNA synthesis. The reduced transcription following Cdk7 disruption is associated with changes on chromatin but not reflected in steady-state RNA levels due to increased RNA stability. These results also reveal a coupled regulation of transcription and RNA degradation. A tissue-specific function of the Cdk7 subcomplex is identified as a physiological roadblock to adipogenesis by phosphorylating the master transcription factor of adipogenic program-peroxisome proliferator-activated receptor gamma (PPARγ). The observation that the Cdk7 subcomplex is absent from adipose tissues indicates the so-called basal transcription machinery has very diverse composition in differentiated cells. CCRK is involved in regulating formation of primary cilium, a sensory organelle acting as a signaling hub in the cell. CCRK promotes cell cycle progression by inhibiting ciliogenesis. In glioblastoma cells, reducing the deregulated high level of CCRK or two related substrate kinases of CCRK restores cilia, leading to decreased glioblastoma cell proliferation. Here is identified the first kinase cascade used by tumor cells to disrupt cilia for a growth advantage and offered new therapeutic possibilities.
  • Ismail, Khadeeja (2012)
    Obesity is associated with life styles involving overconsumption of high-energy food and having low amount of physical activity but the heritability of obesity has also been shown to be high. Results from genome wide association studies (GWAS), however, could explain only 5% of this heritability. This evidence points towards epigenetics acting as a mediator that allows the environment to affect the phenotype without changing the genotype, and epigenetics as a factor that may explain the missing heritability. DNA methylation, which plays an important role in cell differentiation and which has already been associated with diseases such as cancer and diabetes, is the most studied epigenetic factor. DNA methylation is the addition of a methyl group to a cytosine occurring next to a guanine connected by the phosphate backbone, the positions known as CpG sites. This thesis is based on the study of DNA methylation in obesity, using monozygotic twins discordant for obesity where obesity discordance is defined as having a difference in body mass index (BMI) greater than 3m2/kg. MZ twin pairs share the same genome and are matched for age, sex, cohort effects, intrauterine environment and the environment in which they grow up after birth. This helps to cancel out many confounding factors that may affect the results otherwise. The samples for this analysis was obtained from 22 obesity-discordant pairs and 8 obesity-concordant pairs. DNA from whole-blood was bisulfite-converted and hybridized to the Infinium HumanMethylation450 BeadChip. The data was then preprocessed and analyzed for within-pair differences in twins discordant for BMI, and this showed no CpG sites as differentially methylated within pairs. The analysis was then repeated on twins discordant for both BMI and liver-fat and this showed 180 CpG sites as significantly differentially methylated within pairs. However, it was not possible to use these results for pathway analysis using the methods used in gene expression analysis, as too few of these CpG sites mapped to genes on pathways. Gene-set analysis (GSA) was then applied to the methylation data to identify interesting pathways, using predefined groups of CpG sites (probe-sets), each group representing a pathway in the KEGG database. The significant pathways were further analyzed to identify the CpG sites that were most discordant within twin pairs. The results from GSA and the initial paired analysis provided an interesting list of genes and pathways most of which had previously been associated with obesity. However, the analyses can be improved by using a normalization method that is more specific to the Infinium 450K array and also by increasing the sample size. This is listed as future work, together with the analysis of DNA from adipose tissue. The pipeline developed from this analysis will be used in the future analyses, but with modifications wherever necessary.
  • Porola, Pauliina (2012)
    Hepatotoxicity is an undesired feature of many drugs and is one of the main reasons for attrition during the drug development process. Although an in vitro model can never totally correspond to or replace a whole organism, a reliable in vitro model for liver toxicity screening would help to detect liver toxicity earlier in the development process. Effective and early in vitro screening would reduce the need of animal subjects and clinical trials and thus would be both ethically more acceptable and more cost-effective. Currently mostly used models for liver metabolism and toxicity studies are primary hepatocytes, hepatic cell lines and animal models. However, these models have many drawbacks and are not considered reliable. Human embryonic stem cells (hESCs) are pluripotent cells that can be differentiated into many specialized cell types including hepatocytes. They are also self-renewable and thus represent an unlimited and promising source of hepatocytes to be used as a tool in in vitro liver toxicity testing of drug candidates. The aim of this study was to produce hepatocytes from hESCs via multiple steps following the in vivo pathway of developing hepatocytes: first hESCs were differentiated into definitive endoderm cells, after which they were differentiated into hepatic progenitor cells. Finally, hepatocyte-like cells (HLCs) were induced from the progenitor cells. Our specific interest was the use of hepatic cell derived acellular matrix as a differentiation basis for hepatic progenitors and hepatocytes. We also studied the effect of Matrigel overlay on the hepatic differentiation. Differentiation method without the Matrigel overlay was promising. HLCs showed correct hepatocyte-like morphology and expressed hepatocyte markers such as albumin, α-antitrypsin, CYP3A4 and HNF4α both on mRNA and protein level shown by qPCR and flow cytometry and immunofluorescence staining, respectively. Accordingly, the expression of stem cells marker SSEA-3 showed a tendency to decrease as the differentiation proceeded. HLCs also functionally resembled hepatocytes shown by albumin production. However, we could not detect other hepatocyte functions such as urea production or CYP activity. With Matrigel overlay, the hepatocyte-like morphology of the cells was lost, no albumin production was shown and the expression of several hepatocyte markers was lower than in the experiment done without the Matrigel overlay. Thus, Matrigel overlay was shown to be unbeneficial for hepatocyte differentiation. In conclusion, we showed that differentiation of hESCs on the acellular matrix with specific growth factors and without the Matrigel overlay seems promising as a method to produce HLCs. This preliminary study serves as a basis for future studies, in which the differentiation method should still be further studied and developed to yield functional HLCs of uniform quality.
  • Tervonen, Topi (Helsingin yliopisto, 2008)
    Multipotent stem cells can self-renew and give rise to multiple cell types. One type of mammalian multipotent stem cells are neural stem cells (NSC)s, which can generate neurons, astrocytes and oligodendrocytes. NSCs are likely involved in learning and memory, but their exact role in cognitive function in the developing and adult brain is unclear. We have studied properties of NSCs in fragile X syndrome (FXS), which is the most common form of inherited mental retardation. FXS is caused by the lack of functional fragile X mental retardation protein (FMRP). FMRP is involved in the regulation of postsynaptic protein synthesis in a group I metabotropic glutamate receptor 5 (mGluR5)-dependent manner. In the absence of functional FMRP, the formation of functional synapses is impaired in the forebrain which results in alterations in synaptic plasticity. In our studies, we found that FMRP-deficient NSCs generated more neurons and less glia than control NSCs. The newborn neurons derived from FMRP-deficient NSCs showed an abnormally immature morphology. Furthermore, FMRP-deficient NSCs exhibited aberrant oscillatory Ca2+ responses to glutamate, which were specifically abolished by an antagonist of the mGluR5 receptor. The data suggested alterations in glutamatergic differentiation of FMRP-deficient NSCs and were further supported by an accumulation of cells committed to glutamatergic lineage in the subventricular zone of the embryonic Fmr1-knockout (Fmr1-KO) neocortex. Postnatally, the aberrant cells likely contributed to abnormal formation of the neocortex. The findings suggested a defect in the differentiation of distinct glutamatergic mGluR5 responsive cells in the absence of functional FMRP. Furthermore, we found that in the early postnatal Fmr1-KO mouse brain, the expression of mRNA for regulator of G-protein signalling-4 (RGS4) was decreased which was in line with disturbed G-protein signalling in NSCs lacking FMRP. Brain derived neurotrophic factor (BDNF) promotes neuronal differentiation of NSCs as the absence of FMRP was shown to do. This led us to study the effect of impaired BDNF/TrkB receptor signaling on NSCs by overexpression of TrkB.T1 receptor isoform. We showed that changes in the relative expression levels of the full-length and truncated TrkB isoforms influenced the replication capacity of NSCs. After the differentiation, the overexpression of TrkB.T1 increased neuronal turnover. To summarize, FMRP and TrkB signaling are involved in normal differentiation of NSCs in the developing brain. Since NSCs might have potential for therapeutic interventions in a variety of neurological disorders, our findings may be useful in the design of pharmacological interventions in neurological disorders of learning and memory.
  • Huhtala, Paula (2000)
    The aim of this study is to analyze the development of competence and the work contents of vocational teachers in three vocational education areas: home economics field, social field and care field. The majority of teachers and studets in these fields are women. The theory of this study is based on neoweberian profession theory. This theory includes two dimensions: the monopoly and the autonomy of the vocation. The goal of the vocation is to achieve monopoly, when the practising of the vocation is not possible without competence. The goal of the vocation is also to achieve autonomy, because the competence having have a wide command to their work. The neoweberian theory enphasis also the means to achieve monopoly. This study analyzes, how the profession develpoment goes on and what is the terminal of the development. This study examines also, how the development of vocational education and the development of society have been connected to the profession development of teachers. Furthermore, this study also examinates, how the government has promoted the profession development and how the teachers self have influenced on their profession development. This study is by character history of sociology. The research perioid is 1879-1990. Research material consists of laws and degrees, which have defined the position and the work of teachers and the preparation documents of these statutes. Teachers have not reached the profession position at the end of the research perioid. The monopoly position of teachers has increased but the autonomy position has decreased during the research perioid. There has been many reasons, which have set limits to the profession development of teachers. We can search reasons from the role of teachers' work, from the last birth of vocational education and from the development of society. The government advanced the progress to reach the monopoly postion but not the autonomy position. Also teachers' own activity to advance their profession development has been minimal. The content of the work of vocational teachers makes it impossible to achieve profession position defined at neoweberian way. At the end of the research perioid we have come to the situation, that the profession must define in a new way.
  • Huhtala, Paula (2000)
    Tutkimuksessa analysoidaan opettajan pätevyysvaatimusten ja työn sisällön kehitystä kolmella ammatillisen koulutuksen alueella: kotitalousala, sosiaaliala ja terveydenhuoltoala. Enemmistö sekä opettajista että opiskelijoista näillä koulutusaloilla on naisia. Tutkimuksen teoriana käytetään uusweberiläistä professioteoriaa. Teorian mukaan professio koostuu kahdesta dimensiosta: ammatin monopoli- ja autonomia -asema. Ammatin harjoittajien pyrkimys on saavuttaa monopoliasema, jolloin muilla kuin tutkinnon suorittaneilla ei ole lupaa harjoittaa ammattia. Ammatin harjoittajien pyrkimyksenä on myös saavuttaa autonomia -asema, sillä se takaa laajan päätäntävallan työssä. Uusweberiläinen teoria korostaa myös niitä keinoja, joita käyttämällä ammatti voi saavuttaa professioaseman. Tutkimuksessa analysoidaan professiokehityksen etenemistä ja saavutettua professioasemaa. Tutkimuksessa tarkastellaan myös, miten ammatillisen koulutuksen kehitys ja yhteiskuntakehitys ovat yhteydessä opettajan professiokehitykseen. Tutkimuksessa tarkastellaan myös, miten valtiovalta on edistänyt professiokehitystä ja miten opettajat itse ovat vaikuttaneet professiokehitykseensä. Tutkimus on sosiologista historiantutkimusta. Tutkimuksessa tarkastellaan vuosien 1879 ja 1990 välistä aikaa. Tutkimusmateriaali koostuu niistä laeista ja asetuksista, jotka ovat säätäneet opettajan asemaa ja työtä sekä näiden valmisteluasiakirjoista. Opettajat eivät olleet saavuttaneet professioasemaa tarkastelujakson lopussa. Opettajien monopoliasema on kasvanut tarkastelujakson aikana, mutta autonomia -asema on kaventunut. Useat syyt ovat vaikuttaneet siihen, että opettajat eivät ole saavuttaneet professioasemaa. Syitä voidaan etsiä opettajan työn luonteesta, ammatillisen koulutuksen myöhäsyntyisyydestä ja yhteiskuntakehityksestä. Valtiovalta on tukenut monopoliaseman kehittymistä mutta ei autonomia -aseman kehittymistä. Myös opettajien oma aktiivisuus professioaseman saavuttamiseksi on ollut vähäistä. Ammatillisen koulutuksen opettajan työn luonne on sellainen, että ammatin ei ole mahdollista saavuttaa professioasemaa, joka on määritelty uusweberiläisen teorian mukaan. Tarkastelujakson lopussa on tultu kehitysvaiheeseen, jossa professiokäsite on määriterltävä uudella tavalla.
  • Joffe, Grigori (Helsingin yliopisto, 1999)
  • Keyriläinen, Jani (Helsingin yliopisto, 2004)