Immune mechanisms in atherosclerosis; Focus on the role of the complement system

Atherosclerosis is an inflammatory disease characterized by accumulation of lipids in the inner layer of the arterial wall. During atherogenesis, various structures that are recognized as non-self by the immune system, such as modified lipoproteins, are deposited in the arterial wall. Accordingly, atherosclerotic lesions and blood of humans and animals with atherosclerotic lesions show signs of activation of both innate and adaptive immune responses. Although immune attack is initially a self-protective reaction, which is meant to destroy or remove harmful agents, a chronic inflammatory state in the arterial wall accelerates atherosclerosis. Indeed, various modulations of the immune system of atherosclerosis-prone animals have provided us with convincing evidence that immunological mechanisms play an important role in the pathogenesis of atherosclerosis. This thesis focuses on the role of complement system, a player of the innate immunity, in atherosclerosis. Complement activation via any of the three different pathways (classical, alternative, lectin) proceeds as a self-amplifying cascade, which leads to the generation of opsonins, anaphylatoxins C3a and C5a, and terminal membrane-attack complex (MAC, C5b-9), all of which regulate the inflammatory response and act in concert to destroy their target structures. To prevent uncontrolled complement activation or its attack against normal host cells, complement needs to be under strict control by regulatory proteins. The complement system has been shown to be activated in atherosclerotic lesions, modified lipoproteins and immune complexes containing oxLDL, for instance, being its activators. First, we investigated the presence and role of complement regulators in human atherosclerotic lesions. We found that inhibitors of the classical and alternative pathways, C4b-binding protein and factor H, respectively, were present in atherosclerotic lesions, where they localized in the superficial proteoglycan-rich layer. In addition, both inhibitors were found to bind to arterial proteoglycans in vitro. Immunohistochemical stainings revealed that, in the superficial layer of the intima, complement activation had been limited to the C3 level, whereas in the deeper intimal layers, complement activation had proceeded to the terminal C5b-9 level. We were also able to show that arterial proteoglycans inhibit complement activation in vitro. These findings suggested to us that the proteoglycan-rich layer of the arterial intima contains matrix-bound complement inhibitors and forms a protective zone, in which complement activation is restricted to the C3 level. Thus, complement activation is regulated in atherosclerotic lesions, and the extracellular matrix is involved in this process. Next, we studied whether the receptors for the two complement derived effectors, anaphylatoxins C3a and C5a, are expressed in human coronary atherosclerotic lesions. Our results of immunohistochemistry and RT-PCR analysis showed that, in contrast to normal intima, C3aR and C5aR were highly expressed in atherosclerotic lesions. In atherosclerotic plaques, the principal cells expressing both C3aR and C5aR were macrophages. Moreover, T cells expressed C5aR, and a small fraction of them also expressed C3aR, mast cells expressed C5aR, whereas endothelial cells and subendothelial smooth muscle cells expressed both C3aR and C5aR. These results suggested that intimal cells can respond to and become activated by complement-derived anaphylatoxins. Finally, we wanted to learn, whether oxLDL-IgG immune complexes, activators of the classical complement pathway, could have direct cellular effects in atherogenesis. Thus, we tested whether oxLDL-IgG immune complexes affect the survival of human monocytes, the precursors of macrophages, which are the most abundant inflammatory cell type in atherosclerotic lesions. We found that OxLDL-IgG immune complexes, in addition to transforming monocytes into foam cells, promoted their survival by decreasing their spontaneous apoptosis. This effect was mediated by cross-linking Fc��� receptors with ensuing activation of Akt-dependent survival signaling. Our finding revealed a novel mechanism by which oxLDL-IgG immune complexes can directly affect the accumulation of monocyte-macrophages in human atherosclerotic lesions and thus play a role in atherogenesis.

Timing of puberty : Genetic regulation

In the general population, the timing of puberty is normally distributed. This variation is determined by genetic and environmental factors, but the exact mechanisms underlying these influences remain elusive. The purpose of this study was to gain insight into genetic regulation of pubertal timing. Contributions of genetic versus environmental factors to the normal variation of pubertal timing were explored in twins. Familial occurrence and inheritance patterns of constitutional delay of growth and puberty, CDGP (a variant of normal pubertal timing), were studied in pedigrees of patients with this condition. To ultimately detect genes involved in the regulation of pubertal timing, genetic loci conferring susceptibility to CDGP were mapped by linkage analysis in the same family cohort. To subdivide the overall phenotypic variance of pubertal timing into genetic and environmental components, genetic modeling based on monozygous twins sharing 100% and dizygous twins sharing 50% of their genes was used in 2309 girls and 1828 boys from the FinnTwin 12-17 study. The timing of puberty was estimated from height growth, i.e. change in the relative height between the age when pubertal growth velocity peaks in the general population and adulthood. This reflects the percentage of adult height achieved at the average peak height velocity age, and thus, pubertal timing. Boys and girls diagnosed with CDGP were gathered through medical records from six pediatric clinics in Finland. First-degree relatives of the probands were invited to participate by letter; altogether, 286 families were recruited. When possible, families were extended to include also second-, third-, or fourth-degree relatives. The timing of puberty in all family members was primarily assessed from longitudinal growth data. Delayed puberty was defined by onset of pubertal growth spurt or peak height velocity taking place 1.5 (relaxed criterion) or 2 SD (strict criterion) beyond the mean. If growth data were unavailable, pubertal timing was based on interviews. In this case, CDGP criteria were set as having undergone pubertal development more than 2 (strict criterion) or 1.5 years (relaxed criterion) later than their peers, or menarche after 15 (strict criterion) or 14 years (relaxed criterion). Familial occurrence of strict CDGP was explored in families of 124 patients (95 males and 29 females) from two clinics in Southern Finland. In linkage analysis, we used relaxed CDGP criteria; 52 families with solely growth data-based CDGP diagnoses were selected from all clinics. Based on twin data, genetic factors explain 86% and 82% of the variance of pubertal timing in girls and boys, respectively. In families, 80% of male and 76% of female probands had affected first-degree relatives, in whom CDGP was 15 times more common than the expected (2.5%). In 74% (17 of 23) of the extended families with only one affected parent, familial patterns were consistent with autosomal dominant inheritance. By using 383 multiallelic markers and subsequently fine-mapping with 25 additional markers, significant linkage for CDGP was detected to the pericentromeric region of chromosome 2, to 2p13-2q13 (multipoint HLOD 4.44, �� 0.41). The findings of the large twin study imply that the vast majority of the normal variation of pubertal timing is attributed to genetic effects. Moreover, the high frequency of dominant inheritance patterns and the large number of affected relatives of CDGP patients suggest that genetic factors also markedly contribute to constitutional delay of puberty. Detection of the locus 2p13-2q13 in the pericentromeric region of chromosome 2 associating with CDGP is one step towards unraveling the genes that determine pubertal timing.

Cow���s milk related gastrointestinal symptoms in adults

The purpose of this study was to evaluate subjective food-related gastrointestinal symptoms and their relation to cow���s milk by determining the genotype of adult-type hypolactasia, measuring antibodies against milk protein, and screening the most common cause for secondary hypolactasia, namely coeliac disease. The whole study group comprised 1900 adults who gave a blood sample for the study when they attended a health care centre laboratory for various reasons. Of these 1885 (99%) completed a questionnaire on food-related gastrointestinal symptoms. Study No. I evaluated the prevalence of adult-type hypolactasia and its correlation to self-reported milk induced gastrointestinal symptoms. The testing for hypolactasia was done by determination of the C/T-13910 genotypes of the study subjects. The results show that patients with the C/C-13910 genotype associated with adult type hypolactasia consume less milk than those with C/T-13910 and T/T-13910 genotypes. Study No. II evaluated the prevalence and clinical characteristics of undiagnosed coeliac disease in the whole study population with transglutaminase and endomysium antibodies and their correlation with gastrointestinal symptoms. The prevalence of coeliac disease was 2 %, which is surprisingly high. Serum transglutaminase and endomysium antibodies are valuable tools for recognising an undiagnosed coeliac disease in outpatient clinics. In the study No. III the evaluation of milk protein IgE related hypersensitivity was carried out by stratifying all 756 study subjects with milk related problems and randomly choosing 100 age and sex matched controls with no such symptoms from the rest of the original study group. In the study No. IV 400 serum samples were randomly selected for analyzing milk protein related IgA and IgG antibodies and their correlation to milk related GI-symptoms. The measurement of milk protein IgA, IgE or IgG (studies No. III and IV) did not correlate clearly to milk induced symptoms and gave no clinically significant information; hence their measurement is not encouraged in outpatient clinics. In conclusion, adult type hypolactasia is often considered the reason for gastrointestinal symptoms in adults and determination of the C/T-13910 genotypes is a practical way of diagnosing adult type hypolactasia in an outpatient setting. Undiagnosed coeliac disease, should be actively screened and diagnosed in order to apply a gluten free diet and avoid the GI-symptoms and nutritional deficiencies. Cow���s milk hypersensitivity in the adult population is difficult to diagnose since the mechanism in which it is mediated is still unclear. Measuring of cow���s milk protein specific antibodies IgE, IgA or IgG do not correlate with subjective milk-related GI-symptoms.

Variations in paediatric upper respiratory surgery rates within and between two Nordic countries

Lasten yl��hengitystiekirurgia (kita-nielurisojen poisto ja t��rykalvon putkitus) on l��nsimaissa eritt��in yleist��. Leikkausten lukum����r��t vaihtelevat niin kansallisesti kuin kansainv��lisestikin, mutta selv���� syyt�� n��ille eroille ei tiedet��. Hoitosuositusten merkitys k��yt��nt��ihin on kyseenalaistettu ja voi olla, ettei hoitosuosituksia noudateta. Leikkaukset saattavat aiheuttaa lapsipotilaille psykologisen vamman, ja lis��ksi niihin sis��ltyy komplikaatioiden, jopa kuoleman, vaara. Jotta haittoja voidaan v��ltt����, on t��rke���� tunnistaa ne lapset, jotka hy��tyv��t leikkauksesta. Ongelma on paitsi l����ketieteellinen, my��s taloudellinen: yl��hengitystiekirurgiasta aiheutuu merkitt��vi�� kuluja. Leikkausm����rien arvioiminen on t��rke����, jotta leikkausk��yt��nt��j�� voidaan j��rkeist����. T��ss�� v��it��skirjaty��ss�� tutkittiin yl��hengitystieleikkausten m����ri�� Suomessa ja Norjassa sek�� n��iden kahden maan v��lill��. Aiempaa tutkimusta aiheesta ei kummassakaan maassa ole tehty. Kitarisanpoiston, v��likorvan putkituksen, t��rykalvopiston, nielurisanpoiston ja kita- ja nielurisanpoiston leikkausm����r��t saatiin kansallisista tietokannoista. Lukuja verrattiin ko. maan lasten lukum����r����n, maantieteelliseen sijoittumiseen sek�� lasten ik����n ja sukupuoleen. Lis��ksi leikkausm����ri�� arvioitiin suhteessa korva-, nen��- ja kurkkul����k��reiden sek�� yleisl����k��reiden m����r����n, maantieteelliseen sijoittumiseen ja l����k��reiden ik����n ja sukupuoleen. Leikkausten m����riss�� havaittiin suurta vaihtelua niin Suomessa kuin Norjassa. Suomessa suurimmat erot leikkausm����riss�� l��ydettiin l��ntisen ja it��isen miljoonapiirin v��lill��. L��ntisess�� piiriss�� tehtiin l��hes kaksin kertaa enemm��n leikkauksia kuin it��isess�� piiriss��. Norjassa suurimmat erot olivat pohjoisen ja it��isen piirin v��lill��. Pohjoisessa piiriss�� tehtiin kaksinkertainen m����r�� leikkauksia it��iseen piirrin verrattuna. Suomessa tehtiin tutkimuksen koko aikav��lill�� enemm��n kitarisanpoistoja kuin Norjassa, mutta ko. leikkausten m����r�� oli maassamme selv��sti laskussa. Vuonna 2002 Suomessa tehtiin 2,5 kertaa enemm��n kitarisanpoistoja kuin Norjassa. (Kita)nielurisanpoistoja tehtiin kuitenkin Suomessa v��hemm��n kuin Norjassa. N��iden leikkausten m����r��t pysyiv��t tutkimuksen aikav��lill�� Suomessa samalla tasolla, kun Norjassa leikkausm����r��t hieman nousivat. Suomalaisia lapsia leikattiin keskim����rin paljon nuorempina kuin norjalaisia lapsia. Tutkimuksessa ei l��ydetty selityst�� yl��hengitystieleikkausten m����r��n suurelle vaihtelulle Suomessa ja Norjassa tai maiden v��lill��. Kuitenkin Suomessa tehtyjen kitarisanpoistojen huomattavan v��henemisen my��t�� maiden yl��hengitystieleikkausten m����r��t l��heniv��t toisiaan.

Sentinel lymph node biopsy as a diagnostic tool in the treatment of breast cancer

The purpose of this study was to evaluate the use of sentinel node biopsy (SNB) in the axillary nodal staging in breast cancer. A special interest was in sentinel node (SN) visualization, intraoperative detection of SN metastases, the feasibility of SNB in patients with pure tubular carcinoma (PTC) and in those with ductal carcinoma in situ (DCIS) in core needle biopsy (CNB) and additionally in the detection of axillary recurrences after tumour negative SNB. Patients and methods. 1580 clinically stage T1-T2 node-negative breast cancer patients, who underwent lymphoscintigraphy (LS), SNB and breast surgery between June 2000 - 2004 at the Breast Surgery Unit. The CNB samples were obtained from women, who participated the biennial, population based mammography screening at the Mammography Screening Centre of Helsinki 2001 - 2004.In the follow- up, a cohort of 205 patients who avoided AC due to negative SNB findings were evaluated using ultrasonography one and three years after breast surgery. Results. The visualization rate of axillary SNs was not enhanced by adjusting radioisotope doses according to BMI. The sensitivity of the intraoperative diagnosis of SN metastases of invasive lobular carcinoma (ILC) was higher, 87%, with rapid, intraoperative immunohistochemistry (IHC) group compared to 66% without it. The prevalence of tumour positive SN findings was 27% in the 33 patients with breast tumours diagnosed as PTC. The median histological tumour size was similar in patients with or without axillary metastases. After the histopathological review, six out of 27 patients with true PTC had axillary metastases, with no significant change in the risk factors for axillary metastases. Of the 67 patients with DCIS in the preoperative percutaneous biopsy specimen , 30% had invasion in the surgical specimen. The strongest predictive factor for invasion was the visibility of the lesion in ultrasound. In the three year follow-up, axillary recurrence was found in only two (0.5%) of the total of 383 ultrasound examinations performed during the study, and only one of the 369 examinations revealed cancer. None of the ultrasound examinations were false positive, and no study participant was subjected to unnecessary surgery due to ultrasound monitoring. Conclusions. Adjusting the dose of the radioactive tracer according to patient BMI does not increase the visualization rate of SNs. The intraoperative diagnosis of SN metastases is enhanced by rapid IHC particularly in patients with ILC. SNB seems to be a feasible method for axillary staging of pure tubular carcinoma in patients with a low prevalence of axillary metatastases. SNB also appears to be a sensible method in patients undergoing mastectomy due to DCIS in CNB. It also seems useful in patients with lesions visible in breast US. During follow-up, routine monitoring of the ipsilateral axilla using US is not worthwhile among breast cancer patients who avoided AC due to negative SN findings.

Morphogenesis of Mammalian Endoplasmic Reticulum and Golgi Apparatus throughout the Cell Cycle

The endoplasmic reticulum (ER) and the Golgi apparatus are organelles that produce, modify and transport proteins and lipids and regulate Ca2+ environment within cells. Structurally they are composed of sheets and tubules. Sheets may take various forms: intact, fenestrated, single or stacked. The ER, including the nuclear envelope, is a single continuous network, while the Golgi shows only some level of connectivity. It is often unclear, how different morphologies correspond to particular functions. Previous studies indicate that the structures of the ER and Golgi are dynamic and regulated by fusion and fission events, cytoskeleton, rate of protein synthesis and secretion, and specific structural proteins. For example, many structural proteins shaping tubular ER have been identified, but sheet formation is much more unclear. In this study, we used light and electron microscopy to study morphological changes of the ER and Golgi in mammalian cells. The proportion, type, location and dynamics of ER sheets and tubules were found to vary in a cell type or cell cycle stage dependent manner. During interphase, ER and Golgi structures were demonstrated to be regulated by p37, a cofactor of the fusion factor p97, and microtubules, which also affected the localization of the organelles. Like previously shown for the Golgi, the ER displayed a tendency for fenestration and tubulation during mitosis. However, this shape change did not result in ER fragmentation as happens to Golgi, but a continuous network was retained. The activity of p97/p37 was found to be important for the reassembly of both organelles after mitosis. In EM images, ER sheet membranes appear rough, since they contain attached ribosomes, whereas tubular membranes appear smooth. Our studies revealed that structural changes of the ER towards fenestrated and tubular direction correlate with loss of ER-bound ribosomes and vice versa. High and low curvature ER membranes have a low and high density of ribosomes, respectively. To conclude, both ER and Golgi architecture depend on fusion activity of p97/p37. ER morphogenesis, particularly of the sheet shape, is intimately linked to the density of membrane bound ribosomes.

Lapsuusi��n kantasolusiirrot HUS:ssa vuosina 1993-2006

Tutkielma kuvaa lapsuusi��n kantasolusiirtojen merkitt��vimm��t tulokset ja komplikaatiot keskeisiss�� tautiryhmiss�� modernin hoidon aikakaudella HUS:ss��. Aineistona on HUS:n Lasten ja nuorten sairaalan veri- ja sy��p��tautien sek�� kantasolusiirtoyksik��n potilaista ker��tty, vuonna 1993 perustetun ProLapsi-rekisterin sis��lt��m�� kliininen kantasolusiirtoaineisto vuosilta 1993-2006. Aineisto sis��lt���� runsaat 90% Suomessa tehdyist�� lasten allogeenisista kantasolusiirroista (n=233) sek�� kaikki HUS:in autologiset siirrot (n=117) ko. aikajaksolla. Tutkielma on toteutettu kvantitatiivisia tutkimusmenetelmi�� k��ytt��en. Suurin allogeenisen kantasolusiirron saaneiden potilaiden diagnoosiryhm�� oli akuutti lymfoblastileukemia, ja suurin autologisen kantasolusiirron saaneiden ryhm�� neuroblastoomapotilaat. Allogeenisista kantasolusiirroista 38% tehtiin HLA-identtiselt�� sukulaisluovuttajalta ja 53% rekisteriluovuttajan soluilla. Kumulatiivinen kokonaisselviytyminen oli merkitsev��sti parempaa sukulaisluovuttajan soluilla tehdyiss�� siirroissa kuin rekisteriluovuttajan (p=0,003). Allogeenisen kantasolusiirron saaneista potilaista 71% sai jonkin asteisen akuutin ja 42% kroonisen k����nteishyljinn��n (GVHD). Sek�� akuutin ett�� kroonisen GVHD:n vaikeus puolestaan korreloi kuolleisuuteen. Allogeenisen kantasolusiirron pitk��aikaisvaikutusta arvioitiin seurantatietojen perusteella. 58%:lla el��m��nlaatu arvioitiin normaaliksi, 35%:lla hieman rajoittuneeksi ja 7%:lla heikoksi.

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN.

Havupuiden erikoismuotojen lis��ysmenetelm��t

Havupuiden erikoismuotoja on k��ytetty koristekasveina jo vuosisatoja ymp��ri maailmaa. Niit�� on lis��tty p����s����nt��isesti pistokkaista ja varttamalla. Suomessa kotimaisten mets��puidemme erikois-muotoja on kartoitettu ja ker��tty kokoelmiin j��rjestelm��llisemmin 1960-luvulta alkaen. Taimisto-viljelij��t, puutarhasuunnittelijat ja kotipuutarhurit ovat olleet enenev��ss�� m����rin kiinnostuneita n��ist�� kotimaisista kest��vist�� havukasveista. Yli 90 prosenttia markkinoillamme olevista havukas-veista tuodaan ulkomailta, joten on selv����, ett�� niiden talvenkest��vyydess�� on ongelmia. T��m��n tutkimuksen tavoitteena oli selvitt���� kotimaisille erikoismuodoille sopivia lis��ysmene-telmi�� ja siten edist���� kotimaisen havukasvituotannon mahdollisuuksia. Aineistona kokeissa oli kotimaisia erikoismuotoja mets��kuusesta (Picea abies (L.) Karsten) ja kotikatajasta (Juniperus communis L.), tavallisia mets��kuusia sek�� kahdeksan ulkomaista havupuutaksonia. Lis��ysmene-telmist�� tutkittiin varttamista ja pistokaslis��yst�� ja kokeet suoritettiin Mets��ntutkimuslaitoksen toimipaikoissa Lopen Haapastensyrj��ss�� sek�� Punkaharjulla. Varttamiskokeessa vertailtiin koti-maisen kuusen erikoismuotokloonien varttamisen onnistumista. Pistokaskokeissa tutkittiin geno-tyypin, emopuun i��n, pistokasoksan sijainnin sek�� hormonik��sittelyn vaikutusta havukasvien pis-tokkaiden juurtumiseen. Tavalliset mets��kuuset toimivat kontrolleina. Tutkimus osoitti, ett�� varttaminen onnistui erinomaisesti kaikilla erikoismuotoklooneilla. Ovat-ko vartteet esteettisesti katsottuna koristek��ytt����n sopivia, j���� viel�� seurattavaksi. Pistokaskokeis-sa havaittiin, ett�� juveniilisuus vaikutti pistokkaiden juurtumiseen, mutta i��kk��ist��kin puista lis����-minen onnistuu, kunhan genotyyppi on sopiva. Keskim����rin alaoksat juurtuivat paremmin kuin latvuksen yl��osista otetut pistokasoksat, mutta vain yhdell�� kloonilla ero oli tilastollisesti merkit-sev��. Hormonik��sittely heikensi selv��sti kotimaisen kuusen ja katajan pistokkaiden juurtumista, mutta ulkomaisiin havupuulajeihin k��sittelyll�� ei ollut vaikutusta. Kotimaisen havukasvituotannon pohjaksi pit��isi tehd�� kloonivalintaa, jossa koristearvon lis��ksi otettaisiin huomioon my��s kloonin lis��tt��vyys. Taimien tuottaminen pistokkaista on selv��sti edul-lisempaa kuin vartteiden tuottaminen, joskin varte kasvaa myyntikuntoon nopeammin kuin pisto-kastaimi. Pistokastaimi on kuitenkin omajuurinen ja stabiilimpi kasvutavaltaan kuin varte. T��m�� korostuu etenkin k����pi��muotoja tuotettaessa.

Kde je j��dro pudla? Miss�� on villakoiran ydin? : El��inten nimist�� johdetut fraasit, idiomit ja muut sanonnat t��ekin ja suomen kieless��

Pro gradu -ty��ss�� tarkastelen t��ekin ja suomen kieless�� esiintyvi�� el��inten nimityksist�� johdettuja fraseologisia ilmauksia ja sanontoja. El��infraseologia muodostaa kieless�� keskeisen osan, jolle ovat tyypillisi�� voimakas tunnelataus, rajoittunut, sovinnainen k��ytt�� ja puhekielenomaisuus. Tarkastelen el��inilmauksia morfologisesti ja semanttis-leksikaalisesti, mutta muitakin piirteit�� esiintyy. Vertailen kumpaakin kielt�� ja selvit��n kielten fraasien, idiomien ja muiden sanontojen yht��l��isyyksi�� ja eroja. Sanonnat (ynn�� johdokset ja sanaparit) jaan nelj����n eri ryhm����n seuraavasti: 1. kummassakin kieless�� olevat samanlaiset ilmaukset, 2. kummassakin kieless�� olevat osittain samanlaiset ilmaukset, 3. tsekkil��iset ilmaukset ja 4. suomalaiset ilmaukset. Ty��ni materiaali on per��isin tsekkil��isist��, suomalaisista ja muunkielisist�� sanakirjoista (l��hinn�� fraseologisista). Selvittelen erityisesti keskeisimpien kotiel��inten nimist�� (koira, kissa, hevonen, lehm��, lammas, sika, kana), joidenkin muiden el��inten nimist�� (karhu, susi, karppi, k����rme) ja joidenkin ulkomaisten el��inten nimist�� (leijona, elefantti, apina) johdettuja fraseologisia ilmauksia. Materiaali k��sitt���� yhteens�� 145 eri el��int��, 163 el��imen nimityst�� ja 585 el��inilmausta. Aineistoni pohjalta voi todeta, ett�� t��ekin ja suomen kieless�� on yll��tt��v��n paljon samantyyppisi�� el��inilmauksia, vaikka kielet poikkeavat huomattavasti toisistaan. Korpuksessani olevista ilmauksista on t��ysin symmetrisi�� 119/20,3 %, osittain samanlaisia (ep��symmetrisi��) 127/21,7 %, pelk��st����n tsekkil��isi�� 161/27,5 % ja pelk��st����n suomalaisia 146/25,0 %. Sanaparit ja sananlaskut, joita k��sittelin erillisen�� ryhm��n�� (32 kpl) muodostivat aineistosta 5,5 % (niist��kin l��ytyi yht��l��isyyksi��). Yleisimmin esiintyv��t el��imet ovat koira ja kissa. Koira on kuitenkin t��ekin fraseologiassa yleisempi el��in kuin suomessa, jossa taas kissa on yleisimmin esiintyv�� el��imen nimi. Yleisi�� ovat my��s mm. hevonen, sika, lintu, kala ja kana. Karitsa, hanhi ja vuohi esiintyv��t paljon useammin t��ekin fraseologiassa, suomessa esiintyy taas usein sika silloin, kun t��ekiss�� on porsas. Joillakin el��inten nimill�� on selv��sti negatiivisempi tunnelataus (susi, k����rme) kuin toisilla (koira, kissa). Toisin kuin suomessa, kissa on t��ekiss�� valheellinen, vuohi herkuttelee, p��ll�� ja apina edustavat viisautta ja oppivaisuutta ja kovakuoriainen hellytt����. Yhteisi�� el��inten nimityksi�� kummassakin kieless�� on aineistossani 106/163 (65,03 %). T��ekin fraseologiassa on l��hes kaksi kertaa enemm��n (37/163 = 22,7 %) sellaisia el��inten nimi��, joita ei esiinny suomen fraseologiassa verrattuna pelk��st����n suomen fraseologiassa esiintyviin el��inten nimiin (20/163 = 12,27 %). Pelk��st����n t��ekiss�� esiintyvi�� el��imi�� ovat mm. lumikko, majava, murmeli, m��yr��, n����t�� ja riikinkukko; pelk��st����n suomen fraseologiassa esiintyv��t puolestaan mm. kiiski, muikku, peippo, poro, sopuli ja telkk��. Vertauskuvat ovat kummassakin kieless�� eritt��in tyypillisi��. El��inten nimet viittaavat useimmiten ihmisen kielteisiin luonteenpiirteisiin tai ominaisuuksiin (mazan�� jako li��ka ja viekas kuin kettu). Aineistoni pohjalta vaikuttaa silt��, ett�� t��ekiss�� on enemm��n vaihtoehtoisia ja eri el��inten lajeista muodostettuja ilmauksia (mm. lintu- ja kalalajeista). Kummassakin kieless�� on my��s huudahduslauseita (Ty jsi ale li��ka pod it��! ja Senkin vanha kettu!), kansainv��lisi�� ilmauksia (j��dro pudla ja villakoiran ydin) ja ns. petollisia yst��vi�� toisiaan erehdytt��v��sti muistuttavia, mutta eri asiaa merkitsevi�� sanontoja (tsekin ko��i���� ��ivot kissanel��m�� tarkoittaa ��sitke��henkisyytt���� ��� ei suomen kissanp��ivi��). Kansallisista erityispiirteist�� ovat esimerkkein�� mm. t��ekin ilmaus m��t se jako husa o Martin�� "voida kuin hanhi Martinp��iv��n��" (suomeksi ��voida kurjasti��; viittaus Martinp��iv��n hanhensy��misperinteeseen) tai suomen ilmaukset kuin hyttysen liraus It��mereen ja sopulilauma.

Vegaani��idit ja -lapset Suomessa Suosituksista k��yt��nt����n

Suomalaisia vegaani��itej�� ja lapsia ei ole aiemmin tutkittu ravitsemustieteen n��k��kulmasta. Suomalaisilla suosituksissa (Valtion ravitsemusneuvottelukunta, Sosiaali- ja terveysministeri��) lasten ja ��itien vegaaniruokavalioon suhtaudutaan varauksellisesti. Pohjois-Amerikassa mm. American Dietetic Association ja American Academy of Pediatrics sen sijaan pit��v��t vegaaniruokavaliota ravitsemuksellisesti riitt��v��n�� my��s raskauden ja imetyksen aikana sek�� pikkulapsilla. Suomalainen tutkimustieto on tarpeen mm. laadittaessa uusia suosituksia tulevaisuudessa. Tutkimukseen osallistui 14 perhett��. Vegaaniruokavaliota oli noudatettu 11 raskauden ja imetyksen ajan. Syntym��st����n saakka vegaanilapsia oli 13. Menetelm��n�� oli kolmeosainen kyselylomake, jonka tutkittavat palauttivat postitse. Raskaus- ja imetysaikaa tarkastellessani k��ytin vertailuaineistona niit�� seitsem���� raskautta, jotka eiv��t t��ytt��neet vegaaniruokavalion m����ritelm����, mutta joiden aikana oli sy��ty tavanomaista sekaruokavaliota kasvispainotteisemmin. Tutkimukseen osallistuneet olivat koulutettuja ja suurin osa asui kaupungissa. Lapset olivat i��lt����n keskim����rin 1 ��-vuotiaita (vaihteluv��li pariviikkoisesta 5-vuotiaaseen). Perheet olivat etsineet itse aktiivisesti tietoa ravitsemusasioista ja tietoa oli saatu my��s Vegaaniliitosta. Virallinen terveydenhuolto ei ollut juurikaan pystynyt tarjoamaan tietoa: kahdeksan perhett�� oli k��ynyt ravitsemusterapeutin vastaanotolla, mutta vain yksi ilmoitti saaneensa tietoa sit�� kautta. Useimmiten perheen ruokavalio oli her��tt��nyt h��mmennyst�� ja ep��tietoisuutta terveydenhuollossa. Jotkut olivat kokeneet eritt��in negatiivista suhtautumista, etenkin l����k��rien taholta, mutta my��s my��nteisi�� kokemuksia oli. Vegaani��itien keskim����r��inen painonnousu raskauden aikana oli normaali ja lapset olivat syntyneet normaalipainoisina. Lasten kasvu oli normaalia. Kaikki ��idit olivat huolehtineet D- ja B12-saannista. My��s kaikki lapset saivat ko. vitamiinit��ydennyksi�� lukuun ottamatta yht�� ep��selv���� tapausta D-vitamiinin suhteen. Vegaani��idit imettiv��t pitk����n ja olivat l��hemp��n�� imetyssuosituksia kuin suomalaiset yleens��. T��m��n tutkimuksen perusteella suomalaisissa vegaaniperheiss�� ollaan tietoisia D- ja B12-vitamiinien t��rkeydest�� ja ravitsemusasioista yleens��. Sellaisia ongelmia ei noussut esille, etteik�� ruokavaliota voisi suositella

Generalizations and Models in Ecology : Lawlikeness, Invariance, Stability, and Robustness

The question at issue in this dissertation is the epistemic role played by ecological generalizations and models. I investigate and analyze such properties of generalizations as lawlikeness, invariance, and stability, and I ask which of these properties are relevant in the context of scientific explanations. I will claim that there are generalizable and reliable causal explanations in ecology by generalizations, which are invariant and stable. An invariant generalization continues to hold or be valid under a special change called an intervention that changes the value of its variables. Whether a generalization remains invariant during its interventions is the criterion that determines whether it is explanatory. A generalization can be invariant and explanatory regardless of its lawlike status. Stability deals with a generality that has to do with holding of a generalization in possible background conditions. The more stable a generalization, the less dependent it is on background conditions to remain true. Although it is invariance rather than stability of generalizations that furnishes us with explanatory generalizations, there is an important function that stability has in this context of explanations, namely, stability furnishes us with extrapolability and reliability of scientific explanations. I also discuss non-empirical investigations of models that I call robustness and sensitivity analyses. I call sensitivity analyses investigations in which one model is studied with regard to its stability conditions by making changes and variations to the values of the model s parameters. As a general definition of robustness analyses I propose investigations of variations in modeling assumptions of different models of the same phenomenon in which the focus is on whether they produce similar or convergent results or not. Robustness and sensitivity analyses are powerful tools for studying the conditions and assumptions where models break down and they are especially powerful in pointing out reasons as to why they do this. They show which conditions or assumptions the results of models depend on. Key words: ecology, generalizations, invariance, lawlikeness, philosophy of science, robustness, explanation, models, stability

The function of NR3B and NR4A orphan nuclear receptors in osteoblasts

Nuclear receptors (NRs) comprise a large family of proteins that mediate the effects of small lipophilic molecules such as steroid hormones. In addition, there are a group of NRs which lack identified natural ligands and are referred as orphan NRs. In this thesis, the function of two such orphan NR families, the NR3B (ERR��, ERR�� and ERR��) and the NR4A family (NGFI-B, Nurr1 and Nor1), was studied. NR3B and NR4A receptors regulate many biological processes such as energy metabolism and carcinogenesis. In addition, NR3B and NR4A receptors are expressed in bone. Therefore, the signaling and function of NR3B and NR4A orphan nuclear receptors was studied specifically in osteoblasts. NR4A receptors were found to be regulated by NR3B receptors and the Wnt/��-catenin signaling pathway as ERR��, ERR�� and ��-catenin repressed the transcriptional activity of NR4A receptors in U2-OS cells. NGFI-B was found to repress the transcriptional activity of ERR�� in HeLa cells. The phytoestrogen equol was identified as a new agonist for ERR�� and ERR�� in PC-3, U2-OS, and SaOS-2 cells. Equol increased the transcriptional activity of ERR�� by increasing ERR�� co-activator binding and by inducing a conformational change in the ligand binding pocket of ERR��. The growth inhibitory effect of equol on PC-3 prostate cancer cells was decreased by blocking ERR�� expression by siRNA. Therefore, ERR�� could mediate some of the beneficial health effects of equol. The Wnt/��-catenin signaling pathway is important for the differentiation and function of osteoblasts. NR3B and NR4A receptors were found to repress the transcriptional activity mediated by ��-catenin in U2-OS cells. The mesenchymal stem cells (MSCs) isolated from ERR�� knockout (KO) mice showed diminished proliferation and osteoblastic differentiation compared to the wild-type cells. The overexpression of ERR�� in osteoblastic MC3T3-E1 cell line increased their mineralization. Bone sialoprotein (BSP) was shown to be a direct target gene for ERR�� and ERR�� as the BSP promoter was activated by ERR�� or ERR�� and PGC-1�� in HeLa cells. The adipogenic differentiation of ERR�� KO MSCs was also decreased and they expressed less adipogenic marker genes. In conclusion, the studies described in this thesis demonstrated that the transcriptional activity of NR3B and NR4A receptors can be regulated by other orphan NRs and signaling pathways in osteoblasts. NR3B receptors can also be regulated by ligands and a new agonist, equol, was identified for ERR�� and ERR��. New roles for NR3B and NR4A were also identified as they were shown to converge with the Wnt signaling pathway in osteoblasts, ERR�� was shown to mediate the growth inhibitory effect of equol in prostate cancer cells, and ERR�� was shown to regulate positively MSC proliferation, osteoblastic differentiation and adipogenesis.

Juverh��lsoproblem orsakade av Streptococcus agalactiae p�� stora mj��lkg��rdar med mj��lkningsrobot

Streptococcus agalactiae ���juverinflammation var tidigare ett stort problem i m��nga l��nder, inklusive Finland. I och med f��rb��ttrad mj��lkningshygien och antibiotikabehandlingar har bakterien s�� gott som eradikerats fr��n mj��lkbes��ttningarna. Nu verkar bakterien i viss m��n ha kommit tillbaka till v��ra stora mj��lkg��rdar. Avhandlingens experimentella del utf��rdes p�� en mj��lkg��rd, med ca 180 mj��lkande och tre mj��lkningsrobotar, som haft problem med Str. agalactiae. Man hoppades utreda hur stort problemet p�� g��rden var samt m��jliga smittov��gar. Man unders��kte ocks�� m��jligheten att anv��nda mj��lkningsrobotens automatiska provtagningsutrustning f��r provtagning av bakteriella prov. PCRmetoden j��mf��rdes med konventionell odling vid diagnostik av juverinflammationer orsakade av Str. agalactiae. P�� g��rden gick man igenom anteckningar samt h��lso- och seminkort f��r att f�� en bild ��ver situationen. Man gjorde en uppf��ljning av mj��lkningen f��r tolv kor vid den ena mj��lkningsroboten. Man tog 47 stycken kospecifika mj��lkprov samt ett prov fr��n mj��lktanken. Mj��lkprov i tre serier b��de mj��lkade f��r hand och direkt fr��n mj��lkuppsamlaren p�� mj��lkningsroboten togs. Man tog sammanlagt 23 renlighetsprov fr��n mj��lkningsroboten, tre fr��n den automatiska provtagningsutrustningen samt tv�� fr��n djursk��tarnas h��nder. Fr��n den automatiska provtagningsutrustningen togs ��ven ett genomsk��ljningsprov. Av mj��lkprov som tidigare tagits p�� g��rden hade man hittat Str. agalactiae i ca 17%. I denna studie hittades Str. agalactiae i tre kospecifika mj��lkprov, vilket motsvarar en prevalens p�� ca 2%. Vid uppf��ljningen av mj��lkningarna uppt��cktes inget alarmerande, men spenarnas h��lsa samt tommj��lkningar ��r n��got som b��r f��ljas upp. Av renlighetsproven hittades Str. agalactiae i ett prov taget fr��n borsth��llaren. Svaren fr��n mj��lkproven tagna i serier tyder p�� att den automatiska provtagningsutrustningen inte g��r att anv��nda till bakteriella prov, eftersom mj��lken fr��n en Str. agalactiae ���infekterad ko verkar p��verka resultatet ocks�� hos f��ljande kor. Resultatet ��r v��ntat, eftersom mj��lkprov alltid skall tas aseptiskt och det g��r inte med den automatiska provtagningsutrustningen s�� som den i dagsl��get ��r utvecklad. Fr��n sju av nio mj��lkprov, d��r man hittat Str. agalactiae med PCR-metoden, hittades bakterien ocks�� med konventionell odling. Fr��n tankmj��lksprovet kunde man inte hitta Str. agalactiae med konventionell odling. PCR-metoden verkar enligt den h��r studien vara mer k��nslig att uppt��cka Str. agalactiae j��mf��rt med konventionell odling.

Suomalainen sotilasidentiteetti yhteiskunnan muutoksessa toisen maailmansodan j��lkeen

Toisen maailmansodan p����ttyminen vuonna 1945 ja sit�� seurannut Suomen poliittinen uudelleenasemointi asettivat my��s suomalaisen identiteettipolitiikan uudelleenarvioitavaksi. Erityisesti puolustusvoimissa ja ylip����t����n suomalaisen sotilaan identiteetin kohdalla muutos oli suuri, sill�� toista maailmansotaa edelt��nyt kansalaissotilaan luominen oli perustunut pitk��lti Neuvostoliiton ja Ven��j��n uhkaan. Sotaa muita kuin it��ist�� naapuria vastaan ei pidetty uskottavana. Tilanteen muututtua pohjaa maanpuolustustahdolle, is��nmaalle ja ylip����t����n sotilaalliselle varautumiselle oli haettava muista l��hteist��. Tutkielma k��sittelee suomalaisen sotilasidentiteetin tilaa 1960-luvun alussa (1960-1965). Asiaa tarkastellaan puolustusvoimien ja sen piiriss�� toimineiden henkil��iden n��k��vinkkelist��. Tarkoituksena on selvitt����, miten he n��kiv��t tilanteen, sen kehityksen ja mit�� toimenpiteit�� kenties tarvittiin identiteetin ohjaamiseksi oikeaan suuntaan. Alkuper��isl��htein�� ty��ss�� on k��ytetty p����asiassa puolustusvoimain vaikutuspiiriss�� julkaistuja sanoma- ja aikakauslehti�� tutkimusjaksolta. Aikaisempaa historiantutkimusta aiheesta ko. tutkimusjaksolta on julkaistu v��h��n. Tutkimus peilaa vahvasti Juha M��lkin v��it��stutkimukseen (2008), jossa tutkittiin suomalaisen kansalaissotilaan luomisty��t�� 1920- ja 1930-luvuilla. M��lkin tutkimus toimii ty��ss�� monin paikoin vertailukohtana sotaa edelt��neeseen tilanteeseen. Toisena t��rke��n�� metodologisena l��ht��kohtana tutkielmalle on Vilho Harlen ja Sami Moision (2000) k��sitys suomalaisesta identiteettiprojektista ja suomalaisen identiteetin rakentamisesta ���toiseutta��� vastaan. Tutkielma selvitt���� suomalaisen sotilasidentiteetin rakentumista kolmella tasolla. Ensimm��isell�� tasolla selvitet����n, millaisena suomalainen sotilas n��htiin luonteensa valossa ja millaisia piirteit�� yhdistettiin h��nen persoonaansa yleisell�� tasolla. Samalla selvitet����n, miten n��m�� piirteet vaikuttivat sotilaalliseen kurinpitoon ja johtamiseen. Toinen taso kartoittaa, miten poliittisen johdon valitsema puolueettomuuspolitiikka vaikutti identiteetin perustaan, siihen miten is��nmaallisuus haluttiin m����ritell�� sek�� niihin k��yt��nn��n toimiin, joita valittu linja vaati. Kolmas taso keskittyy asevelvollisi��ss�� olleeseen nuorisoon ja siihen, miten heid��t n��htiin muun muassa 1960-luvun nuorisoradikalismin ja rauhanaatteiden valossa. Tutkielman loppup����telm�� on, ett�� suomalainen oli kansallisten ominaispiirteidens�� puolesta pitk��lti hyv��ksytty ���aikuinen��� kansalainen. My��s sotilaille kielteiset piirteet, kuten vaikkapa ���purnaaminen��� oli otettu osaksi suomalaisen sotilaan kuvaa. Samalla puolustusvoimain piiriss�� oltiin kuitenkin huolestuneita kansalaisten sitoutumisesta is��nmaahan ja maanpuolustukseen henkisell�� tasolla. Esimerkiksi nuorison radikaalit aatteet n��htiin uhkana oikeanlaiselle identiteetille. Edellytyksen�� hyv��ksytt��v��lle sotilasidentiteetille n��htiin poliittisen johdon valitseman puolueettomuusasenteen laaja ja ehdoton hyv��ksyminen. T��lt�� osin kaikkien suomalaisten olisi ajateltava samalla tavoin.