Assessment of total cardiovascular risk in hypertensive subjects

Valtimotautiriskin arviointi verenpainepotilailla Valtimotaudit ovat yleisin kuolinsyy koko maailmassa. Väestön elintapojen muuttuminen ja ikääntyminen uhkaavat edelleen lisätä valtimotautien esiintyvyyttä. Kokemäenjokilaakson valtimotautien ehkäisyprojektin tavoitteena oli löytää 45–70-vuotiaasta väestöstä henkilöt, joilla on kohonnut riski sairastua valtimotauteihin. Kaksivaiheisen seulontamenetelmän avulla voitiin terveydenhoitajan antama elintapaneuvonta kohdistaa riskihenkilöihin ja rajoittaa lääkärin vastaanoton tarve niihin potilaisiin, jotka todennäköisesti hyötyvät ennaltaehkäisevästä lääkityksestä. Suomalainen tyypin 2 diabeteksen sairastumisriskin arviointikaavake ja hoitajan toteama kohonnut verenpaine osoittautuivat käytännöllisiksi menetelmiksi seuloa väestöstä riskihenkilöitä. Valtimotautien ehkäisyprojektissa Harjavallassa ja Kokemäellä todettiin verenpainetauti 1 106 henkilöllä, jotka eivät sairastaneet valtimotautia tai aiemmin todettua diabetesta. Heidän tutkimustulostensa avulla voidaan arvioida kohonneen verenpaineen vaikutusta sokeriaineenvaihduntaan ja verenpaineen aiheuttamiin kohde-elinvaurioihin. Sokeriaineenvaihdunnan häiriöt ovat verenpainetautia sairastavilla yleisempiä kuin väestössä muutoin. Käyttämällä metabolisen oireyhtymän kriteerejä sokerirasituskokeen suorittamisen edellytyksenä voidaan tutkimusten määrää vähentää kolmanneksella ja silti löytää lähes kaikki diabetesta tai sen esiastetta sairastavat verenpainepotilaat. Verenpainepotilaista etenkin metabolista oireyhtymää sairastavilla naisilla on suurentunut munuaisten vajaatoiminnan riski. Jos verenpainepotilaan munuaisten toimintaa arvioidaan pelkästään plasman kreatiniini -arvon perusteella, kolme neljästä munuaisten vajaatoimintaa potevasta jää toteamatta verrattuna laskennallisen glomerulusten suodattumisnopeuden määritykseen seulontamenetelmänä. Joka kolmannella verenpainetautia sairastavalla voidaan todeta alaraajavaltimoiden kovettumista; useammin niillä, joiden ylä- ja alaverenpaineen erotus, pulssipaine on yli 65 mmHg. Verenpainetauti on itsenäinen perifeerisen valtimotaudin vaaratekijä. Tutkimuksessa käytetty menetelmä nilkka-olkavarsipainesuhteen määrittämiseksi soveltunee hyvin perusterveydenhuollon käyttöön riskihenkilöiden löytämiseksi. Valtimotautien kokonaisriskin arviointimenetelmät tai uuden riskitekijän, herkän C-reaktiivisen proteiinin määritys eivät voi korvata kohde-elinvaurioiden mittaamista verenpainepotilaan valtimotautiriskin huolellisessa arvioinnissa.

Yritysmuodon vaikutus verotuksen edullisuuteen, case Lahden Betonilattiat Oy / Tmi MR-Rakennus & Remontti

Suomessa verotuksen tarkoituksena ei ole vaikuttaa yritysmuodon valintaan. Yritystä perustettaessa kiinnitetään kuitenkin usein erityistä huomiota verotukseen. Yrityksen ja omistajayrittäjän verotukseen vaikuttavat monet eri tekijät. Yleispäteviä saantoja yritysmuodon vaikutuksesta verotuksen edullisuuteen on mahdoton antaa ja siksi harkinta täytyy tehdä aina tilannekohtaisesti. Tärkeintä verotuksen edullisuuslaskelmissa on kokonaisrasituksen mittaaminen. Tutkimuksessa on vertailtu kahden samalla toimialalla toimivan pienyrityksen yritysmuodon vaikutusta verotuksen edullisuuteen. Tutkimuksen tavoitteena on ollut selvittää omistajayrittäjille jäävän nettotulon määrä. Tutkimuksen kohteena olevat yritykset ovat Lahden Betonilattiat Oy ja Tmi MR-Rakennus & Remontti, joista ensimmäinen on yritysmuodoltaan osakeyhtiö ja toinen yksityisliike. Tutkimusongelman ratkaisemiseksi tutkimuksessa on perehdytty yritysten kirjanpitoon ja tilinpaatostietoihin. Niiden avulla on laskettu yritysten nettovarallisuus, tulonmuodostus ja verot. Siten on saatu konkreettinen tulos siitä, kuinka paljon on ollut omistajayrittäjien kokonaisverorasitus ja käteen jäävän nettotulon määrä. Tutkimuksessa on oletettu tilikauden voiton otetun kokonaisuudessaan osakkaan käyttöön. Lisäksi on tutkittu miten tilanne muuttuu voiton ja nettovarallisuuden kasvaessa. Tutkimuksen tulosten perusteella todetaan yksityisliikkeen olevan verotuksen kannalta osakeyhtiötä edullisempi vaihtoehto. Yritysten voiton ja nettovarallisuuden kasvaessa havaitaan yksityisliikkeen lähes aina olevan osakeyhtiötä edullisempi yritysmuoto. Osakeyhtiö on yksityisliikettä edullisempi vaihtoehto ainoastaan silloin, kun sen nettovarallisuus on huomattavan suuri ja paljon yksityisliikkeen nettovarallisuutta suurempi.

Total Cost of Ownership - Elinkaarilaskennan sovellus

Ostotapahtumassa kiinnitetään usein huomiota hintaan, mutta hankintapäätökseen vaikuttavat myös muutkin kustannukset. Ongelman asiassa aiheuttaa kokonaiskustannusvaikutuksien arvioinnin ja mittauksen haasteellisuus, sekä kunnollisen raportointijärjestelmän puuttuminen. Hankinnan kokonaiskustannusten selvittäminen pitkällä aikavälillä on kuitenkin tärkeää, koska hankintojen osuus yritysten liikevaihdoista on jatkuvassa kasvussa. Työn tarkoituksena oli tarkastella Total cost of ownershipia, eli TCO:ta, elinkaarilaskennan sovellusta. Tarkastelun aluksi työlle luotiin teoreettinen pohja käyttäen hyväksi kirjallisuutta, artikkeleita sekä www-dokumentteja. Teoriaosuus rakentui kustannuslaskennan osalta kustannusten tunnistamisesta, jakamisesta ja kohdistamisesta. TCO:sta luotiin mahdollisimman laaja-alainen teoreettinen kuvaus. Seuraavaksi työssä käsiteltiin TCO:n soveltamista sen perinteisimpiin käyttökohteisiin: taloudellisesti merkittäviin hankintoihin, ulkoistamispäätöksiin, hinnoitteluun sekä toimittajien suorituskyvyn seurantaan ja analysointiin. TCO:n soveltamista käsittelevä osuus päätettiin kotimaisilla esimerkeillä TCO:n soveltamisesta IT-hankintojen apuvälineenä. Työ päätettiin käymällä läpi työtä tehdessä kypsyneet ajatukset sekä johtopäätökset.

Multilevel converter modulation: implementation and analysis

Multilevel converters provide an attractive solution to bring the benefits of speed-controlled rotational movement to high-power applications. Therefore, multilevel inverters have attracted wide interest in both the academic community and in the industry for the past two decades. In this doctoral thesis, modulation methods suitable especially for series connected H-bridge multilevel inverters are discussed. A concept of duty cycle modulation is presented and its modification is proposed. These methods are compared with other well-known modulation schemes, such as space-vector pulse width modulation and carrier-based modulation schemes. The advantage of the modified duty-cycle modulation is its algorithmic simplicity. A similar mathematical formulation for the original duty cycle modulation is proposed. The modified duty cycle modulation is shown to produce well-formed phase-to-neutral voltages that have lower total harmonic distortion than the space-vector pulse width modulation and the duty cycle modulation. The space-vector-based solution and the duty cycle modulation, on the other hand, result in a better-quality line-to-line voltage and current waveform. The voltage of the DC links in the modules of the series-connected H-bridge inverter are shown to fluctuate while they are under load. The fluctuation causes inaccuracies in the voltage production, which may result in a failure of the flux estimator in the controller. An extension for upper-level modulation schemes, which changes the switching instants of the inverter so that the output voltage meets the reference voltage accurately regardless of the DC link voltages, is proposed. The method is shown to reduce the error to a very low level when a sufficient switching frequency is used. An appropriate way to organize the switching instants of the multilevel inverter is to make only one-level steps at a time. This causes restrictions on the dynamical features of the modulation schemes. The produced voltage vector cannot be rotated several tens of degrees in a single switching period without violating the above-mentioned one-level-step rule. The dynamical capabilities of multilevel inverters are analyzed in this doctoral thesis, and it is shown that the multilevel inverters are capable of operating even in dynamically demanding metal industry applications. In addition to the discussion on modulation schemes, an overvoltage in multilevel converter drives caused by cable reflection is addressed. The voltage reflection phenomenon in drives with long feeder cables causes premature insulation deterioration and also affects the commonmode voltage, which is one of the main reasons for bearing currents. Bearing currents, on the other hand, cause fluting in the bearings, which results in premature bearing failure. The reflection phenomenon is traditionally prevented by filtering, but in this thesis, a modulationbased filterless method to mitigate the overvoltage in multilevel drives is proposed. Moreover, the mitigation method can be implemented as an extension for upper-level modulation schemes. The method exploits the oscillations caused by two consecutive voltage edges so that the sum of the oscillations results in a mitigated peak of the overvoltage. The applicability of the method is verified by simulations together with experiments with a full-scale prototype.

Epidemiology of Cytochrome P450-mediated Drug-Drug Interactions

Drug-drug interactions (DDIs) comprise an important cause of adverse drug reactions leading to excess hospitalizations. Drug metabolism is catalyzed by 75% by cytochrome P450 (CYP) enzymes and thus they are often involved in pharmacokinetic DDIs. In general, DDIs are studied in randomized controlled clinical trials in selected study populations. The overall aim of the present studies was to perform observational pharmacoepidemiological surveys on CYP-mediated DDIs in diseases important at the population level. The prevalence of co-administrations of four prodrugs (losartan, codeine, tramadol, and clopidogrel), three sulphonylureas (glibenclamide, glimepiride, and glipizide), or two statins (lovastatin and simvastatin) with well established agents altering CYP activity, as well as of statins with fibrates, was studied in Finland utilizing data from a university hospital medication database (inpatients) and the National Prescription Register of the Social Insurance Institution of Finland, Kela (outpatients). Clinical consequences of potential DDIs were estimated by reviewing laboratory data, and information from hospital care and cause-of-death registers. Concomitant use of study substrates with interacting medication was detected in up to one fifth of patients in both hospital and community settings. Potential CYP3A4 interactions in statin users did not manifest in clear adverse laboratory values but pharmacodynamic DDIs between statins and fibrates predisposed patients to muscular toxicity. Sulphonylurea DDIs with CYP2C9 inhibitors increased the risk of hypoglycaemia. CYP3A4 inhibitor use with clopidogrel was not associated with significant changes in mortality but non-fatal thrombosis and haemorrhage complications were seen less often in this group. Concomitant administration of atorvastatin with clopidogrel moderately attenuated the antithrombotic effect by clopidogrel. The overall mortality was increased in CYP3A4 inducer and clopidogrel co-users. Atorvastatin used concomitantly with prodrug clopidogrel seems to be beneficial in terms of total and LDL cholesterol concentrations, and overall mortality compared with clopidogrel use without interacting medication. In conclusion, CYP-mediated DDIs are a common and often unrecognized consequence of irrational drug prescribing.

Use Of Systems Approach with Total Quality Management in Industrial Organizations

The objective of the work has been to study why systems thinking should be used in combination with TQM, what are the main benefits of the integration and how it could best be done. The work analyzes the development of systems thinking and TQM with time and the main differences between them. The work defines prerequisites for adopting a systems approach and the organizational factors which embody the development of an efficient learning organization. The work proposes a model based on combination of an interactive management model and redesign to be used for application of systems approach with TQM in practice. The results of the work indicate that there are clear differences between systems thinking and TQM which justify their combination. Systems approach provides an additional complementary perspective to quality management. TQM is focused on optimizing operations at the operational level while interactive management and redesign of organization are focused on optimization operations at the conceptual level providing a holistic system for value generation. The empirical study demonstrates the applicability of the proposed model in one case study company but its application is tenable and possible also beyond this particular company. System dynamic modeling and other systems based techniques like cognitive mapping are useful methods for increasing understanding and learning about the behavior of systems. The empirical study emphasizes the importance of using a proper early warning system.

The health effects of sea buckthorn berries and oil

Sea buckthorn (Hippophaë) berries are ingredients of the Chinese traditional medicine. In addition to China, they are nowadays cultivated for food in several European countries, Russia, Canada, the USA, and Japan. Sea buckthorn berries are a rich source of flavonoids, mainly flavonol glycosides and proanthocyanidins. Depending on the genetic background, growth conditions, and ripeness of the berries, vitamin C concentrations up to over 1 g/100 ml juice, have been reported. Sea buckthorn berries contain inositols and methyl inositols, components of messenger molecules in humans. Sea buckthorn seed oil is rich in essential aplha-linolenic and linoleic acids, whereas the most abundant fatty acids in the berry oil are palmitoleic, palmitic and oleic acids. Other potentially beneficial lipophilic compounds of sea buckthorn seeds and berries include carotenoids, phytosterols, tocopherols and tocotrienols. The effects of sea buckthorn fractions on inflammation, platelet aggregation, oxidation injuries, the liver, skin and mucosa, among others, have been reported. The aim of the thesis work was to investigate the health effects of sea buckthorn berries and oil in humans. The physiological effects of sea buckthorn berries, berry components, and oil have mostly been studied in vitro and in animal models, leaving a demand for more clinical trials. In the first randomized, placebo-controlled trial of this thesis healthy adults consumed 28 g/day of sea buckthorn berries for three months. The main objective was to investigate the effects on the common cold. In addition, effects on other infections, inflammation and circulating lipid markers associated with cardiovascular disease risk were studied. In the second randomized, placebocontrolled trial participants reporting dry eye symptoms consumed 2 g/day of sea buckthorn oil from the seeds and berries for three months. The effects on symptoms and clinical signs of dry eye were monitored. In addition, the effects on circulating markers of inflammation and liver functions were analyzed. Sea buckthorn berries did not affect the common cold or other infections in healthy adults. However, a decrease in serum C-reactive protein was detected, indicating effects on inflammation. Fasting concentrations of serum flavonols, typical to sea buckthorn berry, increased without affecting the circulating total, HDL, LDL cholesterol, or triacylglycerol concentrations. Tear film hyperosmolarity and activation of inflammation at the ocular surface are among the core mechanisms of dry eye. Combined sea buckthorn berry and seed oil attenuated the rise in tear film osmolarity taking place during the cold season. It also positively affected some of the dry eye symptoms. Based on the tear film fatty acid analysis, the effects were not mediated through direct incorporation of sea buckthorn oil fatty acids to tear film lipids. It is likely that the fatty acids, carotenoids, tocopherols and tocotrienols of sea buckthorn oil affected the inflammation of the ocular surface, lacrimal and/or meibomian glands. The effects on the differentiation of meibomian gland cells are also possible. Sea buckthorn oil did not affect the serum concentrations of inflammation markers or liver enzymes investigated. In conclusion, this thesis work suggests positive effects of sea buckthorn berries and oil on inflammation and dry eye, respectively, in humans.

Reflexive model of research-based theatre – processing innovation at the crossroads of theatre, reflection and practice-based innovation activities

Contemporary organisations have to embrace the notion of doing ‘more with less’. This challenges knowledge production within companies and public organisations, forcing them to reorganise their structures and rethink what knowledge production actually means in the context of innovation and how knowledge is actually produced among various professional groups within the organisation in their everyday actions. Innovations are vital for organisational survival, and ‘ordinary’ employees and customers are central but too-often ignored producers of knowledge for contemporary organisations. Broader levels of participation and reflexive practices are needed. This dissertation discusses the missing links between innovation research conducted in the context of industrial management, arts, and culture; applied drama and theatre practices (specifically post-Boalian approaches); and learning – especially organising reflection – in organisational settings. This dissertation (1) explores and extends the role of research-based theatre to organising reflection and reflexive practices in the context of practice-based innovation, (2) develops a reflexive model of RBT for investigating and developing practice-based organisational process innovations in order to contribute to the development of a tool for innovation management and analysis, and (3) operationalises this model within private- and publicsector organisations. The proposed novel reflexive model of research-based theatre for investigating and developing practice-based organisational process innovations extends existing methods and offers a different way of organising reflection and reflexive practices in the context of general innovation management. The model was developed through five participatory action research processes conducted in four different organisations. The results provide learning steps – a reflection path – for understanding complex organisational life, people, and relations amid renewal and change actions. The proposed model provides a new approach to organising and cultivating reflexivity in practice-based innovation activities via research-based theatre. The results can be utilised as a guideline when processing practice-based innovation within private or public organisations. The model helps innovation managers to construct, together with their employees, temporary communities where they can learn together through reflecting on their own and each others’ experiences and to break down assumptions related to their own perspectives. The results include recommendations for practical development steps applicable in various organisations with regard to (i) application of research-based theatre and (ii) related general innovation management. The dissertation thus contributes to the development of novel learning approaches in knowledge production. Keywords: practice-based innovation, research-based theatre, learning, reflection, mode 2b knowledge production

JNK, a versatile regulator of kinesin-1 transport and cytoskeleton dynamics

C-Jun N-terminal kinase (JNK) is traditionally recognized as a crucial factor in stress response and inducer of apoptosis upon various stimulations. Three isoforms build the JNK subfamily of MAPK; generally expressed JNK1 and JNK2 and brain specific JNK3. Degenerative potency placed JNK in the spotlight as potential pharmacological option for intervention. Unfortunately, adverse effects of potential drugs and observation that expression of only JNK2 and JNK3 are induced upon stress, restrained initial enthusiasm. Notably, JNK1 demonstrated atypical high constitutive activity in neurons that is not responsive to cellular stresses and indicated existence of physiological activity. This thesis aimed at revealing the physiological functions of JNK1 in actin homeostasis through novel effector MARCKS-Like 1 (MARCKSL1) protein, neuronal trafficking mediated by major kinesin-1 motor protein and microtubule (MT) dynamics via STMN2/SCG10. The screen for novel physiological JNK substrates revealed specific phosphorylation of C-terminal end of MARCKSL1 at S120, T148 and T183 both ex vivo and in vitro. By utilizing site-specific mutagenesis, various actin dynamics and migrations assays we were able to demonstrate that JNK1 phosphorylation specifically facilitates F-actin bundling and thus filament stabilisation. Consecutively, this molecular mechanism was proved to enhance formation of filopodia; cell surface projections that allow cell sensing surrounding environment and migrate efficiently. Our results visualize JNK dependent and MARCKSL1 executed induction of filopodia in neurons and fibroblast indicating general mechanism. Subsequently, inactivation of JNK action on MARCKSL1 shifts cellular actin machinery into lamellipodial dynamic arrangement. Tuning of actin cytoskeleton inevitably melds with cell migration. We observed that both active JNK and JNK pseudo-phosphorylated form of MARCKSL1 reduce actin turnover in intact cells leading to overall diminished cell motility. We demonstrate that tumour transformed cells from breast, prostate, lung and muscle-derived cancers upregulate MARCKSL1. We showed on the example of prostate cancer PC-3 cell line that JNK phosphorylation negatively controls MARCKSL1 ability to induce migration, which precedes cancer cell metastasis. The second round of identification of JNK physiological substrates resulted in detection of predominant motor protein kinesin-1 (Kif5). Mass spectrometry detailed analysis showed evident endogenous phosphorylation of kinesin-1 on S176 within motor domain that interacts with MT. In vitro phosphorylation of bacterially expressed kinesin heavy chain by JNK isoforms displayed higher specificity of JNK1 when compared to JNK3. Since, JNK1 is constitutively active in neurons it signified physiological aspect of kinesin-1 regulation. Subsequent biochemical examination revealed that kinesin-1, when not phosphorylated on JNK site, exhibits much higher affinity toward MTs. Expression of the JNK non-phosphorable kinesin-1 mutant in intact cells as well as in vitro single molecule imaging using total internal reflection fluorescence microscopy indicated that the mutant loses normal speed and is not able to move processively into proper cellular compartments. We identify novel kinesin-1 cargo protein STMN2/SCG10, which along with known kinesin-1 cargo BDNF is showing impaired trafficking when JNK activity is inhibited. Our data postulates that constitutive JNK activity in neurons is crucial for unperturbed physiologically relevant transport of kinesin-1 dependant cargo. Additionally, my work helps to validate another novel physiological JNK1 effector STMN2/SCG10 as determinant of axodendritic neurites dynamics in the developing brain through regulation of MT turnover. We show successively that this increased MT dynamics is crucial during developmental radial migration when brain layering occurs. Successively, we are able to show that introduction of JNK phosphorylation mimicking STMN2/SCG10 S62/73D mutant rescues completely JNK1 genetic deletion migration phenotype. We prove that STMN2/SCG10 is predominant JNK effector responsible for MT depolymerising activity and neurite length during brain development. Summarizing, this work describes identification of three novel JNK substrates MARCKSL1, kinesin-1 and STMN2/SCG10 and investigation of their roles in cytoskeleton dynamics and cargo transport. This data is of high importance to understand physiological meaning of JNK activity, which might have an adverse effect during pharmaceutical intervention aiming at blocking pathological JNK action.

Lean, Six Sigma ja Total Welding Management hitsaavassa verkostossa

Diplomityössä tarkastellaan hitsaavan verkoston laadunhallintaa ja siinä ilmeneviä erilaisia ongelmakohtia. Tämän lisäksi työssä tarkastellaan kolmen eri laatutyökalun Lean, Six Sigma ja Total Welding Management soveltamista hitsaavan verkoston laadunhallinnassa. Teoriaosassa käsitellään sekä yleisesti että hitsauksen osalta laatua ja laadunhallintaa, sekä edellä mainittuja laatutyökaluja. Tutkimusosaan tietoja hitsaavista verkostoista kerättiin kaikkiaan kolmesta eri verkostosta. Näiden kerättyjen tietojen pohjalta tarkasteltiin valittujen laatutyökalujen soveltuvuutta verkostomaiseen käyttöön. Verkostoitunut toiminta aiheuttaa monia uusia haasteita yritysten laadunhallinnalle verrattuna yksittäisiin hitsaaviin yrityksiin. Suurimpia tutkimuksessa havaittuja ongelmakohtia ovat suunnittelun ja valmistuksen yhteistyön erilaiset puutteet, laatutasoon ja sen varmistukseen liittyvät asiat, sekä verkoston sisälle syntyvä niin sanottu hiljainen tieto ja sen häviäminen. Tutkimuksen tarkastelujen perusteella havaittiin, että kaikkien tutkimukseen valitun kolmen laatutyökalun soveltaminen myös verkostomaisessa toiminnassa on mahdollista, mutta se vaatii huomattavasti suurempaa työpanosta kuin soveltaminen yksittäisessä yrityksessä. Myös näiden kaikkien kolmen työkalun yhtä aikainen käyttö on mahdollista. Juuri oikean työkalun valitseminen kullekin hitsaavalle verkostolle vaatii tarkkaa perehtymistä verkostoon ja sen tilanteeseen.

Coping with international atrocities through criminal law : a study into the typical features of international criminality and the reflection of these traits in international criminal law

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Fionnula Hunt : a reflection

julkaisumaa: 372 IE IRL Irlanti