Somatic gene therapy for hypertension

Gene therapy for hypertension is needed for the next generation of antihypertensive drugs. Current drugs, although effective, have poor compliance, are expensive and short-lasting (hours or one day). Gene therapy offers a way to produce long-lasting antihypertensive effects (weeks, months or years). We are currently using two strategies: a) antisense oligodeoxynucleotides (AS-ODN) and b) antisense DNA delivered in viral vectors to inhibit genes associated with vasoconstrictive properties. It is not necessary to know all the genes involved in hypertension, since many years of experience with drugs show which genes need to be controlled. AS-ODN are short, single-stranded DNA that can be injected in naked form or in liposomes. AS-ODN, targeted to angiotensin type 1 receptors (AT1-R), angiotensinogen (AGT), angiotensin converting enzyme, and ß1-adrenergic receptors effectively reduce hypertension in rat models (SHR, 2K-1C) and cold-induced hypertension. A single dose is effective up to one month when delivered with liposomes. No side effects or toxic effects have been detected, and repeated injections can be given. For the vector, adeno-associated virus (AAV) is used with a construct to include a CMV promoter, antisense DNA to AGT or AT1-R and a reporter gene. Results in SHR demonstrate reduction and slowing of development of hypertension, with a single dose administration. Left ventricular hypertrophy is also reduced by AAV-AGT-AS treatment. Double transgenic mice (human renin plus human AGT) with high angiotensin II causing high blood pressure, treated with AAV-AT1-R-AS, show a normalization of blood pressure for over six months with a single injection of vector. We conclude that ODNs will probably be developed first because they can be treated like drugs for the treatment of hypertension with long-term effects. Viral vector delivery needs more engineering to be certain of its safety, but one day may be used for a very prolonged control of blood pressure.

Biopolttoaineiden ongelmat

Biopolttoaineilla on tärkeä rooli tulevaisuuden energiahuollossa. Biopolttoaineiden käyttöä pyritäänkin lisäämään monin keinoin. Ensimmäisen sukupolven biopolttoaineet ovat jo olleet aikansa markkinoilla ja toisen sukupolven polttoaineet ovat saapumassa markkinoille. Tässä työssä tutkitaan eri biopolttoaine vaihtoehtoja ensimmäisestä toiseen sukupolveen sekä tutkitaan niiden käytön ongelmia. Biopolttoaineiden käyttö on lisääntynyt huomattavasti viime vuosien aikoina, jonka myötä on tullut esiin monia ongelmia. Ongelmia aiheuttavat niin ilmastolliset, taloudelliset, teknologiset kuin valtapoliittiset asiat.

Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

Renin is an enzyme involved in the stepwise generation of angiotensin II. Juxtaglomerular cells are the main source of plasma renin, but renin activity has been detected in other cell types. In the present study we evaluated the presence of renin mRNA in adult male Wistar rat and mouse (C-57 Black/6) mesangial cells (MC) and their ability to process, store and release both the active and inactive forms of the enzyme. Active renin and total renin content obtained after trypsin treatment were estimated by angiotensinogen consumption analyzed by SDS-PAGE electrophoresis and quantified by angiotensin I generation by HPLC. Renin mRNA, detected by RT-PCR, was present in both rat and mouse MC under basal conditions. Active renin was significantly higher (P<0.05) in the cell lysate (43.5 ± 5.7 ng h-1 10(6) cells) than in the culture medium (12.5 ± 2.5 ng h-1 10(6) cells). Inactive prorenin content was similar for the intra- and extracellular compartments (9.7 ± 3.1 and 3.9 ± 0.9 ng h-1 10(6) cells). Free active renin was the predominant form found in both cell compartments. These results indicate that MC in culture are able to synthesize and translate renin mRNA probably as inactive prorenin which is mostly processed to active renin inside the cell. MC secrete both forms of the enzyme but at a lower level compared with intracellular content, suggesting that the main role of renin synthesized by MC may be the intracellular generation of angiotensin II.

Lightweight, liquid-cooled, direct-drive generator for highpower wind turbines: motivation, concept, and performance

Thesis: A liquid-cooled, direct-drive, permanent-magnet, synchronous generator with helical, double-layer, non-overlapping windings formed from a copper conductor with a coaxial internal coolant conduit offers an excellent combination of attributes to reliably provide economic wind power for the coming generation of wind turbines with power ratings between 5 and 20MW. A generator based on the liquid-cooled architecture proposed here will be reliable and cost effective. Its smaller size and mass will reduce build, transport, and installation costs. Summary: Converting wind energy into electricity and transmitting it to an electrical power grid to supply consumers is a relatively new and rapidly developing method of electricity generation. In the most recent decade, the increase in wind energy’s share of overall energy production has been remarkable. Thousands of land-based and offshore wind turbines have been commissioned around the globe, and thousands more are being planned. The technologies have evolved rapidly and are continuing to evolve, and wind turbine sizes and power ratings are continually increasing. Many of the newer wind turbine designs feature drivetrains based on Direct-Drive, Permanent-Magnet, Synchronous Generators (DD-PMSGs). Being low-speed high-torque machines, the diameters of air-cooled DD-PMSGs become very large to generate higher levels of power. The largest direct-drive wind turbine generator in operation today, rated just below 8MW, is 12m in diameter and approximately 220 tonne. To generate higher powers, traditional DD-PMSGs would need to become extraordinarily large. A 15MW air-cooled direct-drive generator would be of colossal size and tremendous mass and no longer economically viable. One alternative to increasing diameter is instead to increase torque density. In a permanent magnet machine, this is best done by increasing the linear current density of the stator windings. However, greater linear current density results in more Joule heating, and the additional heat cannot be removed practically using a traditional air-cooling approach. Direct liquid cooling is more effective, and when applied directly to the stator windings, higher linear current densities can be sustained leading to substantial increases in torque density. The higher torque density, in turn, makes possible significant reductions in DD-PMSG size. Over the past five years, a multidisciplinary team of researchers has applied a holistic approach to explore the application of liquid cooling to permanent-magnet wind turbine generator design. The approach has considered wind energy markets and the economics of wind power, system reliability, electromagnetic behaviors and design, thermal design and performance, mechanical architecture and behaviors, and the performance modeling of installed wind turbines. This dissertation is based on seven publications that chronicle the work. The primary outcomes are the proposal of a novel generator architecture, a multidisciplinary set of analyses to predict the behaviors, and experimentation to demonstrate some of the key principles and validate the analyses. The proposed generator concept is a direct-drive, surface-magnet, synchronous generator with fractional-slot, duplex-helical, double-layer, non-overlapping windings formed from a copper conductor with a coaxial internal coolant conduit to accommodate liquid coolant flow. The novel liquid-cooling architecture is referred to as LC DD-PMSG. The first of the seven publications summarized in this dissertation discusses the technological and economic benefits and limitations of DD-PMSGs as applied to wind energy. The second publication addresses the long-term reliability of the proposed LC DD-PMSG design. Publication 3 examines the machine’s electromagnetic design, and Publication 4 introduces an optimization tool developed to quickly define basic machine parameters. The static and harmonic behaviors of the stator and rotor wheel structures are the subject of Publication 5. And finally, Publications 6 and 7 examine steady-state and transient thermal behaviors. There have been a number of ancillary concrete outcomes associated with the work including the following. X Intellectual Property (IP) for direct liquid cooling of stator windings via an embedded coaxial coolant conduit, IP for a lightweight wheel structure for lowspeed, high-torque electrical machinery, and IP for numerous other details of the LC DD-PMSG design X Analytical demonstrations of the equivalent reliability of the LC DD-PMSG; validated electromagnetic, thermal, structural, and dynamic prediction models; and an analytical demonstration of the superior partial load efficiency and annual energy output of an LC DD-PMSG design X A set of LC DD-PMSG design guidelines and an analytical tool to establish optimal geometries quickly and early on X Proposed 8 MW LC DD-PMSG concepts for both inner and outer rotor configurations Furthermore, three technologies introduced could be relevant across a broader spectrum of applications. 1) The cost optimization methodology developed as part of this work could be further improved to produce a simple tool to establish base geometries for various electromagnetic machine types. 2) The layered sheet-steel element construction technology used for the LC DD-PMSG stator and rotor wheel structures has potential for a wide range of applications. And finally, 3) the direct liquid-cooling technology could be beneficial in higher speed electromotive applications such as vehicular electric drives.

Utilization of AMI-Technology in a Multilayered Demand Response Service Environment

This thesis studied the performance of Advanced metering infrastructure systems in a challenging Demand Response environment. The aim was to find out what kind of challenges and bottlenecks could be met when utilizing AMI-systems in challenging Demand Response tasks. To find out the challenges and bottlenecks, a multilayered demand response service concept was formed. The service consists of seven different market layers which consist of Nordic electricity market and the reserve markets of Fingrid. In the simulations the AMI-systems were benchmarked against these seven market layers. It was found out, that the current generation AMI-systems were capable of delivering Demand Response on the most challenging market layers, when observed from time critical viewpoint. Additionally, it was found out, that to enable wide scale Demand Response there are three major challenges to be acknowledged. The challenges hindering the utilization of wide scale Demand Response were related to poor standardization of the systems in use, possible problems in data connectivity solutions and the current electricity market regulation model.

Kerrostalon kiinteistösähkönkulutuksen kompensointi aurinkosähköjärjestelmällä

Aurinkopaneeleiden hinta on laskenut reilusti viime vuosien aikana. Hinnan laskun seurauksena aurinkosähköjärjestelmiä on asennettu paljon yksityisiin rakennuksiin sekä Suomessa että muualla maailmassa. Tässä kandidaatintyössä tutkitaan kerrostalon kiinteistösähkönkulutuksen kompensointia aurinkosähköjärjestelmällä. Kompensointia tutkitaan, koska näin saadaan taloudellisesti paras hyöty aurinkosähköjärjestelmästä. Kerrostalon kiinteistösähkönkulutuksella tarkoitetaan talon teknisten järjestelmien kuluttamaa sähköä. Järjestelmän sijoitusta tutkitaan katolle ja parvekekaiteisiin. Katolle sijoitettuna aurinkopaneelien tuotantoa tutkitaan siten, että paneelit ovat asennettu 45° ja 15° tasokulmaan. Aurinkosähköjärjestelmän investoinnin kannattavuutta tutkitaan taloyhtiön näkökulmasta.

Y-sukupolven johtaminen – odotukset esimiestyöltä

Y-sukupolven oikeantyylinen johtaminen sekä osaamisen hyödyntäminen ja kehittäminen ovat johtamisen haasteena organisaatioissa, jotka toimivat digitaalista osaamista vaativien tuotteiden ja palvelujen parissa. Tämän tutkimuksen tarkoituksena oli tutkia, minkälaisia odotuksia Y-sukupolvella on esimiestyötä ja johtamista kohtaan. Tutkimuksen tavoitteena oli tuottaa tutkimuksen kohdeyrityksen johtamisen kehittämistä varten nuorten työntekijöiden odotukset heihin kohdistuvasta esimiestyöstä. Tutkimuksen tavoitteena oli myös tuottaa tutkittua tietoa Y-sukupolven johtamista koskevaan keskusteluun. Tutkimus oli laadullinen tutkimus, joka toteutettiin haastattelemalla kohdeyrityksen nimeämästä joukosta 12 Y-sukupolven edustajaa. Tutkimusmenetelmänä oli puolistrukturoitu teemahaastattelu. Haastatteluissa kohderyhmään kuuluvat kertoivat omiin mielipiteisiinsä perustuen ajatuksiaan ja odotuksiaan tutkijan määrittämiin teemoihin. Haastatteluteemat olivat: työ ja työn merkitys, kokemukset ja odotukset esimieheen liittyen sekä heidän oman osaamisen hyödyntäminen ja kehittäminen. Tutkimuksen tuloksena havaittiin, että Y-sukupolvi odottaa esimiestyöltä ensisijaisesti johtamista. Esimiehen täytyy pitää organisaatiossa langat käsissään; toimia suunnannäyttäjänä, organisoida ja olla jämäkkä. Esimiehen tulee olla ominaisuuksiltaan kyvyiltään sellainen, jonka johtaminen on selkeää, oikeudenmukaista ja vuorovaikutteista. Y-sukupolvi odottaa selkeitä tavoitteita, oikeudenmukaista ja tasapuolista kohtelua ja palkkaa sekä jatkuvaa palautteeseen ja sparraamiseen liittyvää vuorovaikutusta esimiehen kanssa. Y-sukupolvi odottaa myös, että esimies hyödyntää ja kehittää heidän osaamistaan.

Kaarityypin ja suojakaasun vaikutus roiskeisuuteen teräksen MAG-hitsauksessa

Tässä kandidaatintyössä tutkitaan suojakaasun ja kaarityypin vaikutuksia roiskeisuuden muodostumiselle teräksen MAG-hitsauksessa (nro. 135). Roiskeisuuden tutkimisessa tutkitaan kolmea (3) eri kaarityyppiä ja kahta (2) eri suojakaasua ja niiden keskenäisiä vaikutuksia roiskeiden syntymiselle. Tutkittavat kaarityypit ovat pulssi-, kuumakaari sekä Kemppi Oy:n WiseFusion erikoiskaarisovellus. Suojakaasuina käyetään AGAn Corgon 3 ja Mison 18 suojakaasuja. Hitsauskokeita suoritetaan kuusi (6) kappaletta alapienana jalkoasennossa (PA). Työn alussa perehdytään MAG-hitsauksen laitteistoon ja teoriaan sekä perehdytään mitkä eri asiat vaikuttavat roiskeiden muodostumiseen. Työn lopussa verrataan tieteellisistä julkaisuista löydettyjä tietoja ja tuloksia itsetehtyihin koetuloksiin.

Immunogenicity of a 23-valent pneumococcal polysaccharide vaccine in Brazilian elderly

Serum antibodies specific for the capsular polysaccharides of Streptococcus pneumoniae provide protection against invasive pneumococcal infection. In Brazil, this vaccine has been used for people over 65 years with clinical risk to develop pneumococcal infection since 1999. We evaluated the immune response of 102 elderly subjects (75.5% females and 24.5% males) with a mean age of 71 years, and 19 young healthy adults (63.2% females and 36.8% males) with a mean age of 27 years. The elderly study group consisted of outpatients who received follow-up care in the Geriatric Department of General Hospital, Faculty of Medicine, University of São Paulo. None had acute illness at the time of vaccination. Both groups were immunized with one intra-deltoid injection with 0.5 ml of a 23-valent pneumococcal polysaccharide vaccine. The total IgG specific antibody concentrations to capsular polysaccharides 1, 3, 5, 6B, 8, and 14 were determined against pre- and 1-month post-vaccination sera. All samples were analyzed according to the second-generation pneumococcal polysaccharide ELISA protocol. We observed that the pneumococcal polysaccharide vaccine evoked consistent antibody increase for serotypes 1, 5, 6B, 8, and 14 (geometric mean concentration increase of 2.46 in the elderly and 2.84 in the young adults). Otherwise, we observed no increase in antibody concentration for serotype 3 in both groups.

Talo, kartano, puutarha. Kauppahuoneen omistaja Marie Hackman ja hänen kulutusvalintansa varhaismodernissa Viipurissa

Tutkimuksessa keskitytään tutkimaan kuluttamista elämäntavan ja identiteetin muovaajana yhden yksilön elämän kautta. Kuluttamista tutkitaan statuskuluttamisen (conspicious consumption), tilallisuuden ja sukupuolihistorian käsitteistöä hyväksi käyttäen. Tutkimuksen lähteinä on käytetty liikekirjeitä ja tilikirjoja, yksityistä kirjeenvaihtoa, päiväkirjoja ja sanomalehtiä sekä aikalaismuistelmia. Naista lähdemateriaaleista on koottu sekä tilastollista aineistoa että kvalitatiivista, lähilukuun ja mikrohistorialliseen tutkimusotteeseen nojautuvaa tutkimusta. Tutkimus alkaa vuodesta 1799 ja päättyy 1830-luvulle, jolloin seuraava sukupolvi otti vastuun liiketoimista ja lähdeaineistossa tapahtui muutoksia kuluttamisen kirjaamisen suhteen. Tutkimuksen keskeiset käsitteet ovat statuskuluttaminen ja identiteetti. Näitä käsitteitä lähestytään Thorstein Veblenin, Norbert Eliaksen ja Pierre Bourdieun tutkimuksia apuna käyttäen. Tutkimus käsittelee erottautumisen ja jäljittelyn tematiikkaa merkittävimpänä kuluttamisen motivaattoreina. Lisaksi tutkimus nostaa esille hyvän maun ja muodinmukaisuuden kulutusvalintojen taustalla. Statuskuluttaminen kytkeytyy sosiaaliseen kanssakäymiseen. Kuluttamisen kohteet ovat esineitä ja asioita, joita pidetään esillä seurapiireissä. Kuluttaminen tapahtuu seuraelämän ehdoilla, sen mukavoittamiseksi, aseman osoittamiseksi seurapiireissä tai sosiaalisen paineen vuoksi. Tutkimus osoittaa kotitalouden merkityksen kuluttamisen paikkana ja kohteena. Tutkimus myös osoittaa naisten toimintakentän olleen kytköksissä kotitalouden asemaan yhteisössään sekä osoittaa, että sukupuolta pitää tarkastella suhteessa yksilön sosiaaliseen asemaan. Tutkimus osoittaa, että Marie Hackmanin kuluttaminen muuttui ikääntymisen myötä. Aseman osoittaminen oli merkittävämpää nuorena ja aseman ollessa vielä vakiintumattomampi.

Leijukattilan savukaasujen loppulämpötilan hallinta

Nykyaikaista leijukattilaa voidaan ohjata ja säätää erilaisten säätöpiirien ja sekvenssien kautta erittäin tarkasti. Toiminnot on optimoitu parhaan hyötysuhteen saavuttamiseksi ja kunnossapitokustannusten minimoimiseksi. Tehokkaasta automaatiosta ja nykyaikaisista laitevalinnoista huolimatta leijukattiloissa on usein yksi osa-alue, jota ei pystytä hallitsemaan tehokkaasti. Useilla voimalaitoksilla savukaasu poistuu liian korkeassa lämpötilassa viimeiseltä lämpöpinnalta. Kun kattilahyötysuhdetta tarkastellaan epäsuoralla menetelmällä, savukaasuhäviö on merkittävin tekijä kaikista häviöstä. Tässä diplomityössä on etsitty mahdollisuuksia savukaasun loppulämpötilan hallintaan kattilan ajoarvojen muutoksella sekä lämpöpintoja muuttamalla. Tutkimus keskittyy Järvi-Suomen Voima Oy:n Ristiinan voimalaitokselle. Tutkimus on tehty yhteistyössä laitoksen omistajien Pohjolan Voima Oy:n, UPM-Kymmene Oyj:n sekä laitetoimittaja Valmet Oyj:n kanssa.

Recovery boilers - history and future

Recovery boilers are built all over the world. The roots of recovery technology are longer than the roots of recovery boilers. But it wasn’t until the invention of recovery boilers before the Second World War that the pulping technology was revolutionalized. This led to long development of essentially the same type of equipment, culminating into units that are largest biofuel boilers in the world. Early recovery technology concentrated on chemical recovery as chemicals cost money and if one could recycle these chemicals then the profitability of pulp manufacture would improve. For pulp mills the significance of electricity generation from the recovery boiler was for long secondary. The most important design criterion for the recovery boiler was a high availability. The electricity generation in recovery boiler process can be increased by elevated main steam pressure and temperature or by higher black liquor dry solids as well as improving its steam cycle. This has been done in the modern Scandinavian units.

Comparison of pre- versus post-incision administration of intraplantar indomethacin and MK886 in a rat model of postoperative pain

The amplification of pain long after the initial stimulus may be avoided if the treatment of pain is introduced before its initiation. However, conflicting evidence exists about the efficacy of such preemptive analgesia for the management of postoperative pain. This study compares the efficacy of intraplantar administration of indomethacin (a non-selective inhibitor of cyclooxygenase) and MK886 (an inhibitor of 5-lipoxygenase-activating protein), separately or in combination to produce preemptive analgesia in a model of surgical incisional pain in male Wistar rats. All incised rats (5 to 6 rats per group) had allodynia at 2, 6, and 24 h after surgery as evaluated using von Frey filaments. MK886, but not indomethacin (50 to 200 µg/paw), reduced the allodynia when injected either 1 h before or 1 h after surgery. The effect of preoperative MK886 (160 µg/paw) against incisional allodynia had a magnitude apparently similar to that produced by postoperative MK886. Pre-, but not postoperative MK886 (80 µg/paw) reduced the allodynia but the effect was seen only at 6 h after surgery. In contrast, MK886 (40 µg/paw) intensified the allodynia observed 2 h after the incision either injected before or after surgery. MK886 or indomethacin alone did not provide preemptive analgesia in the model of incisional pain. In contrast, the combination of MK886 with indomethacin reduced the allodynia more effectively when used before than after surgery, thus fulfilling the criteria for preemptive analgesia. In conclusion, preoperative inhibition of the local generation of both prostaglandins and leukotrienes by surgical incision may be an alternative to provide preemptive analgesia.

Two pedigrees with restless legs syndrome in Brazil

Numerous studies have suggested a substantial genetic contribution in the etiology of the primary form of restless legs syndrome (RLS) and periodic leg movements (PLM). We describe the symptoms, the sleep profiles and physiological parameters of two families in which several members present RLS/PLM. The proband of family 1 is a 70-year-old woman and the proband of family 2 is a 57-year-old woman; both have exhibited the symptoms since the age of 20 years. All patients in both families were diagnosed with RLS according to the criteria of the International RLS Study Group. Polysomnographic recordings were performed to quantify and to describe PLM during sleep. Sleep parameters showed decreased sleep efficiency, increased sleep latency in the arousal index and the presence of PLM in all subjects. One of the families showed an exact profile of dominant inheritance with anticipation of age at onset. In the other family, the founders were blood relatives and there was no affected member in the third generation suggesting a recessive mode of inheritance. RLS/PLM is a prevalent sleep disorder affecting about 5 to 15% of the population and one that substantially impairs healthy sleep patterns. Efforts to understand the underlying pathophysiology will contribute to improve the sleep and life quality of these patients.

A simple model for circadian timing by mammals

Circadian timing is structured in such a way as to receive information from the external and internal environments, and its function is the timing organization of the physiological and behavioral processes in a circadian pattern. In mammals, the circadian timing system consists of a group of structures, which includes the suprachiasmatic nucleus (SCN), the intergeniculate leaflet and the pineal gland. Neuron groups working as a biological pacemaker are found in the SCN, forming a biological master clock. We present here a simple model for the circadian timing system of mammals, which is able to reproduce two fundamental characteristics of biological rhythms: the endogenous generation of pulses and synchronization with the light-dark cycle. In this model, the biological pacemaker of the SCN was modeled as a set of 1000 homogeneously distributed coupled oscillators with long-range coupling forming a spherical lattice. The characteristics of the oscillator set were defined taking into account the Kuramoto's oscillator dynamics, but we used a new method for estimating the equilibrium order parameter. Simultaneous activities of the excitatory and inhibitory synapses on the elements of the circadian timing circuit at each instant were modeled by specific equations for synaptic events. All simulation programs were written in Fortran 77, compiled and run on PC DOS computers. Our model exhibited responses in agreement with physiological patterns. The values of output frequency of the oscillator system (maximal value of 3.9 Hz) were of the order of magnitude of the firing frequencies recorded in suprachiasmatic neurons of rodents in vivo and in vitro (from 1.8 to 5.4 Hz).