A matter of scale: apparent niche differentiation of diploid and tetraploid plants may depend on extent and grain of analysis

Aim: Emerging polyploids may depend on environmental niche shifts for successful establishment. Using the alpine plant Ranunculus kuepferi as a model system, we explore the niche shift hypothesis at different spatial resolutions and in contrasting parts of the species range. Location: European Alps. Methods: We sampled 12 individuals from each of 102 populations of R. kuepferi across the Alps, determined their ploidy levels, derived coarse-grain (100x100m) environmental descriptors for all sampling sites by downscaling WorldClim maps, and calculated fine-scale environmental descriptors (2x2m) from indicator values of the vegetation accompanying the sampled individuals. Both coarse and fine-scale variables were further computed for 8239 vegetation plots from across the Alps. Subsequently, we compared niche optima and breadths of diploid and tetraploid cytotypes by combining principal components analysis and kernel smoothing procedures. Comparisons were done separately for coarse and fine-grain data sets and for sympatric, allopatric and the total set of populations. Results: All comparisons indicate that the niches of the two cytotypes differ in optima and/or breadths, but results vary in important details. The whole-range analysis suggests differentiation along the temperature gradient to be most important. However, sympatric comparisons indicate that this climatic shift was not a direct response to competition with diploid ancestors. Moreover, fine-grained analyses demonstrate niche contraction of tetraploids, especially in the sympatric range, that goes undetected with coarse-grained data. Main conclusions: Although the niche optima of the two cytotypes differ, separation along ecological gradients was probably less decisive for polyploid establishment than a shift towards facultative apomixis, a particularly effective strategy to avoid minority cytotype exclusion. In addition, our results suggest that coarse-grained analyses overestimate niche breadths of widely distributed taxa. Niche comparison analyses should hence be conducted at environmental data resolutions appropriate for the organism and question under study.

Terutroban, A TP-receptor antagonist, reduces portal pressure in cirrhotic rats.

Increased production of vasoconstrictive prostanoids, such as thromboxane A2 (TXA2 ), contributes to endothelial dysfunction and increased hepatic vascular tone in cirrhosis. TXA2 induces vasoconstriction by way of activation of the thromboxane-A2 /prostaglandin-endoperoxide (TP) receptor. This study investigated whether terutroban, a specific TP receptor blocker, decreases hepatic vascular tone and portal pressure in rats with cirrhosis due to carbon tetrachloride (CCl4 ) or bile duct ligation (BDL). Hepatic and systemic hemodynamics, endothelial dysfunction, liver fibrosis, hepatic Rho-kinase activity (a marker of hepatic stellate cell contraction), and the endothelial nitric oxide synthase (eNOS) signaling pathway were measured in CCl4 and BDL cirrhotic rats treated with terutroban (30 mg/kg/day) or its vehicle for 2 weeks. Terutroban reduced portal pressure in both models without producing significant changes in portal blood flow, suggesting a reduction in hepatic vascular resistance. Terutroban did not significantly change arterial pressure in CCl4 -cirrhotic rats but decreased it significantly in BDL-cirrhotic rats. In livers from CCl4 and BDL-cirrhotic terutroban-treated rats, endothelial dysfunction was improved and Rho-kinase activity was significantly reduced. In CCl4 -cirrhotic rats, terutroban reduced liver fibrosis and decreased alpha smooth muscle actin (α-SMA), collagen-I, and transforming growth factor beta messenger RNA (mRNA) expression without significant changes in the eNOS pathway. In contrast, no change in liver fibrosis was observed in BDL-cirrhotic rats but an increase in the eNOS pathway. CONCLUSION: Our data indicate that TP-receptor blockade with terutroban decreases portal pressure in cirrhosis. This effect is due to decreased hepatic resistance, which in CCl4 -cirrhotic rats was linked to decreased hepatic fibrosis, but not in BDL rats, in which the main mediator appeared to be an enhanced eNOS-dependent vasodilatation, which was not liver-selective, as it was associated with decreased arterial pressure. The potential use of terutroban for portal hypertension requires further investigation.

Performance and Methodological Aspects in Positron Emission Tomography

Performance standards for Positron emission tomography (PET) were developed to be able to compare systems from different generations and manufacturers. This resulted in the NEMA methodology in North America and the IEC in Europe. In practices, the NEMA NU 2- 2001 is the method of choice today. These standardized methods allow assessment of the physical performance of new commercial dedicated PET/CT tomographs. The point spread in image formation is one of the factors that blur the image. The phenomenon is often called the partial volume effect. Several methods for correcting for partial volume are under research but no real agreement exists on how to solve it. The influence of the effect varies in different clinical settings and it is likely that new methods are needed to solve this problem. Most of the clinical PET work is done in the field of oncology. The whole body PET combined with a CT is the standard investigation today in oncology. Despite the progress in PET imaging technique visualization, especially quantification of small lesions is a challenge. In addition to partial volume, the movement of the object is a significant source of error. The main causes of movement are respiratory and cardiac motions. Most of the new commercial scanners are in addition to cardiac gating, also capable of respiratory gating and this technique has been used in patients with cancer of the thoracic region and patients being studied for the planning of radiation therapy. For routine cardiac applications such as assessment of viability and perfusion only cardiac gating has been used. However, the new targets such as plaque or molecular imaging of new therapies require better control of the cardiac motion also caused by respiratory motion. To overcome these problems in cardiac work, a dual gating approach has been proposed. In this study we investigated the physical performance of a new whole body PET/CT scanner with NEMA standard, compared methods for partial volume correction in PET studies of the brain and developed and tested a new robust method for dual cardiac-respiratory gated PET with phantom, animal and human data. Results from performance measurements showed the feasibility of the new scanner design in 2D and 3D whole body studies. Partial volume was corrected, but there is no best method among those tested as the correction also depends on the radiotracer and its distribution. New methods need to be developed for proper correction. The dual gating algorithm generated is shown to handle dual-gated data, preserving quantification and clearly eliminating the majority of contraction and respiration movement

Reações de contração de anel promovidas por sais de tálio(III)

Thallium(III) salts promote a number of different reactions useful in organic synthesis. In this paper, the ring contraction of ketones and olefins, mediated by thallium(III) salts, is exhaustively reviewed.

Síntese de indanos: uma seleção de métodos gerais e eficientes

The indan ring system is present in several compounds with important pharmacological properties. In this account recent examples of selected methods (Friedel-Crafts acylation, cycloaddition reactions, ring contraction, cyclization and resolution) for the synthesis of indans are discussed.

DWI and complex brain network analysis predicts vascular cognitive impairment in spontaneous hypertensive rats undergoing executive function tests

The identification of biomarkers of vascular cognitive impairment is urgent for its early diagnosis. The aim of this study was to detect and monitor changes in brain structure and connectivity, and to correlate them with the decline in executive function. We examined the feasibility of early diagnostic magnetic resonance imaging (MRI) to predict cognitive impairment before onset in an animal model of chronic hypertension: Spontaneously Hypertensive Rats. Cognitive performance was tested in an operant conditioning paradigm that evaluated learning, memory, and behavioral flexibility skills. Behavioral tests were coupled with longitudinal diffusion weighted imaging acquired with 126 diffusion gradient directions and 0.3 mm(3) isometric resolution at 10, 14, 18, 22, 26, and 40 weeks after birth. Diffusion weighted imaging was analyzed in two different ways, by regional characterization of diffusion tensor imaging (DTI) indices, and by assessing changes in structural brain network organization based on Q-Ball tractography. Already at the first evaluated times, DTI scalar maps revealed significant differences in many regions, suggesting loss of integrity in white and gray matter of spontaneously hypertensive rats when compared to normotensive control rats. In addition, graph theory analysis of the structural brain network demonstrated a significant decrease of hierarchical modularity, global and local efficacy, with predictive value as shown by regional three-fold cross validation study. Moreover, these decreases were significantly correlated with the behavioral performance deficits observed at subsequent time points, suggesting that the diffusion weighted imaging and connectivity studies can unravel neuroimaging alterations even overt signs of cognitive impairment become apparent.

Hobbes et Gassendi: la psychologie dans le projet mécaniste

L'amitié et l'affinité intellectuelle qui caractérisèrent les rapports de Hobbes avec Gassendi forment un tissu ténu dont il n'est point aisé de démêler la trame. Aux côtés de points de convergence clairement définis, telle la commune aversion envers le dualisme et l'innéisme cartésiens, et par-delà des divergences non moins nettes dans leurs orientations philosophiques particulières, le sens des parcours maintes fois parallèles doit encore être éclairé de façon circonstanciée. Le terrain privilégié sur lequel élever une confrontation étroite entre deux auteurs est sans doute la construction d'une psychologie profondément marquée par des prémisses empiriques et dont l'orientation vise à établir une relation très étroite entre les processus de la perception, du désir (appetitus) et de la volonté avec ce qui les détermine matériellement et mécaniquement. On peut même affirmer que les écrits de Gassendi rédigés au tout début des années 1640 définissent une série d'hypothèses innovatrices sur lesquelles s'inscrit une certaine convergence avec les élaborations de Hobbes à elles contemporaines. Sous ce profil, le groupe de textes remontant aux années 1640-41, et où le philosophe d'Aix s'interroge sur la nature des phénomènes lumineux, est emblématique. L'explication du comportement des corps lumineux en terme de systole et de diastole, l'interprétation de la propagation de la lumière s'inspirant de la pure actualité cinématique (en polémique ouverte et explicite envers les thèses de la Dioptrique de Descartes sur la luminosité comme simple inclinaison au mouvement), le vacuisme (qui est propre à Gassendi, servant justement à rendre compte des phénomènes d'expansion et de contraction des sources lumineuses et qui, à cette époque, n'était pas encore exclu par Hobbes), la représentation, enfin, tout à fait matérielle et mécanique des phénomènes d'irradiation, voilà autant d'aspects de la recherche de Gassendi qui peuvent facilement être confrontés aux écrits de Hobbes.

Anchor or Accelerate – A Study on Cancer Cell Adhesion and Motility

Cell migration and adhesion to the extracellular matrix (ECM) are crucial in many biological and pathological processes such as morphogenesis, tissue repair, inflammatory responses, survival, and cancer. Cell-matrix adhesion is mediated by the integrin family of transmembrane receptors, which not only anchor cells to their surroundings, but also transmit bidirectional signalling at the cell surface and couple the ECM to the cytoskeleton. Another group of adhesion receptors are the syndecan proteoglycans, which engage the ECM and possess signalling activity in response to a variety of ligands. Cell migration is a complex process that requires spatial and temporal coordination of adhesion, cell contractility, intracellular traffic of integrins, and matrix turnover by matrix metalloproteinases (MMPs). Thus, integrins and syndecans, as well as MMPs, play essential roles in cancer cell migration and invasion. The understanding of the cooperation of syndecans and integrins was broadened in this thesis study. The results reveal that syndecan-1 functions in concert with 21 integrin in cell adhesion to collagen, whereas syndecan-4 is essential in 21 integrin-mediated matrix contraction. Finally, oncogenic K-Ras was shown to regulate 21 integrin, membrane-type 1 MMP, and syndecan-1 and -4 expression and their cooperation in cell invasion. Epithelial-mesenchymal transition (EMT) is fundamental during embryogenesis and organ development. Activation of EMT processes, including the upregulation of mesenchymal intermediate filament protein vimentin, has also been implicated in the acquisition of a malignant phenotype by epithelial cancer cells. Members of the protein kinase C (PKC) superfamily are involved in cell migration and various integrindependent cellular functions. One aim of this work was to shed light on the role of vimentin in the regulation of integrin traffic and cell motility. In addition, the mechanism by which vimentin participates in EMT was investigated. The results show that integrin recycling and motility are dependent on the PKC–mediated phosphorylation of vimentin. In addition, vimentin was found to be a positive regulator of EMT and regulate the expression of several migratory genes. Specifically, vimentin governs the expression of receptor tyrosine kinase Axl, which is implicated in tumour growth and metastasis. Taken together, the findings described in this thesis reveal novel aspects of the complex interplay between distinct cellular components: integrins, syndecans, and the vimentin cytoskeleton, which all contribute to the regulation of human cancer cell adhesion, migration, and invasion.

Studies on Neuromuscular Blocking Agents and Their Antagonists During Anaesthesia

Neuromuscular blocking agents (NMBAs) are widely used in clinical anaesthesia and emergency medicine. Main objectives are to facilitate endotracheal intubation and to allow surgery by reducing muscle tone and eliminating sudden movements, which may otherwise lead to trauma and complications. The most commonly used NMBAs are non-depolarizing agents with a medium duration of action, such as rocuronium and cisatracurium. They bind to the acetylcholine receptors in the neuromuscular junction, thus inhibiting the depolarization of the postsynaptic (muscular) membrane, which is a prerequisite for muscle contraction to take place. Previously, it has been assumed that nitrous oxide (N2O), which is commonly used in combination with volatile or intravenous anaesthetics during general anaesthesia, has no effect on NMBAs. Several studies have since claimed that N2O in fact does increase the effect of NMBAs when using bolus administration of the relaxant. The effect of N2O on the infusion requirements of two NMBAs (rocuronium and cisatracurium) with completely different molecular structure and pharmacological properties was assessed. A closed-loop feedback controlled infusion of NMBA with duration of at least 90 minutes at a 90% level of neuromuscular block was used. All patients received total intravenous anaesthesia (TIVA) with propofol and remifentanil. In both studies the study group (n=35) received N2O/Oxygen and the control group (n=35) Air/Oxygen. There were no significant differences in the mean steady state infusion requirements of NMBA (rocuronium in Study I; cisatracurium in Study II) between the groups in either study. In Study III the duration of the unsafe period of recovery after reversal of rocuronium-induced neuromuscular block by using neostigmine or sugammadex as a reversal agent was analyzed. The unsafe period of recovery was defined as the time elapsed from the moment of no clinical (visual) fade in the train-of-four (TOF) sequence until an objectively measured TOF-ratio of 0.90 was achieved. The duration of these periods were 10.3 ± 5.5 and 0.3 ± 0.3 min after neostigmine and sugammadex, respectively (P < 0.001). Study IV investigated the possible effect of reversal of a rocuronium NMB by sugammadex on depth of anaesthesia as indicated by the bispectral index and entropy levels in thirty patients. Sugammadex did not affect the level of anaesthesia as determined by EEG-derived indices of anaesthetic depth such as the bispectral index and entropy.

The regulation and function of collagenase-3 (MMP-13) in cutaneous wound healing and squamous cell carcinoma

Matrix metalloproteinase-13 (MMP-13) is a potent proteolytic enzyme, whose expression has been previously associated with fetal bone development and postnatal bone remodeling and with adult gingival wound healing. MMP-13 is also known to be involved in the growth and invasion of various cancers including squamous cell carcinoma (SCC) of the skin. The aim of this study was to further elucidate the function and regulation of MMP-13 in wound repair and cancer. In this study, it was shown that fetal skin fibroblasts express MMP-13 in response to transforming growth factor-β in a p38 MAP kinase dependent manner. In addition, MMP-13 was found to be expressed in vivo by wound fibroblasts in human fetal skin grafted on SCID mice. Adenovirally delivered expression of MMP-13 enhanced collagen matrix contraction by fibroblasts in vitro in association with altered cytoskeletal structure, enhanced proliferation and survival. These results indicate that MMP-13 is involved in cell-mediated collagen matrix remodeling and suggest a role for MMP-13 in superior matrix remodeling and scarless healing of fetal skin wounds. Using an MMP-13 deficient mouse strain, it was shown that MMP-13 is essential for the normal development of experimental granulation tissue in mice. MMP-13 was implicated in the regulation of myofibroblast function and angiogenesis and the expression of genes involved in cellular proliferation and movement, immune response, angiogenesis and proteolysis. Finally, epidermal mitogen, keratinocyte growth factor (KGF) was shown to suppress the malignant properties of skin SCC cells by downregulating the expression of several target genes with potential cancer promoting properties, including MMP-13, and by reducing SCC cell invasion. These results provide evidence that MMP-13 potently regulates cell viability, myofibroblast function and angiogenesis associated with wound healing and cancer. In addition, fibroblasts expressing MMP-13 show high collagen reorganization capacity. Moreover, the results suggest that KGF mediates the anti-cancer effects on skin SCC

Sotilaslentäjän fyysinen suorituskyky sekä työperäiset tuki- ja liikuntaelinoireet

Kirjallisuudesta välittyy useitten vuosikymmenten ajalta tietämys sotilaslentämisen fyysisestä kuormittavuudesta. G-voimista aiheutuva kuormittuminen näyttää johtavan joko akuutisti tai pitkäaikaisesti lentäjän tuki- ja liikuntaelimistön toimintakykyä alentaviin ongelmiin. Erityisesti on selvitetty niskan alueen työperäisten ongelmien syntyä, jolloin on havaittu lentotoiminnan fyysisen kuormittavuuden johtavan ennenaikaiseen rakenteelliseen rappeumaan, haittaa aiheuttavan oireen lisäksi. Kansainvälisen kirjallisuuden mukaan ammatista johtuvista eli työperäisistä oireista kärsii vähintään 2/3 kaikista sotilaslentäjistä. Tietyin edellytyksin lentäjien kaularangan alueen rappeuma on Suomessa hyväksytty ammattitaudiksi vuodesta 1995 alkaen. On arveltu, että hyvästä fyysisestä suorituskyvystä olisi apua tuki- ja liikuntaelin (TULE)-oireilun ennaltaehkäisemisessä ja toimintakyvyn ylläpitämisessä. Tutkimusnäyttö tästä on lentäjien osalta ollut toistaiseksi erittäin niukkaa. Tämän tutkimuksen tavoitteena oli selvittää suomalaisten sotilaslentäjien työperäisen TULE-oireilun esiintyvyyttä, oireista koetun haitan tasoa, lentäjien fyysisen kunnon tasoja virkauran aikana ja näitten kaikkien välisiä yhteyksiä sekä työperäisen TULE-oireen merkitystä sotilaan toimintakykyyn. Tutkimus jakautui kahteen osaan. Poikkileikkauksena lentotoimintaperäisiä TULE-oireita kartoitettiin kyselytutkimuksella, johon vastasi vuositarkastuksen yhteydessä 267 lentäjää vuosina 2004-2005. Joukosta poimittiin ne 195 lentäjää, jotka olivat suorittaneet yleissotilaalliset kuntotestit puolen vuoden sisällä kyselyyn vastaamisesta, ja mitatut testitulokset yhdistettiin kyselytutkimusaineistoon. Tässä aineistossa toteutettiin fyysisesti erilailla kuormittuvien lentäjäryhmien välisiä vertailuja fyysisen kunnon, TULE-esiintyvyyden ja koetun haitan suhteen. Poikkileikkausosassa tutkittiin myös lentäjien virkauran aikaisia tasoeroja yleissotilaallisissa kuntotesteissä (n=195) verrattuna muihin suomalaisiin sotilaisiin. Lisäksi (N=289) selvitettiin ilmailulääketieteellisen tarkastuksen yhteydessä mitattuja, ns. ammatillisia fyysisiä erityisominaisuuksia eri ikäluokissa. Pitkittäisosassa seurattiin 67:n Hawk-suihkuharjoituskoneella aloittaneen Ilmavoimien sotilaslentäjien lentouran aikaista lentotoimintaperäisten TULE-oireitten esiintyvyyttä vuosien 1996 ja 2008 välillä. Lisäksi tutkittiin lentäjien kontakteja työterveyshuoltoon, oireen aiheuttamaa lentokelvottomuusaikaa, työn kuormituksen kumulatiivista kertymää lentotuntien lisääntyessä ja TULE-oireiden esiintyvyyden kannalta kriittisiä ajankohtia lentouran aikana. Tulokset osoittivat, että kaikki seurannassa olleet suomalaiset sotilaslentäjät kokivat jonkinasteisen lentotoimintaperäisen TULE-oireen uransa aikana. Niskan ammattitautiluokituksen tasoisen ongelman esiintyvyys oli 4 % koko lentäjäpopulaatiosta ja 10 % suihkuharjoituskonevaiheen jo läpäisseistä, mutta vastaavanlaisia TULE-ongelmia, ilman riittävää näyttöä ammattitaudista, esiintyi lähes joka kolmannella sotilaslentäjällä. Alaselän osalta lentäjät oireilivat lähes samassa määrin, mutta näitä oireita ei toistaiseksi ole mahdollista määrittää ammattitaudiksi. Lentäjät kävivät varsin vähän valittamassa oireistaan työterveyshuoltoon, jossa käytäneen vasta silloin, kun oire jo selvästi heikentää työtehtävissä vaadittavaa toimintakykyä. Merkittävin lentotoimintaperäisten oireitten esiintymisen kasvu ajoittui 200 Hawk-lentotunnin kohdalle, jolloin koneella saavutetaan eräänlainen optimaalinen G-indeksi eli taktisen liikehtelyn G-tasoylitysten vaihtelu. Tämän jälkeen lentäjät ovat erityisen alttiina akuuteille lennonaikaisille TULE-ongelmille. Oireitten esiintyminen kasvoi eksponentiaalisesti noin 600 lentotuntiin asti. Monimuuttujamallien mukaan työperäisen TULE-oireen esiintyvyysriskiä vähensivät alaraajojen hyvä motoriikka, korkeat valintapisteet ja korkea kaulan fleksion voimataso maksimaalisessa isometrisessä testissä. Yleissotilaallisilla kuntotasoilla ei ollut yhteyttä oireiluun, mutta lihaskunnoltaan voimakkaimmat lentäjät kärsivät tilastollisesti merkittävästi vähemmän haittaa lentotoimintaperäisistä TULE-oireistaan. Yleissotilaallisissa kuntotesteissä lentäjät olivat parempia kuin muut suomalaiset sotilaat. Aktiivisimman lentouran aikana, 30-40-vuotiaina, lentäjien fyysinen suorituskyky oli normaaliväestöön nähden vain keskimääräinen ja urheilijoihin nähden keskimääräistä heikompi. Käytännössä lentäjät eivät kyenneet ylläpitämään valintavaiheen fyysistä suorituskykyään edes kadettivaiheen loppuun asti. Huomattavaa oli lisäksi, että aktiivisen lentouran päätyttyä fyysinen kunto näytti jossain määrin palautuvan kohti lähtötasoa lentäjien ikääntymisestä huolimatta. Lentäjien valintavaiheen aikana mitatun fyysisen suorituskyvyn tason säilyminen aktiivisen lentopalveluksen loppuun asti vaatisi lentäjien fyysisen toimintakyvyn ylläpidon ja kehittämisen tehostamista koulutuksen ja työuran eri vaihessa. Tähän tavoitteeseen nähden Ilmavoimien fyysisen kasvatuksen järjestelyt vaikuttivat alimitoitetuilta. Operatiivisesti huolestuttavaa oli Ilmavoimien ohjaajien fyysisen suorituskyvyn heikentyminen silloin, kun heidän taitojensa puolesta olisi pitänyt olla suorituskykyisimpiä taistelutehtäviinsä. Myös lentäjän terveyttä ja toimintakykyä pitäisi pystyä reaaliaikaisemmin seuraamaan koko lentouran aikana. Ilmavoimille suositellaan moniammatillista lähestymistä sotilaslentäjien toimintakyvyn ylläpitämiseen ja terveysriskien hallintaan yhdessä liikunnan, työterveyshuollon, lentoturvallisuusalan ja operatiivisen suunnittelun asiantuntijoitten kanssa. Lisäksi suositellaan avoimempaa ja eettisesti kestävämpää suhtautumista ammattiin liittyvien terveysongelmien kuvaamiseen sekä fyysisen kunnon kysymyksiin jo lentäjien rekrytointivaiheessa.

Power cycling lifetime estimation of IGBT power modules based on chip temperature modeling

In this doctoral thesis, methods to estimate the expected power cycling life of power semiconductor modules based on chip temperature modeling are developed. Frequency converters operate under dynamic loads in most electric drives. The varying loads cause thermal expansion and contraction, which stresses the internal boundaries between the material layers in the power module. Eventually, the stress wears out the semiconductor modules. The wear-out cannot be detected by traditional temperature or current measurements inside the frequency converter. Therefore, it is important to develop a method to predict the end of the converter lifetime. The thesis concentrates on power-cycling-related failures of insulated gate bipolar transistors. Two types of power modules are discussed: a direct bonded copper (DBC) sandwich structure with and without a baseplate. Most common failure mechanisms are reviewed, and methods to improve the power cycling lifetime of the power modules are presented. Power cycling curves are determined for a module with a lead-free solder by accelerated power cycling tests. A lifetime model is selected and the parameters are updated based on the power cycling test results. According to the measurements, the factor of improvement in the power cycling lifetime of modern IGBT power modules is greater than 10 during the last decade. Also, it is noticed that a 10 C increase in the chip temperature cycle amplitude decreases the lifetime by 40%. A thermal model for the chip temperature estimation is developed. The model is based on power loss estimation of the chip from the output current of the frequency converter. The model is verified with a purpose-built test equipment, which allows simultaneous measurement and simulation of the chip temperature with an arbitrary load waveform. The measurement system is shown to be convenient for studying the thermal behavior of the chip. It is found that the thermal model has a 5 C accuracy in the temperature estimation. The temperature cycles that the power semiconductor chip has experienced are counted by the rainflow algorithm. The counted cycles are compared with the experimentally verified power cycling curves to estimate the life consumption based on the mission profile of the drive. The methods are validated by the lifetime estimation of a power module in a direct-driven wind turbine. The estimated lifetime of the IGBT power module in a direct-driven wind turbine is 15 000 years, if the turbine is located in south-eastern Finland.

Anatomical and functional characteristics of the pelvic floor in nulliparous women submitted to three-dimensional endovaginal ultrasonography: case control study and evaluation of interobserver agreement

PURPOSE: To determine anatomical and functional pelvic floor measurements performed with three-dimensional (3-D) endovaginal ultrasonography in asymptomatic nulliparous women without dysfunctions detected in previous dynamic 3-D anorectal ultrasonography (echo defecography) and to demonstrate the interobserver reliability of these measurements. METHODS: Asymptomatic nulliparous volunteers were submitted to echo defecography to identify dynamic dysfunctions, including anatomical (rectocele, intussusceptions, entero/sigmoidocele and perineal descent) and functional changes (non-relaxation or paradoxical contraction of the puborectalis muscle) in the posterior compartment and assessed with regard to the biometric index of levator hiatus, pubovisceral muscle thickness, urethral length, anorectal angle, anorectal junction position and bladder neck position with the 3-D endovaginal ultrasonography. All measurements were compared at rest and during the Valsalva maneuver, and perineal and bladder neck descent was determined. The level of interobserver agreement was evaluated for all measurements. RESULTS: A total of 34 volunteers were assessed by echo defecography and by 3-D endovaginal ultrasonography. Out of these, 20 subjects met the inclusion criteria. The 14 excluded subjects were found to have posterior dynamic dysfunctions. During the Valsalva maneuver, the hiatal area was significantly larger, the urethra was significantly shorter and the anorectal angle was greater. Measurements at rest and during the Valsalva maneuver differed significantly with regard to anorectal junction and bladder neck position. The mean values for normal perineal descent and bladder neck descent were 0.6 cm and 0.5 cm above the symphysis pubis, respectively. The intraclass correlation coefficient ranged from 0.62-0.93. CONCLUSIONS: Functional biometric indexes, normal perineal descent and bladder neck descent values were determined for young asymptomatic nulliparous women with the 3-D endovaginal ultrasonography. The method was found to be reliable to measure pelvic floor structures at rest and during Valsalva, and might therefore be suitable for identifying dysfunctions in symptomatic patients.

Muscarinic toxins : characterization of adrenoceptor binding and applicability of membrane anchoring via glycosylphosphatidylinositol tail

Adrenoceptors (ARs), G-protein coupled receptors (GPCRs) at the plasma membrane, respond to endogenous catecholamines noradrenaline and adrenaline. These receptors mediate several important physiological functions being especially important in the cardiovascular system and in the regulation of smooth muscle contraction. Impairments in the function of these receptors can thus lead to severe diseases and disorders such as to cardiovascular diseases and benign prostatic hyperplasia. The Eastern green mamba (Dendroaspis angusticeps) venom has been shown to contain toxins that can antagonize the functions of GPCRs. The most well-known are muscarinic toxins (MTs) targeting muscarinic acetylcholine receptors (mAChRs) with high affinity and selectivity. However, some reports have indicated that these toxins might also act on the α1- and α2-ARs which can be divided into various subtypes; the α1-ARs to α1A-, α1B- and α1D-ARs and α2-ARs to α2A-, α2B- and α2C-ARs. In this thesis, the interaction of four common MTs (MT1, MT3, MT7 and MTα) with the adrenoceptors was characterized. It was also evaluated whether these toxins could be anchored to the plasma membrane via glycosylphosphatidylinositol (GPI) tail. Results of this thesis reveal that muscarinic toxins are targeting several α-adrenoceptor subtypes in addition to their previously identified target receptors, mAChRs. MTα was found to interact with high affinity and selectivity with the α2B-AR whereas MT7 confirmed its selectivity for the M1 mAChR. Unlike MTα and MT7, MT1 and MT3 have a broad range of target receptors among the α-ARs. All the MTs characterized were found to behave as non-competitive antagonists of receptor action. The interaction between MTα and the α2B-AR was studied more closely and it was observed that the second extracellular loop of the receptor functions as a structural entity enabling toxin binding. The binding of MTα to the α2B-AR appears to be rather complex and probably involves dimerized receptor. Anchoring MTs to the plasma membrane did not interfere with their pharmacological profile; all the GPI-anchored toxins created retained their ability to block their target receptors. This thesis shows that muscarinic toxins are able to target several subtypes of α-ARs and mAChRs. These toxins offer thus a possibility to create new subtype specific ligands for the α-AR subtypes. Membrane anchored MTs on the other hand could be used to block α-AR and mAChR actions in disease conditions such as in hypertension and in gastrointestinal and urinary bladder disorders in a cell-specific manner and to study the physiological functions of ARs and mAChRs in vivo in model organisms.