The Regulation of Skeletal and Cardiac Muscle Blood Flow in Humans. Studies by positron emission tomography with special reference to exercise, adenosine and nitric oxide

Virtually every cell and organ in the human body is dependent on a proper oxygen supply. This is taken care of by the cardiovascular system that supplies tissues with oxygen precisely according to their metabolic needs. Physical exercise is one of the most demanding challenges the human circulatory system can face. During exercise skeletal muscle blood flow can easily increase some 20-fold and its proper distribution to and within muscles is of importance for optimal oxygen delivery. The local regulation of skeletal muscle blood flow during exercise remains little understood, but adenosine and nitric oxide may take part in this process. In addition to acute exercise, long-term vigorous physical conditioning also induces changes in the cardiovasculature, which leads to improved maximal physical performance. The changes are largely central, such as structural and functional changes in the heart. The function and reserve of the heart’s own vasculature can be studied by adenosine infusion, which according to animal studies evokes vasodilation via it’s a_2A receptors. This has, however, never been addressed in humans in vivo and also studies in endurance athletes have shown inconsistent results regarding the effects of sport training on myocardial blood flow. This study was performed on healthy young adults and endurance athletes and local skeletal and cardiac muscle blod flow was measured by positron emission tomography. In the heart, myocardial blood flow reserve and adenosine A_2A receptor density, and in skeletal muscle, oxygen extraction and consumption was also measured. The role of adenosine in the control of skeletal muscle blood flow during exercise, and its vasodilator effects, were addressed by infusing competitive inhibitors and adenosine into the femoral artery. The formation of skeletal muscle nitric oxide was also inhibited by a drug, with and without prostanoid blockade. As a result and conclusion, it can be said that skeletal muscle blood flow heterogeneity decreases with increasing exercise intensity most likely due to increased vascular unit recruitment, but exercise hyperemia is a very complex phenomenon that cannot be mimicked by pharmacological infusions, and no single regulator factor (e.g. adenosine or nitric oxide) accounts for a significant part of exercise-induced muscle hyperemia. However, in the present study it was observed for the first time in humans that nitric oxide is not only important regulator of the basal level of muscle blood flow, but also oxygen consumption, and together with prostanoids affects muscle blood flow and oxygen consumption during exercise. Finally, even vigorous endurance training does not seem to lead to supranormal myocardial blood flow reserve, and also other receptors than A_2A mediate the vasodilator effects of adenosine. In respect to cardiac work, atheletes heart seems to be luxuriously perfused at rest, which may result from reduced oxygen extraction or impaired efficiency due to pronouncedly enhanced myocardial mass developed to excel in strenuous exercise.

Past, present and future - assessing changes in aquatic environments using subfossil diatoms

The deterioration of surface waters is one of the most important issues in the environmental management of the European Union. Thus, the EU Water Framework Directive 2000/60/EC (WFD) requires “good ecological and chemical status” of surface waters by 2015 allowing only a slight departure from ecological reference conditions characterized by the biological communities typical for the conditions of minimal anthropogenic impact. The WFD requires the determination of ecological reference conditions and the present ecological status of surface waters. To meet this legislative demand, sedimentary diatom assemblages were used in these studies with various methods 1) to assess natural and human activity induced environmental changes, 2) to characterize background conditions 3) to evaluate the present ecological status and 4) to predict the future of the water bodies in the light of palaeolimnological data. As the WFD refers to all surface waters, both coastal and inland sites were included. Two long and two short sediment cores from the Archipelago Sea in the northern Baltic Sea were examined for their siliceous microfossils in order to assess (1) the Holocene palaeoenvironmental history and (2) the recent eutrophication of the area. The diatom record was divided into local diatom assemblage zones (LDAZ, long cores) and diatom assemblage zones (DAZ, short cores). Locally weighted weighted averaging regression and calibration (LWWA) was applied for the quantitative reconstruction of past TN concentrations (short cores). An age model for the long cores was constructed by using independent palaeomagnetic and AMS-14C methods. The short cores were dated using radiometric (210Pb, 226Ra and 137Cs) methods. The long cores date back to the early history of the Archipelago Sea, which was freshwater – no salinity increase referable to the brackish phase of the Yoldia Sea is recognized. The nutrient status of the lacustrine phase was slightly higher in the Archipelago Sea than in the Baltic Proper. Initial brackish-water influence is observed at 8 150 ±80 cal. BP (LDAZ4), but fully brackish conditions were established at 7 700 ±80 cal. BP (LDAZ5). The diatom assemblages indicate increasing salinity, warming climate and possible eutrophic conditions during the lacustrine to brackish-water transition. The decreasing abundance of Pseudosolenia calcar-avis (Schultze) Sundström and the increasing abundance of the ice-cover indicator species Pauliella taeniata (Grunow) Round and Basson indicate decreasing salinity and climatic cooling after ca. 5 000 cal. BP. Signs of eutrophication are visible in the most recent diatom assemblage zones of both short cores. Diatom-inferred total nitrogen (DI-TN) reconstructions partially fail to trace the actual measured total nitrogen concentrations especially from the late 1980s to the mid 1990s. This is most likely due to the dominating diatom species Pauliella taeniata, Thalassiosira levanderi Van Goor and Fragilariopsis cylindrus (Grunow) W. Krieger being more influenced by factors such as the length of the ice-season rather than nutrient concentrations. It is concluded that the diatom assemblages of the study sites are principally governed by climate fluctuations, with a slight influence of eutrophication visible in the most recent sediments. There are indications that global warming, with reduced ice cover, could impact the spring blooming diatom species composition in the Archipelago Sea. In addition, increased sediment accumulation in the early 90s coincides with the short ice-seasons suggesting that warming climate with decreasing ice-cover may increase sedimentation in the study area. The diverse diatom assemblages dominated by benthic species (54 %) in DAZ1 in the Käldö Fjärd core can be taken as background diatom assemblages for the Archipelago Sea. Since then turbidity has increased and the diatom assemblages have been dominated by planktonic diatoms from around the mid 1800s onwards. The reconstructed reference conditions for the total nitrogen concentrations fluctuate around 400 μg l-1. Altogether two short sediment cores and eight short cores for top-bottom analysis were retrieved from Lake Orijärvi and Lake Määrjärvi to assess the impact of the acid mine drainage (AMD) derived metals from the Orijärvi mine tailings on the diatom communities of the lakes. The Cu (Pb, Zn) mine of Orijärvi (1757 – 1956) was the first one in Finland where flotation techniques (1911 – 1955) were used to enrich ore and large quantities of tailings were produced. The AMD derived metal impact to the lakes was found to be among the heaviest thus far recorded in Finland. Concentrations of Cu, Pb and Zn in Lake Orijärvi sediments are two to three orders of magnitude higher than background values. The metal inputs have affected Lake Orijärvi and Lake Määrjärvi diatom communities at the community levels through shifts in dominant taxa (both lakes) and at the individual level through alteration in frustule morphology (Lake Orijärvi). At present, lake water still has elevated heavy metal levels, indicating that the impact from the tailings area continues to affect both lakes. Lake Orijärvi diatom assemblages are completely dominated by benthic species and are lacking planktonic diatoms. In Lake Määrjärvi the proportion of benthic and tychoplanktonic diatoms has increased and the planktonic taxa have decreased in abundance. Achnanthidium minutissimum Kützing and Brachysira vitrea (Grun.) R. Ross in Hartley were the most tolerant species to increased metal concentrations. Planktonic diatoms are more sensitive to metal contamination than benthic taxa, especially species in the genus Cyclotella (Kützing) Brébisson. The ecological reference conditions assessed in this study for Lake Orijärvi and Lake Määrjärvi comprise diverse planktonic and benthic communitites typical of circumneutral oligotrophic lakes, where the planktonic diatoms belonging to genera Cyclotella , Aulacoseira Thwaites, Tabellaria Ehrenberg and Asterionella Hassall dominate in relative abundances up to ca. 70%. The benthic communities are more diverse than the planktonic consisting of diatoms belonging to the genera Achnanthes Bory, Fragilaria Lyngbye and Navicula St. Vincent. This study clearly demonstrates that palaeolimnological methods, especially diatom analysis, provide a powerful tool for the EU Water Frame Work Directive for defining reference conditions, natural variability and current status of surface waters. The top/bottom approach is a very useful tool in larger-scale studies needed for management purposes. This “before and after” type of sediment sampling method can provide a very time and cost effective assessment of ecological reference conditions of surface waters.

Design of an adsorbent employing activated carbon fiber to remove lead

Zorflex® activated carbon fibers (ACF), reference FM100 198B, are used before and after an oxidizing procedure with H3PO4 to study the adsorption of Pb2+. The point of zero charge was determined for the modified and unmodified fiber giving values of 2.3 and 4.3, respectively. After oxidizing the ACF, the fiber showed to have a greater Pb2+ adsorption capacity in comparison with the unmodified fiber, which is related with the acid sites increase, where lead was mainly adsorbed. Determination of the BET area was carried out by nitrogen physisorption at 77K. ACFs presented superficial areas between 1000 and 1500 m²/g showing mostly, a microporous structure. The preliminary design of an adsorbent using the modified fiber is presented where the fiber superior physicochemical properties over the unmodified one are observed.

Elemental analysis of wood materials by external millibeam thick target PIXE

PIXE (Particle Induce X-ray Emission spectrometry) was used for analysing stem bark and stem wood of Scots pine, Norway spruce and Silver birch. Thick samples were irradiated, in laboratory atmosphere, with 3 MeV protons and the beam current was measured indirectly using a photo multiplicator (PM) tube. Both point scans and bulk analyses were performed with the 1 mm diameter proton beam. In bulk analyses, whole bark and sectors of discs of the stem wood were dry ashed at 550 ˚C. The ashes were homogenised by shaking and prepared to target pellets for PIXE analyses. This procedure generated representative samples to be analysed, but the enrichment also enabled quantification of some additional trace elements. The ash contents obtained as a product of the sample preparation procedure also showed to be of great importance in the evaluation of results in environmental studies. Spot scans from the pith of pine wood outwards, showed clearly highest concentrations of manganese, calcium and zinc in the first spot irradiated, or 2-3 times higher than in the surrounding wood. For stem wood from the crown part of a pine this higher concentration level was found in the first four spots/mms, including the pith and the two following growth rings. Zinc showed increasing concentrations outwards in sapwood of the pine stem, with the over-all lowest concentrations in the inner half of the sapwood. This could indicate emigration of this element from sapwood being under transformation to heartwood. Point scans across sapwood of pine and spruce showed more distinct variations in concentrations relative to hearth wood. Higher concentrations of e.g. zinc, calcium and manganese were found in earlywood than in denser latewood. Very high concentrations of iron and copper were also seen for some earlywood increments. The ash content of stem bark is up to and order higher than for the stem wood. However, when the elemental concentration in ashes of bark and wood of the same disc were compared, these are very similar – this when trees are growing at spots with no anthropogenic contamination from the atmosphere. The largest difference was obtained for calcium which appeared at two times high concentrations in ashes of bark than in ashes of the wood (ratio of 2). Pine bark is often used in monitoring of atmospheric pollution, where concentrations in bark samples are compared. Here an alternative approach is suggested: Bark and the underlying stem wood of a pine trees are dry ashed and analysed. The elemental concentration in the bark ash is then compared to the concentration of the same element in the wood ash. Comparing bark to wood includes a normalisation for the varying availability of an element from the soil at different sites. When this comparison is done for the ashes of the materials, a normalisation is also obtained for the general and locally different enrichment of inorganic elements from wood to bark. Already a ratio >2 between the concentration in the bark ash and the concentration in the wood ash could indicate atmospheric pollution. For monitoring where bark is used, this way of “inwards” comparison is suggested - instead of comparing to results from analyses of bark from other trees (read reference areas), growing at sites with different soil and, locally, different climate conditions. This approach also enables evaluation of atmospheric pollution from sampling of only relative few individual trees –preferable during forest felling.

Fibroblast Growth Factor 8 and its Receptors in The Growth and Angiogenesis of Experimental Breast Cancer . With Special Reference to Thrombospondin-1 as a Novel Target Gene for FGF-8

The growth of breast cancer is regulated by hormones and growth factors. Recently, aberrant fibroblast growth factor (FGF) signalling has been strongly implicated in promoting the progression of breast cancer and is thought to have a role in the development of endocrine resistant disease. FGFs mediate their auto- and paracrine signals through binding to FGF receptors 1-4 (FGFR1-4) and their isoforms. Specific targets of FGFs in breast cancer cells and the differential role of FGFRs, however, are poorly described. FGF-8 is expressed at elevated levels in breast cancer, and it has been shown to act as an angiogenic, growth promoting factor in experimental models of breast cancer. Furthermore, it plays an important role in mediating androgen effects in prostate cancer and in some breast cancer cell lines. We aimed to study testosterone (Te) and FGF-8 regulated genes in Shionogi 115 (S115) breast cancer cells, characterise FGF-8 activated intracellular signalling pathways and clarify the role of FGFR1, -2 and -3 in these cells. Thrombospondin-1 (TSP-1), an endogenous inhibitor of angiogenesis, was recognised as a Te and FGF-8 regulated gene. Te repression of TSP-1 was androgen receptor (AR)-dependent. It required de novo protein synthesis, but it was independent of FGF-8 expression. FGF-8, in turn, downregulated TSP-1 transcription by activating the ERK and PI3K pathways, and the effect could be reversed by specific kinase inhibitors. Differential FGFR1-3 action was studied by silencing each receptor by shRNA expression in S115 cells. FGFR1 expression was a prerequisite for the growth of S115 tumours, whereas FGFR2 expression alone was not able to promote tumour growth. High FGFR1 expression led to a growth advantage that was associated with strong ERK activation, increased angiogenesis and reduced apoptosis, and all of these effects could be reversed by an FGFR inhibitor. Taken together, the results of this thesis show that FGF-8 and FGFRs contribute strongly to the regulation of the growth and angiogenesis of experimental breast cancer and support the evidence for FGF-FGFR signalling as one of the major players in breast cancers.

Singular Reference Without Singular Thought

Abstract In this paper I challenge the widespread assumption that the conditions for singular reference are more or less the same as the conditions for singular thought. I claim that we refer singularly to things without thinking singularly about them more often than it is usually believed. I first argue that we should take the idea that singular thought is non-descriptive thought very seriously. If we do that, it seems that we cannot be so liberal about what counts as acquaintance; only perception (and memory) will do. I also briefly discuss and reject semantic instrumentalism. Finally, I argue that while singular reference is cheap, singular thought comes only at a price.

Customer reference marketing and utilization of social media as an integral part of customer references

The objective of this Bachelor's Thesis is to find out the role of social media in the B-to-B marketing environment of the information technology industry and to discover how IT-firms utilize social media as a part of their customer reference marketing. To reach the objectives the concepts of customer reference marketing and social media are determined. Customer reference marketing can be characterized as one of the most practically relevant but academically relatively overlooked ways in which a company can leverage its customers and delivered solutions and use them as references in its marketing activities. We will cover which external and internal functions customer references have, that contribute to the growth and performance of B-to-B firms. We also address the three mechanisms of customer reference marketing which are 'status transfer', 'validation through testimonials' and 'demonstration of experience and prior performance'. The concept of social media stands for social interaction and creation of user-based content which exclusively occurs through Internet. The social media are excellent tools for networking because of the fast and easy access, easy interaction and vast amount of multimedia attributes. The allocation of social media is determined. The case company helps clarify the specific characteristics of social media usage as part of customer-reference-marketing activities. For IT-firms the best channels to utilize social media in their customer reference marketing activities are publishing and distribution services of content and networking services.

Segregation of powder mixtures in silos with particular reference to dry mineral-based construction materials

Segregering eller segregation är ett fenomen som kan förekomma inom olika områden av samhället. Inom samhällsvetenskaperna kan segregering definieras som det rumsliga åtskiljandet av befolkningsgrupper på urval av ras eller etniskt ursprung, kön, social härkomst, religion, ålder, yrke, osv. Segregering av befolkningsgrupper sker ofta mer eller mindre frivilligt och är motsatsen till integration. Inom partikelteknologi definieras segregering oftast som det rumsliga åtskiljandet av beståndsdelarna i en blandning av olika partiklar. Segregering sker då på urval av bl.a. partiklarnas storlek, densitet, form, elektrostatiska eller mekaniska egenskaper, och kan beskrivas som motsatsen till blandning. Segregeringsmekanismer används för att förklara hur och varför en partikelblandning segregerar samt vad slutresultatet i form av den rumsliga fördelningen av partiklarna blir till följd av att blandningen utsetts för en viss behandling. I denna avhandling har segregering av partikelblandningar och speciellt torra mineralbaserade byggmaterial (t.ex. murbruk) till följd av lagring i siloer studerats. Vid industriell produktion av mineralbaserade byggmaterial används siloer för korttidslagring av slutprodukterna precis innan förpackning. Segregering leder till kraftiga variationer i sammansättningen för partikelströmmen ut ur silon, vilket gör att slutprodukterna inte uppfyller kvalitetskraven och kan därmed inte säljas till kunder. Detta leder till arbetsam och dyr bearbetning (återcirkulation) av produkterna med påföljder för produktionsekonomin samt hållbara utvecklingen. I avhandlingen identifierades de väsentligaste segregeringsmekanismerna för torra mineralbaserade byggmaterial i siloer. Dessutom klargjordes effekterna av materialegenskaper, processbetingelser och siloparametrar. Slutligen behandlas möjliga åtgärder för minskning av partikelsegregering i siloer samt tillämpning av matematiska metoder för simulering av partikelflöden med hjälp av datorer.

Factors Affecting Cancer Behavior with Special Reference to Lymphatic Vessels, Macrophages, EGFR, and Pim-1 in Colorectal Cancer

Syövän käyttäytymiseen ja ennusteeseen vaikuttavat monet tekijät, muun muassa muutokset syöpäsoluissa sekä kasvainta ympäröivässä mikroympäristössä. Tutkimuksen tavoitteena oli tutkia uusia prediktiivisiä ja prognostisia ennustetekijöitä syöpäsoluissa (EGFR geenikopiomäärä, EGFR, onkogeeni pim-1) sekä syöpäkasvaimen mikroympäristöön kuuluvissa imuteissä (CLEVER-1, podoplaniini), makrofageissa (CD68, CLEVER-1) ja T lymfosyyteissä (CD3) kolorektaalisyövässä. Lisäksi tutkittiin imuteiden molekulaarisia ominaisuuksia tarkemmin (CD73, LYVE-1, podoplaniini) kuten myös lymfosyyttien ja dendriittisolujen liikennöintiä imuteissä. Tutkimustulokset osoittavat että korkea Pim-1 ekspressiotaso, suuri peritumoraalinen CD68+ makrofagimäärä sekä varhaisen vaiheen taudissa suuri CLEVER-1+ peritumoraalinen makrofagimäärä ovat hyvän ennusteen tekijöitä kolorektaalisyövässä. Metastaattisessa taudissa sen sijaan suuri määrä CLEVER-1+ makrofageja, sekä intra- että peritumoraalisesti, liittyy huonoon tautiennusteeseen. EGFR geenikopiomäärä, EGFR proteiinipitoisuuden ohjaaman hopea in situ hybridisaatiomenetelmän avulla määritettynä, ennusti vastetta anti-EGFR hoidolle metastaattisessa kolorektaalisyövässä tarkemmin kuin nykyisin rutiinisti käytössä oleva KRAS määritys. Lisäksi havaittiin että imutiet ovat monimuotoisia imutiemarkkeri ekspressionsa suhteen sekä normaali- että syöpäkudoksissa. CD73 molekyylin funktio imuteissä poikkesi selvästi molekyylin funktiosta verisuonissa. Yhteenvetona voidaan todeta että kolorektaalisyövän ennusteeseen vaikuttavien tekijöiden merkitys vaihtelee taudin levinneisyysasteen sekä imuteiden että makrofagien sijainnin perusteella. Korkea Pim-1 ilmentyminen on yhteydessä hyvään kolorektaalisyöpäennusteeseen. Lisäksi EGFR geenikopiomäärä osoittautui lupaavaksi uudeksi prediktiiviseksi ennustetekijäksi KRAS villintyypin metastaattista kolorektaalisyöpää sairastavilla potilailla.

Marketing in the pre-development process of agricultural machines: a reference model

The theme of the research is the development of the domain of marketing knowledge in the design of agricultural machinery. It is developed throughout the design of agricultural machinery in order to identify the corporate and customers needs and to develop strategies to satisfy these needs. The central problem of the research questions which marketing tools to apply on pre-development process of farm machinery, in order to increase the market value of the products and of the company and, consequently, generate competitive advantage to the manufacturers of agricultural machinery. As methodology, it was developed bibliographical research and multicase study of the development process of agricultural machinery developed by small, medium and large companies and the academy. As a result, a marketing reference model was elaborated for the pre-development stage of agricultural machinery, which outlines the activities, tasks, mechanisms and controls that can be used in strategic planning and in products planning of agricultural machinery manufacturers, contributing to explain the explicit knowledge in the marketing field.

Evaluation of empirical methods to estimate reference evapotranspiration in Uberaba, State of Minas Gerais, Brazil

Evapotranspiration is the process of water loss of vegetated soil due to evaporation and transpiration, and it may be estimated by various empirical methods. This study had the objective to carry out the evaluation of the performance of the following methods: Blaney-Criddle, Jensen-Haise, Linacre, Solar Radiation, Hargreaves-Samani, Makkink, Thornthwaite, Camargo, Priestley-Taylor and Original Penman in the estimation of the potential evapotranspiration when compared to the Penman-Monteith standard method (FAO56) to the climatic conditions of Uberaba, state of Minas Gerais, Brazil. A set of 21 years monthly data (1990 to 2010) was used, working with the climatic elements: temperature, relative humidity, wind speed and insolation. The empirical methods to estimate reference evapotranspiration were compared with the standard method using linear regression, simple statistical analysis, Willmott agreement index (d) and performance index (c). The methods Makkink and Camargo showed the best performance, with "c" values ​​of 0.75 and 0.66, respectively. The Hargreaves-Samani method presented a better linear relation with the standard method, with a correlation coefficient (r) of 0.88.

Impact of the substitution of reference annual streamflow by monthly streamflow on the potential use of water resources

The consideration of the streamflow seasonality has a high potential to improve the water use. In order to give subsidies to the optimization of water use, it was evaluated the impact of the change of reference annual streamflow by the monthly streamflows in the potential water use throughout the hydrography of Paracatu sub-Basin. It was evaluated the impact on Q7,10 (lowest average streamflow during a 7-day period with an average recurrence of 10 years) and on Q95 (permanent flow present 95% of the time). The use of monthly streamflow to substitute the annual streamflow had a high potential of improvement of water resources use in the sub-Basin studied. The use of monthly Q 7,10 in substitution of annual Q 7,10 increases the potential water use that vary from about 10% in the months of lower water availability to values exceeding 200% in the months with higher availability of surface water resources. The use of monthly Q95 in substitution of the annual Q95 implies in changes oscillating from reduction of 37% in months of higher water restriction to values exceeding 100% in the months of higher availability, so the use of monthly Q95 instead of the annual Q95 enables the more rational and safe use of water resources.