Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability

In recent years, mGlu4 has received great attention and research effort because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric modulators of mGlu4 have been developed. To better understand the role of mGlu4 in healthy and disease conditions, we are interested in developing an mGlu4 selective radioligand for in vivo studies. Thus, we had synthesized and studied [(11)C]2 as a PET tracer for mGlu4, which demonstrated some promising features as a PET radioligand as well as the limitation need to be improved. In order to develop an mGlu4 ligand with enhanced affinity and improved metabolic stability, we have modified, synthesized and evaluated a series of new N-phenylpicolinamide derivatives. The SAR study has discovered a number of compounds with low nM affinity to mGlu4. The dideuteriumfluoromethoxy modified compound 24 is identified as a very promising mGlu4 ligand, which has demonstrated enhanced affinity, improved in vitro microsomal stability, good selectivity and good permeability

Aivoinfarkti ja TIA : KÄYPÄ HOITO -SUOSITUS (Päivitystiivistelmä)

Teema : Akuuttilääketiede. Käypä hoito -suositus. Päivitystiivistelmä. English summar

Improved synthesis of [18F] fallypride and characterization of a Huntington’s disease mouse model, zQ175DN KI, using longitudinal PET imaging of D2/D3 receptors

Dopamine receptors are involved in pathophysiology of neuropsychiatric diseases, including Huntington’s disease (HD). PET imaging of dopamine D2 receptors (D2R) in HD patients has demonstrated 40% decrease in D2R binding in striatum, and D2R could be a reliable quantitative target to monitor disease progression. A D2/3R antagonist, [18F] fallypride, is a high-affinity radioligand that has been clinically used to study receptor density and occupancy in neuropsychiatric disorders. Here we report an improved synthesis method for [18F]fallypride. In addition, high molar activity of the ligand has allowed us to apply PET imaging to characterize D2/D3 receptor density in striatum of the recently developed zQ175DN knock-in (KI) mouse model of HD.Peer reviewe

AAV2-VEGF-B gene therapy failed to induce angiogenesis in ischemic porcine myocardium due to inflammatory responses

Therapeutic angiogenesis induced by gene therapy is a promising approach to treat patients suffering from severe coronary artery disease. In small experimental animals, adeno-associated viruses (AAVs) have shown good transduction efficacy and long-term transgene expression in heart muscle and other tissues. However, it has been difficult to achieve cardiac-specific angiogenic effects with AAV vectors. We tested the hypothesis whether AAV2 gene transfer (1 x 10(13) vg) of vascular endothelial growth factor B (VEGF-B186) together with immunosuppressive corticosteroid treatment can induce long-term cardiac-specific therapeutic effects in the porcine ischemic heart. Gene transfers were delivered percutaneously using direct intramyocardial injections, improving targeting and avoiding direct contact with blood, thus reducing the likelihood of immediate immune reactions. After 1- and 6-month time points, the capillary area was analyzed, myocardial perfusion reserve (MPR) was measured with radiowater positron emission tomography ([O-15]H2O-PET), and fluorodeoxyglucose ([F-18]FDG) uptake was used to evaluate myocardial viability. Clinical chemistry and immune responses were analyzed using standard methods. After 1- and 6-month follow-up, AAV2-VEGF-B186 gene transfer failed to induce angiogenesis and improve myocardial perfusion and viability. Here, we show that inflammatory responses attenuated the therapeutic effect of AAV2 gene transfer by significantly reducing successful transduction and long-term gene expression despite the efforts to reduce the likelihood of immune reactions and the use of targeted local gene transfer methods.</p

Sinkkipadan vaihto : Esimerkkinä Caverion Industria Oy Ylivieskan tehdas

Opinnäytetyöni aiheena oli suunnitella ja toteuttaa noin kymmenen vuoden välein toistettava sinkkipadan vaihto Caverion Industria Oy:n Ylivieskan tehtaalle. Työ oli hyvin ajankohtainen, koska sinkkipata oli vaihdettu tehtaalle viimeksi vuonna 2007 ja padan vaihto alkoi olla ajankohtainen. Tässä työssä tarkastellaan padanvaihtoprosessi padan vaihdon suunnittelusta sinkitysprosessin aloitukseen asti. Työn tarkoituksena on myös tuottaa dokumentoitu malli myöhempiä vaihtokertoja varten ja koota siihen mukana olleiden henkilöiden ”hiljaista tietoa”. Työn julkinen osuus palvelee laajemminkin alan yrityksiä ja Kuumasinkitysyhdistystä. Työssä esitetty aikataulu on esitetty tarkoituksellisesti hyvin pienellä fontilla ja sillä on tarkoitus esittää koko vaihtoprosessin aikajännettä.The objective of this thesis was to design and accomplish the changing of the galvanizing kettle that is to be carried out approximately every ten years at the Caverion Industria Oy Ylivieska factory. The subject of the thesis was an actual issue because the last kettle had been changed in 2007 and the changing of the kettle began to be timely. In this thesis the changing of the galvanizing kettle process from the planning of the change to the beginning of the galvanizing process is examined. The purpose of the thesis is also to produce a documented model for the future for subsequent change times and collect the “silent knowledge” of the people involved. The public part of the thesis serves companies in the sector and hot dip galvanizing association. The schedule shown in this work are shown intentionally in a very small font and it has to be presented throughout the switching process time span

Valkuaisvajaus ja tuontivalkuaisen korvaaminen kotimaisella valkuaisella lypsylehmien ruokinnassa

vokKirjasto Aj-

Effect of full-fat rapeseed on digestibility and rumen fermentation in cattle

Julkaisussa on vanha ISSN 0024-8835.vokkirjasto Aj-KRypsinsiemenen vaikutus rehun sulavuuteen ja pötsifermentaatioon märehtijäll

Effect of full-fat rapeseed on digestibility and rumen fermentation in cattle

The effect of whole crushed rapeseed on ration digestibility was determined with three bulls, average live weight 155 kg, and the effect on rumen fermentation with a heifer fitted with a rumen fistula. The basal diet (B) contained 50 % of grass silage and 50 % of rolled barley of total DM. In experimental diets 30 % of barley was replaced with crushed rapeseed fed either untreated (URS) or treated with 1.2% of Gasol solution (GRS). The feeding level was 80 g DM/kg W0.75 for the bulls and 60 g DM/kg W0.75 for the heifer. The average digestibilities of the diets were 73.9 (B), 71.6 (URS) and 72.7 % (GRS) for organic matter. There were no significant differences in apparent digestibility of crude protein or crude fibre. The digestibility of ether extract was higher (P < 0.05) and that of NFE lower (P < 0.01) on rapeseed diets. Nitrogen retentions were 28.4, 30.9 and 33.7 g/d, respectively, for the three treatments. On rapeseed diets the rumen pH was higher (P < 0.05) and the total VFA and ammonia N concentration lower (P < 0.01, P < 0.05) than on control diet. Rapeseed increased the proportion of propionic acid (P < 0.01) and decreased the proportion of butyric acid (P < 0.01) in rumen VFA. The rate of degradation of DM and CP in the rumen was slower for Gasol-treated rapeseed than for untreated rapeseed. Rapeseeds did not have a negative effect on the rate of degradation of silage or hay in the rumen determined by nylon bag method. But replacement of barley with rapeseed tended to decrease the degradation rate of silage crude protein. There were no significant differences between the treatments in blood constituents

Rypsinsiemenen vaikutus rehun sulavuuteen ja pötsifermentaatioon märehtijällä

The effect of whole crushed rapeseed on ration digestibility was determined with three bulls, average live weight 155 kg, and the effect on rumen fermentation with a heifer fitted with a rumen fistula. The basal diet (B) contained 50 % of grass silage and 50 % of rolled barley of total DM. In experimental diets 30 % of barley was replaced with crushed rapeseed fed either untreated (URS) or treated with 1.2% of Gasol solution (GRS). The feeding level was 80 g DM/kg W0.75 for the bulls and 60 g DM/kg W0.75 for the heifer. The average digestibilities of the diets were 73.9 (B), 71.6 (URS) and 72.7 % (GRS) for organic matter. There were no significant differences in apparent digestibility of crude protein or crude fibre. The digestibility of ether extract was higher (P < 0.05) and that of NFE lower (P < 0.01) on rapeseed diets. Nitrogen retentions were 28.4, 30.9 and 33.7 g/d, respectively, for the three treatments. On rapeseed diets the rumen pH was higher (P < 0.05) and the total VFA and ammonia N concentration lower (P < 0.01, P < 0.05) than on control diet. Rapeseed increased the proportion of propionic acid (P < 0.01) and decreased the proportion of butyric acid (P < 0.01) in rumen VFA. The rate of degradation of DM and CP in the rumen was slower for Gasol-treated rapeseed than for untreated rapeseed. Rapeseeds did not have a negative effect on the rate of degradation of silage or hay in the rumen determined by nylon bag method. But replacement of barley with rapeseed tended to decrease the degradation rate of silage crude protein. There were no significant differences between the treatments in blood constituents.Murskatun rypsinsiemenen vaikutusta rehuannoksen sulavuuteen tutkittiin kolmella sonnilla, joiden elopaino oli keskimäärin 155 kg, ja pötsifermentaatioon fistelöidyllä hieholla. Perusdieetti (I) koostui 50 %:sta nurmisäilörehua ja 50 %:sta ohraa kuiva-aineesta. Koedieeteissä 30 % ohran kuiva-aineesta korvattiin murskatulla rypsinsiemenellä, joka annettiin joko käsittelemättömänä (II) tai käsiteltynä 1.2 %:lla Gasol-liuosta (III). Ruokintataso oli sonneilla 80 g ka/kg W0.75 ja hieholla 60 g ka/kg W0.75. Rehuannoksen orgaanisen aineen sulavuus oli 73.9 71.6 ja 72.7 % ruokinnoilla I, II ja III. Raakavalkuaisen ja-kuidun näennäisessä sulavuudessa ei ollut eroa ruokintojen välillä. Raakarasvan sulavuus oli parempi (P < 0.05) ja typettömien uuteaineiden huonompi (P < 0.01) rypsinsiementä sisältävillä ruokinnoilla. Typpitase oli ruokinnoilla I, II ja III 28.4, 30.9, ja 33.9 g/pv. Perusdieetillä pötsinesteen pH oli alempi (P < 0.05), VFA:n kokonaismäärä ja ammoniakkipitoisuus korkeampi (

Rypsirouhe ja Gasol-käsitelty ohra lihanaudoilla vapaalla säilörehuruokinnalla

Grass silage was offered ad libitum to 16 Ayrshire cattle in a 2 x 2 factorial experiment lasting 196 days. The silage was supplemented with barley preserved with 0.85 % of propionic acid (PAB) or 1.28 % Gasol solution (GB) 45 g DM/kg W0.75. Four of the animals in PAB and GB groups received no protein supplement(NPS) and four of the animals in both groups received extracted rapeseed meal as protein supplement(RSM). RSM was fed according to UDP (undegradable feed protein) requirements. The average age of the animals at the beginning of the experiment was 86 days and the average liveweight 106 kg. The average daily gains were 1066 and 1070 g/d for PAB and GB groups and 1012 and 1124 g/d (P < 0.01) for NPS and RSM groups. In feed intake and feed conversion there were no significant differences between the groups. Supplementation of silage barley diet with RSM increased the digestibility of organic matter from 71.1 to 73.5 % (P < 0.05), of crude protein from 62.8 to 67.4 % (P < 0.05) and of crude fibre from 57.2 to 60.2 % (P < 0.05). Both barleys were well preserved and there was no deterioration during the storage. The degradation rates of DM, crude protein and starch determined by nylon bag method were lower in GB than in PAB. Crude protein disappearances in 9 hours were 46.6 % for GB and 76.4 % for PAB. The utilization of absorbed protein calculated by factorial method averaged 0.566 ± 0.01 in the four different groups. Plasma urea N level was higher (P < 0.05) in the RSM than in the NPS group. The proportion of acetic acid in the rumen VFA was lower (P < 0.05) and that of propionic acid higher (P < 0.01) in the RSM than in the NPS group. PAB resulted in a higher (P < 0.05) proportion of propionic acid in rumen VFA than did GB.Rypsirouheen ja ohran suojauskäsittelyn vaikutusta vapaalla säilörehuruokinnalla tutkittiin 16 Ay-vasikalla 196 päivää kestäneessä ruokintakokeessa. Koe tehtiin 2x2 faktorikokeena, jossa faktoreina olivat viljan käsittely ja valkuaistäydennys. Ohran säilöntäaineena käytettiin joko 0.85 % propionihappoa (P) tai 1.28 % Gasol-liuosta (G). Ohra-annos oli 45 g kuiva-ainetta/kg W0.75. Puolet sekä P- että G-ryhmän eläimistä sai valkuaistäydennyksenä rypsirouhetta (R) UDP-tarpeen (pötsissä hajoamaton rehuvalkuainen) mukaan, puolet ei saanut valkuaistäydennystä (0). Koe-eläinten keskimääräinen elopaino kokeen alussa oli 106 kg ja ikä 86 pv. Lisäkasvu oli 1066 ja 1070 g/pv ja P- ja G-ryhmällä sekä 1012 ja 1124 g/pv (P < 0.01) 0- ja R-ryhmällä. Vastaavat rehunkulutukset kasvukiloa kohti olivat 3.77, 3.64, 3.75 ja 3.66 ry. Rehun syöntiin rypsirouheella ei ollut vaikutusta. Rypsirouhe paransi merkitsevästi (P < 0.05) orgaanisen aineen, raakavalkuaisen ja raakakuidun sulavuutta. Sulavuudet olivat R-ruokinnalla 73.5, 67.4 ja 60.2 % sekä 0-ruokinnalla 71.1, 62.8 ja 57.2 %. Laadultaan säilötyt viljat olivat hyviä. Gasolilla säilötyssä ohrassa vesiliukoisen typen osuus oli alempi ja nailonpussimenetelmällä määritetty raakavalkuaishävikki oli 9 tunnissa 46.6 % vastaavan hävikin ollessa P-ohralla 76.4 %. Samoin Gasol-käsittely vähensi kuiva-aineen ja tärkkelyksen hajoamisnopeutta pötsissä. Imeytyneiden aminohappojen hyväksikäyttö oli faktoriaalisti laskettuna eri ruokinnoilla 0.566 ± 0.010. Plasman ureapitoisuus oli R-ruokinnalla korkeampi (P < 0.05) kuin 0-ruokinnalla. Etikkahapon osuus pötsinesteen VFA:sta oli R-ryhmällä alempi (P < 0.05) ja propionihapon korkeampi (P < 0.01) kuin 0-ryhmällä. G-ohralla propionihapon osuus VFA:sta oli alempi (P < 0.05) kuin G-ohralla