The Val66Met polymorphism in the BDNF gene is associated with epilepsy in fragile X syndrome

The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype. We investigated the impact of polymorphisms in the BDNF gene on clinical features in fragile X syndrome (FXS). In our study sample, the Met66 allele associated with epilepsy of finnish FXS men. Abnormalities in BDNF-mediated plasticity are shown in FXS and the present data suggest that the Met66 allele might predispose FXS mates to epilepsy. (C) 2009 Published by Elsevier B.V.The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype. We investigated the impact of polymorphisms in the BDNF gene on clinical features in fragile X syndrome (FXS). In our study sample, the Met66 allele associated with epilepsy of finnish FXS men. Abnormalities in BDNF-mediated plasticity are shown in FXS and the present data suggest that the Met66 allele might predispose FXS mates to epilepsy. (C) 2009 Published by Elsevier B.V.The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype. We investigated the impact of polymorphisms in the BDNF gene on clinical features in fragile X syndrome (FXS). In our study sample, the Met66 allele associated with epilepsy of finnish FXS men. Abnormalities in BDNF-mediated plasticity are shown in FXS and the present data suggest that the Met66 allele might predispose FXS mates to epilepsy. (C) 2009 Published by Elsevier B.V.Peer reviewe

Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Paroxetine suppresses recombinant human P2X7 responses

P2X7 receptor (P2X7) activity may link inflammation to depressive disorders. Genetic variants of human P2X7 have been linked with major depression and bipolar disorders, and the P2X7 knockout mouse has been shown to exhibit anti-depressive-like behaviour. P2X7 is an ATP-gated ion channel and is a major regulator of the pro-inflammatory cytokine interleukin 1β (IL-1β) secretion from monocytes and microglia. We hypothesised that antidepressants may elicit their mood enhancing effects in part via modulating P2X7 activity and reducing inflammatory responses. In this study, we determined whether common psychoactive drugs could affect recombinant and native human P2X7 responses in vitro. Common antidepressants demonstrated opposing effects on human P2X7-mediated responses; paroxetine inhibited while fluoxetine and clomipramine mildly potentiated ATP-induced dye uptake in HEK-293 cells stably expressing recombinant human P2X7. Paroxetine inhibited dye uptake mediated by human P2X7 in a concentration-dependent manner with an IC50 of 24 μM and significantly reduces ATP-induced inward currents. We confirmed that trifluoperazine hydrochloride suppressed human P2X7 responses (IC50 of 6.4 μM). Both paroxetine and trifluoperazine did not inhibit rodent P2X7 responses, and mutation of a known residue (F 95L) did not alter the effect of either drug, suggesting neither drug binds at this site. Finally, we demonstrate that P2X7-induced IL-1β secretion from lipopolysaccharide (LPS)-primed human CD14+ monocytes was suppressed with trifluoperazine and paroxetine

TPH2 Gene Polymorphisms and Major Depression – A Meta-Analysis

BACKGROUND: Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme in the synthetic pathway for brain serotonin and is considered key factor for maintaining normal serotonin transmission in the central neuron system (CNS). Gene-disease association studies have reported a relationship between TPH2 and major depressive disorder (MDD) in different populations, however subsequent studies have produced contradictory results. OBJECTIVES: We performed a systematic overview and a meta-analysis with all available data up-to-date. METHODS: We scrutinized PubMed, Embase, HuGNet and China National Knowledge Infrastructure (CNKI ) and last update was held on October 2011. We also searched the manuscripts and the supplementary documents of the published genome-wide association studies in the field. Effect sizes of independent loci that have been studied in more than 3 articles were synthesized using fixed and random effects models. RESULTS: We found 27 eligible articles that studied a total of 74 single nucleotide polymorphisms (SNPs). Finally, 12 independent loci were included in the meta-analysis. The synthesis of the data shown that two SNPs (rs4570625 and rs17110747) were associated with MDD using fixed effects models. SNP rs4570625 had low heterogeneity and remained significant using the more conservative random effects calculations with a summary OR = 0.83 (95% CI: 0.73-0.96). CONCLUSION: The current study identified a SNP (rs4570625) with strong epidemiological credibility; however more studies are required to provide robust evidence for other weak associations

Adipose tissue gene expression analysis reveals changes in inflammatory, mitochondrial respiratory and lipid metabolic pathways in obese insulin-resistant subjects

<p>Abstract</p> <p>Background</p> <p>To get insight into molecular mechanisms underlying insulin resistance, we compared acute in vivo effects of insulin on adipose tissue transcriptional profiles between obese insulin-resistant and lean insulin-sensitive women.</p> <p>Methods</p> <p>Subcutaneous adipose tissue biopsies were obtained before and after 3 and 6 hours of intravenously maintained euglycemic hyperinsulinemia from 9 insulin-resistant and 11 insulin-sensitive females. Gene expression was measured using Affymetrix HG U133 Plus 2 microarrays and qRT-PCR. Microarray data and pathway analyses were performed with Chipster v1.4.2 and by using in-house developed nonparametric pathway analysis software.</p> <p>Results</p> <p>The most prominent difference in gene expression of the insulin-resistant group during hyperinsulinemia was reduced transcription of nuclear genes involved in mitochondrial respiration (mitochondrial respiratory chain, GO:0001934). Inflammatory pathways with complement components (inflammatory response, GO:0006954) and cytokines (chemotaxis, GO:0042330) were strongly up-regulated in insulin-resistant as compared to insulin-sensitive subjects both before and during hyperinsulinemia. Furthermore, differences were observed in genes contributing to fatty acid, cholesterol and triglyceride metabolism (FATP2, ELOVL6, PNPLA3, SREBF1) and in genes involved in regulating lipolysis (ANGPTL4) between the insulin-resistant and -sensitive subjects especially during hyperinsulinemia.</p> <p>Conclusions</p> <p>The major finding of this study was lower expression of mitochondrial respiratory pathway and defective induction of lipid metabolism pathways by insulin in insulin-resistant subjects. Moreover, the study reveals several novel genes whose aberrant regulation is associated with the obese insulin-resistant phenotype.</p

Hiilidioksidipohjainen metanolisynteesi

Tämän diplomityön tavoitteena oli tutkia suoraa metanolisynteesiä hiilidioksidista ja vedystä miedoissa olosuhteissa. Työssä arvioitiin myös metanolisynteesin kannattavuutta sekä ongelmakohtia teollisessa mittakaavassa. Hiilidioksidin hyödyntäminen lähtöaineena eri kemikaalien ja polttoaineiden valmistuksessa on yksi keino hillitä ilmastonmuutosta. Katalyyttinen metanolisynteesi on laajasti tutkittu aihealue. Kuitenkin tiedetään, että termodynamiikka ja kinetiikka asettavat omat rajoituksensa eksotermiselle hiilidioksidipohjaiselle metanolisynteesille. Tärkeimmät reaktionopeuteen vaikuttavat muuttujat ovat lämpötila ja paine. Paineen kasvattaminen suosii metanolisynteesiä. Lämpötilan taas tulee olla riittävä hiilidioksidin aktivoimiseksi, mutta mahdollisimman alhainen käänteisen vesikaasun siirtoreaktion välttämiseksi. Tyypillisesti metanolisynteesin reaktiolämpötila on välillä 220–280 °C, jolloin metanolin teoreettinen saanto ilmanpaineessa on alle yhden prosentin. Hiilidioksidin reaktioreittiä metanoliksi ei ole vielä toistaiseksi pystytty varmistamaan. Katalyytti nopeuttaa reaktiota alentamalla aktivaatioenergiaa. Kirjallisuusselvityksessä kuparipohjaiset katalyytit osoittautuivat metanolisynteesissä eniten tutkituiksi katalyyteiksi. Muita tutkittuja metalleja ovat muun muassa palladium, mangaani, platina sekä nikkeli. Selvityksen perusteella tähän työhön valittiin seitsemän lupaavaa katalyyttiä tarkempaan tarkasteluun. Näistä mietoihin reaktio-olosuhteisiin lupaavimmilta vaikuttivat MnOX/m-Co₃O₄ sekä Cu-ZnO/ZrO₂ katalyytit, jotka valmistettiin tutkittavaksi ja testattavaksi. MnOX/m-Co₃O₄ valmistettiin kapillaarisella inkluusiolla ja Cu-ZnO/ZrO₂ valmistettiin yhteissaostuksella. Katalyyttien valmistuksessa saavutettiin halutun kaltaiset rakenteet. Vertailukohdaksi otettiin kaupallinen kuparipohjainen katalyytti (Cu/ZnO/Al₂O₃). Tutkittavien katalyyttien aktiivisuus metanolisynteesiin selvitettiin laboratoriomittakaavassa jatkavatoimisella kiintopetireaktorilla. Sen avulla tutkittiin lämpötilan (100–350 °C) ja vaihtuman (10 000–75 000 h⁻¹) vaikutusta reaktioon ilmanpaineessa. Lisäksi tutkittiin magneettikentän vaikutusta Cu-ZnO/ZrO₂ katalyytin aktiivisuuteen. Kaikkien tutkittavien katalyyttien todettiin toimivan ilmanpaineessa metanolisynteesissä, ainakin jossakin määrin. Kokeissa havaittiin hiilidioksidin konversion selkeä riippuvuus lämpötilasta, sillä konversio kasvoi miltei lineaarisesti lämpötilan noustessa. Alle 175 °C:ssa konversio pysyi nollassa kaikilla katalyyteillä. Kuparia sisältävät katalyytit tarvitsivat yli 200 °C:n lämpötilan, jotta hiilidioksidin havaittiin reagoivan. MnOX/m-Co₃O₄ katalyytillä saavutettiin suurin hiilidioksidin konversio, mutta vähäisin metanolin saanto. Tutkimuksissa ilmeni lämpötilariippuvuus myös metanolin ja sivutuotteen, hiilimonoksidin, selektiivisyyksille. Itsetehdyillä katalyyteillä havaittiin myös muita sivutuotteita (metaani, eteeni ja etanoli). Tutkitulla lämpötila-alueella kuparikatalyyteillä metanolin selektiivisyys laski ja hiilimonoksidin selektiivisyys kasvoi lämpötilan kasvaessa. MnOX/m-Co₃O₄ katalyytillä sen sijaan metaanin selektiivisyys kasvoi lämpötilan mukana. Virtausnopeuden nosto laski hiilidioksidin konversiota, mutta paransi metanolin massa-aikasaantoa vaihtumaan 60 000 h⁻¹ asti. Cu-ZnO/ZrO₂ katalyytillä saavutettiin parhaimmillaan noin 29 mg/gkath massa-aikasaanto vaihtumalla 60 000 h⁻¹ ja 265 °C:ssa. Tällöin hiilidioksidin konversio oli 4,2 % ja metanolin selektiivisyys 6,2 %. Muilla tutkituilla katalyyteillä massa-aikasaanto oli selkeästi heikompi. Magneettikentällä ei havaittu olevan vaikutusta Cu-ZnO/ZrO₂ katalyytin suorituskykyyn. Metanolisynteesi hiilidioksidista ja vedystä ilmanpaineessa todistettiin olevan teknisesti mahdollista, muttei taloudellisesti kannattavaa. Pelkästään raaka-ainekustannukset ovat yli 1000-kertaiset metanolin markkinahintaan verrattuna. Tähän tulokseen päästiin tässä työssä tehtyjen kokeiden perusteella parhaassa tapauksessa ilman lauhtumattomien kaasujen kierrätystä, kun käytettään talteenotettua hiilidioksidia ja elektrolyysivetyä. Jatkokehitystä tarvitaan vielä ennen kuin tekniikka on taloudellisesti kaupallistettavissa.The aim of the thesis was to study direct methanol synthesis from CO₂ and H₂ in mild conditions. In addition, the profitability and the problems in the industrial scale were investigated. Use of CO₂ as a starting material in the manufacturing of various chemicals and fuels is one way to mitigate the climate change. Catalytic synthesis of methanol is widely studied field. It is known that both thermodynamics and kinetics limit the exothermic reaction to methanol. Temperature and pressure are the most important parameters effecting the rate of reaction. Pressure increase favors methanol synthesis and temperature needs to be high enough to activate carbon dioxide, but as low as possible in order to avoid the reverse water-gas shift reaction. Methanol yield is less than one percent in the atmospheric pressure in the typical reaction temperature range (220–280 °C). The reaction route from CO₂ to methanol has not yet been confirmed. Catalysts speed up reactions by lowering the activation energy. Based on the literature, the most studied catalysts for methanol synthesis are copper based. Other studied metals are for example palladium, manganese, platinium, and nickel. The seven most promising catalysts were selected for closer inspection. When mild conditions were considered, the most promising ones of these seven were MnOX/m-Co₃O₄ and Cu-ZnO/ZrO₂ catalysts, which were synthesized and tested. MnOX/m-Co₃O₄ was prepared with capillary inclusion and Cu-ZnO/ZrO₂ with co-precipitation. Catalyst preparation came of very well. Commercial catalyst (Cu/ZnO/Al₂O₃) was chosen for comparison. Catalysts activity in methanol synthesis was studied on laboratory scale in continuous flow fixed-bed reactor. The effect of the temperature (100–350 °C) and the space velocity (10 000–75 000 h⁻¹) was studied in ambient pressure. In addition, the effect of magnetic field tested on Cu-ZnO/ZrO₂ catalyst. With all catalysts studied in ambient pressure methanol formation was seen, at least to some extent. Clear dependence on the temperature was observed for CO₂ conversion as the conversion increased nearly linearly with temperature. Bellow 175 °C the conversion stayed at zero for all catalysts. Copper based catalysts needed over 200 °C before the CO₂ conversion started. MnOX/m-Co₃O₄ had the highest CO₂ conversion but the smallest methanol yield. Temperature dependence was noticed for the selectivities of methanol and the side product CO. For synthesized catalysts also other side products (CH₄, C₂H₄, and C₂H₅OH) were detected. For copper based catalysts methanol selectivity decreased and CO selectivity increased with the temperature. For MnOX/m-Co₃O₄ catalyst CH₄ selectivity increased with the temperature. Increase in the space velocity reduced CO₂ conversion but increased methanol weight-time yield up to 60 000 h⁻¹. The Cu-ZnO/ZrO₂ catalyst had at the best weight-time yield of around 29 mg/gcath with space velocity of 60 000 h⁻¹ at 265 °C. In this case CO₂ conversion was 4.2% and methanol selectivity 6.2%. For other catalysts, the weight-time yield was clearly lower. The magnetic field had no observable effect on the Cu-ZnO/ZrO₂ catalysts performance. Methanol synthesis from CO₂ and H₂ was proven to be technically possible in the atmospheric pressure but not economically viable. Based on the experiments, already the raw material costs are over 1000 times higher than the methanol market price in the best case scenario without recycling the non-reacted gases. This is when using recovered CO₂ and electrolytic H₂. Further development is needed to make this technology economically viable

In Vitro Comparison of the Blood Handling by the Constrained Vortex and Twin Roller Blood Pumps

(J. Extra-Corpor. Technol. 19[3] p. 316-321 Fall 1987, 30 ref.) Several authors and manufacturers refer to the superior blood handling capability of the constrained vortex blood pump (CVP) design compared to the roller pump (RP). Little, if any, scientific evidence has been presented to support this thinking. The hypothesis that the RP and the CVP are equivalent in regard to trauma to blood cellular elements and proteins was tested. The RP, a Cobe Roller Pump (CRP), was tested utilizing a new longterm formulation of PVC tubing. Two models of the CVP were tested, the Bio-Medicus Centrifugal Pump (BCP) and the Sarns Centrifugal Pump (SCP). Similar circuits were constructed for the three pumps and fresh human blood was recirculated at 35°C for 48 hours. The circuits allowed control of pH, pCO2, pO2 and after load. An aliquot of test blood was maintained at 35°C for a control. The results from three separate trials were computed. The BCP test blood exhibited less hemolysis (p.05) in the titer of clottable fibrinogen between the other groups. The SCP and the CRP were equivalent with regard to blood handling for up to 32 hours of in vitro recirculation. The BCP caused less alteration of red blood cells and fibrinogen than the SCP and CRP