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His.se

UKPMC Funders Group
Author Manuscript
Mol Psychiatry
. Author manuscript; available in PMC 2009 January 22.
Mol Psychiatry. 2008 July ; 13(7): 658–660. doi:10.1038/mp.2008.47.
D-Amino acid oxidase (DAO) activity and expression are
increased in schizophrenia
PWJ Burnet, SL Eastwood, GC Bristow, BR Godlewska, P Sikka, M Walker, and PJ Harrison
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, United
Kingdom.

Keywords
Glutamate; bipolar disorder; DAAO; NMDA receptor; D-serine; polymorphism D-amino acid oxidase (DAO, DAAO) metabolises the NMDA receptor (NMDAR) modulatorD-serine.1 Enhanced DAO activity is thus a potential cause of reduced D-serine and thenceimpaired NMDAR functioning in schizophrenia,2 and an explanation for the geneticcontribution that DAO may make to the disorder.3,4 Here we report that DAO activity, andexpression, are increased in the cerebellum in schizophrenia, but not in bipolar disorder, andare not related to SNPs in DAO or its putative activator gene G72/G30.3 We measured DAO enzyme activity, and DAO mRNA by qRT-PCR, using establishedmethods, in cerebellar tissue from subjects with schizophrenia, bipolar disorder, and controls, from the Stanley Microarray Collection (Supplementary Table 1). We genotyped subjects fortwo schizophrenia-associated tag SNPs in DAO and G72/G30. We used cerebellar tissue fromrats administered haloperidol or clozapine for 14 days to investigate antipsychotic effects onDAO activity. For demographic and methodological details, see Supplementary Materials.
As shown in Fig. 1A, DAO activity differed between groups (F2,100=4.79, p=0.010), beingincreased in schizophrenia compared to controls (+37%, p=0.027) and compared to bipolardisorder (+57%, p=0.004). The latter groups did not differ (p=0.45). DAO activity was notcorrelated with post mortem interval, brain pH, or antipsychotic exposure (Supplementary Fig.
1) or age (R=0.03, p=0.79). DAO activity was unrelated to alcohol or substance misuse history(using a five-point scale), smoking, sex, or suicide. DAO activity increased with duration ofschizophrenia (R=0.34, p=0.05, n=35). Within the bipolar disorder group, DAO activity didnot vary according to a history of psychotic symptoms. DAO activity correlated with DAOmRNA (R=0.43, p=0.0001, n=97). DAO affinity showed no group differences (Fig. 1B). DAOactivity in rat cerebellum was unaffected by antipsychotics (Supplementary Table 2).
Normalised DAO mRNA differed between groups (F2,88=3.84, p=0.025), being increasedcompared to controls in schizophrenia (p=0.01) and bipolar disorder (p=0.04; Fig. 1C). DAOmRNA was not related to antipsychotic exposure, post mortem interval, brain pH, or RIN, butwas affected by death-to-refrigeration interval (Supplementary Fig. 1).
Neither DAO activity nor DAO mRNA were influenced by the DAO or G72/G30 SNPs(Supplementary Table 3), apart from a trend for higher DAO activity in allele 2 carriers of Correspondence: Dr Harrison. paul.harrison@psych.ox.ac.uk Tel: +44 1865 223730 Fax +44 1865 251076.
G72/G30 rs3918342 (p=0.08 vs 1/1 homozygotes). There were no genotype-by-diagnosisinteractions.
Our data show an elevation of DAO activity in schizophrenia accompanied by increased gene expression. The activity increase confirms the results of a pilot study,5 and the elevated DAOmRNA replicates findings in a separate cohort.6 There were no correlations of DAO activityor expression with medication exposure, and no effect of haloperidol or clozapine on DAOactivity in rat brain. Other confounders (e.g. smoking) did not have a demonstrable influenceeither. Hence, within the constraints of a post mortem study, our findings appear related to thediagnosis of schizophrenia. We focused on the cerebellum because DAO is abundant and activetherein; it will be important to ascertain whether DAO activity is affected elsewhere inschizophrenia, but problematic since forebrain DAO activity is extremely low, despite robustexpression. Parenthetically, this discrepancy is complemented by a difference in the cellularlocalization of DAO: it is glial in the cerebellum, but mainly neuronal in the cerebral cortex.6 Elevated DAO activity will presumably enhance metabolism of D-serine and, other thingsbeing equal, contribute to a reduced synaptic availability of D-serine, potentially impairingNMDAR function.1 As such, our findings support the hypothesized involvement of DAO, andthence D-serine, in the NMDAR hypofunction of schizophrenia and its potential therapeuticamelioration.2,7,8 Clearly any such conclusions are tentative, since many other factors likelyalso influence D-serine availability, e.g. its synthesis by serine racemase,6,9 and its release andreuptake.10 Alterations in these processes could counteract – or exacerbate – enhanced DAOactivity. Moreover, since DAO also metabolises other D-amino acids,1 D-serine is not the onlysubstrate that might be affected by an increase in DAO activity. For example, D-alanine ispresent in the cerebellum, is an NMDAR modulator, and may be therapeutically beneficial inschizophrenia.7 Overall, whilst a primary effect on D-serine, and thence NMDARs, is anattractive interpretation of the DAO increase in schizophrenia, further studies are needed toconfirm the biochemical consequences, as well as the causes, of the elevation. (SeeSupplementary Materials for further discussion).
As the DAO and G72/G30 SNPs did not influence DAO activity or expression, our data provideno evidence that they are functional (nor indexing SNPs that are), nor have we identified amechanism whereby variation in these genes might confer schizophrenia susceptibility. Theremay be other SNPs that are relevant in this respect; alternatively, the DAO SNPs might operateat other places and times, whilst G72/G30 SNPs could act via a DAO-independent pathway.
In summary, DAO activity and expression are increased in schizophrenia, but not related toDAO or G72/G30 genotype. Any pathophysiological consequences of increased DAO activityseem most likely to impact on D-serine metabolism and thence NMDAR function, but thisremains to be established.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
References
1. Mothet JP, Parent AT, Wolosker H, Brady RO, Linden DJ, Ferris CD, et al. Proc Natl Acad Sci USA 2. Tsai GC, Coyle JT. Annu Rev Pharmacol Toxicol 2002;42:165–79. [PubMed: 11807169] 3. Chumakov I, Blumenfeld M, Guerrasimenko O, Cavarec L, Palicio M, Abderrahim H, et al. Proc Natl Acad Sci USA 2002;99:13675–80. [PubMed: 12364586] 4. Boks MPM, Rietkerk T, van de Beek MH, Sommer IE, de Koning TJ, Kahn RS. Eur Neuropsychopharmacol 2007;17:567–72. [PubMed: 17250995] Mol Psychiatry. Author manuscript; available in PMC 2009 January 22.
5. Kapoor R, Lim KS, Cheng A, Garrick T, Kapoor V. Brain Res 2006;1106:205–10. [PubMed: 6. Verrall L, Walker M, Rawlings N, Benzel I, Kew JNC, Harrison PJ, Burnet PJW. Eur J Neurosci 7. Javitt D. Biol Psychiatry 2008;63:6–8. [PubMed: 18082555] 8. Adage T, Trillat A-C, Quattropani A, Perrin D, Cavarec L, Shaw J, et al. Eur Neuropsychopharmacol 9. Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, Agam G. Schizophr Res 10. Burnet PJW, Hutchinson L, von Hesling M, Gilbert E-J, Harrison PJ. Schizophr Res. in press Mol Psychiatry. Author manuscript; available in PMC 2009 January 22.
Figure 1.
Cerebellar DAO activity and expression in 35 control subjects (CON, white bars), 35 with
schizophrenia (SCZ, black bars), and 34 with bipolar disorder (BPD, shaded bars). A) DAO
activity (Vmax, nmol D-proline/min/mg protein) is higher in subjects with schizophrenia
compared to controls and to subjects with bipolar disorder. Bipolar disorder subjects have lower
DAO activity than those with schizophrenia. B) DAO affinity (Km, nM) is not different
between groups. C) DAO mRNA, measured by Taqman qRT-PCR and normalised to the
geometric mean of four housekeeping genes (β2M, GAPDH, GUSB, TFRC; see
Supplementary Materials), is increased in subjects with schizophrenia and in bipolar disorder.
5 subjects (1 CON, 1 SCZ, 3 BPD) were excluded due to amplification failure. The death-to-
Mol Psychiatry. Author manuscript; available in PMC 2009 January 22.
refrigeration interval was included as a covariate in this analysis as it correlated negativelywith DAO mRNA (Supplementary Figure 1D). Repeating the ANOVA without this covariateretained the overall diagnostic effect (F2,95=3.422, p=0.037) and the increase in schizophrenia(p=0.01) but rendered the bipolar disorder increase non-significant (p=0.22).
Mol Psychiatry. Author manuscript; available in PMC 2009 January 22.

Source: http://www.his.se/PageFiles/3233/Pilleriin_Sikka_4.pdf

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