Amphetamine (AMPH) induces behavioral sensitization and neurotoxicity primarily by enhancing the dopamine-mediated neurotransmission. However, the involvement of the N-methyl-D-aspartate (NMDA) receptor in AMPH-induced neuropathology is also known. Recent investigation has found that high concentration of dopamine could inhibit NMDA receptor-mediated responses by blocking the NMDA receptor channel. 3 H]TCP binding suggested that the high-potency inhibition was produced by decreasing agonist-induced activation of the NMDA receptor channel. On the other hand, the low-potency inhibition was produced by competing with [ 3 H]TCP binding in the NMDA receptor channel, like the action of noncompetitive antagonist of the NMDA receptor. However, AMPH analogs were less potent in inhibiting NMDA-and glycine-induced cultured cell death. Thus, this result indicates that AMPH could antagonize the NMDA receptor-mediated responses in vitro by two different mechanisms, probably, through directly interacting with two distinct sites on this receptor/channel complex.Amphetamine (AMPH), a commonly abused psychostimulant, induces behavioral sensitization or neurotoxcity primarily by enhancing the activities of dopaminergic systems (Robinson and Becker, 1986;Kalivas and Stewart, 1991;Segal and Kuczenski, 1992;Robinson and Berridge, 1993). However, available evidences have indicated the involvement of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors. Administration of NMDA receptor antagonists effectively prevented or attenuated a variety of AMPH-induced responses such as behavioral sensitization, neuronal degeneration, and gene expression, indicating that activation of the NMDA receptor is required for the development and expression of AMPH-induced neuropathological responses (Karler et al., 1989;Lowy, 1990; HemrickLuecke et al., 1992;Bristow et al., 1994;Wang et al., 1994;Konradi et al., 1996). The recruitment of the NMDA receptormediated neurotransmission in AMPH-mediated response has been thought to be as a result of an increase in glutamate release Yamamoto, 1992, 1993) and an increase in the sensitivity to glutamate agonist (White et al., 1995) of the dopaminergic neurons after repeatedly being exposed to AMPH. Recent investigation had shown that dopamine at concentrations higher than 100 M was able to inhibit the NMDA receptor-mediated electrophysiological responses in a concentration-dependent manner by directly blocking the NMDA receptor channel (Castro et al., 1999). Given that AMPH shares a structural similarity with dopamine ( Fig. 1) and that the dopamine transporter could potently uptake both compounds, we proposed that AMPH might be able to regulate directly the NMDA receptor-mediated activities. To test this possibility, we determined whether AMPH analogs could affect the NMDA receptor-mediated responses in vitro, including NMDA-and glycine-stimulated [ 3 H]TCP binding in

No abstract

Sézary syndrome (SS) is an aggressive cutaneous T cell lymphoma with pruritic skin inflammation and immune dysfunction, driven by neoplastic, clonal memory T cells in both peripheral blood and skin. To gain insight into abnormal gene expression promoting T cell dysfunction, lymphoproliferation and transformation in SS, we first compared functional transcriptomic profiles of both resting and activated CD4 + CD45RO + T cells from SS patients and normal donors to identified differential expressed genes. Next, a meta-analysis was performed to compare our SS data to public microarray data from a novel benign disease control, lymphocytic-variant hypereosinophilic syndrome (L-HES). L-HES is a rare, clonal lymphoproliferation of abnormal memory T cells that produces similar clinical symptoms as SS, including severe pruritus and eosinophilia. Comparison revealed gene sets specific for either SS (370 genes) or L-HES (519 genes), and a subset of 163 genes that were dysregulated in both SS and L-HES T cells compared to normal donor T cells. Genes confirmed by RT-qPCR included elevated expression of PLS3, TWIST1 and TOX only in SS, while IL17RB mRNA was increased only in L-HES. CDCA7 was increased in both diseases. In an L-HES patient who progressed to peripheral T cell lymphoma, the malignant transformation identified increases in the expression of CDCA7 , TIGIT , and TOX , which are highly expressed in SS, suggesting that these genes contribute to neoplastic transformation. In summary, we have identified gene expression biomarkers that implicate a common transformative mechanism and others that are unique to differentiate SS from L-HES.

Congenital heart defects (CHDs) are the most prevalent and serious of all birth defects in the United States. However, little is known about the impact of CHD-affected pregnancies on subsequent maternal health. Thus, there is a need to characterize the metabolic alterations associated with CHD-affected pregnancies. Fifty-six plasma samples were identified from post-partum women who participated in the National Birth Defects Prevention Study between 1997 and 2011 and had (1) unaffected control offspring (n = 18), (2) offspring with tetralogy of Fallot (ToF, n = 22), or (3) hypoplastic left heart syndrome (HLHS, n = 16) in this pilot study. Absolute concentrations of 408 metabolites using the AbsoluteIDQ® p400 HR Kit (Biocrates) were evaluated among case and control mothers. Twenty-six samples were randomly selected from above as technical repeats. Analysis of covariance (ANCOVA) and logistic regression models were used to identify significant metabolites after controlling for the maternal age at delivery and body mass index. The receiver operating characteristic (ROC) curve and area-under-the-curve (AUC) are reported to evaluate the performance of significant metabolites. Overall, there were nine significant metabolites (p < 0.05) identified in HLHS case mothers and 30 significant metabolites in ToF case mothers. Statistically significant metabolites were further evaluated using ROC curve analyses with PC (34:1), two sphingolipids SM (31:1), SM (42:2), and PC-O (40:4) elevated in HLHS cases; while LPC (18:2), two triglycerides: TG (44:1), TG (46:2), and LPC (20:3) decreased in ToF; and cholesterol esters CE (22:6) were elevated among ToF case mothers. The metabolites identified in the study may have profound structural and functional implications involved in cellular signaling and suggest the need for postpartum dietary supplementation among women who gave birth to CHD offspring.

No abstract