Using a sensitive histofluorescence staining method that allows for a quantitation of neuronal death, we compared the protective effects of gangliosides (a group of naturally occurring glycosphingolipids), phencyclidine (PCP), and MK-801 (dibenzocyclohepteneimine) on glutamate-and kainate-induced neuronal death in primary cultures of cortical and cerebellar neurons prepared from neonatal rats. PCP and MK-801 block neurotoxicity induced by glutamate doses 50 times higher than the LD50 (LD50 in Mg2+ free medium, 10 ,uM) but only partially block the kainate neurotoxicity (LD50 in presence of Mg2+, 100 ,uM). In contrast, pretreatment with gangliosides (GT1b > GD1b > GM1) results in complete and insurmountable protection against the neurotoxicity elicited by glutamate or kainate. In primary cultures of cerebellar granule cells gangliosides, unlike PCP and MK-801, fail to block glutamate-gated cationic currents and the glutamate-evoked increase of (i) inositol phospholipid hydrolysis, (ii) c-fos mRNA content, and (iii) nuclear accumulation of c-fos protein. Protection of glutamate neurotoxicity by gangliosides does not require their presence in the incubation medium; however, it is proportional to the amount of glycosphingolipid accumulated in the neuronal membranes. The ganglioside concentration (30-60 ,uM) that blocks glutamate-elicited neuronal death also prevents glutamate-and kainate-induced protein kinase C translocation from cytosol to neuronal membranes.High-affinity glutamate binding sites that recognize Nmethyl-D-aspartate (NMDA) are located on a specific excitatory amino acid receptorial domain that operates ionotropic (1)(2)(3)(4) and/or metabolotropic (4-10) signal transduction. These glutamate receptorial domains, in addition to the recognition site for the putative excitatory neurotransmitter, include two kinds of noncompetitive inhibitory sites regulated by Mg2 + and by an unknown natural ligand acting on a site that recognizes phencyclidine (PCP) (1,4,(11)(12)(13). Moreover, positive and/or negative allosteric centers modulate NMDA-sensitive glutamate recognition sites (13)(14)(15); these are believed to have glycine (13,14) or kynurenate (15) as putative endogenous modulators, respectively. These NMDAsensitive recognition sites operate cationic channels (1, 4), stimulate inositol phospholipid hydrolysis (4-6), or release arachidonic acid (7) and cause a Ca2 -dependent accumulation of cGMP (4,8). Transduction mechanisms operated by activation of NMDA-sensitive glutamate recognition sites elicit a sequelae ofevents, including an increase in c-fos protooncogene mRNA content (9) and the nuclear accumulation of c-fos protein, which in turn promotes the coordinated expression of selected mRNAs encoding proteins (16) (19,(23)(24)(25), a possible therapeutic application of these drugs to limit secondary neurotoxicity occurring in brain regions surrounding ischemic areas has been proposed (19,24,25). Gangliosides and sphingosine applied to primary cultures of neonatal rat cerebellar granule cells pre...

L-Glutamic, L-aspartic acids and a number of their structural analogs, including quisqualic, kainic, ibotenic, quinolinic, and N-methyl-D-aspartic (NMDA) acids, increase inositol phospholipid hydrolysis when added to primary cultures of cerebellar granule cells, as is reflected by an enhanced formation of 3H-inositolmonophosphate (3H-IP1) in the presence of Li+. L-Glutamic acid also enhances the formation of the initial products of inositol phospholipid hydrolysis, 3H-inositol di-(3H-IP2) and triphosphate (3H-IP3). In the absence of extracellular Ca2+, L-glutamic acid fails to enhance 3H-IP1 formation, but still increases 3H-IP2 and 3H-IP3 formation. The stimulation of 3H-IP1 formation elicited by L-glutamic acid is reduced by DL-2-amino-5-phosphonovaleric acid (APV) and gamma-glutamylglycine and, to a lesser extent, by 2,3-cis-piperidindicarboxylic acid (PDA). The stimulation of 3H-IP1 formation by kainic acid is antagonized by PDA and gamma-glutamylglycine, but it is almost unaffected by APV. The increase in 3H-IP1 formation elicited by quisqualic acid is not reduced by any of the dicarboxylic amino acid receptor antagonists that we have tested. We conclude that different subtypes of excitatory amino acid recognition sites are associated with inositol phospholipid metabolism in primary cultures of cerebellar granule cells.

Ratios of urinary 8-hydroxy-2'-deoxyguanosine to urinary creatinine (8-OHdG/creatinine) have been considered as a good biological indicator of DNA oxidation. Urinary 8-OHdG/ creatinine levels of lung cancer patients were evaluated by enzyme-linked iramunosorbent assay using a monoclonal antibody N45.1 during radiotherapy and chemotherapy. An increase in urinary 8-OHdG/creatinine was found in non-small-cell carcinoma (non-SCC) patients during the course of radiotherapy. SCC patients showed higher levels of urinary 8-OHdG/creatinine than the controls. Furthermore, SCC patients with complete or partial response to the chemotherapy showed a significant decrease in urinary 8-OHdG/creatinine while patients with no change or progressive disease showed an increase.

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Several studies have shown the opioid antagonist naltrexone to be effective when combined with psychosocial therapies for the treatment of patients who are dependent on alcohol with fixed medication and time (12 weeks). In this study, 121 nonabstinent outpatients with alcohol dependence (DSM-IV) were treated with sessions of cognitive coping skills (N = 67) or supportive therapy (N = 54) and either naltrexone 50 mg/day (N = 63) or placebo (N = 58) daily for the first 12 weeks and thereafter for 20 weeks only when craving alcohol (i.e., targeted medication) in a prospective one-center, dual, double-blind, randomized clinical trial. The dropout rate for all subjects was 16.5% during the first 12-week period and approximately twice that level by the end of the study. There were no significant group differences in study completion and therapy participation rates. After the continuous medication (12 weeks), the coping/naltrexone group had the best outcome, and coping/placebo had the worst. This difference remained during the targeted medication period (the following 20 weeks). Naltrexone was not better than placebo in the supportive groups, but it had a significant effect in the coping groups: 27% of the coping/naltrexone patients had no relapses to heavy drinking throughout the 32 weeks, compared with only 3% of the coping/placebo patients. The authors' data confirm the original finding of the efficacy of naltrexone in conjunction with coping skills therapy. In addition, their data show that detoxification is not required and that targeted medication taken only when craving occurs is effective in maintaining the reduction in heavy drinking.

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All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria for, interferon-free DAA reimbursement among countries in the European Union and European Economic Area, and Switzerland. Reimbursement documentation was reviewed between Nov 18, 2016, and Aug 1, 2017. Primary outcomes were fibrosis stage, drug or alcohol use, prescriber type, and HIV co-infection restrictions. Among the 35 European countries and jurisdictions included, the most commonly reimbursed DAA was ombitasvir, paritaprevir, and ritonavir, with dasabuvir, and with or without ribavirin (33 [94%] countries and jurisdictions). 16 (46%) countries and jurisdictions required patients to have fibrosis at stage F2 or higher, 29 (83%) had no listed restrictions based on drug or alcohol use, 33 (94%) required a specialist prescriber, and 34 (97%) had no additional restrictions for people co-infected with HIV and hepatitis C virus. These findings have implications for meeting WHO targets, with evidence of some countries not following the 2016 hepatitis C virus treatment guidelines by the European Association for the Study of Liver.