Dopamine toxicity in neuroblastoma cells: role of glutathione depletion by -BSO and apoptosis

Dopamine (DA), while an essential neurotransmitter, is also a known neurotoxin that potentially plays an etiologic role in several neurodegenerative diseases. DA metabolism and oxidation readily produce reactive oxygen species (ROS) and DA can also be oxidized to a reactive quinone via spontaneous, enzyme-catalyzed or metal-enhanced reactions. A number of these reactions are cytotoxic, yet the precise mechanisms by which DA leads to cell death remain unknown. In this study, the neuroblastoma cell line, SK-N-SH, was utilized to examine DA toxicity under varying oxidant states. Cells pretreated with the glutathione (GSH)-depleting compound, -buthionine sulfoximine (-BSO), exhibited enhanced sensitivity to DA compared to controls (non-GSH-depleted cells). Furthermore, in cells pretreated with -BSO, the addition of ascorbate (250 μM) afforded significant protection against DA-induced toxicity, while pyruvate (500 μM) had no protective effect. To further characterize the possibility that DA is associated with oxidative stress, additional studies were carried out with manganese (30 μM) as a pro-oxidant. Manganese and DA (200 μM), although not cytotoxic when individually administered to SK-N-SH cells, had a synergistic action on cytotoxicity. Finally, morphological and molecular markers of programmed cell death (apoptosis) were observed in cells treated with DA and -BSO. These markers included membrane blebbing and internucleosomal DNA fragmentation. These results suggest that DA toxicity is tightly linked to intracellular oxidant/antioxidant levels, and that environmental factors, such as excessive Mn exposure, may modulate cellular sensitivity to DA.     

Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration.

Cocaine-responsive gene expression changes have been described after either no drug abstinence or short periods of abstinence. Little data exist on the persistence of these changes after long-term abstinence. Previously, we reported that after discrete-trial cocaine self-administration and 10 days of forced abstinence, incubation of cocaine reinforcement was observable by a progressive ratio schedule. The present study used rat discrete-trial cocaine self-administration and long-term forced abstinence to examine extinction responding, mRNA abundance of known cocaine-responsive genes, and chromatin remodeling. At 30 and 100 days of abstinence, extinction responding increased compared to 3-day abstinent rats. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens c-fos, Nr4a1, Arc, and EGR1 mRNA were observed, and in most cases persisted, for 100 days of abstinence. The signaling peptides CART and neuropeptide Y (NPY) transiently increased in the mPFC, but returned to baseline levels following 10 days of abstinence. To investigate a potential regulatory mechanism for these persistent mRNA changes, levels of histone H3 acetylation at promoters for genes with altered mRNA expression were examined. In the mPFC, histone H3 acetylation decreased after 1 and 10 days of abstinence at the promoter for EGR1. H3 acetylation increased for NPY after 1 day of abstinence and returned to control levels by 10 days of abstinence. Behaviorally, these results demonstrate incubation after discrete-trial cocaine self-administration and prolonged forced abstinence. This incubation is accompanied by changes in gene expression that persist long after cessation of drug administration and may be regulated by chromatin remodeling.     

The Experience of Self‐Management in Adolescent Women with Spina Bifida

It is essential for youth with chronic health conditions like spina bifida (SB) to develop self‐management skills to combat vulnerability, achieve self‐sufficiency, and transition to adulthood. The purpose of this qualitative study was to describe the experience of self‐management in 31 adolescent women with SB. Three themes emerged from this study: (1) opportunities to engage in self‐management activities—knowledge, skills, and aspirations; (2) dance of individuation—parental impact on self‐management; and (3) advocacy within self‐management—confronting discrimination and stigma. The findings indicate that assessment and interventions to enhance self‐management in adolescent women with SB are critical for supporting the range of condition‐related and life skills needed for a transition to adulthood and independent living.     

Candida albicans mannan- and protein-induced humoral, cellular and cytokine responses in atopic dermatitis patients

BACKGROUND: The cytokine observed most often in atopic dermatitis (AD) is IL-4, but a role for IL-5 and IFN-gamma in the late and delayed phase reactions has been suggested. In AD with head, neck and shoulder distribution, hypersensitivity to saprophytic yeasts is an important pathogenetic factor. The yeast allergens include both the mannan polysaccharides and the proteins. Mannans are major cross-reacting allergens likely to be involved in the pathogenesis of AD. OBJECTIVE: To characterize the humoral, lymphoproliferative and cytokine (IL-2, 4, 5 and IFN-gamma) responses of peripheral blood mononuclear cells (PBMCs) induced by Candida albicans mannan and protein antigens in AD. METHODS: Fifteen AD patients and seven healthy controls were included. Ficoll-isolated PBMCs were stimulated by PHA and laboratory-generated mannan and protein extracts of C. albicans. Lymphocyte proliferation was measured and cytokine production was studied by ELISA. The antigen-specific IgG and IgE antibodies were analysed by ELISA and nitrocellulose RAST. RESULTS: In AD mannan (P < 0.005) and protein (P < 0.002), specific IgE levels were higher than in healthy controls. Both mannan and protein-specific lymphoproliferations (both: P < 0.02) were higher in AD than in healthy controls. Mannan, but not protein, induced long lasting IL-2 and IL-4 productions from 24 h lasting up to 66-96 h and IL-5 and IFN-gamma productions with elevated levels at 66 and 96 h. The mannan-induced IL-2 (P = 0.015) and IFN-gamma (P < 0.005) were increased in AD as compared with healthy controls. Significant correlations were seen between the protein-induced proliferation responses and both serum total IgE (r = 0.59, P < 0.01) and protein-specific IgE (r = 0.65, P < 0.005). The mannan-induced IL-2 responses correlated with the specific IgE (r = 0.62, P < 0.01) and proliferation (r = 0.51, P < 0.02) and S-IgE level (r = 0.71, P < 0. 002). Mannan-induced IL-4 and IFN-gamma productions also correlated (r = 0.43, P < 0.05). CONCLUSIONS: C. albicans mannan induced elevated IL-2 and IFN-gamma responses in AD patients. The correlations of the cytokine responses with mannan-induced IgE and proliferation responses suggest that C. albicans mannan induced TH1 type cytokine responses are involved in AD.     

The impact of imagining completed versus interrupted smoking on cigarette craving

A brief imagery procedure was used to determine the effects of imagining completed versus interrupted smoking on self-reported craving, mood, autonomic functioning, and reaction time to an auditory probe. Cigarette smokers (N = 60) imagined actively participating in 3 types of scenarios in which they (a) engaged in smoking behavior, (b) attempted to smoke but were interrupted by a lack of cigarettes, and (c) were not confronted with smoking cues. Imagining both completed and interrupted smoking produced equivalent increases in craving compared with imagining neutral scenarios. Imagery of interrupted smoking was associated with higher heart rate and increased negative mood relative to the other scenario types, whereas imagery of completed smoking was associated with slower reaction time on the probe reaction-time task. Theoretical and methodological implications of the results are discussed.     

The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) project: An open-label pragmatic randomised control trial comparing the efficacy of differing therapeutic agents for primary care detoxification from either street heroin or methadone [ISRCTN07752728]

Background

Heroin is a synthetic opioid with an extensive illicit market leading to large numbers of people becoming addicted. Heroin users often present to community treatment services requesting detoxification and in the UK various agents are used to control symptoms of withdrawal. Dissatisfaction with methadone detoxification [8] has lead to the use of clonidine, lofexidine, buprenorphine and dihydrocodeine; however, there remains limited evaluative research. In Leeds, a city of 700,000 people in the North of England, dihydrocodeine is the detoxification agent of choice. Sublingual buprenorphine, however, is being introduced. The comparative value of these two drugs for helping people successfully and comfortably withdraw from heroin has never been compared in a randomised trial. Additionally, there is a paucity of research evaluating interventions among drug users in the primary care setting. This study seeks to address this by randomising drug users presenting in primary care to receive either dihydrocodeine or buprenorphine.

Methods/design

The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) project is a pragmatic randomised trial which will compare the open use of buprenorphine with dihydrocodeine for illicit opiate detoxification, in the UK primary care setting. The LEEDS project will involve consenting adults and will be run in specialist general practice surgeries throughout Leeds. The primary outcome will be the results of a urine opiate screening at the end of the detoxification regimen. Adverse effects and limited data to three and six months will be acquired.

     

父母的母语与儿童预防性医疗行为的差异有关

目的:研究父母的母语为非英语的婴儿比父母的母语为英语的婴儿是否更不易接受推荐的预防性医疗行为。研究设计:笔者对1999年1月1日至2000年9月30日期间在华盛顿州出生的所有38793例参加医疗救助的1岁婴儿进行回顾性组群研究。主要因素为自己报告的父母的母语。笔者使用多参数回