Plasma endocannabinoids in cocaine dependence and their interaction with cocaine craving and metabotropic glutamate receptor 5 density in the human brain

Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N=103; 69 recreational CU and 34 dependent CU) and stimulant-naïve healthy controls (N=92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N=33; controls: N=43). In an additional analysis using$^{11}$C-ABP688 positron emission tomography (PET) in a male subsample (CU: N=18; controls: N=16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence

Plasma endocannabinoids in cocaine dependence and their relation to cerebral metabotropic glutamate receptor 5 density

Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N = 103; 69 recreational CU and 34 dependent CU) and stimulant-naïve healthy controls (N = 92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N = 33; controls: N = 43). In an additional analysis using $^{11}$C-ABP688 positron emission tomography (PET) in a male subsample (CU: N = 18; controls: N = 16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence

What do measures of patient satisfaction with the doctor tell us?

Objective: To gain an understanding of how patient satisfaction (PS) with the doctor (PSD) is conceptualized through an empirical review of how it is currently being measured. The content of PS questionnaire items was examined to (a) determine the primary domains underlying PSD, and (b) summarize the specific doctor-related characteristics and behaviors, and patient-related perceptions, composing each domain. Methods: A scoping review of empirical articles that assessed PSD published from 2000 to November 2013. MEDLINE and PsycINFO databases were searched. Results: The literature search yielded 1726 articles, 316 of which fulfilled study inclusion criteria. PSD was realized in one of four health contexts, with questions being embedded in a larger questionnaire that assessed PS with either: (1) overall healthcare, (2) a specific medical encounter, or (3) the healthcare team. In the fourth context, PSD was the questionnaire's sole focus. Five broad domains underlying PSD were revealed: (1) Communication Attributes; (2) Relational Conduct; (3) Technical Skill/Knowledge; (4) Personal Qualities; and (5) Availability/Accessibility. Conclusions: Careful consideration of measurement goals and purposes is necessary when selecting a PSD measure. Practice implications: The five emergent domains underlying PSD point to potential key areas of physician training and foci for quality assessment

Cotinine concentrations in semen, urine, and blood of smokers and nonsmokers.

Cotinine levels in the semen, urine, and blood of 88 male smokers and nonsmokers, aged 18 and 35, were analyzed via radioimmunoassay. Detectable cotinine levels were found in all three body fluids, and cotinine levels in all three fluids were highly correlated. Cotinine levels in semen and blood were of similar magnitude; cotinine levels in urine were an order of magnitude or more higher. In all three fluids, cotinine levels increased with an increase in cigarette smoke exposure.Cotinine levels in the semen, urine, and blood of 88 male smokers and nonsmokers, aged 18 and 35, were analyzed via radioimmunoassay. Detectable cotinine levels were found in all three body fluids, and cotinine levels in all three fluids were highly correlated. Cotinine levels in semen and blood were of similar magnitude; cotinine levels in urine were an order of magnitude or more higher. In all three fluids, cotinine levels increased with an increase in cigarette smoke exposure

Comparison of DNA adducts from exposure to complex mixtures in various human tissues and experimental systems

DNA adducts derived from complex mixtures of polycyclic aromatic compounds emitted from tobacco smoke are compared to industrial pollution sources (e.g., coke ovens and aluminum smelters), smoky coal burning, and urban air pollution. Exposures to coke oven emissions and smoky coal, both potent rodent skin tumor initiators and lung carcinogens in humans, result in high levels of DNA adducts compared to tobacco smoke in the in vitro calf thymus DNA model system, in cultured lymphocytes, and in the mouse skin assay. Using tobacco smoke as a model in human studies, we have compared relative DNA adduct levels detected in blood lymphocytes, placental tissue, bronchoalveolar lung lavage cells, sperm, and autopsy tissues of smokers and nonsmokers. Adduct levels in DNA isolated from smokers were highest in human heart and lung tissue with smaller but detectable differences in placental tissue and lung lavage cells. Comparison of the DNA adduct levels resulting from human exposure to different complex mixtures shows that emissions from coke ovens, aluminum smelters, and smoky coal result in higher DNA adduct levels than tobacco smoke exposure. These studies suggest that humans exposed to complex combustion mixtures will have higher DNA adduct levels in target cells (e.g., lung) as compared to nontarget cells (e.g., lymphocytes) and that the adduct levels will be dependent on the genotoxic and DNA adduct-forming potency of the mixture

Withaferin a-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species

Withaferin A (WA), a promising anticancer constituent of Ayurvedic medicinal plant Withania somnifera, inhibits growth of MDA-MB-231 and MCF-7 human breast cancer cells in culture and MDA-MB-231 xenografts in vivo in association with apoptosis induction, but the mechanism of cell death is not fully understood. We now demonstrate, for the first time, that WA-induced apoptosis is mediated by reactive oxygen species (ROS) production due to inhibition of mitochondrial respiration. WA treatment caused ROS production in MDA-MB-231 and MCF-7 cells, but not in a normal human mammary epithelial cell line (HMEC). The HMEC was also resistant to WA-induced apoptosis. WA-mediated ROS production as well as apoptotic histone-associated DNA fragment release into the cytosol was significantly attenuated by ectopic expression of Cu,Zn-superoxide dismutase in both MDA-MB-231 and MCF-7 cells. ROS production resulting from WA exposure was accompanied by inhibition of oxidative phosphorylation and inhibition of complex III activity. Mitochondrial DNA-deficient Rho-0 variants of MDA-MB-231 and MCF-7 cells were resistant to WA-induced ROS production, collapse of mitochondrial membrane potential, and apoptosis compared with respective wild-type cells. WA treatment resulted in activation of Bax and Bak in MDA-MB-231 and MCF-7 cells, and SV40 immortalized embryonic fibroblasts derived from Bax and Bak double knockout mouse were significantly more resistant to WA-induced apoptosis compared with fibroblasts derived from wild-type mouse. In conclusion, the present study provides novel insight into the molecular circuitry of WA-induced apoptosis involving ROS production and activation of Bax/Bak. © 2011 Hahm et al

Assessment of health care needs and utilization in a mixed public-private system: the case of the Athens area

BACKGROUND: Given the public-private mix of the Greek health system, the purpose of this study was to assess whether variations in the utilisation of health services, both primary and inpatient care, were associated with underlying health care needs and/or various socio-economic factors. METHODS: Data was obtained from a representative sample (N = 1426) residing in the broader Athens area (response rate 70.6%). Perceived health-related quality of life (HRQOL), as measured by the physical and mental summary component scores of the SF-36 Health Survey, was used as a proxy of health care need. Health care utilization was measured by a) last-month visits to public sector physicians, b) last-month visits to private sector physicians, c) last-year visits to hospital emergency departments and d) last-year hospital admissions. Statistical analysis involved the implementation of logistic regression models. RESULTS: Health care need was the factor most strongly associated with all measures of health care utilization, except for visits to public physicians. Women, elderly, less wealthy and individuals of lower physical health status visited physicians contracted to their insurance fund (public sector). Women, well educated and those once again of lower physical health status were more likely to visit private providers. Visits to hospital emergency departments and hospital admissions were related to need and no socio-economic factor was related to the use of those types of care. CONCLUSION: This study has demonstrated a positive relationship between health care need and utilisation of health services within a mixed public-private health care system. Concurrently, interesting differences are evident in the utilization of various types of services. The results have potential implications in health policy-making and particularly in the proper allocation of scarce health resources