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Neuropeptides have been implicated in experimental drug addiction. Desglycinamide (Arg8) vasopressin (DGAVP) attenuates heroin and cocaine intake during initiation of drug self-administration in rats. beta-Endorphin is self-administered in rats and a role of endogenous opioids in cocaine reward has been proposed. The present studies deal with voluntary alcohol consumption in monkeys under free choice conditions. Monkeys initiated alcohol drinking within a few days and after a stable drinking pattern was acquired increased their ethanol consumption during a short period following interruption of the alcohol supply (relapse). The alcohol drinking behavior seems under the control of reinforcement principles. DGAVP reduced the acquisition of alcohol drinking in the majority of treated monkeys. Initiation of alcohol drinking induced modifications in neuroendocrine homeostasis e.g. an increased plasma beta-endorphin. Both the opioid antagonist naltrexone and the opioid agonist morphine dose-dependently decreased alcohol intake during continuous supply and after imposed abstinence. The monkeys were more sensitive to both drugs after imposed abstinence. The effects are interpreted in the context of the endorphin compensation hypothesis of addictive behavior. It is suggested that endorphins may be particularly implicated in craving for addictive drugs and in relapse of addictive behavior.

AbstractlncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNAs structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their down-stream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs we demonstrate first the significant association of a SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.

Abstract Corrosion of metallic well and process materials can be caused by water that is co-produced with oil and gas. The corrosion processes involve electrochemical reactions that are dependent on the composition of the produced water. Variation of the produced water composition during oil and gas production can be investigated using electrolyte simulation tools that model the chemical reactions (chemical equilibria) that control the composition of the produced water. This paper describes how electrolyte simulation was used to investigate the failure of 2205 duplex stainless steel (UNS S31803) process pipework on the Shearwater installation, operated by Shell Exploration and Production, in the Central North Sea. The failure of the 2205 duplex stainless steel (22Cr) involved stress corrosion cracking (SCC) initiated from both the outside and inside of the pipework. Cracks initiated from the outside were attributable to a known chloride SCC failure mode of 22Cr. The mechanism involved a high degree of evaporation of seawater on the pipework surface. However, the mechanism that initiated cracks from the inside was unusual because oxygen was not present. Electrolyte simulation tools were used to establish the chemical environment associated with the cracks initiated from the inside. It was demonstrated that evaporation of produced water, resulting from a 90 bar to 15 bar pressure reduction at ~136°C, had created brines with very high calcium and magnesium chloride concentrations. The resulting "exotic" brines had not been anticipated and were outside the range of environments for which the process materials had been qualified. Subsequent laboratory materials testing replicated the field failure in the presence of these brines. This study highlights the need for materials selection to include rigorous evaluation of steady state and transient process environments using both electrolyte and hydrocarbon simulation tools. Special attention should be given to projects that apply materials and processing concepts in novel combinations. The failure illustrated that surface wetting of pipework can initiate corrosion failure even at very low water volume fraction (< 0.5 vol%).

HIV-related immune-suppression increases the risk of malaria (infection, disease and treatment failure) and probably the circulating parasite biomass, favoring the emergence of drug resistance parasites.The additional malaria parasite biomass related to HIV-1 co-infection in sub-Saharan Africa was estimated by a mathematical model. Parasite biomass was computed as the incidence rate of clinical malaria episodes multiplied by the number of parasites circulating in the peripheral blood of patients at the time symptoms appear. A mathematical model estimated the influence of HIV-1 infection on parasite density in clinical malaria by country and by age group, malaria transmission intensity and urban/rural area. In a multivariate sensitivity analysis, 95% confidence intervals (CIs) were calculated using the Monte Carlo simulation.The model shows that in 2005 HIV-1 increased the overall malaria parasite biomass by 18.0% (95%CI: 11.6-26.9). The largest relative increase (134.9-243.9%) was found in southern Africa where HIV-1 prevalence is the highest and malaria transmission unstable. The largest absolute increase was found in Zambia, Malawi, the Central African Republic and Mozambique, where both malaria and HIV are highly endemic. A univariate sensitivity analysis shows that estimates are sensitive to the magnitude of the impact of HIV-1 infection on the malaria incidence rates and associated parasite densities.The HIV-1 epidemic by increasing the malaria parasite biomass in sub-Saharan Africa may also increase the emergence of antimalarial drug resistance, potentially affecting the health of the whole population in countries endemic for both HIV-1 and malaria.

Alcohol is often consumed to reduce tension and improve mood when exposed to stressful situations. Previous studies showed that moderate alcohol consumption may reduce stress when alcohol is consumed prior to a stressor, but data on the effect of alcohol consumption after a mental stressor is limited. Therefore, our objective was to study whether moderate alcohol consumption immediately after a mental stressor attenuates the stress response. Twenty-four healthy men (age 21-40 y, BMI 18-27 kg/m2) participated in a placebo-controlled trial. They randomly consumed 2 cans (660 mL, ∼26 g alcohol) of beer or alcohol-free beer immediately after a mental stressor (Stroop task and Trier Social Stress Test). Physiological and immunological stress response was measured by monitoring heart rate and repeated measures of the hypothalamic-pituitary-adrenal axis (HPA-axis), white blood cells and a set of cytokines. After a mental stressor, cortisol and adrenocorticotropic hormone (ACTH) concentrations were 100% and 176% more reduced at 60 min (P = 0.012 and P = 0.001, respectively) and 92% and 60% more reduced at 90 min (P < 0.001 and P = 0.056, respectively) after beer consumption as compared to alcohol-free beer consumption. Heart rate and dehydroepiandrosterone (DHEA) were not influenced by alcohol consumption. Plasma IL-8 concentrations remained lower during the stress recovery period after beer consumption than after alcohol-free beer consumption (P < 0.001). In conclusion, consumption of a moderate dose of alcohol after a mental stressor may facilitate recovery of the endocrine stress response as reflected by decreasing plasma ACTH and cortisol.

AbstractThe high incidence of lung cancer in Xuanwei County, China has been attributed to exposure to indoor smoky coal emissions that contain polycyclic aromatic hydrocarbons (PAHs). The inflammatory response induced by coal smoke components may promote lung tumor development. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and lung cancer risk in a population‐based case–control study (122 cases and 122 controls) in Xuanwei. A total of 1,360 tag SNPs in 149 gene regions were included in the analysis. FCER2 rs7249320 was the most significant SNP (OR: 0.30; 95% CI: 0.16–0.55; P: 0.0001; false discovery rate value, 0.13) for variant carriers. The gene regions ALOX12B/ALOX15B and KLK2 were associated with increased lung cancer risk globally (false discovery rate value <0.15). In addition, there were positive interactions between KLK15 rs3745523 and smoky coal use (OR: 9.40; Pinteraction = 0.07) and between FCER2 rs7249320 and KLK2 rs2739476 (OR: 10.77; Pinteraction = 0.003). Our results suggest that genetic polymorphisms in innate immunity genes may play a role in the genesis of lung cancer caused by PAH‐containing coal smoke. Integrin/receptor and complement pathways as well as IgE regulation are particularly noteworthy. Environ. Mol. Mutagen., 2009. Published 2009 Wiley‐Liss, Inc.

AbstractAdolescence is an important developmental period associated with increased risk for excessive alcohol use, but also high rates of recovery from alcohol use-related problems, suggesting potential resilience to long-term effects compared to adults. The aim of this systematic review is to evaluate the current evidence for a moderating role of age on the impact of chronic alcohol exposure on the brain and cognition. We searched Medline, PsycInfo, and Cochrane Library databases up to February 3, 2021. All human and animal studies that directly tested whether the relationship between chronic alcohol exposure and neurocognitive outcomes differs between adolescents and adults were included. Study characteristics and results of age-related analyses were extracted into reference tables and results were separately narratively synthesized for each cognitive and brain-related outcome. The evidence strength for age-related differences varies across outcomes. Human evidence is largely missing, but animal research provides limited but consistent evidence of heightened adolescent sensitivity to chronic alcohol’s effects on several outcomes, including conditioned aversion, dopaminergic transmission in reward-related regions, neurodegeneration, and neurogenesis. At the same time, there is limited evidence for adolescent resilience to chronic alcohol-induced impairments in the domain of cognitive flexibility, warranting future studies investigating the potential mechanisms underlying adolescent risk and resilience to the effects of alcohol. The available evidence from mostly animal studies indicates adolescents are both more vulnerable and potentially more resilient to chronic alcohol effects on specific brain and cognitive outcomes. More human research directly comparing adolescents and adults is needed despite the methodological constraints. Parallel translational animal models can aid in the causal interpretation of observed effects. To improve their translational value, future animal studies should aim to use voluntary self-administration paradigms and incorporate individual differences and environmental context to better model human drinking behavior.