Risk Pathways Contributing to the Alcohol Harm Paradox: Socioeconomic Deprivation Confers Susceptibility to Alcohol Dependence via Greater Exposure to Aversive Experience, Internalizing Symptoms and Drinking to Cope

This is the final version. Available on open access from Frontiers MediaData Availability Statement: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Socioeconomic deprivation is associated with greater alcohol problems despite lower alcohol consumption, but the mechanisms underpinning this alcohol harm paradox remain obscure. Fragmented published evidence collectively supports a multistage causal risk pathway wherein socioeconomic deprivation increases the probability of exposure to aversive experience, which promotes internalizing symptoms (depression and anxiety), which promotes drinking alcohol to cope with negative affect, which in turn accelerates the transition from alcohol use to dependence. To evaluate this proposed risk pathway, 219 hazardous drinkers from an undergraduate population completed questionnaires assessing these constructs in a single, cross sectional, online survey. Partial correlation coefficients revealed that each variable showed the strongest unique association with the next variable in the proposed multistage model, when adjusting for the other variables. Bootstrapped serial mediation analysis revealed that the indirect pathway linking all the variables in the proposed serial order was significant, while all other permutations were non-significant. Network centrality analysis corroborated the serial order of this indirect path. Finally, risk ratios estimated by categorizing the variables suggested that socioeconomic deprivation increased the risk of aversive experience by 32%, which increased the risk of internalizing symptoms by 180%, which increased the risk of drinking to cope by 64%, which increased susceptibility to alcohol dependence by 59%. These preliminary findings need to be corroborated by future research, nevertheless, they call for prevention strategies founded on social justice and the minimization of aversive experience in socially deprived individuals to mitigate mental health problems, maladaptive coping and addiction.Alcohol Research UKMedical Research Council (MRC

The direct effect of drinking to cope on alcohol problems is not mediated by alcohol consumption: Invariance across gender and countries

This is the final version. Available on open access from Elsevier via the DOI in this recordData availability: Data will be made available on request.BACKGROUND: Drinking to cope with negative affect confers a direct risk of alcohol problems independently of greater alcohol consumption (i.e., confers susceptibility to the alcohol harm paradox). However, it remains unclear whether this risk is common across gender and countries. METHODS: The current study applied path analysis to two cross-sectional samples of 18-25-year-old undergraduate hazardous drinking students recruited from the UK (Study 1; N = 873) and internationally (Study 2; N = 4064 recruited in Argentina, Canada, South Africa, Spain, Uruguay, USA, and England). The Drinking Motives Questionnaire (DMQ) measured drinking to cope with negative affect and drinking to enhance positive affect (i.e., enhancement motives). The Alcohol Use Disorders Identification Test (AUDIT) measured alcohol consumption and problems. RESULTS: In both studies, drinking to cope with negative affect had a direct effect on alcohol problems (S1: β = 0.259, SE = 0.031, p <.001; S2: β = 0.255, SE = 0.017, p <.001), and only a negligible proportion of this effect was mediated by alcohol consumption (S1: 2.58 %, p =.550; S2: 0.79 %, p=.538). By contrast, drinking to enhance positive affect had a smaller direct effect on alcohol problems (S1: β = 0.000, SE = 0.033, p =.989; S2: β = 0.044, SE = 0.017, p =.009), and a substantial proportion of this effect was mediated by greater alcohol consumption (S1: 99.76 %, p <.001; S2: 60.36 %, p <.001). Crucially, in both studies, the direct effect of drinking to cope on alcohol problems was invariant across gender and countries. CONCLUSIONS: These findings suggest that individuals who endorse drinking to cope with negative affect are uniquely susceptible to the alcohol harm paradox, that is, greater alcohol problems which cannot be explained by greater alcohol consumption, and this susceptibility is common across gender and countries.Alcohol Change UKMedical Research Council (MRC

Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation

Aims: Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. Methods and results: We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012). Conclusions: Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage

The role of impulsivity in the aetiology of drug dependence: reward sensitivity versus automaticity

Journal ArticleResearch Support, Non-U.S. Gov'tCopyright © The Author(s) 2011.RATIONALE: Impulsivity has long been known as a risk factor for drug dependence, but the mechanisms underpinning this association are unclear. Impulsivity may confer hypersensitivity to drug reinforcement which establishes higher rates of instrumental drug-seeking and drug-taking behaviour, or may confer a propensity for automatic (non-intentional) control over drug-seeking/taking and thus intransigence to clinical intervention. METHOD: The current study sought to distinguish these two accounts by measuring Barratt Impulsivity and craving to smoke in 100 smokers prior to their completion of an instrumental concurrent choice task for tobacco (to measure the rate of drug-seeking) and an ad libitum smoking test (to measure the rate of drug-taking-number of puffs consumed). RESULTS: The results showed that impulsivity was not associated with higher rates of drug-seeking/taking, but individual differences in smoking uptake and craving were. Rather, nonplanning impulsivity moderated (decreased) the relationship between craving and drug-taking, but not drug-seeking. CONCLUSIONS: These data suggest that whereas the uptake of drug use is mediated by hypervaluation of the drug as an instrumental goal, the orthogonal trait nonplanning impulsivity confers a propensity for automatic control over well-practiced drug-taking behaviour.MR

Engineered hexavalent Fc proteins with enhanced Fc-gamma receptor avidity provide insights into immune-complex interactions

Tania Rowley et al. present multivalent Fc molecules with enhanced avidity for Fc gamma receptors in order to improve the treatment of autoantibody-mediated human diseases. They found several key amino acids involved in Fc receptor binding interactions

Proteomic Analyses of Host and Pathogen Responses during Bovine Mastitis

The pursuit of biomarkers for use as clinical screening tools, measures for early detection, disease monitoring, and as a means for assessing therapeutic responses has steadily evolved in human and veterinary medicine over the past two decades. Concurrently, advances in mass spectrometry have markedly expanded proteomic capabilities for biomarker discovery. While initial mass spectrometric biomarker discovery endeavors focused primarily on the detection of modulated proteins in human tissues and fluids, recent efforts have shifted to include proteomic analyses of biological samples from food animal species. Mastitis continues to garner attention in veterinary research due mainly to affiliated financial losses and food safety concerns over antimicrobial use, but also because there are only a limited number of efficacious mastitis treatment options. Accordingly, comparative proteomic analyses of bovine milk have emerged in recent years. Efforts to prevent agricultural-related food-borne illness have likewise fueled an interest in the proteomic evaluation of several prominent strains of bacteria, including common mastitis pathogens. The interest in establishing biomarkers of the host and pathogen responses during bovine mastitis stems largely from the need to better characterize mechanisms of the disease, to identify reliable biomarkers for use as measures of early detection and drug efficacy, and to uncover potentially novel targets for the development of alternative therapeutics. The following review focuses primarily on comparative proteomic analyses conducted on healthy versus mastitic bovine milk. However, a comparison of the host defense proteome of human and bovine milk and the proteomic analysis of common veterinary pathogens are likewise introduced

Conservation of Complex Nuclear Localization Signals Utilizing Classical and Non-Classical Nuclear Import Pathways in LANA Homologs of KSHV and RFHV

ORF73 latency-associated nuclear antigen (LANA) of the Kaposi's sarcoma-associated herpesvirus (KSHV) is targeted to the nucleus of infected cells where it binds to chromatin and mediates viral episome persistence, interacts with cellular proteins and plays a role in latency and tumorigenesis. A structurally related LANA homolog has been identified in the retroperitoneal fibromatosis herpesvirus (RFHV), the macaque homolog of KSHV. Here, we report the evolutionary and functional conservation of a novel bi-functional nuclear localization signal (NLS) in KSHV and RFHV LANA. N-terminal peptides from both proteins were fused to EGFP or double EGFP fusions to examine their ability to induce nuclear transport of a heterologous protein. In addition, GST-pull down experiments were used to analyze the ability of LANA peptides to interact with members of the karyopherin family of nuclear transport receptors. Our studies revealed that both LANA proteins contain an N-terminal arginine/glycine (RG)-rich domain spanning a conserved chromatin-binding motif, which binds directly to importin β1 in a RanGTP-sensitive manner and serves as an NLS in the importin β1-mediated non-classical nuclear import pathway. Embedded within this domain is a conserved lysine/arginine-(KR)-rich bipartite motif that binds directly to multiple members of the importin α family of nuclear import adaptors in a RanGTP-insensitive manner and serves as an NLS in the classical importin α/β-mediated nuclear import pathway. The positioning of a classical bipartite kr-NLS embedded within a non-classical rg-NLS is a unique arrangement in these viral proteins, whose nuclear localization is critical to their functionality and to the virus life cycle. The ability to interact with multiple import receptors provides alternate pathways for nuclear localization of LANA. Since different import receptors can import cargo to distinct subnuclear compartments, a multifunctional NLS may provide LANA with an increased ability to interact with different nuclear components in its multifunctional role to maintain viral latency