"Drinking in the Dark" (DID): a simple mouse model of binge-like alcohol intake

One of the greatest challenges that scientists face when studying the neurobiology and/or genetics of alcohol (ethanol) consumption is that most preclinical animal models do not voluntarily consume enough ethanol to achieve pharmacologically meaningful blood ethanol concentrations (BECs). Recent rodent models have been developed that promote binge-like levels of ethanol consumption associated with high BECs (i.e., ≥100 mg/dl). This unit describes procedures for an animal model of binge-like ethanol drinking which has come to be called "drinking in the dark" (DID). The "basic" variation of DID involves replacing the water bottle with a bottle containing 20% ethanol for 2 to 4 hr, beginning 3 hr into the dark cycle, on cages of singly-housed C57BL/6J mice. Using this procedure, mice typically consume enough ethanol to achieve BECs >100 mg/dl and to exhibit behavioral evidence of intoxication. An alternative two-bottle (ethanol and water) procedure is also described

Genetic relationship between predisposition for binge alcohol consumption and blunted sensitivity to adverse effects of alcohol in mice

BACKGROUND: Initial sensitivity to ethanol (EtOH) and the capacity to develop acute functional tolerance (AFT) to its adverse effects may influence the amount of alcohol consumed and may also predict future alcohol use patterns. The current study assessed sensitivity and AFT to the ataxic and hypnotic effects of EtOH in the first replicate of mice (HDID-1) selectively bred for high blood EtOH concentrations (BECs) following limited access to EtOH in the Drinking in the Dark (DID) paradigm. METHODS: Naïve male and female HDID-1 and HS/Npt mice from the progenitor stock were evaluated in 3 separate experiments. In Experiments 1 and 2, EtOH-induced ataxia was assessed using the static dowel task. In Experiment 3, EtOH-induced hypnosis was assessed by using modified restraint tubes to measure the loss of righting reflex (LORR). RESULTS: HDID-1 mice exhibited reduced initial sensitivity to both EtOH-induced ataxia (p < 0.001) and hypnosis (p < 0.05) relative to HS/Npt mice. AFT was calculated by subtracting the BEC at loss of function from the BEC at recovery (Experiments 1 and 3) or by subtracting BEC at an initial recovery from the BEC at a second recovery following an additional alcohol dose (Experiment 2). The dowel test yielded no line differences in AFT, but HS/Npt mice developed slightly greater AFT to EtOH-induced LORR than HDID-1 (p < 0.05). CONCLUSIONS: These results suggest that HDID-1 mice exhibit aspects of blunted ataxic and hypnotic sensitivity to EtOH which may influence their high EtOH intake via DID, but do not display widely different development of AFT. These findings differ from previous findings with the high alcohol-preferring (HAP) selected mouse lines, suggesting that genetic predisposition for binge, versus other forms of excessive alcohol consumption, is associated with unique responses to EtOH-induced motor incoordination

Increased Nitric Oxide and Attenuated Diastolic Blood Pressure Variability in African Americans with Mildly Impaired Renal Function

We investigated the relationship between renal function, blood pressure variability (BPV), and nitric oxide (NO) in a group of African Americans with normal or mildly impaired renal function. 24-hour ambulatory blood pressure monitoring was performed, NO measured, and glomerular filtration rate (GFR) calculated in 38 African Americans. Participants were categorized as having normal (GFR > 90 mL/min per 1.73 m2) or mildly impaired (GFR 60–89 mL/min per 1.73 m2) renal function. Diastolic BPV was significantly lower in the mildly impaired renal function group. Regression analyses revealed a significant positive association between GFR and diastolic BPV for the entire study group. Plasma NO levels were significantly higher in the mildly impaired renal function group and negatively correlated with diastolic BPV. In conclusion, diastolic BPV was reduced in African Americans with mildly impaired renal function, which may be the result of increased NO production. These results conflict with previous findings in diseased and nonblack populations and could provide rationale for studying BPV early in the disease state when BP-buffering mechanisms are still preserved

Photo-induced anticancer activity and singlet oxygen production of prodigiosenes

© 2018 The Royal Society of Chemistry and Owner Societies. The photo-induced cytotoxicity of prodigiosenes is reported. One prodigiosene represents a synthetic analogue of the natural product prodigiosin, and two are conjugated to molecules that target the estrogen receptor (ER). A comparison of incubation and irradiation frameworks for the three prodigiosenes is reported, with activity against ER- and ER+ lines explored. Furthermore, the ability of the three prodigiosenes to photosensitise the production of singlet oxygen is demonstrated, shedding mechanistic light onto possible photodynamic therapeutic effects of this class of tripyrroles

The anti-microbial peptide (Lin-SB056-1)2-K reduces pro-inflammatory cytokine release through interaction with Pseudomonas aeruginosa lipopolysaccharide

The ability of many anti-microbial peptides (AMPs) to modulate the host immune response has highlighted their possible therapeutic use to reduce uncontrolled inflammation during chronic infections. In the present study, we examined the anti-inflammatory potential of the semi-synthetic peptide lin-SB056-1 and its dendrimeric derivative (lin-SB056-1)2-K, which were previously found to have anti-microbial activity against Pseudomonas aeruginosa in in vivo-like models mimicking the challenging environment of chronically infected lungs (i.e., artificial sputum medium and 3-D lung mucosa model). The dendrimeric derivative exerted a stronger anti-inflammatory activity than its monomeric counterpart towards lung epithelial-and macrophage-cell lines stimulated with P. aeruginosa lipopolysaccharide (LPS), based on a marked decrease (up to 80%) in the LPS-induced production of different pro-inflammatory cytokines (i.e., IL-1β, IL-6 and IL-8). Accordingly, (lin-SB056-1)2-K exhibited a stronger LPS-binding affinity than its monomeric counterpart, thereby suggesting a role of peptide/LPS neutralizing interactions in the observed anti-inflammatory effect. Along with the anti-bacterial and anti-biofilm properties, the anti-inflammatory activity of (lin-SB056-1)2-K broadens its therapeutic potential in the context of chronic (biofilm-associated) infections

Hazard ranking method for populations exposed to arsenic in private water supplies: relation to bedrock geology

Approximately one million people in the UK are served by private water supplies (PWS) where main municipal water supply system connection is not practical or where PWS is the preferred option. Chronic exposure to contaminants in PWS may have adverse effects on health. South West England is an area with elevated arsenic concentrations in groundwater and over 9000 domestic dwellings here are supplied by PWS. There remains uncertainty as to the extent of the population exposed to arsenic (As), and the factors predicting such exposure. We describe a hazard assessment model based on simplified geology with the potential to predict exposure to As in PWS. Households with a recorded PWS in Cornwall were recruited to take part in a water sampling programme from 2011 to 2013. Bedrock geologies were aggregated and classified into nine Simplified Bedrock Geological Categories (SBGC), plus a cross-cutting “mineralized” area. PWS were sampled by random selection within SBGCs and some 508 households volunteered for the study. Transformations of the data were explored to estimate the distribution of As concentrations for PWS by SBGC. Using the distribution per SBGC, we predict the proportion of dwellings that would be affected by high concentrations and rank the geologies according to hazard. Within most SBGCs, As concentrations were found to have log-normal distributions. Across these areas, the proportion of dwellings predicted to have drinking water over the prescribed concentration value (PCV) for As ranged from 0% to 20%. From these results, a pilot predictive model was developed calculating the proportion of PWS above the PCV for As and hazard ranking supports local decision making and prioritization. With further development and testing, this can help local authorities predict the number of dwellings that might fail the PCV for As, based on bedrock geology. The model presented here for Cornwall could be applied in areas with similar geologies. Application of the method requires independent validation and further groundwater-derived PWS sampling on other geological formation

Reviewing research evidence and the case of participation in sport and physical recreation by black and minority ethnic communities

The paper addresses the implications of using the process of systematic review in the many areas of leisure where there is a dearth of material that would be admitted into conventional Cochrane Reviews. This raises important questions about what constitutes legitimate knowledge, questions that are of critical import not just to leisure scholars, but to the formulation of policy. The search for certainty in an area that lacks conceptual consensus results in an epistemological imperialism that takes a geocentric form. While clearly, there is a need for good research design whatever the style of research, we contend that the wholesale rejection of insightful research is profligate and foolhardy. A mechanism has to be found to capitalise on good quality research of whatever form. In that search, we draw upon our experience of conducting a review of the material available on participation in sport and physical recreation by people from Black and minority ethnic groups. The paper concludes with a proposal for a more productive review process that makes better use of the full panoply of good quality research available. © 2012 © 2012 Taylor & Francis

Comparative transcriptome analysis of embryonic and adult stem cells with extended and limited differentiation capacity

Comparison of the transcriptomes of pluripotent embryonic stem cells, multipotent adult progenitor cells and lineage restricted mesenchymal stem cells identified a unique gene expression profile of multipotent adult progenitor cells

Effects of Moderate Aerobic Exercise Training on Vascular Health and Blood Pressure in African Americans

As healthcare progresses toward individualized medicine, understanding how different racial groups respond to lifestyle interventions is valuable. It is established that African Americans have disproportionate levels of cardiovascular disease and impaired vascular health, and clinical practice guidelines suggest lifestyle interventions as the first line of treatment. Recently, the authors reported that 6 months of aerobic exercise improved inflammatory markers, flow-mediated dilation (FMD), and levels of circulating endothelial microparticles (EMPs) in African American adults. This study is a subgroup analysis of the aerobic exercise–induced changes in vascular health and blood pressure (BP) measures, including carotid artery intima-media thickness (IMT), nitroglycerin-mediated dilation (NMD), ambulatory BP, and office BP. Sedentary African American adults (53.4±6.2 years; 21 women and 5 men) showed improved vascular health but no change in BP. Carotid artery IMT decreased 6.4%, plasma nitric oxide levels increased 76.6%, plasma EMP levels decreased, percentage of FMD increased 59.6%, and FMD/NMD ratio increased 36.2% (P<.05 for all). Six months of aerobic exercise training is sufficient to elicit improvements in vascular structure and function in African Americans, even without improvements in BP measures or NMD (ie, smooth muscle function). To our knowledge, this is the first study to report such findings in African Americans