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Background and PurposeVarenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*‐containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption.Experimental ApproachRats were trained to consume ethanol using the intermittent‐access two‐bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core‐shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast‐scan cyclic voltammetry (FSCV).Key ResultsMicroinfusion of varenicline into the NAc core and core‐shell border, but not into the NAc shell or VTA, reduced ethanol intake following long‐term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc.Conclusion and ImplicationsFollowing long‐term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption.

The substrate specificity, pH activity curves, inhibition characteristics and in vitro stabilities of the human ADH isozymes characteristic of the structural loci, ADH1, ADH2 and ADH3, have been investigated using crude tissue extracts and partially purified material. Alcohol substrates: Seventeen different alcohols were tested. The products of the three loci showed differences in their relative activities with the different substrates. Thus ADH1 isozymes were most active with ethanol, allyl alcohol, sec propanol and cyclohexanol; the 'usual' ADH2 were most active with ethanol, butanol, octanol and sec butanol; the 'atypical' ADH2 isozymes were most active with ethanol and octanol, but showed relatively low activity with butanol and Ronicol; the ADH3 isozymes were relatively very active with long straight chain primary alcohols. Aldehyde substrates: Six different aldehydes were tested. No significant differences between the isozyme products of the three loci were detected except in the case of chloral hydrate. The ADH1 and 'usual' ADH2 isozymes showed activity with chloral hydrate but this was a very poor substrate for the ADH3 and 'atypical' ADH2 isozymes. pH activity profiles: With ethanol as substrate the pH optimum for the ADH1, 'usual' ADH2 and the ADH3 isozymes was around pH 11.5 and for the 'atypical' ADH2 isozymes was about pH 8.8. With acetaldehyde as substrate the pH optima for the ADH1, 'usual' ADH2, 'atypical' ADH2 and ADH3 isozymes were about pH 8.8, 6.0, 7.0-7.5 and 6.5, resp. Inhibitors: Trichloroethanol was found to be a potent inhibitor of the ADH1 isozymes; isobutyramide an inhibitor of ADH3; and pyrazole and thiourea were shown to be powerful inhibitors of the 'atypical' ADH2 isozymes. In vitro stability: The ADH1 isozymes appeared to be relatively less stable than the 'usual' ADH2 and ADH3 isozymes. The 'atypical' ADH2 isozymes were found to be relatively very labile and particularly susceptible to freezing and thawing or storage at 10° C. The ADH 1;3 and ADH 2;3 isozymes were not demonstrably different in the properties tested.

As atmospheric greenhouse gas concentrations continue to rise, temperature and humidity will increase further, causing potentially dire increases in human heat stress. On physiological and biophysical grounds, exposure to higher levels of humidity should worsen heat stress by decreasing sweat evaporation. However, population-scale epidemiological studies of heat exposure and response often do not detect associations between high levels of humidity and heat-related mortality or morbidity. These divergent, disciplinary views regarding the role of humidity in heat-related health risks limit confidence in selecting which interventions are effective in reducing health impacts and in projecting future heat-related health risks.Via our multidisciplinary perspective we seek to a) reconcile the competing realities concerning the role of humidity in heat-related health impacts and b) help ensure robust projections of heat-related health risks with climate change. These objectives are critical pathways to identify and communicate effective approaches to cope with present and future heat challenges.We hypothesize six key reasons epidemiological studies have found little impact of humidity on heat-health outcomes: a) At high temperatures, there may be limited influence of humidity on the health conditions that cause most heat-related deaths (i.e., cardiovascular collapse); b) epidemiological data sets have limited spatial extent, a bias toward extratropical (i.e., cooler and less humid), high-income nations, and tend to exist in places where temporal variations in temperature and humidity are positively correlated; c) analyses focus on older, vulnerable populations with sweating, and thus evaporative, impairments that may be further aggravated by dehydration; d) extremely high levels of temperature and humidity (seldom seen in the historical record) are necessary for humidity to substantially impact heat strain of sedentary individuals; e) relationships between temperature and humidity are improperly considered when interpreting epidemiological model results; and f) sub-daily meteorological phenomena, such as rain, occur at high temperatures and humidity, and may bias epidemiological studies based on daily data. Future research must robustly test these hypotheses to advance methods for more accurate incorporation of humidity in estimating heat-related health outcomes under present and projected future climates. https://doi.org/10.1289/EHP11807.

AbstractDengue is a mosquito-borne viral infection that has spread throughout the tropical world over the past 60 years and now affects over half the world’s population. The geographical range of dengue is expected to further expand due to ongoing global phenomena including climate change and urbanization. We applied statistical mapping techniques to the most extensive database of case locations to date to predict global environmental suitability for the virus as of 2015. We then made use of climate, population and socioeconomic projections for the years 2020, 2050 and 2080 to project future changes in virus suitability and human population at risk. This study is the first to consider the spread of Aedes mosquito vectors to project dengue suitability. Our projections provide a key missing piece of evidence for the changing global threat of vector-borne disease and will help decision-makers worldwide to better prepare for and respond to future changes in dengue risk.

AbstractProgression of chronic infections to end‐stage diseases and poor treatment results are frequently associated with alcohol abuse. Alcohol metabolism suppresses innate and adaptive immunity leading to increased viral load and its spread. In case of hepatotropic infections, viruses accelerate alcohol‐induced hepatitis and liver fibrosis, thereby promoting end‐stage outcomes, including cirrhosis and hepatocellular carcinoma (HCC). In this review, we concentrate on several unexplored aspects of these phenomena, which illustrate the combined effects of viral/bacterial infections and alcohol in disease development. We review alcohol‐induced alterations implicated in immunometabolism as a central mechanism impacting metabolic homeostasis and viral pathogenesis in Simian immunodeficiency virus/human immunodeficiency virus infection. Furthermore, in hepatocytes, both HIV infection and alcohol activate oxidative stress to cause lysosomal dysfunction and leakage and apoptotic cell death, thereby increasing hepatotoxicity. In addition, we discuss the mechanisms of hepatocellular carcinoma and tumor signaling in hepatitis C virus infection. Finally, we analyze studies that review and describe the immune derangements in hepatotropic viral infections focusing on the development of novel targets and strategies to restore effective immunocompetency in alcohol‐associated liver disease. In conclusion, alcohol exacerbates the pathogenesis of viral infections, contributing to a chronic course and poor outcomes, but the mechanisms behind these events are virus specific and depend on virus–alcohol interactions, which differ among the various infections.

Astronauts are exposed to charged particles during space travel, and charged particles are also used for cancer radiotherapy. Premature ovarian failure is a well-known side effect of conventional, low linear energy transfer (LET) cancer radiotherapy, but little is known about the effects of high LET charged particles on the ovary. We hypothesized that lower LET (16.5 keV/µm) oxygen particles would be less damaging to the ovary than we previously found for iron (LET = 179 keV/µm). Adult female mice were irradiated with 0, 5, 30 or 50 cGy oxygen ions or 50 cGy oxygen plus dietary supplementation with the antioxidant alpha lipoic acid (ALA). Six-hour after irradiation, percentages of ovarian follicles immunopositive for γH2AX, a marker of DNA double strand breaks, 4-HNE, a marker of oxidative lipid damage and BBC3 (PUMA), a proapoptotic BCL-2 family protein, were dose dependently increased in irradiated mice compared to controls. One week after irradiation, numbers of primordial, primary and secondary follicles per ovary were dose dependently decreased, with complete absence of follicles in the 50 cGy groups. The ED50 for primordial follicle destruction was 4.6 cGy for oxygen compared to 27.5 cGy for iron in our previous study. Serum FSH and LH concentrations were significantly elevated in 50 cGy groups at 8 week. Supplementation with ALA mitigated the early effects, but not the ultimate depletion of ovarian follicles. In conclusion, oxygen charged particles are even more potent inducers of ovarian follicle depletion than charged iron particles, raising concern for premature ovarian failure in astronauts exposed to both particles during space travel.

BackgroundAlcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified.MethodsWe conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)‐response behaviors. We tested 1 primate‐specific gene for expression differences in case/control postmortem brain tissue.ResultsWe detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta‐analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling‐induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self‐administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc).ConclusionsWe detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.