bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ethanol Attenuation of Long‐Term Depression in the Nucleus Accumbens Can Be Overcome by Activation of TRPV1 Receptors
Authors: Renteria Rafael , Jeanes Zachary M. , Morrisett Richard A. 
Published: November 2014

BackgroundAltered expression of synaptic plasticity within the nucleus accumbens (NAc) constitutes a critical neuroadaptive response to ethanol (EtOH) and other drugs of abuse. We have previously reported that N‐methyl‐D‐aspartate receptor (NMDAR)‐dependent long‐term depression (LTD) is markedly affected by chronic intermittent ethanol exposure in vivo; however, endocannabinoid (eCB)‐dependent synaptic depression, despite being very well‐documented in the dorsal striatum, is much less well understood in the NAc.MethodsWhole cell patch clamp electrophysiology was used to investigate interactions between these different plasticity‐induction systems. Excitatory postsynaptic currents (EPSCs) were measured in the NAc shell and NMDAR‐LTD was induced by a pairing protocol (500 stimuli at 1 Hz stimulation [low‐frequency stimulation (LFS)] paired with postsynaptic depolarization to −50 mV). AM251, a CB1 receptor antagonist, was used to determine whether this form of LTD is modulated by eCBs. To determine the effect of EtOH on a purely eCB‐dependent response in the NAc, depolarization‐induced suppression of excitation (DSE) was used in the presence of 40 mM EtOH. Finally, we determined whether the enhancement of eCB signaling with URB597, a fatty acid amide hydrolase inhibitor, and AM404, an anandamide re‐uptake inhibitor would also modulate LFS LTD in the presence of NMDAR blockade or EtOH.ResultsIn the presence of AM251, the LFS pairing protocol resulted in NMDAR‐dependent long‐term potentiation that was blocked with either EtOH or DL‐APV. We also found that DSE in the NAc shell was blocked by AM251 and suppressed by EtOH. Enhanced eCB signaling rescued NAc‐LTD expression in the presence of EtOH through a distinct mechanism requiring activation of TRPV1 receptors.ConclusionsEtOH modulation of synaptic plasticity in the NAc is dependent upon a complex interplay between NMDARs, eCBs, and TRPV1 receptors. These findings demonstrate a novel form of TRPV1‐dependent LTD in the NAc shell that may be critical for EtOH dependence.
Methods to Analyze Treatment Effects in the Presence of Missing Data for a Continuous Heavy Drinking Outcome Measure When Participants Drop Out from Treatment in Alcohol Clinical Trials
Authors: Witkiewitz Katie , Falk Daniel E. , Kranzler Henry R. , Litten Raye Z. , Hallgren Kevin A. , O'Malley Stephanie S. , Anton Raymond F. ,   In conjunction with the Alcohol Clinical Trials Initiative (ACTIVE) Workgroup
Published: November 2014

BackgroundAttrition is common in alcohol clinical trials and the resultant loss of data represents an important methodological problem. In the absence of a simulation study, the drinking outcomes among those who are lost to follow‐up are not known. Individuals who drop out of treatment and continue to provide drinking data, however, may be a reasonable proxy group for making inferences about the drinking outcomes of those lost to follow‐up.MethodsWe used data from the COMBINE study, a multisite, randomized clinical trial, to examine drinking during the 4 months of treatment among individuals who dropped out of treatment but continued to provide drinking data (i.e., “treatment dropouts;” n = 185). First, we estimated the observed treatment effect size for naltrexone versus placebo in a sample that included both treatment completers (n = 961) and treatment dropouts (n = 185; total N = 1,146), as well as the observed treatment effect size among just those who dropped out of treatment (n = 185). In both the total sample (N = 1,146) and the dropout sample (n = 185), we then deleted the drinking data after treatment dropout from those 185 individuals to simulate missing data. Using the deleted data sets, we then estimated the effect of naltrexone on the continuous outcome percent heavy drinking days using 6 methods to handle missing data (last observation carried forward, baseline observation carried forward, placebo mean imputation, missing = heavy drinking days, multiple imputation (MI), and full information maximum likelihood [FIML]).ResultsMI and FIML produced effect size estimates that were most similar to the true effects observed in the full data set in all analyses, while missing = heavy drinking days performed the worst.ConclusionsAlthough missing drinking data should be avoided whenever possible, MI and FIML yield the best estimates of the treatment effect for a continuous outcome measure of heavy drinking when there is dropout in an alcohol clinical trial.
Chronic Binge Alcohol Administration Accentuates Expression of Pro‐Fibrotic and Inflammatory Genes in the Skeletal Muscle of Simian Immunodeficiency Virus–Infected Macaques
Authors: Dodd Tracy , Simon Liz , LeCapitaine Nicole J. , Zabaleta Jovanny , Mussell Jason , Berner Paul , Ford Stephen , Dufour Jason , Bagby Gregory J. , Nelson Steve , Molina Patricia E. 
Published: November 2014

BackgroundChronic binge alcohol (CBA) administration exacerbates skeletal muscle (SKM) wasting at the terminal stage of simian immunodeficiency virus (SIV) infection in rhesus macaques. This is associated with a pro‐inflammatory and oxidative milieu which we have previously shown to be associated with a disrupted balance between anabolic and catabolic mechanisms. In this study, we attempted to characterize the SKM gene expression signature in CBA‐administered SIV‐infected macaques, using the same animals from the previous study.MethodsAdministration of intragastric alcohol or sucrose to male rhesus macaques began 3 months prior to SIV infection and continued throughout the duration of study. Gene transcriptomes of SKM excised at necropsy (~10 months post‐SIV) from healthy na\xEFve control (Control), sucrose‐administered, SIV‐infected (SUC‐SIV), and CBA‐administered, SIV‐infected (CBA‐SIV) macaques were evaluated in microarray data sets. The Protein Analysis Through Evolutionary Relationships classification tool was used to filter differentially regulated genes based on their predicted function into select biological processes relevant to SKM wasting which were inflammation, extracellular matrix (ECM) remodeling, and metabolism.ResultsIn total, 1,124 genes were differentially regulated between SUC‐SIV and Controls, 2,022 genes were differentially expressed between the CBA‐SIV and Controls, and 836 genes were differentially expressed between CBA‐SIV and SUC‐SIV animals. The relevance of altered gene expression was reflected in the up‐regulation of pro‐inflammatory CCL‐2, CCL‐8, CX3CL1, SELE, HP, and TNFRS10A mRNA expression. In addition, ECM remodeling was reflected in the up‐regulation of TIMP‐1, MMP 2, and MMP 9 mRNA expression and transforming growth factor‐beta 1 protein expression. In addition, hydroxyproline content and picrosirius staining reflected increased collagen deposition in the CBA‐SIV muscle tissue.ConclusionsThe results of the study demonstrate SKM inflammation as an important underlying mechanism for muscle wasting. In addition, the study provides evidence of SKM fibrotic transformation as a factor in CBA‐induced accentuation of SIV‐associated muscle wasting.
Stress‐Related Alcohol Consumption in Heavy Drinkers Correlates with Expression of miR‐10a, miR‐21, and Components of the TAR‐RNA‐Binding Protein‐Associated Complex
Authors: Beech Robert D. , Leffert Janine J. , Lin Aiping , Hong Kwangik A. , Hansen Julie , Umlauf Sheila , Mane Shrikant , Zhao Hongyu , Sinha Rajita 
Published: November 2014

BackgroundAlterations in stress‐related gene expression may play a role in stress‐related drinking and the risk of alcohol dependence.MethodsMicroarrays were used to measure changes in gene expression in peripheral blood in nonsmoking, social drinking subjects exposed to 3 types of personalized imagery: neutral, stressful (but not alcohol related), and alcohol‐related cues. Gene expression was measured at baseline, immediately after, and 1 hour after stimulus presentation. Subjects were allowed to drink up to 750 cc of beer in a “taste test” following stimulus presentation in each imagery condition, and the amount of beer consumed was recorded. Gene‐expression levels were compared in 2 groups of nonsmoking subjects (n = 11/group): heavy drinkers (HD; defined as regular alcohol use over the past year of at least 8 standard drinks per week for women and at least 15 standard drinks per week for men), and moderate drinkers (MD; defined as up to 7 standard drinks per week for women and 14 standard drinks per week for men). Expression of microRNA‐10a (miR‐10a) and microRNA‐21 (miR‐21) was assessed by quantitative real‐time polymerase chain reaction.ResultsAfter correction for multiple testing (false discovery rate < 0.05), 79 genes were identified that changed by >1.3‐fold in the HD group, but not the MD group, following exposure to stress. No changes were observed for any of these genes in either group following exposure to neutral or alcohol‐related imagery. Pathway analysis suggested that many of these genes, form part of the transactivation responsive (TAR)‐RNA‐binding protein (TRBP)‐associated complex and are positively regulated by miR‐10a and miR‐21. Expression of both miR‐10a and miR‐21 was up‐regulated following psychological stress in HD, but not MD subjects; however, the differences between groups were not statistically significant. Expression levels of both microRNAs was correlated (miR‐10a, R2 = 0.59, miR‐21 R2 = 0.57) with amount drunk in HD, but not MD subjects.ConclusionsExpression of miR‐10a, miR‐21, and several of their target genes is regulated by acute psychological stress and is correlated with stress‐induced drinking in a laboratory setting. Alterations in miRNA expression may be one mechanism linking psychological stress with changes in gene expression and increased alcohol intake in binge/HD.
Heavy Alcohol Use in Lung Donors Increases the Risk for Primary Graft Dysfunction
Authors: Lowery Erin M. , Kuhlmann Erica A. , Mahoney Erin L. , Dilling Daniel F. , Kliethermes Stephanie A. , Kovacs Elizabeth J. 
Published: November 2014

BackgroundHeavy alcohol use is known to increase the risk of acute lung injury and the acute respiratory distress syndrome. This is in part due to increased production of reactive oxygen species. We hypothesized that recipients of lungs from heavy drinkers would be more susceptible to lung injury following transplantation.MethodsIn this retrospective cohort study, donor histories and transplant outcomes were reviewed in 192 consecutive lung transplant recipients. Donors were classified as No Alcohol Use, Moderate Alcohol Use, or Heavy Alcohol Use based on documented donor histories.ResultsFreedom from mechanical ventilation took longer in the lung transplant recipients whose donors had Heavy Alcohol Use, compared with those whose donors had No Alcohol Use or Moderate Alcohol Use (p = 0.01). At admission to the intensive care unit, the Heavy Alcohol Use group had median PaO2/FiO2 ratio 219 (interquartile range [IQR]: 162 to 382), compared with 305 (IQR: 232 to 400) in the Moderate Alcohol Use group and 314 (IQR: 249 to 418) in the No Alcohol Use group (p = 0.005). The odds of developing severe primary graft dysfunction (PGD) in the Heavy Alcohol Use group versus the No Alcohol Use group were 8.7 times greater (95% confidence interval 1.427 to 53.404, p = 0.019) after controlling for factors known to be associated with PGD.ConclusionsRecipients of donors with a heavy alcohol use history had an over 8 times greater risk of developing severe PGD following lung transplant. The increase in PGD resulted in poorer gas exchange in the recipients of donor lungs from heavy alcohol users, and these recipients subsequently required mechanical ventilation for a longer time following transplant. Further investigation into lung donors with heavy alcohol use histories is necessary to determine those at highest risk for PGD following transplant.
Social Isolation Rearing Increases Nucleus Accumbens Dopamine and Norepinephrine Responses to Acute Ethanol in Adulthood
Authors: Karkhanis Anushree N. , Locke Jason L. , McCool Brian A. , Weiner Jeffrey L. , Jones Sara R. 
Published: November 2014

BackgroundEarly‐life stress is associated with increased vulnerability to alcohol addiction. However, the neural substrates linking chronic childhood/adolescent stress and increased risk of alcohol addiction are not well understood. In the nucleus accumbens (NAc), dopamine (DA) and norepinephrine (NE) signaling can be profoundly influenced by stress, anxiety, and drugs of abuse, including ethanol (EtOH). Here, we employed a rodent model of early‐life stress that results in enduring increases in behavioral risk factors of alcoholism to gain a better understanding of how chronic adolescent stress may impact the EtOH sensitivity of DA and NE release in the NAc.MethodsMale Long–Evans rats were either group housed (GH; 4 rats/cage) or socially isolated (SI; 1 rat/cage) for 6 weeks beginning on postnatal day 28. SI and GH rats were tested in adulthood for anxiety‐like behaviors (elevated plus maze), and the effects of EtOH (1 and 2 g/kg; intraperitoneally.) on NAc DA and NE were assessed by microdialysis.ResultsSI animals showed increased anxiety‐like behavior compared to GH animals. Although SI had no effect on baseline levels of DA or NE, baseline DA levels were positively correlated with anxiety measures. In addition, while no significant differences were observed with 1 g/kg EtOH, the 2 g/kg dose induced significantly greater DA release in SI animals. Moreover, EtOH (2 g/kg) only elevated NAc NE levels in SI rats.ConclusionsThese results suggest that chronic early‐life stress sensitizes accumbal DA and NE release in response to an acute EtOH challenge. A greater EtOH sensitivity of DA and NE release dynamics in the NAc may contribute to increases in behavioral risk factors of alcoholism, like greater EtOH self‐administration, that are observed in SI rats.
Prenatal Alcohol Exposure Alters Response of Kisspeptin‐ir Neurons to Estradiol and Progesterone in Adult Female Rats
Authors: Sliwowska Joanna H. , Bodnar Tamara S. , Weinberg Joanne 
Published: November 2014

BackgroundPrenatal alcohol exposure (PAE) has adverse effects on reproductive function and hypothalamic–pituitary–gonadal (HPG) activity. Kisspeptin neurons play a role in mediating feedback effects of estradiol (E2) and progesterone (P4) on the HPG axis. We hypothesized that PAE will have long‐term effects on the response of kisspeptin neurons to E2 and P4.MethodsAdult female rats (53 to 58 days) from prenatal ad libitum‐fed control (C), pair‐fed (PF), and alcohol‐exposed (PAE) groups were subjected to Sham ovariectomy (OVX) or OVX without or with replacement with low or high physiological levels of E2 and P4, and terminated under basal conditions. E2 and P4 levels, and the response of kisspeptin‐ir neurons in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei to these hormones, were measured. As the E2 signal is conveyed to kisspeptin neurons via estrogen receptor‐α (ER‐α), we investigated PAE effects on the number of kisspeptin‐ir/ER‐α‐ir neurons. To determine whether PAE alters interactions between kisspeptin and gonadotropin‐releasing hormone (GnRH) neurons, close contacts between kisspeptin‐ir fibers and GnRH‐ir cell bodies were examined.ResultsOur data present the novel finding that kisspeptin‐ir neurons in the ARC of PAE females show differential responses to E2 and to the combined treatment with E2 and P4 compared with controls: (i) OVX increased the number of kisspeptin‐ir neurons in C and PF, but not PAE females compared with their Sham counterparts; (ii) E2 replacement restored kisspeptin‐ir cell numbers to Sham levels in C and PF females but caused a robust down‐regulation of kisspeptin‐ir neurons below Sham levels in PAE females; (iii) OVX and replacement with high physiological concentrations of E2 resulted in fewer kisspeptin‐ir cells in PAE than C females; (iv) OVX and replacement with high levels of both E2 and P4 markedly decreased the number of kisspeptin‐ir neurons, below levels observed following E2 alone, in PF and C females, but had no significant effect in PAE females.ConclusionsThese data suggest that a possible mechanism underlying adverse effects of PAE on HPG function involves actions of alcohol on the kisspeptin system.
Adolescent Alcohol Exposure Alters GABAA Receptor Subunit Expression in Adult Hippocampus
Authors: Centanni Samuel W. , Teppen Tara , Risher Mary‐Louise , Fleming Rebekah L. , Moss Julia L. , Acheson Shawn K. , Mulholland Patrick J. , Pandey Subhash C. , Chandler L. Judson , Swartzwelder H. S. 
Published: November 2014

BackgroundThe long‐term consequences of adolescent alcohol abuse that persist into adulthood are poorly understood and have not been widely investigated. We have shown that intermittent exposure to alcohol during adolescence decreased the amplitude of GABAA receptor (GABAAR)‐mediated tonic currents in hippocampal dentate granule cells in adulthood. The aim of this study was to investigate the enduring effects of chronic intermittent alcohol exposure during adolescence or adulthood on the expression of hippocampal GABAARs.MethodsWe used a previously characterized tissue fractionation method to isolate detergent resistant membranes and soluble fractions, followed by Western blots to measure GABAAR protein expression. We also measured mRNA levels of GABAAR subunits using quantitative real‐time polymerase chain reaction.ResultsAlthough the protein levels of α1‐, α4‐, and δ‐GABAAR subunits remained stable between postnatal day (PD) 30 (early adolescence) and PD71 (adulthood), the α5‐GABAAR subunit was reduced across that period. In rats that were subjected to adolescent intermittent ethanol (AIE) exposure between PD30 and PD46, there was a significant reduction in the protein levels of the δ‐GABAAR, in the absence of any changes in mRNA levels, at 48 hours and 26 days after the last ethanol (EtOH) exposure. Protein levels of the α4‐GABAAR subunit were significantly reduced, but mRNA levels were increased, 26 days (but not 48 hours) after the last AIE exposure. Protein levels of α5‐GABAAR were not changed by AIE, but mRNA levels were reduced at 48 hours but normalized 26 days after AIE. In contrast to the effects of AIE, chronic intermittent ethanol (CIE) exposure during adulthood had no effect on expression of any of the GABAAR subunits examined.ConclusionsAIE produced both short‐ and long‐term alterations of GABAAR subunits mRNA and protein expression in the hippocampus, whereas CIE produced no long‐lasting effects on those measures. The observed reduction of protein levels of the δ‐GABAAR, specifically, is consistent with previously reported altered hippocampal GABAAR‐mediated electrophysiological responses after AIE. The absence of effects of CIE underscores the emerging view of adolescence as a time of distinctive vulnerability to the enduring effects of repeated EtOH exposure.
The P Wave Time‐Frequency Variability Reflects Atrial Conduction Defects before Paroxysmal Atrial Fibrillation
Authors: Alcaraz Raúl , Martínez Arturo , Rieta José J. 
Published: November 2014

BackgroundThe study of atrial conduction defects associated with the onset of paroxysmal atrial fibrillation (PAF) can be addressed by analyzing the P wave from the surface electrocardiogram (ECG). Traditionally, signal‐averaged ECGs have been mostly used for this purpose. However, this alternative hinders the possibility to quantify every single P wave, its variability over time, as well as to obtain complimentary and evolving information about the arrhythmia. This work analyzes the time progression of several time and frequency P wave features as potential indicators of atrial conduction variability several hours preceding the onset of PAF.MethodsThe longest sinus rhythm interval from 24‐hour Holter recordings of 46 PAF patients was selected. Next, the 2 hours before the onset of PAF were extracted and divided into two 1‐hour periods. Every single P wave was automatically delineated and characterized by 16 time and frequency metrics, such as its duration, absolute energy in several frequency bands and high‐to‐low‐frequency energy ratios. Finally, the P wave variability over each 1‐hour period was estimated from the 16 features making use of a least‐squares linear fitting. As a reference, the same parameters were also estimated from a set of 1‐hour ECG segments randomly chosen from a control group of 53 healthy subjects age‐, gender‐, and heart rate‐matched.ResultsAll the analyzed metrics provided an increasing P wave variability trend as the onset of PAF approximated, being P wave duration and P wave high‐frequency energy the most significant individual metrics. The linear fitting slope α associated with P wave duration was (2.48 ± 1.98)×10‐2 for healthy subjects, (23.8 ± 14.1)×10‐2for ECG segments far from PAF and for (81.8 ± 48.7)×10‐2ECG segments close to PAF p = 6.96×10‐22. Similarly, the P wave high‐frequency energy linear fitting slope was (2.42 ± 4.97)×10‐9, (54.2 ± 107.1)×10‐9 and (274.2 ± 566.1)×10‐9, respectively (p = 2.85×10‐20). A univariate discriminant analysis provided that both P wave duration and P wave high‐frequency energy could discern among the three ECG sets with diagnostic ability around 80%, which was improved up to 88% by combining these metrics in a multivariate discriminant analysis.ConclusionAlterations in atrial conduction can be successfully quantified several hours before the onset of PAF by estimating variability over time of several time and frequency P wave features.
Synthesis of Novel Hybrids Inspired from Bromopyrrole Alkaloids Inhibiting MMP‐2 and ‐12 as Antineoplastic Agents
Authors: Rane Rajesh A. , Naphade Shital S. , Bangalore Pavan Kumar , Palkar Mahesh B. , Patel Harun M. , Shaikh Mahamadhanif S. , Alwan Wesam S. , Karpoormath Rajshekhar 
Published: November 2014

Synthesis of novel set of forty semicarbazide/thiosemicarbazide hybrids inspired from marine bromopyrrole alkaloids is reported. Biological screening of these hybrids against a panel of five human cancer cell lines identified a number of hits endowed with interesting cytotoxicity profile. Compounds 5c and 5e (IC50 = 0.03 μm), 5t (IC50 = 0.03 μm), 4s (IC50 = 0.07 μm), and 5n (IC50 = 0.01 μm) displayed maximum cytotoxicity toward hormone‐dependent breast cancer cells MCF7, hepatic cancer cells WRL68, colon cancer cells CaCO2 and mouth and oral cancer cells KB403, respectively. The most active hits were further investigated for their potential to inhibit MMP‐2 and MMP‐12. Compound 5e showed maximum activity (IC50 = 1.8 μm) toward MMP‐2. Further, we preformed anti‐invasive assay on the most active compounds, where CaCO2 tumor cell migration was significantly decreased (77.9%) by hybrid 5e. The non‐toxicity toward human VERO cells (IC50 = 83.1 to 231.8 μm) indicated the selectivity of most active hits (5c, 5e, 5t and 5n) toward cancer cells.