Genome‐wide and digital polymerase chain reaction epigenetic assessments of alcohol consumption

The lack of readily employable biomarkers of alcohol consumption is a problem for clinicians and researchers. In 2014, we published a preliminary DNA methylation signature of heavy alcohol consumption that remits as a function of abstinence. Herein, we present new genome‐wide methylation findings from a cohort of additional subjects and a meta‐analysis of the data. Using DNA from 47 consecutive heavy drinkers admitted for alcohol detoxification in the context of alcohol treatment and 47 abstinent controls, we replicate the 2014 results and show that 21,221 CpG residues are differentially methylated in active heavy drinkers. Meta‐analysis of all data from the 448,058 probes common to the two methylation platforms shows a similarly profound signature with confirmation of findings from other groups. Principal components analyses show that genome‐wide methylation changes in response to alcohol consumption load on two major factors with one component accounting at least 50% of the total variance in both smokers and nonsmoking alcoholics. Using data from the arrays, we derive a panel of five methylation probes that classifies use status with a receiver operator characteristic area under the curve (AUC) of 0.97. Finally, using droplet digital polymerase chain reaction (PCR), we convert these array‐based findings to two marker assays with an AUC of 0.95 and a four marker set AUC of 0.98. We conclude that DNA methylation assessments are capable of quantifying alcohol use status and suggest that readily employable digital PCR approaches for substance consumption may find widespread use in alcohol‐related research and patient care.     

Influence of ethanol concentration in the phagocytic function of neutrophils against Klebsiella pneumoniae isolates in an experimental model

Background/Purpose

Although the prevalence of pneumonia or other extrapulmonary infections is higher in people with alcoholism or acute alcohol intoxication, the possible relationship of acute alcohol intoxication to phagocytic function has not been investigated. Our aim was to determine whether acute alcohol intoxication suppresses phagocytic function in human neutrophils.

Early signs of cardiovascular dysregulation in young adult binge drinkers

Binge drinking is widespread on American college campuses, but its effects on the cardiovascular system are poorly understood. This study sought evidence of preclinical cardiovascular changes in binge drinking young adults (n = 24) compared to nondrinking (n = 24) and social drinking (n = 23) peers during baseline, paced sighing (0.033 Hz), and paced breathing (0.1 Hz) tasks. Binge drinkers showed consistent but often statistically nonsignificant evidence of greater sympathetic activation and reduced baroreflex sensitivity. Interestingly, the structure of group‐averaged baseline heart rate spectra was considerably different between groups in the low frequency range (0.05–0.15 Hz). In particular, the binge drinking group–averaged spectra showed several spectral peaks not evident in the other groups, possibly indicating two functionally distinct subranges (0.05–0.08 and 0.08–0.15 Hz) that reflect vascular tone baroreflex activity and heart rate baroreflex activity, respectively. Vascular tone baroreflex gain and power in two peaks in the 0.05–0.08 Hz range were associated with years of drinking in the binge drinking group. Vascular dysfunction may be an early indicator of drinking‐related change in the cardiovascular system.     

臭牡丹根正丁醇提取物镇痛作用的研究

目的:研究臭牡丹根正丁醇提取物对疼痛小鼠的影响。方法:化学方法制备臭牡丹根正丁醇提取物。镇痛试验中,采用扭体实验和热板法,在热板法中小鼠分别注射臭牡丹正丁醇与纳洛酮或吗啡与纳洛酮,探测药物对不良刺激的延迟时间。炎性疼痛试验中,采用角叉菜胶诱发大鼠脚趾肿胀模型,前列腺素类含量的测定通过紫外可见光分光光度法,经过0.5mol/L氢氧化钾甲醇溶液,在50℃的温度中为异构后,在波长为278nm处检测。结果:腹腔注射臭牡丹提取物,发现能明显抑制0.6%醋酸诱发疼痛(P<0.01),在热板法中,在给臭牡丹药15分钟、30分钟、60分钟、90分钟后小鼠明显延长对不良刺激反应时间。实验表明同时给予臭牡丹提取物与纳洛酮15分钟、30分钟、60分钟、90分钟后小鼠明显延长对不良刺激反应时间,提示纳洛酮不能翻转其镇痛作用。在抗炎试验中,臭牡丹提取物呈剂量依赖性地抑制由角叉菜胶诱发炎性肿胀的前列腺素生成。结论:臭牡丹正丁醇提取物具有镇痛作用,该作用阿片受体无关,与抑制前列腺素合成有关。     

利培酮治疗酒精所致精神障碍对照研究

目的探讨利培酮治疗酒精所致精神障碍的临床疗效及安全性。方法将60例酒精所致精神障碍患者随机分为利培酮组和氯丙嗪组,每组各30例,疗程6w。治疗前与治疗第6w末采用阳性与阴性症状量表评定临床疗效,副反应量表评定不良反应。结果利培酮组有效率73.3%,氯丙嗪组有效率46.7%,两组差异有显著性(P<0.05)。利培酮组不良反应明显低于氯丙嗪组。结论利培酮对酒精所致精神障碍的疗效优于氯丙嗪,且不良反应较少。     

Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in humans

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are most abundant in the liver, are the main enzymes involved in ethanol metabolism in humans. Gender-related differences in total liver ADH and ALDH activity among different animal species have been observed in many studies. We measured total ADH and ALDH activity, and the activity of class I-IV ADH in the livers of male and female patients. Total ADH and class I and II ADH activities were significantly higher in males than in females (P=0.0052, P=0.0074, P=0.020, respectively). Class III and IV ADH and total ALDH activities were not significantly different between the genders (P=0.2917, P=0.0590, P=0.2940, respectively). The results of our study clearly show that there is a difference in enzymatic activity between male and female patients for those isoenzymes that actively participate in ethanol oxidation in the liver (class I and II ADH), although the main form of ADH in this organ is class III ADH.     

Effects of 4-Methylpyrazole on Ethanol Neurobehavioral Toxicity in CD-1 Mice

OBJECTIVES: 4-Methylpyrazole (4-MP), an alcohol dehydrogenase (ADH) antagonist, is used for the treatment of ethylene glycol and methanol ingestions. However, ethanol is frequently co-ingested by those who ingest these more toxic alcohols. Several in vitro and in vivo studies have shown a decrease in the elimination rate of ethanol after the administration of 4-MP, but none has evaluated the effects of 4-MP administration on the neurobehavioral toxicity of ethanol. This was a study to determine whether ADH blockade with 4-MP prolongs ethanol neurobehavioral toxicity in a murine model. METHODS: D-1 mice were pretreated with 4-MP, with observation of its effect on ethanol dose-response curves. 4-MP (25 mg/kg) or an equal volume of saline was administered intraperitoneally. Ten minutes later, incremental ethanol doses of 1-5 g/kg were administered intraperitoneally. Pretreated and control groups were composed of ten mice each for each dose of ethanol tested. Outcomes for assessing ethanol neurobehavioral toxicity were successful performance on the rotarod test and presence of the righting reflex, two established and validated outcome measures for ethanol-induced neurobehavioral toxicity in mice. RESULTS: The dose of ethanol at which 50% of the animals failed a particular outcome test (toxic dose 50 [TD(50)]) was decreased with 4-MP administration for both the rotarod test and the righting reflex. The TD(50) intergroup differences (control vs. 4-MP) were statistically significant at 60, 120, and 180 minutes (p < 0.05). CONCLUSIONS: Pretreatment with 4-MP significantly prolonged ethanol neurobehavioral toxicity in CD-1 mice, presumably by inhibiting its metabolism by ADH. Further investigation is warranted to evaluate this interaction.