Vatsalya

Effects of Varenicline on Neural Correlates of Alcohol Salience in Heavy Drinkers.

Background: Preclinical and emerging clinical evidence indicates that varenicline, a nicotinic partial agonist approved for smoking cessation, attenuates alcohol seeking and consumption. Reductions of alcohol craving have been observed under varenicline treatment and suggest effects of the medication on alcohol reward processing, but this hypothesis remains untested. Methods: In this double-blind, placebo-controlled randomized experimental medicine study, 29 heavy drinkers underwent a functional magnetic resonance imaging scan after 2 weeks of varenicline (2mg/d) or placebo administration. During functional magnetic resonance imaging, participants performed the Alcohol-Food Incentive Delay task, where they could earn points for snacks or alcohol. At baseline and after 3 weeks of medication, participants underwent intravenous alcohol self-administration sessions in the laboratory. Results: During the functional magnetic resonance imaging scan, participants in the varenicline group (N=17) reported lower feelings of happiness and excitement on subjective mood scales when anticipating alcohol reward compared with the placebo group (N=12). Linear mixed effects analysis revealed that anticipation of alcohol reward was associated with significant blood oxygen level dependent activation of the ventral striatum, amygdala, and posterior insula in the placebo group; this activation was attenuated in the varenicline group. The varenicline group showed no difference in intravenous alcohol self-administration relative to the placebo group for either session. Participants with higher insula activation when anticipating alcohol reward showed higher alcohol self-administration behavior across groups. Conclusions: Our findings suggest that varenicline decreases blood oxygen level dependent activation in striato-cortico-limbic regions associated with motivation and incentive salience of alcohol in heavy drinkers. This mechanism may underlie the clinical effectiveness of varenicline in reducing alcohol intake and indicates its potential utility as a pharmacotherapy for alcohol use disorders.

Exposure-Response Relationships during Free-Access Intravenous Alcohol Self-Administration in Nondependent Drinkers: Influence of Alcohol Expectancies and Impulsivity.

Abstract Background: Self-administration is a hallmark of all addictive drugs, including alcohol. Human laboratory models of alcohol self-administration have characterized alcohol-seeking behavior and served as surrogate measures of the effectiveness of pharmacotherapies for alcohol use disorders. Intravenous alcohol self-administration is a novel method that assesses alcohol exposure driven primarily by the pharmacological response to alcohol and may have utility in characterizing unique behavioral and personality correlates of alcohol-seeking and consumption. Methods: This study examined exposure-response relationships for i.v. alcohol self-administration, and the influence of impulsivity and alcohol expectancy, in healthy, nondependent drinkers (n=112). Participants underwent a 2.5-hour free-access i.v. alcohol self-administration session using the Computerized Alcohol Infusion System. Serial subjective response measures included the Drug Effects Questionnaire and Alcohol Urge Questionnaire. To characterize the motivational aspects of alcohol consumption prior to potential acute adaptation, the number of self-infusions in the first 30 minutes of the free-access session was used to classify participants as low- and high-responders. Results: High-responders showed greater subjective responses during i.v. alcohol self-administration compared with low responders, reflecting robust exposure-driven hedonic responses to alcohol. High-responders also reported heavier drinking patterns and lower scores for negative alcohol expectancies on the Alcohol Effects Questionnaire. High-responders also showed higher measures of impulsivity on a delayed discounting task, supporting previous work associating impulsivity with greater alcohol use and problems. Conclusions: These findings indicate that early-phase measures of free-access i.v. alcohol self-administration are particularly sensitive to the rewarding and motivational properties of alcohol and may provide a unique phenotypic marker of alcohol-seeking behavior.

Vulnerability for Alcohol Use Disorder and Rate of Alcohol Consumption

OBJECTIVE Although several risk factors have been identified for alcohol use disorder, many individuals with these factors do not go on to develop the disorder. Identifying early phenotypic differences between vulnerable individuals and healthy control subjects could help identify those at higher risk. Binge drinking, defined as reaching a blood alcohol level of 80 mg%, carries a risk of negative legal and health outcomes and may be an early marker of vulnerability. Using a carefully controlled experimental paradigm, the authors tested the hypothesis that risk factors for alcohol use disorder, including family history of alcoholism, male sex, impulsivity, and low level of response to alcohol, would predict rate of binging during an individual alcohol consumption session. METHOD This cross-sectional study included 159 young social drinkers who completed a laboratory session in which they self-administered alcohol intravenously. Cox proportional hazards models were used to determine whether risk factors for alcohol use disorder were associated with the rate of achieving a binge-level exposure. RESULTS A greater percentage of relatives with alcoholism (hazard ratio: 1.04, 95% CI=1.02-1.07), male sex (hazard ratio: 1.74, 95% CI=1.03-2.93), and higher impulsivity (hazard ratio: 1.17, 95% CI=1.00 to 1.37) were associated with a higher rate of binging throughout the session. Participants with all three risk factors had the highest rate of binging throughout the session compared with the lowest risk group (hazard ratio: 5.27, 95% CI=1.81-15.30). CONCLUSIONS Binge drinking may be an early indicator of vulnerability to alcohol use disorder and should be carefully assessed as part of a thorough clinical evaluation.

Characterization of hangover following intravenous alcohol exposure in social drinkers: methodological and clinical implications

Hangover refers to the cluster of physiological and behavioral symptoms that occur following the end of a drinking episode. While hangover has been studied after the typical oral consumption of alcohol, the occurrence of hangover following intravenous (IV) alcohol administration in human laboratory studies has not been previously reported. This study characterizes hangover symptoms and post‐infusion drinking behavior following acute IV alcohol administration in social drinkers. Twenty‐one to thirty‐year‐old healthy social drinkers (n = 24) underwent an alcohol clamp session at breath alcohol concentration of 0.06 percent. Hangover symptoms as well as any post‐infusion drinking that occurred between the end of the session and the following morning were assessed using the Acute Hangover Scale, and examined for influences of recent drinking history, family history of alcoholism and Sex. Results indicated a 79 percent prevalence of hangover symptoms, with the most common symptoms being ‘tired’, ‘thirsty’ and ‘headache’. Recent drinking measures showed significant effects on Average Hangover Scale scores, with heavier drinkers showing greater hangover symptoms. There was a significant sex difference in average hangover scores, with females reporting higher scores than males. Subjective measures of stimulation and intoxication were also associated with Average Hangover Scale scores. The probability of post‐infusion drinking was not predicted by hangover scores, but was related to recent drinking history; subjective response to alcohol was a significant mediator of this relationship. These findings demonstrate that hangover symptoms are experienced following IV alcohol administration, and extend previous studies of influences of risk factors for alcohol use disorders including recent drinking on hangover.

Cardiac reactivity during the ascending phase of acute intravenous alcohol exposure and association with subjective perceptions of intoxication in social drinkers.

BACKGROUND The aim of this study was to characterize cardiac reactivity measures, heart rate (HR), and heart rate variability (HRV), following acute intravenous (IV) alcohol administration and their association with subjective responses in social drinkers. METHODS Twenty-four subjects (11 females) received IV alcohol infusions to attain and clamp the breath alcohol concentration (BrAC) at 50 mg% or placebo in separate sessions. Serial 5-minute cardiac recordings at baseline and during the infusion were analyzed to obtain frequency and time domain cardiac measures. Self-reported subjective perceptions were also obtained at the same time points. RESULTS HR showed significant decreases from baseline, while the HRV measure pNN50 showed steady increases during the ascending phase of alcohol infusion. HR was inversely correlated with pNN50 across time and treatment. There was a significant association of HR with subjective feelings of high, intoxication, feeling drug effects, and liking drug effects across time during the ascending phase. CONCLUSIONS Acute IV alcohol resulted in decreases in HR and increases in HRV consistent with autonomic parasympathetic activation. The association of these changes with subjective responses suggests that cardiac reactivity may serve as a physiological marker of subjective alcohol effects. This study broadens the understanding of acute cardiovascular effects of alcohol and clinically significant cardiac conditions such as arrhythmia and cardiomyopathy associated with chronic alcohol drinking.

Clinical Features, Disease Modifiers, and Natural History of Alcoholic Liver Disease

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. The clinical spectrum of ALD includes fatty liver, steatohepatitis with or without fibrosis, and cirrhosis. The diagnosis of ALD is made in patients with evidence of liver injury based on clinical history, physical findings, and laboratory abnormalities, when there is evidence of significant alcohol consumption and after other causes of chronic liver disease have been excluded. Signs and symptoms may be essentially nonexistent in steatosis or possibly mild fatigue and abdominal discomfort. On the other hand, those with decompensated disease may present with massive ascites, muscle wasting, gastrointestinal bleeding, and encephalopathy. Many people drink heavily, yet only a limited number (~35 %) develop more advanced liver diseases (alcoholic hepatitis or cirrhosis). Thus, there must be modifying factors that either prevent or facilitate disease activity/progression. These modifiers can either be fixed (e.g., genetic) or can undergo intervention (e.g., continued drinking, smoking, diet). We review ten disease modifiers of particular importance to ALD. Patients with steatosis only may “normalize” with cessation of drinking; however, outcomes are highly variable once the patient has progressed to cirrhosis. Some subjects die quickly with acute-on-chronic liver disease; other patients who abstain from alcohol and correct other disease modifiers may live a relatively normal life; others may do well for long periods of time only to expire from hepatocellular carcinoma. The biggest variable is continued drinking, and cessation of this and modification of other disease modifiers such as smoking should be aggressively pursued.

Association of serum zinc with markers of liver injury in very heavy drinking alcohol-dependent patients

Zinc deficiency is a frequent complication of alcohol abuse for multiple reasons including poor intake, increased excretion, internal redistribution and altered transporters. Zinc deficiency has been postulated to play a role in the development/progression of alcoholic liver disease (ALD). This study aimed to relate serum zinc levels with alcohol intake, serum albumin concentration and markers of inflammation and liver injury. One hundred and eight male and female very heavy drinking (≥10 drinks/day) individuals without clinical evidence of ALD were grouped by serum zinc concentration: normal-zinc group (zinc level≥71 μg/dl) included 67 patients, and low-zinc group (zinc level<71 μg/dl) included 41 patients. Data were collected on demographics, drinking history in last 90 days (heavy drinking days, HDD90 and total drinks, TD90), lifetime drinking history (LTDH) and clinical/ laboratory assessments. Our data show that in a very well-characterized, chronically heavy-drinking population without clinical evidence of liver disease, about 40% of subjects had low serum zinc levels. Frequency of heavy drinking days (HDD90) was significantly higher in the low-zinc group. Total drinks in past 90 days, LTDH and HDD90 showed significant associations with low zinc levels. The group with the low serum zinc had a higher aspartate aminotransferase/alanine aminotransferase ratio (good marker of alcoholic liver disease). Those in the low-zinc group had the lower albumin levels, a marker of hepatic synthetic function, and the highest C-reactive protein level, a biomarker of inflammation.

Urinary acrolein metabolite levels in severe acute alcoholic hepatitis patients

Alcohol-associated liver disease (ALD) remains a major health concern worldwide. Alcohol consumption gives rise to reactive/toxic acrolein, a pathogenic mediator of liver injury in experimental ALD. Elevated acrolein adducts and metabolites are detectable in blood and urine. This study evaluates the major urinary acrolein metabolite, 3-hydroxypropylmercapturic acid (HPMA), in patients with acute alcoholic hepatitis (AAH) and examines its association with disease severity and markers of hepatic inflammation and injury. Urine HPMA was significantly higher in patients with severe [model for end-stage liver disease (MELD) ≥ 20] AAH compared with nonsevere AAH (MELD ≤ 19) or non-alcohol-consuming controls, suggesting that urine HPMA is a novel noninvasive biomarker in severe AAH. The association between HPMA and MELD in patients with AAH was nonlinear. In patients with nonsevere AAH, there was a positive trend, although not significant, whereas in severe AAH the association was negative, indicative of extensive injury and glutathione depletion. Consistent with the multifactorial etiology of ALD, our data identified strong combined effects of HPMA and proinflammatory cytokines on hepatocyte cell death, thereby supporting the pathogenic role of acrolein in liver injury. HPMA, together with IL-1β, showed robust associations with cytokeratin 18 caspase-cleaved fragment (CK18-M30; adjusted R2 = 0.812, P = 0.016) and cytokeratin 18 full-length protein (CK18-M65; adjusted R2 = 0.670, P = 0.048); similarly, HPMA, with IL-8, correlated with CK18-M30 (adjusted R2 = 0.875, P = 0.007) and CK18-M65 (adjusted R2 = 0.831, P = 0.013). The apoptosis index (CK18-M30:CK18-M65 ratio) strongly correlated with HPMA, together with IL-1β (adjusted R2 = 0.777, P = 0.022) or tumor necrosis factor-α (TNFα; adjusted R2 = 0.677, P = 0.046). In patients with severe AAH, IL-1β, IL-8, and TNFα are the predominant proinflammatory cytokines that interact with HPMA and play important mediating roles in influencing the extent/pattern of liver cell death. NEW & NOTEWORTHY This is the first study to examine the urinary acrolein metabolite 3-hydroxypropylmercapturic acid (HPMA) in alcoholic liver disease. HPMA was higher in patients with severe acute alcoholic hepatitis (AAH) compared with controls or nonsevere AAH and may be a novel selective, noninvasive biomarker for severe AAH. Consistent with the multifactorial etiology of alcohol-associated liver disease, we identified strong combined effects of HPMA and proinflammatory cytokines (IL-1β, IL-8, and TNFα) on the extent/pattern of liver cell death, thereby supporting the pathogenic role of acrolein.

Developments in the Diagnostic Techniques of Infectious Diseases: Rural and Urban Prospective

Objectives: Diagnostics is the first step for the treatment and eradication of infectious microbial diseases. Due to ever evolving pathogens and emerging new diseases, there is an urgent need to identify suitable diagnostic techniques for better management of each disease. The success rate of specific diagnostic technique in any population depends on various factors including type of the microbial pathogen, availability of resources, technical expertise, disease severity and degree of epidemic of disease in the area. One of the important tasks of the policy makers is to identify and implement suitable diagnostic techniques for specific regions based on their specific requirements. In this review we have discussed various techniques available in the literature and their suitability for the target population based on above mentioned criteria. Methods: Diagnostic techniques evaluation of well documented representative microbial diseases; Tuberculosis (bacterial), Malaria (parasitic) and HIV (viral) were included in the study. Identification and collection of information and data was performed focusing on the diagnostic techniques used from the scientific publications from Pubmed, Science Access, Scopus, EMBASE and several regional databases. WHO and CDC database for Tuberculosis, Malaria and HIV were also included. These techniques were compared with respect to the financial resource availability, expertise and management, functional capacity, pathogen virulence and degree of epidemic in the population. Results and Conclusion: In case of Tuberculosis, ELISA and colorimetric techniques are successful in rural and urban communities with 80% – 90% sensitivity. Genotyping and SNP analysis are useful in drug resistant strains. Parasitic disease Malaria also follows the same trend with diagnostic techniques like RDTs being common in both population with fast results and around 90% sensitivity. STD disease like HIV however shows slight different trends due to urgent need of interference in rural epidemics of the disease. Rapid and sensitive immunotechniques like dipsticks and agglutination with almost 100% sensitivity are used in both rural and urban areas. For the confirmation further tests are done like protein Western and NAAT. Advance techniques could be the option for higher epidemic area, drug resistance and disease research, while rapid techniques would be suitable for low income areas and POC facilities. Therefore, suitability of the diagnostic techniques for better management depends not only on the financial resources and assessment skills of a community but sometimes on the disease itself. We have further discussed the technological improvements for specific settings (rural/urban) based on the past research for better management of diseases, which could be implemented for the understanding of understudied and newly emerging diseases.

A Review on the Sex Differences in Organ and System Pathology with Alcohol Drinking

Hazardous consequences of alcohol consumption adversely influence overall health, specifically physical and mental health. Differences in alcohol consumption and manifestations in pathology have been observed between males and females, however research on understanding these differences is limited. Negative consequences of alcohol consumption have now been studied including sex as a significant factor. Some studies have shown differences in the severity of consequences of alcohol consumption between the sexes, both in the mental consequences and changes/ injury in various organ systems. Over time, reports in females on both the dynamics of drinking and on the hazardous consequences of alcohol consumption have grown, primarily because of more awareness, better observation, and the inclusion of sex as a factor in scientific investigations. This paper reviews role of sex differences in pathophysiological and behavioral consequences of alcohol drinking.