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Two simple models for the spread of heavy drinking among a network of individuals are re-introduced and analysed. We provide theorems on the spread of alcohol abuse for these models in cases involving simple connection schemes. Indicators for this spread that resemble the used in disease assessment are suggested and studied. We further provide computations with our models on general application networks and begin to study the reliability of the spread indicators. [ABSTRACT FROM AUTHOR]

Strongyloidiasis is a human parasitosis that is considered a public health problem. Early diagnosis of this infection is extremely important in immunocompromised patients (i.e. subjects with alcoholism). This study aimed to evaluate anti- Strongyloides immunoglobulin G (IgG) and immunoglobulin A (IgA), assess levels of circulating immune complexes (IC) and determine IgG avidity in serum samples from alcoholic and nonalcoholic individuals. A total of 140 blood samples were collected from male individuals (70 alcoholic and 70 nonalcoholic subjects). Serum was obtained and analysed by enzyme-linked immunosorbent assay for IgG, IgA, IC detection and avidity determination. Anti- Strongyloides IgG was detected in 55.7% of alcoholic subjects and 32.8% nonalcoholics, while IC levels showed frequencies of 38.6% and 17.1% in these groups, respectively. Anti- Strongyloides IgA was lower among alcoholics (4.3%) than nonalcoholics (34.3%). Spearman's correlation coefficient reported a positive correlation between IgG, IC and IgA in alcoholic individuals and no correlation in nonalcoholics. The median avidity index was higher in alcoholics (83.8%) than nonalcoholic subjects (73.2%). In conclusion, this study shows that alcoholic subjects produced specific antibodies against S. stercoralis regardless of the possible immunosuppression caused by chronic alcoholism. Considering that alcoholics are more susceptible to the severe forms of strongyloidiasis, the implementation of immunological methods as a complementary approach to parasitological diagnostics (i.e. detection of IgG, IC and antibody avidity) appears to be an alternative method for early diagnosis in these individuals. [ABSTRACT FROM AUTHOR]

Inflammation supports the progression of alcohol-related organ injury. Recent research findings have linked ethanol exposure to changes in histone acetylation and deacetylation in the brain and in peripheral tissues, leading to ethanol-dependence related damage. One of the mechanisms that has been shown to play a major role during inflammation is the cannabinoid system. Previous research has demonstrated that ethanol can modulate cannabinoid receptors' functions. Our lab has shown that the G protein-coupled receptor (GPR55), a novel cannabinoid receptor, is upregulated in binge drinkers and in cells treated acutely with ethanol. Additionally, our group has also uncovered that chronic ethanol exposure leads to an increase in histone modifications, such as acetylation. However, the regulatory mechanism of GPR55 within the immune system under the influence of ethanol is poorly understood. Since changes in histone modifications might lead to changes in gene expression, we hypothesize that the mechanism of ethanol-induced upregulation of GPR55 is linked to epigenetic changes on histone proteins. Taking into account previous findings from our lab, the goal of the present study was to determine whether there is any relevant association between histone hyperacetylation and the regulation of the novel cannabinoid receptor GPR55 in monocyte-derived dendritic cells (MDDCs) of human origin treated acutely with ethanol. Therefore, monocytes were isolated from buffy coats and allowed to differentiate into MDDCs. The cells were treated with ethanol for 24 h, harvested, fixed, and stained with antibodies against GPR55. As expected, based on previous findings, confocal microscopy showed that ethanol exposure increases GPR55 expression. In order to demonstrate the correlation between histone acetylation and GPR55 expression regulation, the cells were treated with ethanol, harvested, and then the chromatin was extracted and fractionated for chromatin immunoprecipitation (ChIP) assay, followed by real-time qPCR for the analysis of DNA fragments. The results showed an enrichment of the histone modification H4K12ac in the GPR55 gene of MDDCs treated with ethanol. Furthermore, siRNA against the histone acetyltransferase Tip60 (responsible for the acetylation of H4K12) resulted in a downregulation of GPR55. In conjunction, these results indicate that in the presence of ethanol, the upregulation of GPR55 expression is accompanied by H4K12 acetylation, which might have a significant effect in the ability of this innate immune system's cells to cope with cellular stress induced by ethanol. However, the causality of ethanol regulation of H4K12ac in GPR55 expression changes still lacks further elucidation; therefore, additional experimental approaches to confirm a significant causality between H4K12 acetylation and ethanol regulation of GPR55 are currently undergoing in our lab. [ABSTRACT FROM AUTHOR]

Alcohol addiction, affecting approximately four percent of the population, contributes significantly to the global burden of diseases and is a substantial cost to the society. The neurochemical mechanisms regulating alcohol mediated behaviors is complex and in more recent years a new physiological role of the gut-brain peptides, traditionally known to regulate appetite and food intake, have been suggested. Indeed, regulators of alcohol-mediated behaviors. One of these gut-brain peptides is the annorexigenic peptide glucagon-like peptide-1 (GLP-1), Preclinical studies show that GLP-1 receptor activation, either by GLP-1 or analogues, attenuate the ability of alcohol to activate the mesolimbic dopamine system as well as decrease alcohol consumption and operant self-administration. In further support for the endogenous GLP-1 system in addiction processes are the experimental data showing that a GLP-1 receptor antagonist increases alcohol intake. Moreover, GLP-1 receptor agonists prevent the ability of other addictive drugs to activate the mesolimbic dopamine system. The number of clinical studies is limited, but show i) that genetic variation in the GLP-1 receptor gene is associated with alcohol addiction as well as increased alcohol infusion in humans, ii) that plasma levels of GLP-1 are associated with the subjective experience of cocaine and iii) that a GLP-1 receptor agonist reduces alcohol intake in patients with type-2 diabetes mellitus. These experimental and clinical studies raises the concern that clinically available GLP-1 receptor agonists deserves to be tested as potential treatments of patients with addictive disorders including alcohol addiction. This article is part of the Special Issue entitled ‘Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.’ [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is an inflammatory disease presenting from mild localized inflammation to severe infected necrotic pancreatic tissue. In the literature, there are a few cases of hypothermia-induced AP. However, the association between hypothermia and AP is still a myth. Generally, mortality from acute pancreatitis is nearly 3-6%. Here, we present a 40-year-old chronic alcoholic female who presented with acute pancreatitis induced by transient hypothermia. A 40-year-old chronic alcoholic female was hypothermic at 81°F on arrival which was improved to 91.7°F with warming blanket and then around 97°F in 8 h. Laboratory tests including complete blood count, lipid panel, and comprehensive metabolic panels were within the normal limit. Serum alcohol level was 0.01, amylase 498, lipase 1,200, ammonia 26, serum carboxyhemoglobin level 2.4, and β-HCG was negative. The entire sepsis workup was negative. During rewarming period, she had one episode of witnessed generalized tonic-clonic seizure. It was followed by transient hypotension. Fluid challenge was successful with 2 L of normal saline. Sonogram (abdomen) showed fatty liver and trace ascites. CAT scan (abdomen and pelvis) showed evidence of acute pancreatitis without necrosis, peripancreatic abscess, pancreatic mass, or radiopaque gallstones. The patient was managed medically and later discharged from the hospital on the 4th day as she tolerated a normal low-fat diet. In our patient, transient hypothermia from chronic alcohol abuse and her social circumstances might predispose to microcirculatory disturbance resulting in acute pancreatitis. Early and aggressive fluid resuscitation prevents complications. [ABSTRACT FROM AUTHOR]

Opioid antagonists such as naltrexone and nalmefene are used in drug therapy for alcoholism. Nalmefene, approved in Europe in February 2013 for the reduction of alcohol consumption, is used in patients with alcohol dependence. We report 11 cases of opioid withdrawal syndrome after a single dose of nalmefene in patients usually treated with methadone, buprenorphine, but also with fentanyl or loperamide. Nalmefene is both a partial agonist and an antagonist of opioid receptors. Regarding to its opioid antagonist activity, nalmefene is contraindicated in patients with an opioid treatment. Therefore, when prescribing or delivering nalmefene, healthcare professionals need to be vigilant about any type of opioid exposure, even masked or hidden, to avoid these potential life-threatening syndromes. [ABSTRACT FROM AUTHOR]

Introduction: Stomach cancer is the third leading cause of cancer related deaths in either sex. Compared to world statistics, India has a lower incidence and prevalence of this cancer. The diversity in dietary habits accounts for regional variations in incidence of stomach cancers across different parts of India. In this retrospective audit, we have tried to analyze the epidemiology of gastric cancers of northern India which were treated in our institution. Material and Methods: Review of the Hospital Based Cancer Registry (HBCR) of PGIMER, Chandigarh showed that 156 stomach cancer patients (only adenocarcinoma and signet ring cell histopathologies included) were treated from August 2012 to December, 2016. Descriptive statistics were employed for analyzing results. Results: The median age of patients was 52 years with a predilection for male sex. Mostly patients were alcoholics (53.2%) but nonsmokers (59.6%). More than 70% patients ate fruits and vegetables and did not consume processed meat. Anorexia and weight loss was the commonest presenting complaint. The commonest stages observed were stage IIIC (21.1%) and IIB (19.2%). More than 90% patients had adenocarcinoma of which intestinal variant was the commonest. Subtotal gastrectomy with D1 lymph node dissection was practiced more than total gastrectomy and/or D2 dissection. Conclusions: Our patients belonged to a low risk population for gastric cancer mostly due to protective dietary habits. Further reports can give better insight into the epidemiological diversity of this cancer. [ABSTRACT FROM AUTHOR]

The gut microbiota includes a community of bacteria that play an integral part in host health and biological processes. Pronounced and repeated findings have linked gut microbiome to stress, anxiety, and depression. Currently, however, there remains only a limited set of studies focusing on microbiota change in substance abuse, including alcohol use disorder. To date, no studies have investigated the impact of vapour alcohol administration on the gut microbiome. For research on gut microbiota and addiction to proceed, an understanding of how route of drug administration affects gut microbiota must first be established. Animal models of alcohol abuse have proven valuable for elucidating the biological processes involved in addiction and alcohol-related diseases. This is the first study to investigate the effect of vapour route of ethanol administration on gut microbiota in mice. Adult male C57BL/6J mice were exposed to 4 weeks of chronic intermittent vapourized ethanol (CIE, N = 10) or air (Control, N = 9). Faecal samples were collected at the end of exposure followed by 16S sequencing and bioinformatic analysis. Robust separation between CIE and Control was seen in the microbiome, as assessed by alpha (p < 0.05) and beta (p < 0.001) diversity, with a notable decrease in alpha diversity in CIE. These results demonstrate that CIE exposure markedly alters the gut microbiota in mice. Significant increases in genus Alistipes (p < 0.001) and significant reductions in genra Clostridium IV and XIVb (p < 0.001), Dorea (p < 0.01), and Coprococcus (p < 0.01) were seen between CIE mice and Control. These findings support the viability of the CIE method for studies investigating the microbiota-gut-brain axis and align with previous research showing similar microbiota alterations in inflammatory states during alcoholic hepatitis and psychological stress. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study was to determine the erosive tooth wear (ETW) status of institutionalized patients for alcohol misuse rehabilitation therapy in the north of Portugal. Material and methods: Descriptive, analytical, and cross-sectional study, conducted on 277 individuals (83.4 % men) with an average age of 43.6 ± 8.4 years, institutionalized at Instituto da Droga e Toxicodependência-Delegação Regional Norte (IDT-Norte). ETW prevalence and severity were assessed by Eccles and Jenkins index. Multivariate logistic regression was used to identify ETW risk factors. Subjects with ETW risk identification according to biological and behavioral exposure were determined in the study. Results: ETW prevalence was 98.6 %. In the cohort, 51.3 % showed localized ETW lesions, 40.1 % generalized ETW lesions, and 7.2 % enamel ETW lesions, more frequently localized in maxilla. From the examined dental surfaces ( n = 15,598), 11,493 had erosive wear lesions: 92.4 % (95 % CI 91.7-93.1 %) of all occlusal surfaces, 71.9 % (95 % CI 70.7-73.1 %) of all palatal/lingual, and 56.7 % (95 % CI 55.4-58.1 %) of all buccal surfaces. Buccal and lingual surfaces showed 43.2 and 41.8 % enamel erosive wear lesions; occlusal surfaces had 43.4 % localized erosive wear lesions in dentin. The main ETW risk factors were as follows: age, gastroesophageal reflux disease over 1 year, daily intake of alcohol ≥240 g (grams), and intra-oral location in anterior region; 46.2 % of the participants had erosive risk by exposure to biological and behavioral factors. Conclusions: The ETW status showed high values for disease prevalence and severity, mainly located in the maxilla, and high frequency of erosive wear lesions at occlusal, buccal, and lingual surfaces, resulting from simultaneous exposure to several risk factors. Clinical implications: For ETW differential diagnosis, the association of both clinical and biological/nutritional/behavioral risk factors should be done for each studied population. [ABSTRACT FROM AUTHOR]

Current pharmacotherapies for alcohol used disorder (AUD) are few and relatively ineffective illustrating the need for the development of new, effective medications. Using a translational approach, our laboratory reported that ivermectin, an FDA-approved, human and animal anti-parasitic agent, can significantly reduce ethanol intake in male and female mice across different drinking paradigms. Extending this line of investigation, the current paper investigated the utility of moxidectin (MOX), an analogue of ivermectin, to reduce ethanol intake. Notably, MOX is widely held to have lower neurotoxicity potential and improved margin of safety compared to ivermectin. Using a 24-h-two-bottle choice paradigm, MOX significantly reduced ethanol intake in a dose dependent manner in both male and female C57BL/6J mice, respectively (1.25–7.5 mg/kg) and (1.25–10 mg/kg). Further, multi-day administration of MOX (2.5 mg/kg; intraperitoneal injection) for 5 consecutive days significantly reduced ethanol intake in both the 24-h-two-bottle choice and Drinking-in-the-Dark paradigms in female mice. No overt signs of behavioral toxicity were observed. Notably in both male and female mice, MOX significantly reduced ethanol intake starting approximately 4 h post-injection. Using a Xenopus oocyte expression system, we found that MOX significantly potentiated P2X4 receptor (P2X4R) function and antagonized the inhibitory effects of ethanol on ATP-gated currents in P2X4Rs. This latter finding represents the first report of MOX having activity on P2X4Rs. In addition, MOX potentiated GABA A receptors, but to a lesser degree as compared to ivermectin supporting the hypothesis that MOX would be advantageous (compared to ivermectin) with respect to reducing contraindications. Overall, the results illustrate the potential for development of MOX as a novel pharmacotherapy for the treatment of AUD. [ABSTRACT FROM AUTHOR]

Alcoholism is a chronic relapsing disorder characterized by periods of heavy alcohol consumption and unsuccessful attempts at abstinence. Relapse is one of the most problematic aspects in the treatment of alcoholism and is triggered by ethanol-associated cues. Extinction-based cue exposure therapies have proven ineffective in the treatment of alcoholism. However, positive allosteric modulation of mGlu5 with CDPPB enhances the extinction learning of alcohol-seeking behavior. The current study investigated the impact of chronic alcohol exposure on the extinction of ethanol-seeking behavior. Adult Wistar rats were trained to self-administer alcohol with a light/tone stimulus serving as the alcohol cue. After training, one group of rats was exposed to chronic intermittent ethanol (CIE) daily for a period of 2 weeks to induce ethanol dependence. Control rats were exposed to air for the same period of time. Both groups were then retrained to self-administer ethanol and subsequently tested for changes in extinction learning. CIE exposed rats consumed more ethanol compared to their pre-CIE levels and to control rats. During extinction training, CIE rats responded significantly more on the previously active lever and required more sessions to reach extinction criteria compared to control rats. Treatment with CDPPB facilitated extinction in control rats and attenuated the increased resistance to extinction in CIE-exposed rats. These results demonstrate that chronic ethanol exposure not only alters ethanol intake, but also the extinction of ethanol-seeking behaviors. The ability to attenuate deficits through modulation of mGlu5 provides a potential target for pharmacological manipulation that could ultimately reduce relapse in alcoholics. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the prognostic value of abdominal computed tomography (CT) in patients with alcoholic hepatitis (AH). Methods: This ancillary study was based on data collected during a previous randomized controlled trial in patients with AH. Clinical response was defined as the improvement of the baseline MELD score ≥3 points at 3 months. All patients underwent contrast-enhanced CT of the abdomen. The following parameters were measured: (1) liver density, spleen density, and liver-to-spleen density ratio; (2) liver-to-body weight (LBW) ratio; and (3) subcutaneous fat, visceral fat, and muscular content. Improvers and non-improvers were compared with univariate, multivariate, and ROC analyses. Results were compared with a validation cohort of patients. Results: Fifty-eight patients (mean age, 56 years) were analyzed, including 34 (59 %) improvers. On multivariate analysis, LBW ratio (OR = 3.73; 95 % CI, 1.65-8.46; p = 0.002) and subcutaneous fat (OR = 1.01; 95 % CI, 1.00-1.02; p = 0.022) were associated with clinical response, with AUROC curves of 0.78 ± 0.06 ( p < 0.001) and 0.66 ± 0.07 ( p = 0.043), respectively. LBW ≥2.4 % predicted response with 88 % sensitivity and 63 % specificity. In the validation cohort ( n = 42, 64 % improvers), the same cut-off value predicted response with 93 % sensitivity and 60 % specificity. Conclusions: In patients suffering from AH, the liver volume appears to be a major positive prognostic factor. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae is an opportunistic pathogen that commonly causes nosocomial infections in the urinary tract, respiratory tract, lung, wound sites and blood in individuals with debilitating diseases. Klebsiella pneumoniae is still a cause of severe pneumonia in alcoholics in Africa and Asia, and the predominant primary pathogen of primary liver abscess in Taiwan and Southeast Asia, particularly in Asian and Hispanic patients, and individuals with diabetes mellitus. In the United States and Europe, K. pneumoniae infections are most frequently associated with nosocomial infections. The emergence of antibiotic-resistant strains of K. pneumoniae worldwide has become a cause of concern where extended-spectrum β-lactamases (ESBLs) and carbapenemase-producing strains have been isolated with increasing frequency. The pathogen's ability to form biofilms on inserted devices such as urinary catheter has been proposed as one of the important mechanisms in nosocomially acquired and persistent infections, adding to the increased resistance to currently used antibiotics. In this review, infections caused by K. pneumoniae, antibiotic resistance and formation of biofilm will be discussed. [ABSTRACT FROM AUTHOR]

Background: Skog's collectivity theory of alcohol consumption predicted that changes in alcohol consumption would synchronize across all types of drinkers in a population. The aim of this paper is examine this theory in the Australian context. We examined whether there was a collective change in alcohol use in Australia from 2001 to 2013, estimated alcohol consumption in non-high risk and high risk drinkers, and examined the trends in alcohol treatment episodes. Methods: Data from the 2001-2013 National Drug Strategy Household Surveys (N =127,916) was used to estimate the prevalence and alcohol consumption of abstainers, high risk drinkers and frequent heavy episodic drinkers. Closed treatment episodes recorded in the Alcohol and Other Drug Treatment Services National Minimum Dataset (N= 608,367) from 2001 to 2013 were used to examine the trends of closed alcohol treatment episodes. Results: The prevalence of non-drinkers (abstainers) decreased to the lowest level in 2004 (15.3%) and rebounded steadily thereafter (20.4% in 2013; p < .001). Correspondingly, the per capita consumption of high risk drinkers (2 standard drinks or more on average per day) increased from 20.7 L in 2001 to peak in 2010 (21.5 L; p = .020). Non-high risk drinkers' consumption peaked in 2004 (2.9 L) and decreased to 2.8 L in 2013 (p < .05). There were decreases in alcohol treatment episodes across nearly all birth cohorts in recent years. Conclusion: These findings are partially consistent with and support Skog's collectivity theory. There has been a turnaround in alcohol consumption after a decade-long uptrend, as evident in the collective decreases in alcohol consumption among nearly all types of drinkers. There was also a turnaround in rate of treatment seeking, which peaked at 2007 and then decreased steadily. The timing of this turnaround differs with level of drinking, with non-high risk drinkers reaching its peak consumption in 2004 and high risk drinkers reaching its peak consumption in 2010. [ABSTRACT FROM AUTHOR]

Background: The core symptoms of bulimia nervosa (BN) and binge eating disorder (BED) are recurrent episodes of binge eating. Despite negative psychological and physical consequences, BN/BED patients show uncontrollable approach tendencies towards food. This cognitive bias occurs at an early stage of information processing. Cognitive bias modification (CBM) directly targets such biases and has been shown to be effective in treating several mental disorders. In alcohol addiction, automatic action tendencies towards alcohol cues and relapse rates were successfully reduced by a specific form of CBM, termed approach bias modification. Based on these findings and data from a proof-of-concept study in people with high levels of food craving, CBM is considered a promising new treatment approach for BN/BED. Given the similarities between BN/BED and addictive disorders, the rationale for using approach bias modification appears to be particularly strong. The aim of the present study is to examine whether, compared to a sham training, computerised approach bias modification (10 sessions) can reduce bingeeating episodes in BN/BED patients from pre-treatment to follow-up. Additionally, we will investigate whether this CBM programme also reduces global eating disorder psychopathology, trait and cue-elicited food craving, food intake as well as approach and attentional bias towards visual food cues. Treatment acceptance will be determined by attrition rates and responses on a feedback form. Methods: This is a double-blind, randomised, placebo-controlled, parallel-group superiority trial with two parallel arms. A total of 54 BN/BED patients will be recruited. Approach bias towards food will be retrained by a computer task adopting an implicit learning paradigm. Patients in the control condition (sham) will conduct a similar task but will not be trained to avoid food cues. Methods against bias include public registration, randomisation by a central study office, standardisation of the treatments and blinding of assessors. Furthermore, the session number and duration will be equivalent in the two conditions. Discussion: This is the first registered randomised controlled trial of approach bias modification in a clinical BN/BED sample. Results from this study will provide an indication of the efficacy of approach bias modification training for BN/BED and the potential mechanisms of action underlying this treatment. [ABSTRACT FROM AUTHOR]

Objective: The authors sought to clarify the relationship between marriage and risk for alcohol use disorder.Method: The association between marital status and risk for first registration for alcohol use disorder in medical, criminal, and pharmacy registries was assessed in a population-based Swedish cohort (N=3,220,628) using longitudinal time-dependent survival and co-relative designs.Results: First marriage was associated with a substantial decline in risk for onset of alcohol use disorder in men (hazard ratio=0.41, 95% CI=0.40-0.42) and women (hazard ratio=0.27, 95% CI=0.26-0.28). This association was slightly stronger when the spouse had no lifetime alcohol use disorder, while marriage to a spouse with lifetime alcohol use disorder increased risk for subsequent alcohol use disorder registration in both men (hazard ratio=1.29, 95% CI=1.16-1.43) and women (hazard ratio=1.18, 95% CI=1.06-1.30). In both sexes, the protective effect of marriage was significantly stronger in those with than those without a family history of alcohol use disorder. In both men and women, the associations between marriage and risk for alcohol use disorder in cousins, half siblings, full siblings, and monozygotic twins discordant for marital status were as strong as that seen in the general population.Conclusions: First marriage to a spouse with no lifetime alcohol use disorder is associated with a large reduction in risk for alcohol use disorder. This association cannot be explained by standard covariates or, as indicated by co-relative analyses, familial genetic or shared environmental confounders. These results are consistent with the hypothesis that the psychological and social aspects of marriage, and in particular health-monitoring spousal interactions, strongly protect against the development of alcohol use disorder. The protective effects of marriage on risk for alcohol use disorder are increased in those at high familial risk for alcoholism. [ABSTRACT FROM AUTHOR]

There are many homeostatic mechanisms for coping with stress conditions in cells, including autophagy. In many studies autophagy, as an intracellular pathway which degrades misfolded and damaged protein, and Mallory-Denk Body (MDB) formation have been shown to be protective mechanisms against stress such as alcoholic hepatitis. Alcohol has a significant role in alteration of lipid homeostasis, sterol regulatory element-binding proteins (SREBPs) and peroxidase proliferator-activated receptors through AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK is one of the kinases that regulate autophagy through the dephosphorylation of ATG1. Activation of ATG1 (ULK kinases family) activates ATG6. These two activated proteins relocate to the site of initial autophagosome and activate the other downstream components of autophagocytosis. Many other proteins regulate autophagocytosis at the gene level. CHOP (C/EBP homologous protein) is one of the most important parts of stress-inducible transcription that encodes a ubiquitous transcription factor. In this report we measure the upregulation of the gene that are involved in autophagocytosis in liver biopsies of alcoholic hepatitis and NASH. Electron microscopy was used to document the presence of autophagosomes in the liver cells. Expression of AMPK1, ATG1, ATG6 and CHOP in ASH were significantly ( p value < 0.05) upregulated in comparison to control. Electron microscopy findings of ASH confirmed the presence of autophagosomes, one of which contained a MDB, heretofore undescribed. Significant upregulations of AMPK-1, ATG-1, ATG-6, and CHOP, and uptrending of ATG-4, ATG-5, ATG-9, ATR, and ATM in ASH compared to normal control livers indicate active autophagocytosis in alcoholic hepatitis. [ABSTRACT FROM AUTHOR]

Background: Heart ventricular dysfunction has been characterized as reduced longitudinal function of the right ventricle (RV), and is associated with chronic alcohol abuse. This study investigated the use of two-dimensional speckle tracking echocardiography (2DSTE) to assess the longitudinal systolic and diastolic RV function of patients with alcoholic myocardial damage.Methods: We stratified 92 asymptomatic alcoholic men into three groups of increasing alcohol intake, Groups A-C. Thirty age-matched normal adult men served as the control group. Conventional echocardiography and tricuspid annulus peak systolic excursion (TAPSE) parameters were obtained. 2DSTE parameters were recorded from an apical 4-chamber view of the RV free wall. LV peak global longitudinal systolic strain was calculated from segmental averaging of the three apical long-axis views.Results: In Group C, the RV end diastolic diameter (RVEDD) was dramatically higher than that of Groups A, B and the control, while TAPSE was significantly lower in Group C compared with the other experimental groups. In Group B, the longitudinal early diastolic strain rate (SRe) and late diastolic strain rate (SRa) of the RV free wall, and LV longitudinal strain were significantly lower than that of Group A or the control. In Group C, all the 2DSTE parameters were significantly lower than that of the other groups. A significant negative linear correlation was noted between global RV systolic parameters systolic strain peak (S), peak systolic strain rate (SRs) and TAPSE (r1=-0.84, r2=-0.72, respectively, P <0.05).Conclusions: Two-dimensional STE provided an effective and non-invasive method to assess the RV longitudinal function of patients with alcoholic myocardial damage. This methodology may be useful for diagnosing, directing treatment, and judging prognosis of alcoholic cardiac damage. [ABSTRACT FROM AUTHOR]

Background: The International Restless Legs Scale (IRLS) is the most widely used of the scales rating the severity of restless legs syndrome/Willis-Ekbom disease (RLS/WED). It has been well validated and is the primary end point for most of the therapeutic and nontherapeutic studies of RLS/WED. It has excellent psychometric properties, although it does not capture the severity of RLS under a wide variety of circumstances and times of day. Moreover, the IRLS has a large placebo effect.Methods: The Restless Legs Syndrome-6 Scale (RLS-6), however, takes another potentially valuable approach. Six items are rated on a 0-10 scale from no symptoms at 0 to very severe at 10. In addition to questions on satisfaction with sleep and sleepiness, the scale rates the severity of RLS for the past week under four separate circumstances: while falling asleep, during the night, during the day while sitting or lying, and during the day when moving around. The purpose of the current study is to report the validation of the RLS-6 under baseline and therapeutic conditions.Results: The RLS-6 seems to be an acceptable, reliable, precise, valid, and responsive instrument for the assessment of RLS severity in a specific and pragmatic manner.Conclusions: At present, we view the RLS-6 not as a replacement for the IRLS but as a supplement, as each scale provides information not captured by the other. [ABSTRACT FROM AUTHOR]

Background The main neurobiological theories of the development of addiction, including tolerance, sensitization, incentive-sensitization, and allostasis, have not been tested in longitudinal human alcohol response research. To address this issue, we conducted the first controlled prospective investigation of subjective and neuroendocrine responses to alcohol measured over a 5-year interval in at-risk young adult heavy drinkers (HD) and light drinker control subjects. Methods Participants were 156 individuals, 86 heavy drinkers and 70 light drinkers, undergoing an initial oral alcohol challenge testing (.8 g/kg alcohol vs. placebo) and an identical re-examination testing 5 to 6 years later. Alcohol use disorder (AUD) symptoms and drinking behaviors were assessed in the interim follow-up period. Results At re-examination, HD continued to exhibit higher sensitivity on alcohol’s stimulating and rewarding effects with lower sensitivity to sedative effects and cortisol reactivity, relative to light drinkers. In HD with high AUD symptom trajectories over follow-up, heightened alcohol stimulation and reward persisted at re-examination. HD with low AUD symptoms showed reduced alcohol stimulation over time and lower reward throughout compared with the HD with high and intermediate AUD symptoms. Conclusions Results support the early stage phase of the allostasis model, with persistently heightened reward sensitivity and stimulation in heavy drinkers exhibiting AUD progression in early mid-adulthood. While there are multiple pathways to development of a disorder as complex as AUD, maintenance of alcohol stimulatory and rewarding effects may play an important role in the continuation and progression of alcohol addiction. [ABSTRACT FROM AUTHOR]

A pilot measure of prejudice toward people with alcoholism was developed. Four subconstructs of prejudice were theorized, comprising subscales of Desired Social Distance, Internal Attribution, Labeling, and Antipathy. The measure was administered to 135 respondents. Psychometric analysis included reliability, item-level statistics, and factor analyses. Factor analyses suggest a three-factor structure for the measure, as the association between two scales is strong enough to render them part of the same factor. Reliability results indicate acceptable overall scale consistency. Together, scale items are satisfactory for the purpose of measuring prejudice toward people with alcoholism. Directions for further scale development are discussed. [ABSTRACT FROM AUTHOR]

Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections, γ-irradiated NOD-SCID IL-2Rγnu11 mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteriaassociated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M l monocytes (IL-12+IL-10-CD163- CD14+ cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1+CD163+CD14+ cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag-stimulated monocyte conversion from quiescent monocytes to Ml monocytes. CCL1, which functions to maintain M2b macrophage properties, was produced by M2b monocytes isolated from alcoholic PBMCs. These M2b monocytes reverted to quiescent monocytes (IL-12-IL-10-CCL1-CD163-CD14+ cells) in cultures supplemented with CCL1 antisense oligodeoxynucleotide, and the subsequent quiescent monocytes easily converted to M l monocytes under bacterial Ag stimulation. Alcoholic PBMC chimeras treated with CCL1 antisense oligodeoxynucleotide were resistant against pulmonary infection by K. pneumoniae and sepsis stemming from enterococcal translocation. These results indicate that a majority of monocytes polarize to an M2b phenotype in association with alcohol abuse, and this polarization contributes to the increased susceptibility of alcoholics to gut and lung infections. Bacterial pneumonia and gut bacteria-associated sepsis, frequently seen in alcoholics, can be controlled through the polarization of macrophage phenotypes. [ABSTRACT FROM AUTHOR]

Objective Transient elastography (TE; Fibroscan, Echosens, France) is a non-invasive and reproducible approach to assess liver stiffness (LS). LS has been reported to be associated with fibrosis but central venous pressure (CVP) can also influence LS values. We sought to evaluate the correlation between LS and CVP in a large cohort of children and adults with congenital heart disease. Methods All patients referred in our institution between 2012 and 2013 for diagnostic or interventional right heart catheterisation (RHC) were prospectively enrolled excluding patients with acute heart failure, chronic alcohol abuse, chronic liver disease, severe obesity and ascites. Patients underwent LS measurement and CVP measurement by RHC under general anaesthesia within the same or subsequent day. Results Sixty children (7.4±5.5 years) and 36 adults (38±16 years) were included. Median CVP was 6 mm Hg (range 3-15), median LS was 5 kPa (range 2.8-47.2). LS significantly correlated with CVP (r=0.75, p<10-4). In the two subgroups (ie, children and adults), correlation was r=0.68 and r=0.84 (p<10-4), respectively. In the overall population, the area under the curve of LS for identification of CVP >10 mm Hg was 0.972 (95% CI 0.855 to 1; p<0.05). Optimal cut-off value of LS for detection of CVP >10 mm Hg was 8.8 kPa (sensitivity=91.67%, specificity=96.25%). Conclusions LS measurement using TE is a rapid and reliable method to evaluate CVP in patients with congenital heart disease. [ABSTRACT FROM AUTHOR]

Introduction Substance-induced psychosis (SIP), including alcohol-induced psychotic disorder (AIPD) and substance-induced psychotic disorder (SIPD), is gradually increasing in importance in clinical practice. However, few studies have investigated the epidemiology and progression time from transient to permanent psychiatric disorders for AIPD and SIPD patients. Methods We utilized the National Health Insurance Research Database (NHIRD) to investigate the incidence and prevalence of AIPD and SIPD in Taiwan and determined the timing of AIPD or SIPD followed by the development of persistent psychotic conditions. Results The average incidence and prevalence were 1.97 and 2.94 per 100,000 person-years for AIPD, 3.09 and 5.67 per 100,000 person-years for SIPD in Taiwan. Moreover, 10.9% to 24.3% of subjects with either AIPD or SIPD had a change in diagnosis to either schizophrenia or affective disorder, and ~ 50% of patients had a psychotic or affective transformation in their first year after AIPD and SIPD diagnoses. The mean progression time of psychotic or affective transformation was 1.9 to 2.7 years. Conclusions SIP is a predictive factor for persistent psychotic and affective transformation, and a three-year follow-up may be an optimal clinical practice to prevent psychotic or affective transformation in 60% of patients. [ABSTRACT FROM AUTHOR]

Background and aims Sexual minority women (SMW) are at greater risk for alcohol use disorders (AUDs) compared to heterosexual women. However, there is a dearth of research on sexual orientation disparities in co-occurring disorders among women with AUDs. We examined disparities in lifetime co-occurring psychiatric and drug use disorders among a nationally representative sample of women with lifetime AUDs. Methods Data were analyzed from the 2004–2005 (Wave 2) of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), which was collected in structured diagnostic face-to-face interviews. Adult women with AUDs ( N = 4342) were included in the analyses and approximately 191 of those women self-identified as SMW. Lifetime alcohol and drug use disorders and psychiatric disorders were assessed using DSM-IV criteria. We conducted multivariate logistic regression analyses to compare SMW and heterosexual women with lifetime AUDs on lifetime psychiatric disorders and drug use disorders, while adjusting for sociodemographic variables. Findings While accounting for several covariates, SMW with lifetime AUDs were more likely than heterosexual women with lifetime AUDs to have lifetime psychiatric disorders (e.g., mood, anxiety, panic disorders) and drug use disorders (e.g., prescription drugs, cannabis use disorders). Conclusions Sexual minority women with lifetime alcohol use disorders are at heightened risk for co-occurring psychiatric and drug use disorders than heterosexual women with lifetime alcohol use disorders. The findings warrant the need for more research and empirically based interventions for the comprehensive treatment and prevention of alcohol use disorders among sexual minority women. [ABSTRACT FROM AUTHOR]

Introduction and Aims. Alcohol consumption among adolescents and young adults is a persistent community concern. Little is known about the short-term effects on the young adult drinker's quality of life (QOL), particularly prior to the first use of alcohol and the effect of alcohol consumption on subsequent QOL assessments. There is a need to know more about the QOL of those who decide to use alcohol in adolescence and the effect of alcohol consumption on young adult QOL. Design and Methods. This is a prospective longitudinal study of a birth cohort. Data were taken from the 14- and 21-year follow ups. At both time points,QOL was indicated by a measure of happiness and satisfaction. Alcohol use was also measured at 14- and 21-year follow ups. At the 21-year follow up, alcohol use disorder (AUD) was assessed using the Composite International Diagnostic Interview. Results. At the 14-year follow up, there was a strong association between QOL and quantity of alcohol consumed. QOL at 14 years also predicted more frequent alcohol use at 21 years of age. Poor QOL at 14 years was a strong predictor of earlier age of onset of an AUD. However, when age of onset of AUD was used to predict subsequent QOL, the associations were weak and inconsistent. Discussion and Conclusion. Poor QOL was associated with the early age of onset of alcohol use and AUDs. Addressing adolescent and young adult QOL may reduce the early onset of alcohol use and its potential for harm. [Fischer JA, Najman JM, Plotnikova M, Clavarino AM. Quality of life, age of onset of alcohol use and alcohol use disorders in adolescence and young adulthood: Findings from an Australian birth cohort. [ABSTRACT FROM AUTHOR]

Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = -0.39, P = 0.03; urinary sucralose, r = -0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia. [ABSTRACT FROM AUTHOR]

Marchiafava-Bignami Disease (MBD) is a rare central nervous system (CNS) disease characterized by demyelination of the corpus callosum. It is mostly found in men with alcohol use disorder and malnutrition with cases reported worldwide across all races. The onset of the disease may be sudden presenting with stupor, coma or seizures while some may present with gait abnormality (spasticity), psychiatric problems, hemiparesis, aphasia, apraxia and incontinence with a resultant high morbidity and mortality rates. Case description: patient is a 30 year old left handed African-American, who presented with c/o altered mental status, urinary incontinence, slurred speech and left-sided weakness. The diagnosis of MBD was confirmed with DTI Tractography which showed significantly diminished commissural fibers extending to the right central semiovale lesion, near absent or significantly diminished commissural fiber extending through the corpus callosum indicating demyelination. Discussion: MBD is often an incidental diagnosis with high morbidity and mortality. This is different from previous casas because of earlier onset as opposed to onset around age 45, rapid recovery and minimal disability as he could walk independently before discharge from hospital. This case also shows added benefit of the DTI tractography in the diagnosis of MBD. [ABSTRACT FROM AUTHOR]

The effects of oligomeric procyanidins (OPC) on vascular endothelial function provide a plausible explanation for the reduced incidence of coronary heart disease in red wine drinkers. Grape variety is an important influence on the amounts of OPC in wines. Red wines made from Aglianico, Sagrantino or Tannat grapes typically have higher OPC levels. The endothelial response to OPC induces atheroprotective changes in vascular function, which are likely mediated via oxidant signalling mechanisms originating from the mitochondrial electron transport chain. [ABSTRACT FROM AUTHOR]

Objective: To examine the diagnostic performance of shorter versions of Alcohol Use Disorder Identification Test (AUDIT), including Alcohol Consumption (AUDIT-C), in identifying risky drinkers in primary care settings using conventional performance measures, supplemented by decision curve analysis and reclassification table. Study design and Setting: A cross-sectional study of adult males in general outpatient clinics in Hong Kong. The study included only patients who reported at least sometimes drinking alcoholic beverages. Timeline follow back alcohol consumption assessment method was used as the reference standard. A Chinese translated and validated 10-item AUDIT (Ch-AUDIT) was used as a screening tool of risky drinking. Results: Of the participants, 21.7% were classified as risky drinkers. AUDIT-C has the best overall performance among the shorter versions of Ch-AUDIT. The AUC of AUDIT-C was comparable to Ch-AUDIT (0.898 vs 0.901, p-value = 0.959). Decision curve analysis revealed that when the threshold probability ranged from 15–30%, the AUDIT-C had a higher net-benefit than all other screens. AUDIT-C improved the reclassification of risky drinking when compared to Ch-AUDIT (net reclassification improvement = 0.167). The optimal cut-off of AUDIT-C was at ≥5. Conclusion: Given the rising levels of alcohol consumption in the Chinese regions, this Chinese translated 3-item instrument provides convenient and time-efficient risky drinking screening and may become an increasingly useful tool. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers in the world, with limited options for treatment unless timely diagnosed. Chronic hepatitis C virus (HCV) infection and persistent heavy alcohol consumption are independent risk factors for HCC development, which may induce a specific protein expression pattern different from those caused separately. The aim of the study was to identify protein biomarkers for the detection of HCC in HCV-infected alcoholic patients with cirrhosis in order to improve survival. We compared protein expression profiles of plasma samples from 52 HCV-infected alcoholic patients with and without HCC, using 2-D DIGE coupled with MALDI-TOF/TOF mass spectrometry. The 2-D DIGE results were analyzed statistically using Decyder software, and verified by western-blot and ELISA. In plasma samples from HCV-infected alcoholic patients, we found significantly differential expression profiles of carboxypeptidase-N, ceruloplasmin (CP), complement component 4a (C4a), fibrinogen-alpha (FGA), immunoglobulin mu chain C region, serum albumin, and serum paraoxonase/arylesterase 1 (PON1). Deregulation of plasma/serum levels of the identified proteins was associated to HCV, ethanol consumption, and/or HCC progression. In the validation through ELISA, C4a serum concentration was increased in HCC patients (2.4±1 ng/mg vs 1.8±0.6 ng/mg; p = 0.029), being the only independent predictor of HCC in the multivariate analysis (OR = 2.15; p = 0.015), with an AUROC = 0.70. The combination of C4a, FGA, CP and PON1 improved slightly the predictive ability of C4a alone (AUROC 0.81). In conclusion, we identified proteins related to acute-phase response, oxidative stress, or immune response, whose differential expression in plasma may be attributed to the presence of HCC. Among them, C4a, and its combination with CP, FGA and PON1, could be considered as potentially reliable biomarkers for the detection of HCC in HCV-infected alcoholic patients. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Inflammatory activation of resident hepatic macrophages (Kupffer cells) by portal-derived lipopolysaccharide (LPS) has a primary role in animal models of alcoholic liver disease, but it has not been systematically or longitudinally studied in human alcoholic hepatitis (AH).METHODS:We followed 50 patients with AH for 30 days. 26 patients with stable alcoholic cirrhosis and 20 healthy individuals were controls. We measured the plasma (P) concentrations of soluble CD163 (sCD163; a specific marker of inflammatory macrophage activation) and the expression of CD163 in liver tissue by immunohistochemistry and stereology of liver biopsies. We also measured the key components of the LPS pathway, P-LPS, sCD14, and LPS-binding protein (LBP), by enzyme-linked immunosorbent assay (ELISA). The 84-day mortality was registered.RESULTS:At study entry, the sCD163 concentration was 10-fold higher than in the healthy controls and 30% higher than in the stable cirrhotics (P<0.002), and it correlated with the Glasgow Alcoholic Hepatitis, Model for End-stage Liver Disease, and Child-Pugh scores (r>0.35, P<0.02, all). The liver biopsies confirmed markedly increased CD163 staining (P<0.01). P-LPS, P-CD14, and P-LBP were increased to the same degree as sCD163. During the follow-up, the sCD163 and LPS pathway components all decreased by ∼25% (P<0.05) but remained higher than in both control groups. sCD163 was an independent predictor of the 84-day mortality.CONCLUSIONS:The hepatic inflammation of human AH involves marked activation of hepatic macrophages, likely via the LPS pathway. Hepatic macrophages may thus present a target for biological therapy of AH. [ABSTRACT FROM AUTHOR]

Background: This study presents results from qualitative interviews conducted with participants in a study on the effectiveness of the Location-Based Monitoring and Intervention System for Alcohol Use Disorders (LBMI-A), a smartphone-based, stand-alone intervention application (app) for adults with alcohol use disorders. Materials and Methods: Participants were provided an LBMI-A-enabled smartphone to use during a 6-week pilot study. The LBMI-A was composed of psychoeducational modules, assessment and feedback of alcohol use patterns, geographic high-risk location monitoring and alerts, and in vivo assessment and intervention for alcohol cravings and help with managing psychological distress. Semistructured interviews were conducted with all participants following 6 weeks of interacting with the LBMI-A app (n =26). Interviews explored user perceptions of the ease and utility of LBMI-A features, module helpfulness, barriers to use, and recommendations for improvements to the program. Researchers applied a systematic qualitative coding process to transcripts that included both a priori themes identified as important by the research team and new themes that emerged during the coding process. Results and Conclusions: Narrative analysis found the emergence of five main themes identified by LBMI-A users as the most helpful functions of the phone: (1) Awareness, (2) Accountability, (3) Skill Transference, (4) Tracking Progress, and (5) Prompts. These themes are explored, and implications of these findings for future smartphone-based interventions are discussed. [ABSTRACT FROM AUTHOR]

Objective: Given the evidence that several cognitive and emotional functions are impaired in adult alcohol-dependent patients and the possibility that some of these deficits are transmitted to their children, the objective of the present study was to test the hypothesis that the perception of complex mental states would be reduced in young adults from families with a positive family history of alcohol dependence. It was also anticipated that social-perceptual deficits would confer unique predictive ability beyond that shared with other cognitive risk factors for alcohol dependence and/or substance use risk. Method: Data from 301 youth ages 18-21 years, recruited from an ongoing community longitudinal study of alcoholic and matched control families, were analyzed. Family history of alcohol dependence as well as alcohol-dependence diagnosis in the youth was based on diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. A substance use risk factor measured early problem alcohol/other drug use. The perception of mental states was measured with the computerized version of the Reading the Mind in the Eyes Test (RMET). Results: Children of alcohol-dependent parents did not show impairment in the mental states perception task, nor did social perception skills predict alcohol dependence in the youth. Correlational analysis performed between RMET and the substance use risk factor showed no significant association between the variables. Conclusions: The study results do not confirm the hypothesis that behaviorally measured social perception impairment is more prevalent in the children of alcohol-dependent parents. In addition, social-perceptual deficits were not a unique marker of either alcohol dependence or high risk for alcohol dependence in this young adult sample. [ABSTRACT FROM AUTHOR]

Objectives Carbohydrate-deficient transferrin is a well-known biomarker widely used for detection of chronic excessive alcohol intake. However, under certain clinical conditions particularly frequently met amongst heavy drinkers (steatosis, fibrosis, cirrhosis…), it isn't a reliable biomarker. In this study, we tried to find additional biomarkers to CDT in order to improve detection of chronic excessive alcohol intake. Design and methods We conducted a retrospective cohort study from December 2007 to December 2009. We focused mainly on three different groups: heavy drinking patients with active alcohol consumption ( n = 243), cirrhotic patients (abstinent patients and non alcoholic cirrhosis, n = 44) and control group ( n = 85). Results In our study, CDT showed a poor sensitivity for diagnosis of heavy drinking patients (around 63%, and even lower) for cirrhotic patients and patients at advanced stage of fibrosis. Combination of CDT with trisialotransferrin enabled to improve significantly sensitivity and specificity ( p- value AUC ROC < 0.001). When adding mean corpuscular volume and gamma-glutamyltransferase to this first combination, performances were even better ( p- value < 0.001). This second cluster enabled to make a statistically significant difference between cirrhotic patients with active alcohol consumption compared to abstinent cirrhotic patients and to non alcoholic cirrhotic patients ( p- value < 0.001). Conclusion From our study, trisialotransferrin seems to be a useful additional biomarker to CDT in order to improve detection of chronic excessive alcohol intake. [ABSTRACT FROM AUTHOR]

We previously reported the mechanisms involved in the formation of Mallory-Denk bodies (MDBs) in mice fed DDC. To further provide clinical evidence as to how ubiquitin-like protein (Ubls) modification, gene transcript expression in Ufmylation and FATylation were investigated in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies and frozen liver sections from DDC re-fed mice were used. Real-time PCR analysis showed that all Ufmylation molecules (Ufm1, Uba5, Ufc1, Ufl1 and UfSPs) were significantly downregulated, both in DDC re-fed mice livers and patients' livers where MDBs had formed, indicating that gene transcript changes were limited to MDB-forming livers where the protein quality control system was downregulated. FAT10 and subunits of the immunoproteasome (LMP2 and LMP7) were both upregulated as previously shown. An approximate 176- and 5-fold upregulation (respectively) of FAT10 was observed in the DDC re-fed mice liver and in the livers of human alcoholic hepatitis with MDBs present, implying that there was an important role played by this gene. The FAT10-specific E1 and E2 enzymes Uba6 and USE1, however, were found to be downregulated both in patients' livers and in the liver of DDC re-fed mice. Interestedly, the downregulation of mRNA levels was proportionate to MDB abundance in the liver tissues. Our results show the first systematic demonstration of transcript regulation of Ufmylation and FATylation in the liver of patients who form MDBs, where protein quality control is downregulated. This was also shown in the livers of DDC re-fed mice where MDBs had formed. [ABSTRACT FROM AUTHOR]

Background and Objectives Despite Al-Anon's widespread availability and use, knowledge is lacking about the drinkers in attendees' lives. We filled this gap by describing and comparing Al-Anon newcomers' and members' reports about their 'main drinker' (main person prompting initial attendance). Methods Al-Anon's World Service Office mailed a random sample of groups, yielding completed surveys from newcomers ( N = 362) and stable members ( N = 265). Results Newcomers' and members' drinkers generally were comparable. They had known their drinker for an average of 22 years and been concerned about his or her's drinking for 9 years; about 50% had daily contact with the drinker. Most reported negative relationship aspects (drinker gets on your nerves; you disagree about important things). Newcomers had more concern about the drinker's alcohol use than members did, and were more likely to report their drinkers' driving under the influence. Drinkers' most frequent problem due to drinking was family arguments, and most common source of help was 12-step groups, with lower rates among drinkers of newcomers. Concerns spurring initial Al-Anon attendance were the drinker's poor quality of life, relationships, and psychological status; goals for initial attendance reflected these concerns. Discussion and Conclusions The drinker's alcohol use was of less concern in prompting initial Al-Anon attendance, and, accordingly, the drinker's reduced drinking was a less frequently endorsed goal of attendance. Scientific Significance Family treatments for substance use problems might expand interventions and outcome domains beyond abstinence and relationship satisfaction to include the drinker's quality of life and psychological symptoms and in turn relieve concerns of family members. (Am J Addict 2014;23:329-336) [ABSTRACT FROM AUTHOR]

Abstract: Adolescent alcohol use may interfere with neurodevelopment, increasing the likelihood of adult alcohol use disorders (AUDs). We investigated whether adolescent intermittent ethanol (AIE) exposure alters the adult reward response to ethanol. Adolescent rats were administered ethanol once (moderate exposure; Cohort 1) or three times per day (severe exposure; Cohort 2) in a 2 days on/2 days off pattern. In adulthood, subjects responded for electrical stimulation directed at the posterior lateral hypothalamus in a discrete-trial intracranial self-stimulation (ICSS) procedure that provides current-intensity thresholds as a measure of brain reward function. The effects of ethanol administration and withdrawal were assessed. Control rats showed dose-dependent threshold elevations after acute ethanol, indicating reward deficits. A majority of moderately AIE-exposed rats (Cohort 1) showed threshold lowering after ethanol, suggesting ethanol-induced reward enhancement in this sub-set of rats. Rats exposed to severe AIE (Cohort 2) showed no threshold elevation or lowering, suggesting a blunted affective ethanol response. Daily ethanol induced threshold elevations 24h after administration in control rats but not in either group of AIE-exposed rats, suggesting decreased sensitivity to the negative affective state of ethanol withdrawal. Withdrawal from a 4-day ethanol binge produced robust and enduring threshold elevations in all rats, although threshold elevations were diminished in rats exposed to severe AIE. These results indicate that AIE exposure diminished reward deficits associated with ethanol intoxication and withdrawal and may have increased ethanol-induced reward enhancement in a sub-set of rats. In humans, enhanced ethanol reward accompanied by reduced withdrawal severity may contribute to the development of AUDs. [Copyright &y& Elsevier]

Our study aimed to evaluate the prevalence and severity of sleep disturbance in a population that included people suffering from alcohol use disorder. A questionnaire that assessed alcohol misuse, sleep quality, insomnia severity, levels of fatigue, sleepiness and depression, as well as circadian typology, was filled in by two hundred and twenty one participants (55.7% women, aged 39.7±15.9). Clinical relevant sleep disturbance and alcohol misuse risk was reported by 21% of the participants, and 14.9% respectively. After matching for age and gender, sleep disturbance was three times more frequent amongst alcoholics (35.7%) and sleep loss consequences (fatigue, sleepiness, depression) were more severe amongst them. [ABSTRACT FROM AUTHOR]

Involvement of the type 1 cannabinoid receptor (CB1R) in the effects of alcohol on the brain is supported by animal experiments, but how in vivo CB1R levels are altered in alcoholic patients is still unclear. To assess the short-time effects of a binge drinking episode on CB1R availability, 20 healthy social drinkers underwent [ 18F]MK-9470-positron emission tomography (PET) at baseline and after intravenous ethanol administration (ALC ACU). Moreover, 26 alcoholic patients underwent sequential CB1R PET after chronic heavy drinking (ALC CHR) and after 1 month of abstinence (ALC ABST). Seventeen healthy subjects served as controls. Compared with baseline, ALC ACU resulted in a global increase of CB1R availability (15.8%). In contrast, a global decreased CB1R availability was found in ALC CHR patients (16.1%) compared with controls, which remained unaltered after abstinence (17.0%). Voxel-based analysis showed that ALC CHR patients had reduced CB1R availability, especially in the cerebellum and parieto-occipital cortex. After abstinence, reduced CB1R availability extended also to other areas such as the ventral striatum and mesotemporal lobe. In conclusion, whereas the acute alcohol effect is an increase in CB1R availability, chronic heavy drinking leads to reduced CB1R availability that is not reversible after 1 month of abstinence. Longer follow-up is required to differentiate whether this is a compensatory effect of repeated endocannabinoid overstimulation or an enduring trait-like feature. An enhanced CB1R signaling may offer a new therapeutic direction for treatment of the negative affective state produced by alcohol withdrawal and abstinence, which is critical for the maintenance of alcohol addiction. [ABSTRACT FROM AUTHOR]

This is a case report about a patient who arrived in our emergency department in Western Australia to the care of the urologists having just gotten off a ship with a bacterial infection that would result in a 44-day stay in hospital and have quite devastating lasting effects for the young male. His story was in fact reflective of an emerging global phenomenon. Once thought to generally be a bacterium of threat only to the elderly and alcoholics, causing pneumonia and urinary tract infections, this case report describes the potentially devastating consequences of what is now becoming recognized as a hypervirulent form of Klebsiella pneumoniae with the potential to spread throughout the system rapidly seeding abscesses and causing significant morbidity in nonimmunocompromised patients. Initially noticed in Asia increasingly case reports are emerging in Western countries suggesting a global spread. [ABSTRACT FROM AUTHOR]

Abstract: Although negative affect is a common precipitant of alcohol relapse, there are few interventions for alcohol dependence that specifically target negative affect. In this stage 1a/1b treatment development study, several affect regulation strategies (e.g., mindfulness, prolonged exposure, distress tolerance) were combined to create a new treatment supplement called affect regulation training (ART), which could be added to enhance cognitive–behavioral therapy (CBT) for alcohol dependence. A draft therapy manual was given to therapists and treatment experts before being administered to several patients who also provided input. After two rounds of manual development (stage 1a), a pilot randomized clinical trial (N =77) of alcohol-dependent outpatients who reported drinking often in negative affect situations was conducted (stage 1b). Participants received 12-weekly, 90-minute sessions of either CBT for alcohol dependence plus ART (CBT+ART) or CBT plus a healthy lifestyles control condition (CBT+HLS). Baseline, end-of-treatment, and 3- and 6-month posttreatment interviews were conducted. For both treatment conditions, participant ratings of treatment satisfaction were high, with CBT+ART rated significantly higher. Drinking outcome results indicated greater reductions in alcohol use for CBT+ART when compared to CBT+HLS, with moderate effect sizes for percent days abstinent, drinks per day, drinks per drinking day, and percent heavy drinking days. Overall, findings support further research on affect regulation interventions for negative affect drinkers. [Copyright &y& Elsevier]

Aim To study the profile of delirium associated with alcohol withdrawal syndrome (AWS) in a developing country in terms of symptomatology, associated risk factors/physical complications, and outcome. Methodology Using a prospective design, 112 patients in whom delirium could be attributed to AWS as either the sole or a contributory cause were assessed by Delirium Rating Scale-Revised-98 and the associated etiological factors were assessed by using delirium etiology checklist. Findings In all patients, delirium was acute in onset and all patients had disturbance of sleep-wake cycle and inattention. Other common symptoms were: disorientation (99.1%), fluctuation in symptoms (97.3%), motor agitation (94.6%), and short-term memory disturbance (92.9%). In terms of delirium etiology checklist etiological categories, besides alcohol withdrawal, the most common factors were metabolic/endocrine abnormalities (76%), followed by organ insufficiency and infection (37% and 35%, respectively). Most patients (67%) improved or recovered completely from delirium during the short stay of 4 days. During the short stay of mean duration of 4 days 13.4% of the patients died during the hospital stay. Conclusion Delirium associated with alcohol withdrawal is characterized by an acute onset of symptoms with high prevalence of disturbance of sleep-wake cycle, inattention, disorientation, fluctuation in symptoms, motor agitation, and disturbance in short-term memory. There are certain differences in the symptom profile of delirium associated with alcohol withdrawal and that associated with medical-surgical causes. About one-sixth of the patients developing delirium due to alcohol withdrawal die during the short hospital stay of 4 days. (Am J Addict 2013;22:503-509) [ABSTRACT FROM AUTHOR]

Purpose: To examine the applicability of the newly developed Rivermead Behavioural Memory Test - Third Edition (RBMT-3) as an ecologically-valid memory test in patients with alcohol-related cognitive disorders. Patients and methods: An authorized Dutch translation of the RBMT-3 was developed, equivalent to the UK version, and administered to a total of 151 participants - 49 patients with amnesia due to alcoholic Korsakoff's syndrome, 49 patients with cognitive impairment and a history of chronic alcoholism, not fulfilling the Korsakoff criteria, and 53 healthy controls. Between-group comparisons were made at subtest level, and the test's diagnostic accuracy was determined. Results: Korsakoff patients performed worse than controls on all RBMT-3 subtests (all P-values < 0.0005). The alcoholism group performed worse than controls on most (all P-values < 0.02), but not all RBMT-3 subtests. Largest effects were found between the Korsakoff patients and the controls after delayed testing. The RBMT-3 had good sensitivity and adequate specificity. Conclusion: The RBMT-3 is a valid test battery to demonstrate everyday memory deficits in Korsakoff patients and non-Korsakoff patients with alcohol abuse disorder. Korsakoff patients showed an impaired performance on subtests relying on orientation, contextual memory and delayed testing. Our findings provide valuable information for treatment planning and adjustment in patients with alcohol-related cognitive impairments [ABSTRACT FROM AUTHOR]

Background: Chronic alcohol abuse causes oxidative stress and impairs alveolar epithelial barrier integrity, thereby rendering the lung susceptible to acute edematous injury. Experimentally, alcohol-induced oxidative stress increases the expression of transforming growth factor β1 (TGFβ1) in the lung; however, we do not know the precise contribution of various alveolar cells in this process. In the present study, we focused on cell-cell interactions between alveolar macrophages and epithelial cells and the potential mechanisms by which TGFβ1 may become activated in the alveolar space of the alcoholic lung.Methods: Primary alveolar macrophages and epithelial cells were isolated from control- and alcohol-fed Sprague-Dawley rats. Expression of TGFβ1 and the epithelial integrin αvβ6 were examined by real time PCR and either immunocytochemistry or flow cytometry. Alveolar epithelial cells were cultured on transwell supports in the presence of macrophage cell lysate from control- or alcohol-fed rats or in the presence of viable macrophages ± alcohol. Epithelial barrier function was assessed by transepithelial resistance (TER) and paracellular flux of Texas Red dextran.Results: TGFβ1 expression was increased in alveolar macrophages from alcohol-fed rats, and TGFβ1 protein was predominantly membrane-bound. Importantly, alveolar macrophage cellular lysate from alcohol-fed rats decreased TER and increased paracellular dextran flux in primary alveolar epithelial cell monolayers as compared to the lysates from control-fed rats. Alcohol-induced epithelial barrier dysfunction was prevented by anti-TGFβ1 antibody treatment, indicating the presence of bioactive TGFβ1 in the macrophage lysate. In addition, co-culturing macrophages and epithelial cells in the presence of alcohol decreased epithelial barrier function, which also was prevented by anti-TGFβ1 and anti-αvβ6 treatment. In parallel, chronic alcohol ingestion in vivo, or direct treatment with active TGFβ1 in vitro, increased the expression of αvβ6 integrin, which is known to activate TGFβ1, in alveolar epithelial cells.Conclusions: Taken together, these data suggest that interactions between alveolar epithelial cells and macrophages contribute to the alcohol-mediated disruption of epithelial barrier function via the expression and activation of TGFβ1 at points of cell-cell contact. [ABSTRACT FROM AUTHOR]

Studies have demonstrated poor survival outcomes for patients with resected combined hepatocellular carcinoma-cholangiocarcinoma tumours (CHCC-CC). Our objectives are to report on our institutional experience regarding the clinico-pathological and prognostic features of CHCC-CC and to compare our results with published series. The clinico-pathological features and outcomes of 11 patients with CHCC-CC who had a complete surgical resection for primary liver cancer were reviewed. There were 8 male and 3 female patients. The overall median age was 61 years. Active hepatitis B and hepatitis C infections were present in 6 (54%) and 2 (18%) patients, respectively. Alcoholism was present in one case. Cirrhosis was present in 8 (72%) cases. There were no causative factors identified in 2 patients with non-cirrhotic livers. The median AFP value was 30.56 ng/ml. A single mass located in the right lobe and a single mass located in the left lobe of the liver was noted in 6 (54%) and 4 (36%) patients, respectively. Bilobar involvement was observed in one case. Major and minor resections were performed in 2 (18%) and 9 (81%) cases, respectively. The median tumour size was 3 cm. Tumours measuring >5 cm were identified in only 2 (18%) cases. The majority of the cases were classified as stage I (54%) and stage II (36%). Four patients died 11e50 months after the surgery. Postoperative tumour recurrences were observed in 5 (45.45%) patients within 4 years of surgical resection. The overall 1- and 3-year survival rates in this series were 80% and 69.3%. Our series demonstrated cases of CHCC-CC with more favourable pathological traits and survival outcomes compared with similar studies. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the dental status of alcoholics; to evaluate the relationship of unstimulated and stimulated saliva pH on their decayed/missing/filled teeth (DMFT); and to evaluate the relationship of unstimulated and stimulated salivary flow rate on their DMFT. Method: A cross-sectiona! study was conducted in patients treated for alcohol dependency (n=70; mean age 41.7 years) and a control group of non-alcoholics (n=70; mean age 39.1 years). Examinations for dental caries were conducted using the World Health Organization (WHO) criteria and questionnaires. The correlation between nominal variables was determined using X² test (a=0.05). The correlation between interval variables was determined using Pearson's correlation coefficient. Result: The mean DMFT was similar in alcoholics (14.40) and the control group (13.44) (p>0.05). There was a statistically significant correlation between alcoholism and unstimulated salivary flow rate (p<0.05), but no relationship on DMFT was recorded. No statistically significant differences were found between alcoholics and controls in terms of stimulated salivary flow rate (p>0.05) or stimulated salivary flow on DMFT (p>0.05). There was a statistically significant correlation between alcoholism and the pH value of stimulated saliva (p<0.01). There was no correlation between the amount of alcohol consumed and the number of carious lesions (p>0.05). Conclusions: No major differences were found with respect to overall DMFT in alcoholics compared to the control group. Alcoholism and stimulated salivary flow rate showed no correlation. Unstimulated salivary flow rate as well as the pH values of both unstimulated and stimulated saliva, were lower in the alcoholic group. [ABSTRACT FROM AUTHOR]

SUMMARY A strong association between inactive aldehyde dehydrogenase-2 (ALDH2) and risk of esophageal cancer has been demonstrated in East Asian drinkers. An alcohol flushing questionnaire asking about past and current tendency for facial flushing to occur after drinking a glass (≈180 mL) of beer predicts the presence of inactive ALDH2 among Japanese aged 40 years or older with a sensitivity and specificity of approximately 90%. We invented a health-risk appraisal (HRA) model that makes it possible to identify Japanese men who are at high risk for esophageal cancer based on their past and current alcohol flushing tendency, drinking, smoking, and intake of vegetables and fruits. Between 2008 and 2009, 2221 Japanese men aged 50 years or older filled out the HRA questionnaire before undergoing a screening examination by upper gastrointestinal endoscopy at five medical facilities. The endoscopic examination resulted in a diagnosis of esophageal cancer in 19 subjects, and 117 (5.27%) subjects had an HRA score ≥11. The proportion of subjects with an HRA score ≥11 was higher in the 50-69 age group (6.11-6.88%) than in 70-89 age group (2.84-2.86%). The esophageal cancer detection rate was 4.27% among the subjects with an HRA score ≥11 and only 0.67% among the other subjects. Based on a receiver operating characteristic curve analysis, when an HRA score of ≥9 was used for subjects aged 50-69 years and of ≥8 for those aged 70-89 years as the cutoff value to select individuals with a high risk for esophageal cancer, its sensitivity and false-positive rate was 52.6% and 15.2%, respectively, and the cancer detection rate was 2.91% in the high-risk group, as opposed to 0.48% in the other group. In conclusion, the high detection rates for esophageal cancer in the high-risk groups encouraged screening based on our HRA model in larger Japanese populations. [ABSTRACT FROM AUTHOR]

Background Differentiating steatosis from NASH is key in deciding treatment and follow-up schedules. We hypothesized that sonographic grading of steatosis will correlate with metabolic and pathologic changes of NASH. Methods Fifty-three non-consecutive patients had a semi-quantitative evaluation of hepatic steatosis through ultrasonographic Fatty Liver Indicator ( US- FLI) just prior to liver biopsy. All biopsies demonstrated NAFLD. US- FLI is a new scoring system ranging 2-8 based on the intensity of liver/kidney contrast, posterior attenuation of ultrasound beam, vessel blurring, difficult visualization of gallbladder wall, difficult visualization of the diaphragm and areas of focal sparing. NAFLD is diagnosed by the minimum score ≥2. Ultrasonographic findings were correlated with metabolic and histological data. Inter-observer US- FLI score agreement, evaluated by three different operators in 31 consecutive patients with steatosis, showed 'almost perfect/substantial' agreement ( P < 0.001). Results US- FLI showed a positive correlation with HOMA, insulin, uric acid, ferritin, ALT and bilirubin and was associated with steatosis extent assessed histologically and histological features of NASH, except for fibrosis. US- FLI was an independent predictor of NASH (OR 2.236; P = 0.007) and a US- FLI < 4 had a high negative predictive value (94%) in ruling out the diagnosis of severe NASH according to Kleiner's criteria. Conclusion Data confirm the hypothesis that US-FLI significantly correlates with metabolic derangements and individual pathologic criteria for NASH and may better select patients for liver biopsy. [ABSTRACT FROM AUTHOR]