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Liver fibrosis staging is a key element driving the prognosis of patients with chronic liver disease. Currently, biopsy is the only technique capable of diagnosing liver fibrosis in patients with alcohol‐related liver disease (ArLD) and nonalcoholic fatty liver disease (NAFLD) unequivocally. Noninvasive (e.g. plasma‐based) biomarker assays are attractive tools to diagnose and stage disease, yet must prove that they are reliable and sensitive to be used clinically. Here, we demonstrate proton nuclear magnetic resonance as a method to rapidly quantify the endogenous concentration of ammonium ions from human plasma extracts and show their ability to report upon early and advanced stages of ArLD and NAFLD. We show that, irrespective of the disease etiology, ammonium concentration is a more robust and informative marker of fibrosis stage than current clinically assessed blood hepatic biomarkers. Subject to validation in larger cohorts, the study indicates that the method can provide accurate and rapid staging of ArLD and NAFLD without the need for an invasive biopsy. [ABSTRACT FROM AUTHOR]

Background: The occurrence of overt hepatic encephalopathy (OHE) is associated with increased mortality. HE is commonly precipitated by infection, but whether HE predisposes to new infection is unclear. This study aimed to test if OHE predisposes to de novo infection during hospitalisation and its association with short‐term mortality. Aims and Methods: Seven hundred and fifty‐nine consecutive patients were identified at two institutions from prospectively maintained clinical databases of cirrhotic patients admitted with acute decompensation (AD). Infection and HE data were collected on the day of admission, and the occurrence of de novo infections was assessed for 28 days after admission. EASL‐CLIF organ failure criteria were used to determine the presence of organ failures. Multivariable analysis using the logistic regression model was used to assess predictors of 28‐day mortality and de novo infection. Results: Patients were divided into four groups; no baseline OHE or infection (n = 352); OHE with no baseline Infection (n = 221); no OHE but baseline infection (n = 100) and OHE with baseline infection (n = 86). On multivariate analyses, OHE (OR, 1.532 [95% CI, 1.061–2.300, P = 0.024]), and admission to ITU (OR, 2.303 [95% CI, 1.508–3.517, P < 0.001]) were independent risk factors for de novo infection. 28‐day mortality was 25.3%, 60.2%, 55.0% and 72.1% in the 4‐groups respectively. Age, INR and creatinine were independently predictive of mortality. The presence of overt HE, infection, coagulation, kidney, circulatory, respiratory and liver failures were significantly associated with higher mortality. Conclusion: OHE is an independent risk factor for de novo infection in cirrhotic patients with AD. [ABSTRACT FROM AUTHOR]

Background and Purpose: In hepatic encephalopathy (HE), osmotic stressors promoting brain edema result in a compensatory drop in the astrocyte metabolite myo-inositol (mI). Identifying differences between nonalcoholic steatohepatitis (NASH) with and without HE and healthy controls using proton magnetic resonance spectroscopy (MRS) and evaluating hypoalbuminemia and hyperammonemia as osmotic stressors that predict the reduction of mI allow further understanding of mechanisms that promote brain edema in HE. The aim of this study was to assess brain edema in HE using characteristic MRS markers and serum albumin.Methods: We evaluated between group differences among 19 NASH cirrhosis without HE (Crhs-HE) (age = 63 ± 8.7), 9 NASH cirrhosis with HE (Crhs+HE) (age = 63 ± 9.2), and 16 controls (age = 57.8 ± 11.7) using 1 H MRS. Glutamine (Gln/tCr) and serum albumin were evaluated as predictors of myo-inositol (mI/tCr) using linear regression. Statistical significance was set at P < .05 with adjustment for multiple comparisons.Results: Brain mI/tCr was decreased, and Gln/tCr increased in Crhs+HE compared to Crhs-HE and controls in both brain regions (P < .001 for all). Evaluated together as joint predictors, serum albumin but not Gln/tCr significantly predicted mI/tCr in GM (P = .02 and P = .2, respectively) and PWM (P = .01 and P = .1, respectively).Conclusion: Low mI/tCr and increased Gln/tCr were characteristics of Crhs+HE. Low serum albumin was the strongest predictor of brain osmotic stress indicated by reduced mI/tCr, with no residual independent association seen for brain Gln/tCr concentration. This suggests that hypoalbuminemia in chronic liver disease may promote brain edema in HE. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to investigate whether portal level of high‐mobility group protein B1 (HMGB1) is associated with hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS). Methods: We enrolled 127 consecutive patients who underwent TIPS and collected portal and peripheral blood samples in our department from December 2017 to May 2019. HMGB1 levels were determined using enzyme‐linked immunosorbent assay kits. HMGB1 and other HE related parameters were estimated by competing risk analysis, receiver operating characteristic (ROC) analysis and Kaplan–Meier analysis. Results: Patients with HE after TIPS were older (P =.019) and had higher portal HMGB1 level (P =.038) than those without. Univariate competing risk analysis: age (sHR 1.025, P =.026), hepatorenal syndrome (sHR 3.149, P =.010), model for end‐of‐stage liver disease (MELD) score (sHR 1.055, P =.024), prior HE (sHR 4.029, P =.0005), portal HMGB1 before TIPS (sHR 1.177, P =.001) reached statistical significance. Multivariate analysis: age (sHR 1.025, P =.037), MELD score (sHR 1.062, P =.011), prior HE (sHR 2.492, P =.030) and portal HMGB1 level before TIPS (sHR 1.217, P =.0002) were significantly different. ROC analyses and Kaplan–Meier curve showed portal HMGB1 level changes before and after TIPS (ΔHMGB1) had good predictive value in the cut‐off 0.012 ng/mL (AUC = 0.748, P <.001, Sensitivity = 0.743, Specificity = 0.655). Conclusions: Portal HMGB1 may be a therapeutic target for post‐TIPS HE. [ABSTRACT FROM AUTHOR]

Background Mortality from chronic liver disease is rising exponentially. The liver is intimately linked to the gut via the portal vein, and exposure to gut microbiota and their metabolites translocating across the gut lumen may impact upon both the healthy and diseased liver. Modulation of gut microbiota could prove to be a potential therapeutic target. Aim To characterise the changes in the gut microbiome that occur in chronic liver disease and to assess the impact of manipulation of the microbiome on the liver. Methods We conducted a PubMed search using search terms including 'microbiome', 'liver' and 'cirrhosis' as well as 'non-alcoholic fatty liver disease', 'steatohepatitis', 'alcohol' and 'primary sclerosing cholangitis'. Relevant articles were also selected from references of articles and review of the ClinicalTrials.gov website. Results Reduced bacterial diversity, alcohol sensitivity and the development of gut dysbiosis are seen in several chronic liver diseases, including non-alcoholic fatty liver disease, alcohol-related liver disease and primary sclerosing cholangitis. Perturbations in gut commensals could lead to deficient priming of the immune system predisposing the development of immune-mediated diseases. Furthermore, transfer of stool from an animal with the metabolic syndrome may induce steatosis in a healthy counterpart. Patients with cirrhosis develop dysbiosis, small bowel bacterial overgrowth and increased gut wall permeability, allowing bacterial translocation and uptake of endotoxin inducing hepatic and systemic inflammation. Conclusions Manipulation of the gut microbiota with diet, probiotics or faecal microbiota transplantation to promote the growth of 'healthy' bacteria may ameliorate the dysbiosis and alter prognosis. [ABSTRACT FROM AUTHOR]

Background Intrahepatic microvascular derangements and microcirculatory dysfunction are key in the development of liver cirrhosis and its associated complications. While much has been documented relating to cirrhosis and the dysfunction of the microcirculation in the liver parenchyma, far less is known about the state of the extrahepatic microcirculation and the role this may have in the pathogenesis of multiple organ failure in end stage liver cirrhosis. Aim To provide an update on the role of the microcirculation in the pathophysiology of cirrhosis and its associated complications and briefly discuss some of the imaging techniques which may be used to directly investigate the microcirculation. Methods A Medline literature search was conducted using the following search terms: 'cirrhosis', 'microcirculation', 'circulation', 'systemic', 'inflammation', 'peripheral', 'hepatorenal' and 'hepatopulmonary'. Results Significant heterogeneous microvascular alterations exist in patients with cirrhosis. Data suggest that the systemic inflammation, associated with advanced cirrhosis, induces microcirculatory dysregulation and contributes to haemodynamic derangement. The resultant vasoconstriction and hypoperfusion in the systemic extrahepatic microvasculature, is likely to be instrumental in the pathophysiology of organ failure in decompensated cirrhosis, however the mechanistic action of vasoactive agents used to correct the circulatory disturbance of advanced cirrhosis is poorly understood. Conclusions Further research into the role of the microcirculation in patients with liver cirrhosis, will improve physicians understanding of the pathophysiology of cirrhosis, and may provide a platform for real time evaluation of an individual's microcirculatory response to vasoactive mediators, thus guiding their therapy. [ABSTRACT FROM AUTHOR]

Background & Aims Minimal hepatic encephalopathy is associated with poor prognosis and mortality in patients with cirrhosis. We aimed at investigating whether bacterial- DNA translocation affects hyperammonaemia and neurocognitive scores in patients with mHE according to the use of lactulose. Methods Observational study including 72 mHE cirrhotic patients, as defined by a psychometric hepatic encephalopathy score ( PHES)<−4 and/or a critical flicker frequency ( CFF)<39 Hz. Bacterial- DNA, serum ammonia, pro-inflammatory cytokines and nitric oxide levels were evaluated. A second cohort of 40 lactulose-untreated patients were evaluated before and 6-month after lactulose administration (30-60 mL/d). Results In the first cohort, bacterial- DNA rate was significantly higher in patients without lactulose (39% vs 23%, P=.03). Serum ammonia and inflammatory markers were significantly increased in patients with bacterial- DNA, regardless the use of lactulose, and correlated with the amount of amplified bacterial- DNA. Neurocognitive scores were significantly worse in bacterial- DNA positive vs negative patients ( PHES −7.6±1.1 vs −5.5±1.0; CFF 32.5±2.6 vs 36.2±2.8, P=.01). Lactulose was associated with improved neurocognitive scores in patients without bacterial- DNA. Serum ammonia levels inversely correlated with neurocognitive scores in patients with bacterial- DNA ( PHES r=−.84; CFF r=−.72, P=.001). In the second cohort, lactulose reduced bacterial- DNA translocation (36%-16%, P=.02). Neurocognitive scores were significantly improved in bacterial- DNA positive patients who cleared bacterial- DNA during the period on lactulose. Serum ammonia levels correlated with both neurocognitive scores in patients with bacterial- DNA, either before or after lactulose. Conclusion Bacterial- DNA translocation worsens neurocognitive scores in mHE patients and it is reduced by lactulose, enhancing the relevance of controlling bacterial antigen translocation in these patients. [ABSTRACT FROM AUTHOR]

This study examined the relationship between postpartum metritis, reactive oxygen species (ROS) generation, and plasma lipopolysaccharide (LPS) concentration in peripartum dairy cows. Blood was collected twice weekly from 2 weeks prepartum through 6 weeks postpartum. Whole blood chemiluminescence (WBCL) was measured using the luminol-enhanced zymosan-stimulated chemiluminescence assay. Cows were examined for uterine health disorders and classified into two groups, healthy ( n = 11) and metritis ( n = 5). Metritis had a significant effect on WBCL, with cows with metritis having a higher WBCL. Plasma LPS concentrations in cows with metritis were significantly higher than in healthy cows. To examine the effect of LPS on WBCL, blood was sampled in healthy peripartum cows (1 to 2 weeks prepartum, n = 8; 0 to 3 weeks postpartum, n = 11; and 4 to 8 weeks postpartum, n = 8) and incubated with LPS. At 1 endotoxin units/mL of LPS, similar to the plasma LPS concentration in cows with metritis, the WBCL increased in cows at 0 to 3 weeks postpartum. Results indicate that the increase in ROS generation and plasma LPS concentration are associated with metritis, and LPS may be responsible for enhanced ROS generation in early postpartum dairy cows. [ABSTRACT FROM AUTHOR]

The present study investigated over 9 months the changes of fermentative quality of total mixed rations (TMR) containing grass silage (GS) as a major component, associated with changes in the volatile basic nitrogen (VBN) levels in an experimental dairy farm. Effects of VBN levels in TMR on metabolic parameters, reactive oxygen species (ROS) production by blood polymorphonuclear leukocytes (PMNs) and conception rates for dairy cows were analyzed. According to VBN levels in TMR during survey periods, three distinct phases were identified; phase A with low VBN; phase B with high VBN; and phase C with mid-VBN. Metabolic parameters in blood were all within normal range. However, during phases B and C, nitrogen metabolic indices such as blood urea nitrogen and milk urea nitrogen showed higher levels compared to those in phase A, and a simultaneous increase in ROS production by blood PMNs and the load on hepatic function in metabolic parameters was observed in the cows with a lower conception rate. This suggests that feeding TMR with elevated VBN levels due to poor fermented GS results in stimulation of ROS production by PMNs by ammonia, and negatively affects metabolism and reproductive performance in lactating dairy cow. [ABSTRACT FROM AUTHOR]

Background and Aim Pulmonary monocyte infiltration plays a significant role in the development of angiogenesis in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). Hepatic monocytes are also increased after CBDL, but the origins remain unclear. Splenic reservoir monocytes have been identified as a major source of monocytes that accumulate in injured tissues. Whether splenic monocytes contribute to monocyte alterations after CBDL is unknown. This study evaluates monocyte distributions and assesses effects of splenectomy on monocyte levels and pulmonary vascular and hepatic abnormalities in experimental HPS. Methods Splenectomy was performed in CBDL animals. Monocyte levels in different tissues and circulation were assessed with CD68. Pulmonary alterations of HPS were evaluated with vascular endothelial growth factor-A (VEGF-A) levels, angiogenesis, and alveolar-arterial oxygen gradient (AaPO2). Liver abnormalities were evaluated with fibrosis (Sirius red), bile duct proliferation (CK-19), and enzymatic changes. Results Monocyte levels increased in the lung and liver after CBDL and were accompanied by elevated circulating monocyte numbers. Splenectomy significantly decreased monocyte accumulation, VEGF-A levels, and angiogenesis in CBDL animal lung and improved AaPO2 levels. In contrast, hepatic monocyte levels, fibrosis, and functional abnormalities were further exacerbated by spleen removal. Conclusions Splenic reservoir monocytes are a major source for lung monocyte accumulation after CBDL, and spleen removal attenuates the development of experimental HPS. Liver monocytes may have different origins, and accumulation is exacerbated after depletion of splenic reservoir monocytes. Tissue specific monocyte alterations, influenced by the spleen reservoir, have a significant impact on pulmonary complications of liver disease. [ABSTRACT FROM AUTHOR]

Objective To comparatively review the pathogenesis, clinical presentation, diagnosis, and management of hepatic encephalopathy (HE) in dogs and cats. Data Sources The Medline database was searched for articles related to HE in people, dogs, and cats. Articles published within the last 5 years were given special importance. Human Data Synthesis The pathogenesis of HE is complex and incompletely understood, but ammonia appears to play a central role. Hyperammonemia leads to accumulation of glutamine in astrocytes, with subsequent astrocyte swelling and neurological dysfunction. The development of HE in patients with hepatic cirrhosis is a poor prognostic indicator. The fermentable disaccharide lactulose and the antimicrobial rifaximin are US Food and Drug Administration approved treatments for human HE. Severe protein restriction is no longer recommended for patients with this condition. Veterinary Data Synthesis HE is often associated with portosystemic shunting in dogs and cats. Ammonia plays a central role in the pathogenesis of HE in dogs and cats, but other factors such as manganese and endogenous benzodiazepines may also contribute. Recently, a soy protein-based diet was found to be beneficial in treating canine HE. Severe dietary protein restriction is likely to be detrimental in affected animals. There have been no clinical trials of drugs routinely used in the management HE in veterinary medicine, but lactulose and antimicrobials such as metronidazole are well-established treatments. Conclusions HE is a potentially life-threatening condition that is probably underdiagnosed in companion animals. Although various treatment recommendations have been proposed, there is a lack of evidence in the veterinary literature regarding optimal strategies for the management of this condition. As our understanding of the pathogenesis of HE in dogs and cats evolves, novel diagnostic tests and therapeutic agents may become available. [ABSTRACT FROM AUTHOR]

Neural biomarkers for the active detrimental effects of cocaine dependence (CD) are lacking. Direct comparisons of brain connectivity in cocaine-targeted networks between CD and behavioural addictions (i.e. pathological gambling, PG) may be informative. This study therefore contrasted the resting-state functional connectivity networks of 20 individuals with CD, 19 individuals with PG and 21 healthy individuals (controls). Study groups were assessed to rule out psychiatric co-morbidities (except alcohol abuse and nicotine dependence) and current substance use or gambling (except PG). We first examined global connectivity differences in the corticolimbic reward network and then utilized seed-based analyses to characterize the connectivity of regions displaying between-group differences. We examined the relationships between seed-based connectivity and trait impulsivity and cocaine severity. CD compared with PG displayed increased global functional connectivity in a large-scale ventral corticostriatal network involving the orbitofrontal cortex, caudate, thalamus and amygdala. Seed-based analyses showed that CD compared with PG exhibited enhanced connectivity between the orbitofrontal and subgenual cingulate cortices and between caudate and lateral prefrontal cortex, which are involved in representing the value of decision-making feedback. CD and PG compared with controls showed overlapping connectivity changes between the orbitofrontal and dorsomedial prefrontal cortices and between amygdala and insula, which are involved in stimulus-outcome learning. Orbitofrontal-subgenual cingulate cortical connectivity correlated with impulsivity and caudate/amygdala connectivity correlated with cocaine severity. We conclude that CD is linked to enhanced connectivity in a large-scale ventral corticostriatal-amygdala network that is relevant to decision making and likely to reflect an active cocaine detrimental effect. [ABSTRACT FROM AUTHOR]

Aim The aim was to investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour. Methods This was a randomized, double-blind, placebo-controlled, phase 2 trial. Retosiban was administered intravenously for 48 h to women in spontaneous preterm labour between 300/7 and 356/7 weeks' gestation with an uncomplicated singleton pregnancy in an in-patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery and safety. Results Uterine quiescence was achieved in 62% of women who received retosiban ( n = 30) compared with 41% who received placebo ( n = 34). The relative risk (RR) was 1.53 (95% credible interval [CrI] 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference 8.2 days, 95% CrI 2.7, 13.74). This difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI 7.4%, 33.7%) and 47.2% (95% CrI 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI 0.15, 0.81). There were no deliveries within 7 days in the retosiban group, but there were six (17.6%) births in the placebo group. The maternal, fetal and neonatal adverse events were comparable in the retosiban and placebo groups. Conclusions Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1 week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence and a favourable safety profile. [ABSTRACT FROM AUTHOR]

Objective In recent years, increasing intravenous mephedrone use was reported in several countries. The aim of this study was to describe the characteristics of such a form of mephedrone use, while identifying the differences between injectors and non-injectors in patterns of mephedrone use and psychiatric symptom status. Methods One hundred and forty-five mephedrone users were surveyed on patterns of mephedrone use using a structured questionnaire as well as the Brief Symptom Inventory. Results Majority of users received mephedrone from acquaintances and used it in discos/parties settings regarding both first and current mephedrone use. Intranasal use was the most typical route of administration (84.4%). Injectors (11%) used the drug more frequently and in higher dosages. This group included a greater proportion of opiate users (37.5%) and showed more diffuse psychiatric symptoms. Regarding the predictors of being an injector, heroin use showed the highest odds ratio. Conclusions Intravenous mephedrone use is associated with a higher risk of harmful drug use, elevated psychiatric symptom profile and increased possibility of mephedrone being considered as an addictive substance. These findings might be important in efficient treatment planning. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Cocaine addiction involves persistent deficits to unlearn previously rewarded response options, potentially due to neuroadaptations in learning-sensitive regions. Cocaine-targeted prefrontal systems have been consistently associated with reinforcement learning and reversal deficits, but more recent interspecies research has raised awareness about the contribution of the cerebellum to cocaine addiction and reversal. We aimed at investigating the link between cocaine use, reversal learning and prefrontal, insula and cerebellar gray matter in cocaine-dependent individuals ( CDIs) varying on levels of cocaine exposure in comparison with healthy controls ( HCs). Twenty CDIs and 21 HCs performed a probabilistic reversal learning task ( PRLT) and were subsequently scanned in a 3- Tesla magnetic resonance imaging scanner. In the PRLT, subjects progressively learn to respond to one predominantly reinforced stimulus, and then must learn to respond according to the opposite, previously irrelevant, stimulus-reward pairing. Performance measures were errors after reversal (reversal cost), and probability of maintaining response after errors. Voxel-based morphometry was conducted to investigate the association between gray matter volume in the regions of interest and cocaine use and PRLT performance. Severity of cocaine use correlated with gray matter volume reduction in the left cerebellum (lobule VIII), while greater reversal cost was correlated with gray matter volume reduction in a partially overlapping cluster (lobules VIIb and VIII). Right insula/inferior frontal gyrus correlated with probability of maintaining response after errors. Severity of cocaine use detrimentally impacted reversal learning and cerebellar gray matter. [ABSTRACT FROM AUTHOR]

Background & Aims Probiotics can prevent pathological bacterial translocation in cirrhosis by modulating intestinal microbiota and improving gut barrier and immune disturbances. To evaluate the effect of probiotic VSL#3 on bacterial translocation, intestinal microbiota, gut barrier and inflammatory response in rats with experimental cirrhosis. Methods Forty-six Sprague-Dawley rats with CCl4-induced cirrhosis were randomized into two groups: VSL#3 group ( n = 22) that received VSL#3 in drinking water, and water group ( n = 24) that received water only. Treatment began at week 6 of cirrhosis induction and continued until laparotomy, performed 1 week after development of ascites or at week 20. A control group included 11 healthy rats. At this study end, we evaluated bacterial translocation, intestinal flora, intestinal barrier (ileal claudin-2 and 4, β-defensin-1, occludin and malondialdehyde as index of oxidative damage) and serum cytokines. Results Mortality during this study was similar in the VSL#3 group (10/22, 45%) and the water group (10/24, 42%) ( P = 1). The incidence of bacterial translocation was 1/12 (8%) in the VSL#3 group, 7/14 (50%) in the water group ( P = 0.03 vs. VSL#3 group) and 0/11 in the control group ( P = 0.008 vs. water group). The concentration of ileal and caecal enterobacteria and enterococci was similar in the two groups of cirrhotic rats. The ileal occludin concentration was higher and ileal malondialdehyde and serum levels of TNF-α were lower in the VSL#3 group than in the water group ( P < 0.05). Conclusions VSL#3 decreases bacterial translocation, the pro-inflammatory state and ileal oxidative damage and increases ileal occludin expression in rats with experimental cirrhosis. [ABSTRACT FROM AUTHOR]

In the past decades, the Internet has become one of the most important tools to gather information and communicate with other people. Excessive use is a growing concern of health practitioners. Based on the assumption that excessive Internet use bears resemblance with addictive behaviour, we hypothesized alterations of the fronto-striatal network in frequent users. On magnetic resonance imaging scans of 62 healthy male adults, we computed voxel-based morphometry to identify grey matter ( GM) correlates of excessive Internet use, assessed by means of the Internet Addiction Test ( IAT) and functional connectivity analysis and amplitude of low-frequency fluctuation ( ALFF) measures on resting state data to explore the functional networks associated with structural alterations. We found a significant negative association between the IAT score and right frontal pole GM volume ( P < 0.001, family wise error corrected). Functional connectivity of right frontal pole to left ventral striatum was positively associated with higher IAT scores. Furthermore, the IAT score was positively correlated to ALFF in bilateral ventral striatum. The alterations in the fronto-striatal circuitry associated with growing IAT scores could reflect a reduction of top-down modulation of prefrontal areas, in particular, the ability to maintain long-term goals in face of distraction. The higher activation of ventral striatum at rest may indicate a constant activation in the context of a diminished prefrontal control. The results demonstrate that excessive Internet use may be driven by neuronal circuits relevant for addictive behaviour. [ABSTRACT FROM AUTHOR]

Background Patients with alcohol dependence ( AD) and pathological gambling ( PG) are characterized by dysfunctional reward processing and their ability to adapt to alterations of reward contingencies is impaired. However, most neurocognitive tasks investigating reward processing involve a complex mix of elements, such as working memory, immediate and delayed rewards, and risk-taking. As a consequence, it is not clear whether contingency learning is altered in AD or PG. Therefore, the current study aimed to examine performance in a deterministic contingency learning task, investigating discrimination, reversal, and extinction learning. Methods Thirty-three alcohol-dependent patients ( ADs), 28 pathological gamblers ( PGs), and 18 healthy controls ( HCs) performed a contingency learning task in which they learned stimulus-reward associations that were first reversed and later extinguished while receiving deterministic feedback throughout. Accumulated points, number of perseverative errors and trials required to reach a criterion in each learning phase were compared between groups using nonparametric Kruskal-Wallis rank-sum tests. Regression analyses were performed to compare learning curves. Results PGs and ADs did not differ from HCs in discrimination learning, reversal learning, or extinction learning, on the nonparametric tests. Regression analyses, however, showed differences in the initial speed of learning: PGs were significantly faster in discrimination learning compared to ADs, and both PGs and ADs learned slower than HCs in the reversal learning and extinction phases of the task. Conclusions Learning rates for reversal and extinction were slower for the alcohol-dependent group and PG group compared to HCs, suggesting that reversing and extinguishing learned contingencies require more effort in ADs and PGs. This implicates a diminished flexibility to overcome previously learned contingencies. [ABSTRACT FROM AUTHOR]

Background Alcohol abuse is the world's third leading cause of disease and disability, and one potential sequel of chronic abuse is alcohol-related brain damage ( ARBD). This clinically manifests as cognitive dysfunction and pathologically as atrophy of white matter (WM) in particular. The mechanism linking chronic alcohol intoxication with ARBD remains largely unknown but it is also complicated by common comorbidities such as liver damage and nutritional deficiencies. Liver cirrhosis, in particular, often leads to hepatic encephalopathy (HE), a primary glial disease. Methods In a novel transcriptomic study, we targeted the WM only of chronic alcoholics in an attempt to tease apart the pathogenesis of ARBD. Specifically, in alcoholics with and without HE, we explored both the prefrontal and primary motor cortices, 2 regions that experience differential levels of neuronal loss. Results Our results suggest that HE, along with 2 confounders, gray matter contamination, and low RNA quality are major drivers of gene expression in ARBD. All 3 exceeded the effects of alcohol itself. In particular, low-quality RNA samples were characterized by an up-regulation of translation machinery, while HE was associated with a down-regulation of mitochondrial energy metabolism pathways. Conclusions The findings in HE alcoholics are consistent with the metabolic acidosis seen in this condition. In contrast non- HE alcoholics had widespread but only subtle changes in gene expression in their WM. Notwithstanding the latter result, this study demonstrates that significant confounders in transcriptomic studies of human postmortem brain tissue can be identified, quantified, and 'removed' to reveal disease-specific signals. [ABSTRACT FROM AUTHOR]

Structural neuroimaging studies have provided evidence of differences in local brain volume between cocaine-dependent and healthy control individuals. While sex differences in aetiology, course and brain dysfunction associated with chronic cocaine abuse have been previously documented, evidence of sex-specific differences in brain volume has not been examined thus far. This study examined sex-related differences in grey matter volume between cocaine-dependent and healthy control subjects using voxel-based morphometry. High-resolution T1 structural scans were obtained from 36 inpatient, treatment-engaged 3-week abstinent cocaine-dependent ( CD) individuals. Fifty healthy control subjects were also scanned. Segmentation and registration were performed in SPM8, using New Segment and DARTEL, respectively. The whole-brain statistical analysis was conducted in SPM8 using random field-based cluster-size testing and family-wise error rate correction for multiple comparisons. CD patients were found to have less grey matter volume in anterior prefrontal cortex, including frontopolar and orbitofrontal cortices, and a posterior region surrounding the parietal-occipital sulcus. Female CD patients had less grey matter volume than female controls in left inferior frontal gyrus, insula, superior temporal gyrus and hippocampus. Male CD patients had less grey matter in a superior cortical region that included the precentral gyrus and the mid-cingulate. These sex differences in lower grey matter volume add to the evidence from functional neuroimaging for sex-specific differences in the neurophysiological changes associated with chronic cocaine use. [ABSTRACT FROM AUTHOR]

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V1a, V1b and V2 receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V1b receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V1a agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V2/V1a antagonist, conivaptan and the V2 antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V1a, V1b and V2 antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress induced by a high ammonia concentration has been suggested to be implicated in the pathophysiology of hepatic encephalopathy (HE). Therefore, oxidative damage of brain biomolecules could contribute towards explaining the neurological and motor alterations observed in HE. Methods: Portacaval-shunted (PCS) rats (n = 5) were used as an animal model of chronic HE. Plasma and brain ammonia were measured by the L-glutamate dehydrogenase method. Reactive oxygen species was measured by the dichlorodihydrofluorescein diacetate method.Lipid peroxidation was measured as thiobarbituric acid-reactive substances (TBARS) by a colorimetric method; malondialdehyde (MDA) and 4 hydroxy-2-noneal (HNE) were measured by HPLC and an immunological method respectively. Protein oxidation (carbonylation) was measured as total carbonyl after labelling with 2,4-dinitrophenyl hydrazine (DNPH) using a spectrophotometric ethod. Individual protein oxidation was studied, after labelling with DNPH and its separation by one-dimensional (1D) electrophoresis, by an immunological method. Results: Ammonia-induced oxidative stress in PCS rats was associated with increased MDA and HNE, together with increased protein oxidation, evidenced by total carbonyl quantification and by the analysis of individual protein bands separated by 1D electrophoresis. However, lipid peroxidation measured as TBARS did not show differences. Conclusion: Our data show an increased evidence of oxidative stress in PCS rat brain; moreover, PCS rat brain proteins are oxidized (carbonylated), some proteins being more sensitive to oxidation than others. These data also showthat at least six specific brain proteins in PCS rats are highly sensitive to carbonylation. Identification of these proteins may be crucial for a better understanding of HE pathophysiology. [ABSTRACT FROM AUTHOR]

A short, efficient and highly stereoselective synthesis has been developed for a series of 6-indanyl-3-alkyl-7-aryl/heterocyclic-(3 R, 6 R, 7 R)-2, 5-diketopiperazine amides that are potent and selective oxytocin (OT) antagonists. Property-based design using an estimate of human oral absorption enabled focus to be directed to those templates with the greatest chance of delivering high bioavailability in humans. This led to the 2′, 4′-difluorophenyl dimethylamide [ABSTRACT FROM AUTHOR]

See article in J. Gastroenterol. Hepatol. 2012; 27: 1371-1376. [ABSTRACT FROM AUTHOR]

See article in J. Gastroenterol. Hepatol. 2012; 27: 1329-1335. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Editorial: neutrophil dysfunction in patients with cirrhosis" in the previous issue is presented.