New Diagnostic and Prognostic Models for the Development of Alcoholic Cirrhosis Based on Genetic Predisposition and Alcohol History

Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 cirrhotic patients and 411 non-cirrhotics). At enrollment, the data about lifetime drinking history were collected and all patients were tested for Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, Transmembrane 6 Superfamily 2 (TM6SF2) rs58542926, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 variants. In cross-sectional analyses, models for the diagnosis of cirrhosis were developed using multivariate logistic regression. A predictive score for cirrhosis development over 24 years was built by evaluating time-dependent AUC curves. The best diagnostic accuracy was demonstrated by the model, which also includes daily alcohol consumption, duration of hazardous alcohol use, and genetic variants, with AUCs of 0.951 (95% CI 0.925–0.977) and 0.887 (95% CI 0.925–0.977) for cirrhosis and compensated cirrhosis, respectively. The predictive model for future cirrhosis development (AUC of 0.836 95% CI: 0.769–0.904) accounted for age at onset of at-risk alcohol consumption and the number of PNPLA3 and HSD17B13 variant alleles. We have developed accurate genetic and alcohol consumption models for the diagnosis of alcoholic cirrhosis and the prediction of its future risk

Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring

Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offspring. However, the role of paternal alcohol exposure (PAE) on offspring EtOH sensitivity and neurotrophins has not received much attention. The present study examined whether PAE may disrupt nerve growth factor (NGF) and/or brain-derived neurotrophic factor (BDNF) and affect EtOH preference/rewarding properties in the male offspring. CD1 sire mice were chronically addicted for EtOH or administered with sucrose. Their male offsprings when adult were assessed for EtOH preference by a conditioned place preference paradigm. NGF and BDNF, their receptors (p75NTR, TrkA and TrkB), dopamine active transporter (DAT), dopamine receptors D1 and D2, pro-NGF and pro-BDNF were also evaluated in brain areas. PAE affected NGF levels in frontal cortex, striatum, olfactory lobes, hippocampus and hypothalamus. BDNF alterations in frontal cortex, striatum and olfactory lobes were found. PAE induced a higher susceptibility to the EtOH rewarding effects mostly evident at the lower concentration (0.5 g/kg) that was ineffective in non-PAE offsprings. Moreover, higher ethanol concentrations (1.5 g/kg) produced an aversive response in PAE animals and a significant preference in non-PAE offspring. PAE affected also TrkA in the hippocampus and p75NTR in the frontal cortex. DAT was affected in the olfactory lobes in PAE animals treated with 0.5 g/kg of ethanol while no differences were found on D1/D2 receptors and for pro-NGF or pro-BDNF. In conclusion, this study shows that: PAE affects NGF and BDNF expression in the mouse brain; PAE may induce ethanol intake preference in the male offspring

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Brainstem expression of SLC6A4, HTR2C, NGF, BDNF, TRKANGF, TRKBBDNF and P75NTR following paternal alcohol exposure in the male mouse

We previously showed in the mouse that paternal preconception alcohol exposure (PPAE) affects alcohol sensitivity by analyzing postnatal alcohol preference in the offspring. In this mouse study by using the same animals of the previous investigation we aimed at examining whether or not PPAE may disrupt the epigenetic regulation of postnatal alcohol sensitivity in the offspring by investigating pathways regulating mood, emotion, serotonergic tone and neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). We analyzed the brainstem gene expression of  serotonin transporter Solute Carrier Family 6 Member4 (SLC6A4), 5-Hydroxytryptamine Receptor 2C (HTR2C) binding the neurotransmitter serotonin, and NGF, BDNF and their tropomyosin receptor kinase A (TrkANGF) and B (TrKBBDNF) (high-affinity NGF and BDNF receptors) and p75NTR (low-affinity, pan-neurotrophins receptor) in adult offspring that underwent or not postnatal alcohol exposure. We found SLC6A4 elevation and decreased HTR2C in the offspring of chronic alcohol-exposed sires. We also disclosed p75NTR elevation in the offspring of chronically exposed sires as well as postnatal sensitization to low alcohol doses in the offspring of chronically exposed sires for both TrKBBDNF and BDNF. In our PPAE mouse model, where genotype effects can be carefully measured, we observed that the sires’ exposure to alcohol before mating might disrupt the sensitivity to the serotonergic/neurotrophic-associated effects of alcohol influencing the postnatal alcohol preference in the offspring

DRD2/ANKK1 TaqIA and SLC6A3 VNTR polymorphisms in alcohol dependence: Association and gene-gene interaction study in a population of Central Italy

Dopamine is a neurotransmitter whose functions are mediated by five receptors expressed in several organs and tissues. Dopaminergic system dysfunctions are involved in the etiology or treatment of several pathological conditions, including drug addiction. Alcohol dependence (AD) is a widespread psychiatric disorder, affecting 5.4% of the general population lifetime. Family and twins studies support the role of a genetic component in AD. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to AD. Here, we evaluated both the DRD2/ANKK1 TaqIA (rs1800497) and SLC6A3 40 bp-VNTR SNP and gene-gene interaction analysis in AD patients from a population of Central Italy. The study design was a case-control. In total, 280 alcoholic subjects (213 men and 67 woman) and 280 age- and sex-matched control subjects were recruited for this study. Case subjects met the DSM-IV criteria for AD and they are free from any psychiatric co-morbidities. Controls were subjects who had non-alcohol problem either never drank; those who have smoked at least one pack of cigarettes per day for at least 1 year were excluded. Genotyping was performed by allele-specific PCR and RFLP-PCR. SLC6A3 40 bp 3'UTR-VNTR displays no association with AD. DRD2/ANKK1 TaqIA genotype distribution is significantly associated to AD (O.R.= 1.551, p = 0.023), with A1* allele displaying an O.R.= 1.403 (p = 0.029). Gene-gene interaction analysis using three-way contingency table analysis by a log-linear model yielded no significant result. Our study in a population of Central Italy extends and confirms previous results and, for the first time, tested the gene-gene interaction between SLC6A3 and DRD2 in AD. (C) 2012 Elsevier Ireland Ltd. All rights reserved

Alcoholic patients valued for liver transplant: new predictive factors of relapse

Background and aims. The alcoholic cirrhosis is a consolidated indication to the liver transplant (OLT) and is the first indication in Europe. Ninety-five percent of patients with end-stage alcoholic liver disease has never been formally valued for liver transplant. A documented alcoholic abstinence of almost 6 months is strictly necessary in order to be included in a waiting list. It is important to underline that some factors such as age, socio-economic stability, absence of consumption of other substances have turned out to be prognosis positive factors for the maintaining of posttransplant abstinence. The object of our research is to identify new relevant predictive factors of relapse in these patients. Methods. Since 2004 to date, we have been valuing 231 men and 40 women (total 271 patients) aged 23–68, affected by liver cirrhosis, in order to set alcoholism diagnosis according to DSM-IV criteria and to monitor, as well as sustain abstinence in pre- and post-OLT. Data analysis was performed by using SPSSW 18. Results. 83.5% of patients presented alcoholic dependence diagnosis; 12.9% abuse; 2.6% active polyabuse, while just 1% of patients turned out non-drinker. The average age of first contact with alcoholic beverages was around 15; the risk consumption period was within those aged 25–27, with average consumption of 9 UA/die and maximum of 15 UA/die. Sixty-five percent of patients presented positive familiarity for alcoholism. 53.9% of the sample were smokers. 29.9% of patients consumed illicit drugs in the past; among them 9.2% came out positive to the toxicological exam. A high number of patients (78.9%) presented a stable family support, fundamental for the compliance pre- and post-OLT. The percentage of patients without scholastic failures was 48.3%. Conclusions. The relapse percentage of our sample in pre- (18.5%) and post (13.5%)-OLT is lower than the data present in literature; this can be due to the identification of new predictive factors of relapse ( positive familiarity for alcoholism, premature first contact, risk consumption years, scholastic failures) as well as to a strict monitoring with specific medical management in a specialist alcohol service. Hence, the importance of the figure of the specialist in alcoholism in transplant team

Virtual Morris task responses in individuals in an abstinence phase from alcohol

The present study was aimed at examining spatial learning and memory, in 33 men and 12 women with alcohol use disorder (AUD) undergoing ethanol detoxification, by using a virtual Morris task. As controls, we recruited 29 men and 10 women among episodic drinkers without a history of alcohol addiction or alcohol-related diseases. Elevated latency to the first movement in all trials was observed only in AUD persons; furthermore, control women had longer latencies compared with control men. Increased time spent to reach the hidden platform in the learning phase was found for women of both groups compared with men, in particular during trial 3. As predicted, AUD persons (more evident in men) spent less time in the target quadrant during the probe trial; however, AUD women had longer latencies to reach the platform in the visible condition during trials 6 and 7 that resulted in a greater distance moved. As for the probe trial, men of both groups showed increased virtual locomotion compared with the women of both groups. The present investigation confirms and extends previous studies showing (i) different gender responses in spatial learning tasks, (ii) some alterations due to alcohol addiction in virtual spatial learning, and (iii) differences between AUD men and AUD women in spatial-behaviour-related paradigms