Cross talk between the liver microbiome and epigenome in patients with metabolic dysfunction-associated steatotic liver disease.

Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease), including its severe clinical forms, involves complex processes at all levels of biological organization. This study examined the potential link between the liver microbiome profile and epigenetic factors.

Methods: Liver microbial DNA composition was analysed using high throughput 16S rRNA gene sequencing in 116 individuals, with 55% being female, across the spectrum of liver disease severity.

The influence of host genetics on liver microbiome composition in patients with NAFLD.

Background: Human body microbiotas are influenced by several factors, including the interaction of the host with the environment and dietary preferences. The role of host genetics in modulating the liver microbiota in the context of NAFLD remains unknown. To address this gap, we examined the interplay between the liver metataxonomic profile and host genetics.

Liver mitochondrial DNA damage and genetic variability of Cytochrome b - a key component of the respirasome - drive the severity of fatty liver disease.

Background And Aims: The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis - NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex.

Splice variant rs72613567 prevents worst histologic outcomes in patients with nonalcoholic fatty liver disease.

Hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) is a lipid droplet-associated protein; its gene-encoding variants affect the chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD). To estimate the effect of rs72613567, a splice variant with an adenine insertion (A-INS), on NAFLD susceptibility and severity, we performed a case-control study with 609 individuals. We investigated the effect of carrying the A-INS allele in 356 patients with biopsy-proven disease and explored the relationship between rs72613567 genotypes and the hepatic transcriptome.

A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis.

We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator () gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow-up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis.

Metastasis-associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune-mediated liver damage.

Long noncoding RNAs (lncRNAs) are functional molecules that orchestrate gene expression. To identify lncRNAs involved in nonalcoholic fatty liver disease (NAFLD) severity, we performed a multiscale study that included: (a) systems biology modeling that indicated metastasis-associated lung adenocarcinoma transcript 1 () as a candidate lncRNA for exploring disease-related associations, (b) translational exploration in the clinical setting, and (c) mechanistic modeling. liver profiling was performed in three consecutive phases, including an exploratory stage (liver samples from patients with NAFLD who were morbidly obese [n = 47] and from 13 individuals with normal liver histology); a replication stage (patients with NAFLD and metabolic syndrome [n =49]); and a hypothesis-driven stage (patients with chronic hepatitis C and autoimmune liver diseases, [n = 65]).

Lack of evidence supporting a role of TMC4-rs641738 missense variant-MBOAT7- intergenic downstream variant-in the Susceptibility to Nonalcoholic Fatty Liver Disease.

Current knowledge on the genetic basis of nonalcoholic fatty liver disease (NAFLD) suggests that variants contributing not only to the disease predisposition but histological severity as well are located in genes that regulate lipid metabolism. We explored the role of rs641738 C/T located in TMC4 (transmembrane channel-like 4) exon 1 (p.Gly17Glu) and 500 bases- downstream of MBOAT7 gene (TMC4/MBOAT7), in the genetic risk for developing NAFLD in a case-control study.

Genetic variation in long noncoding RNAs and the risk of nonalcoholic fatty liver disease.

The human transcriptome comprises a myriad of non protein-coding RNA species, including long noncoding RNAs (lncRNAs), which have a remarkable role in transcriptional and epigenetic regulation. We hypothesized that variants in lncRNAs influence the susceptibility to nonalcoholic fatty liver disease (NAFLD). Using next generation sequencing, we performed a survey of genetic variation associated with randomly selected lncRNA-genomic regions located within both experimentally validated and computationally predicted regulatory elements.

Mendelian randomisation suggests no beneficial effect of moderate alcohol consumption on the severity of nonalcoholic fatty liver disease.

Background: Previous epidemiological studies suggest that patients diagnosed with nonalcoholic fatty liver disease (NAFLD) who drink light to moderate amounts of alcohol (up to ~30 g per day) have less severe histological lesions compared with nondrinkers. However, while the cross-sectional nature of current evidence precludes assessment of causality, cumulative lifetime-exposure of moderate alcohol consumption on histological outcomes has never been evaluated.

Aim: To overcome these limitations, a Mendelian randomisation study was performed using a validated genetic variant (rs1229984 A;G) in the alcohol dehydrogenase (ADH1B) gene as a proxy of long-term alcohol exposure.

Mitochondrial genome architecture in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype-oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest.

Nonalcoholic steatohepatitis is associated with a state of betaine-insufficiency.

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) develops from a complex process, which includes changes in the liver methylome. Betaine plays a pivotal role in the regulation of methylogenesis. We performed a two-stage case-control study, which included patients with biopsy-proven NAFLD to explore circulating levels of betaine and its association with the histological spectrum.

Heat Shock Protein 27 is down-regulated in Ballooned Hepatocytes of Patients with Nonalcoholic Steatohepatitis (NASH).

Ballooning degeneration (BD) of hepatocytes is a distinguishing histological feature associated with the progression of nonalcoholic fatty liver disease (NAFLD). Under the assumption that NAFLD severity is associated with metabolic-stress we explored the hypothesis that heat shock 27 kDa protein 1 (HSP27), a protein chaperone involved in stress resistance and cytoskeletal-remodeling, might be deregulated in ballooned hepatocytes. We observed that fasting plasma glucose (fpG) (p = 0.

Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level.

Background: Extensive epidemiologic studies have shown that cardiovascular disease and the metabolic syndrome (MetS) are associated with serum concentrations of liver enzymes; however, fundamental characteristics of this relation are currently unknown.

Objective: We aimed to explore the role of liver aminotransferases in nonalcoholic fatty liver disease (NAFLD) and MetS.

Design: Liver gene- and protein-expression changes of aminotransferases, including their corresponding isoforms, were evaluated in a case-control study of patients with NAFLD (n = 42), which was proven through a biopsy (control subjects: n = 10).

Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA Hydroxymethylation and TET Proteins.

The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing the conversion of 5-methylcytosine to 5-hmC. We hypothesized that epigenetic editing by 5-hmC might be a novel mechanism through which nonalcoholic fatty liver disease (NAFLD)-associated molecular traits could be explained.

Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis.

Objectives: We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome.

Methods: The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls.

Results: Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.

Promoter DNA methylation of farnesoid X receptor and pregnane X receptor modulates the intrahepatic cholestasis of pregnancy phenotype.

The intrahepatic cholestasis of pregnancy (ICP) is a multifactorial liver disorder which pathogenesis involves the interplay among abnormal bile acid (BA) levels, sex hormones, environmental factors, and genetic susceptibility. The dynamic nature of ICP that usually resolves soon after delivery suggests the possibility that its pathobiology is under epigenetic modulation. We explored the status of white blood peripheral cells-DNA methylation of CpG-enriched sites at the promoter of targeted genes (FXR/NR1H4, PXR/NR1I2, NR1I3, ESR1, and ABCC2) in a sample of 88 ICP patients and 173 healthy pregnant women in the third trimester of their pregnancies.

Mild cognitive impairment: risk of dementia according to subtypes.

Unlabelled: Mild cognitive impairment (MCI) has 3 clinical subtypes: amnestic (aMCI), multiple domains (mdMCI) and non-amnestic single domain (na-SD-MCI) whose evolutive possibility to dementia has not been profoundly studied.

Objective: This paper aims to determine the conversion to dementia of the different subtypes of MCI and determine risk factors associated to conversion to dementia.

Methods: A total of 127 patients diagnosed with MCI (age=70.

MM1+2C sporadic Creutzfeldt-Jakob disease presenting as rapidly progressive nonfluent aphasia.

We report a 77-year-old man, presenting with progressive aphasia as an initial symptom, who developed severe dementia over the course of 20 months. Frontal cortex PrPSc western blot was type 2 and codon 129 was MM; brain neuropathology showed cortical vacuoles with perivacuolar PrP immunostaining characteristic of MM2C. Cerebellum showed focal coarse, patchy staining in different sections of the molecular layer, diffuse fine punctuate and coarse PrP immunopositive deposits in the granule cell layer, and focal synaptic immunostaining in the molecular layer, suggestive of MM1+2C by histotyping.

[Disinhibition in psychogeriatry: differential diagnosis with frontotemporal dementia].

Disinhibition is the loss of psychological and physiological inhibition that leads to cognitive and motor impulsivity. The notion of impulsiveness is often linked to the function of the prefrontal cortex, and is usually understood as a lack of response inhibition. In other words, the subject is unable to suppress or withhold a previously rewarding response and the behavior appears impulsive.

[Use and abuse of drugs in cognitive impairment patients].

Introduction: Irrational use of drugs for the treatment of cognitive impairment can increase health costs in developing countries.

Objective: to analyze the pattern of drug prescription related to the treatment of patients with dementia and to compare them with the income of patients.

Patients: 313 community-based outpatients that seeked medical advice for memory problems, in the Memory Center of Zubizarreta General Hospital (Buenos Aires, Argentina), were prospectively assessed during a period of a year.

[Neuropsychiatric symptoms in mild cognitive impairment].

Unlabelled: The mild cognitive impairment (MCI), has emerged as an identifiable condition and in many cases is an intermediate state preceding diagnosable Alzheimer disease (AD) characterized by acquired cognitive deficits, without significant decline in functional activities of daily living. The aim of this study was to determine both the presence and type of neuropsychiatric manifestations in MCI patients and to compare them with both those suffering from mild AD and normal controls.

Methods: 86 subjects were assessed, 27 were classified as having MCI, 39 as having presumable mild AD, and 20 normal controls matched by age and education.

Behavioral flexibility impairment with negative feedback in refractory temporal lobe epileptic patients with unilateral amygdala and hippocampal resection.

Introduction: Patients with amygdala dysfunction generally have behavioral impairment. Temporal lobe surgery might be a model of study of unilateral amygdala resection. The objective of this study was to evaluate behavioral flexibility in epileptic patients who undergo amygdala resection for epilepsy surgery and evaluate its relationship with their neuropsychiatric symptoms.

[Neuropsychological tools for the study of depression].

Depression is a common disorder, affecting approximately one in ten of the population at some time in their lives. The nature and extent of such changes, however, is less clear, and their specificity to mood disorder, their existence before the onset of affective symptoms, their etiology and their relation ship to underlying neuroanatomical abnormalities remain poorly understood. Our objective is to present a comprehensive review of the existing neuropsychological literature on bipolar affective disorder, mayor depression and the differential diagnosis between geriatric depression and the depression as early symptom of Alzheimer's disease.