Evocative gene-environment correlation between genetic risk for schizophrenia and bullying victimization

Bullying exposure concerns over 10% of adolescents in Europe. Moreover, bullying victimization is heritable and victims are liable to psychotic symptoms, partly because of shared heritability with psychosis. The genetic component of bullying victimization has been proposed to involve the social reactions elicited by victims – a mechanism called “evocative gene-environment correlation”. We hypothesized that genetic risk for schizophrenia, a heritable disease also associated with social stress during childhood and adolescence, is related with social experiences during adolescence and is involved in the risk of developing psychotic symptoms. We studied 908 individuals of the TRAILS sample and found that 13-14-year-old adolescents with greater genetic risk for schizophrenia are more exposed to bullying assessed via peer nomination scores than their peers with lower genetic risk. Importantly, bullying victimization mediated the path from genetic risk to the frequency of psychotic symptoms about three years later. These findings provide evidence of a previously unreported form of gene-environment interplay that may be a mechanism of risk for psychosis and schizophrenia. To the extent that genetic risk translation into clinical symptoms is mediated by environmental risk factors, this evidence supports mental health prevention aimed at antagonizing bullying victimization in vulnerable individuals

Impact of COVID-19 emergency on the psychological well-being of susceptible individuals

The current pandemic has exerted an unprecedented psychological impact on the world population, and its effects on mental health are a growing concern. The present study aims to evaluate psychological well-being (PWB) during the COVID-19 crisis in university workers with one or more diseases likely to increase the risk of severe outcomes in the event of SARS-CoV-2 infection, defined as susceptible. 210 susceptible employees of an Italian University (aged 25-71 years) were recruited during the COVID-19 second wave (October-December 2020). A group comprising 90 healthy university employees (aged 26-69 years) was also recruited. The self-report Psychological General Well Being Index (PGWBI) was used to assess global PWB and the influence on six sub-domains: anxiety, depressed mood, positive well-being, self-control, general health, and vitality. We applied non-linear dimension-reduction techniques and regression methods to 45 variables in order to assess the main demographic, occupational, and general-health-related factors predicting PWB during the COVID-19 crisis. PGWBI score was higher in susceptible than in healthy workers, both as total score (mean 77.8 vs 71.3) and across almost all subscales. Age and jobs involving high social interaction before the pandemic were inversely associated with the PWB total score, general health, and self-control subscores. The current data suggest no decline in PWB during the second wave of COVID-19 health emergency in susceptible individuals of working age. Critically, higher risk for mental-health issues appears to be inversely related to age, particularly among individuals deprived of their previous level of social interaction at work

Aspirin Colorectal Cancer Prevention in Lynch Syndrome: Recommendations in the Era of Precision Medicine

Cancer prevention in the era of precision medicine has to consider integrated therapeutic approaches. Therapeutic cancer prevention should be offered to selected cohorts with increased cancer risk. Undoubtedly, carriers of hereditary cancer syndromes have a well-defined high cancer risk. Lynch Syndrome is one of the most frequent hereditary syndromes; it is mainly associated with colorectal cancer (CRC). Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies, initially with contradictory results; however, longer follow-up confirmed a reduced CRC incidence and mortality. The CAPP2 study recruited 861 Lynch syndrome participants randomly assigned to 600 mg of aspirin versus placebo. Like sporadic CRCs, a significant CRC risk reduction was seen after an extended follow-up, with a median treatment time that was relatively short (2 years). The ongoing CAPP3 will address whether lower doses are equally effective. Based on pharmacology and clinical data on sporadic CRCs, the preventive effect should also be obtained with low-dose aspirin. The leading international guidelines suggest discussing with Lynch syndrome carriers the possibility of using low-dose aspirin for CRC prevention. We aim systematically promote this intervention with all Lynch syndrome carriers

Increased oxidative stress associated with the severity of the liver disease in various forms of hepatitis B virus infection

BACKGROUND: Oxidative stress can be defined as an increase in oxidants and/or a decrease in antioxidant capacity. There is limited information about the oxidative status in subjects with hepatitis B virus infection. We aimed to evaluate the oxidative status in patients with various clinical forms of chronic hepatitis B infection. METHODS: Seventy-six patients with hepatitis B virus infection, in whom 33 with chronic hepatitis, 31 inactive carriers and 12 with cirrhosis, and 16 healthy subjects were enrolled. Total antioxidant response and total peroxide level measurement, and calculation of oxidative stress index were performed in all participants. RESULTS: Total antioxidant response was significantly lower in cirrhotics than inactive HbsAg carriers and controls (p = 0.008 and p = 0.008, respectively). Total peroxide level and oxidative stress index was significantly higher in cirrhotic (p < 0.001, both) and chronic hepatitis B subjects (p < 0.001, both) than inactive HbsAg carriers and controls. Total antioxidant response was comparable in chronic hepatitis B subjects, inactive HbsAg carriers and controls (both, p > 0.05/6). Total peroxide level and oxidative stress index were also comparable in inactive HBsAg carriers and controls (both, p > 0.05/6). Serum alanine amino transferase level was positively correlated with total peroxide level and oxidative stress index only in chronic hepatitis B subjects (p = 0.002, r = 0.519 and p = 0.008, r = 0.453, respectively). CONCLUSION: Oxidative stress occurs secondarily to increased total lipid peroxidation and inadequate total antioxidant response and is related to severity of the disease and replication status of virus in hepatitis B infection

Italian good practice recommendations on management of persons with Long-COVID

A significant number of people, following acute SARS-CoV-2 infection, report persistent symptoms or new symptoms that are sustained over time, often affecting different body systems. This condition, commonly referred to as Long-COVID, requires a complex clinical management. In Italy new health facilities specifically dedicated to the diagnosis and care of Long-COVID were implemented. However, the activity of these clinical centers is highly heterogeneous, with wide variation in the type of services provided, specialistic expertise and, ultimately, in the clinical care provided. Recommendations for a uniform management of Long-COVID were therefore needed. Professionals from different disciplines (including general practitioners, specialists in respiratory diseases, infectious diseases, internal medicine, geriatrics, cardiology, neurology, pediatrics, and odontostomatology) were invited to participate, together with a patient representative, in a multidisciplinary Panel appointed to draft Good Practices on clinical management of Long-COVID. The Panel, after extensive literature review, issued recommendations on 3 thematic areas: access to Long-COVID services, clinical evaluation, and organization of the services. The Panel highlighted the importance of providing integrated multidisciplinary care in the management of patients after SARS-CoV-2 infection, and agreed that a multidisciplinary service, one-stop clinic approach could avoid multiple referrals and reduce the number of appointments. In areas where multidisciplinary services are not available, services may be provided through integrated and coordinated primary, community, rehabilitation and mental health services. Management should be adapted according to the patient's needs and should promptly address possible life-threatening complications. The present recommendations could provide guidance and support in standardizing the care provided to Long-COVID patients

Effects of Açai (Euterpe oleracea Mart.) berry preparation on metabolic parameters in a healthy overweight population: A pilot study

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to evaluate the effect of açai fruit pulp on risk factors for metabolic disorders in overweight subjects. The açaí palm (<it>Euterpe oleracea </it>Mart.), which is native to South America, produces a small, black-purple fruit which is edible. The fruit has recently become popular as a functional food due to its antioxidant potential. Although several studies have been conducted in vitro and with animals, little is known about the potential health benefits in humans aside from an increase in plasma anti-oxidant capacity. Metabolic syndrome is a condition which is defined by a cluster of risk factors for cardiovascular disease and/or type-2 diabetes. Preliminary studies indicate that a reduction in reactive oxygen species can assist in the normalization of the metabolic pathways involved in this syndrome.</p> <p>Methods</p> <p>This was an open label pilot study conducted with 10 overweight adults (BMI ≥ 25 kg/m²and ≤ 30 kg/m²) who took 100 g açai pulp twice daily for 1 month. The study endpoints included levels of fasting plasma glucose, insulin, cholesterol, triglycerides, exhaled (breath) nitric oxide metabolites (eNO) and plasma levels of high sensitivity C-reactive protein (hs-CRP). The response of blood glucose, blood pressure and eNO to a standardized meal was determined at baseline and following the 30 day treatment.</p> <p>Results</p> <p>Compared to baseline, there were reductions in fasting glucose and insulin levels following the 30 day treatment (both p < 0.02). There was also a reduction in total cholesterol (p = 0.03), as well as borderline significant reductions in LDL-cholesterol and the ratio of total cholesterol to HDL-cholesterol (both p = 0.051). Compared to baseline, treatment with açai ameliorated the post-prandial increase in plasma glucose following the standardized meal, measured as the area under the curve (p = 0.047). There was no effect on blood pressure, hs-CRP or eNO.</p> <p>Conclusion</p> <p>In this uncontrolled pilot study, consumption of açai fruit pulp reduced levels of selected markers of metabolic disease risk in overweight adults, indicating that further studies are warranted.</p

Mitochondrial Oxidative Stress Alters a Pathway in Caenorhabditis elegans Strongly Resembling That of Bile Acid Biosynthesis and Secretion in Vertebrates

Mammalian bile acids (BAs) are oxidized metabolites of cholesterol whose amphiphilic properties serve in lipid and cholesterol uptake. BAs also act as hormone-like substances that regulate metabolism. The Caenorhabditis elegans clk-1 mutants sustain elevated mitochondrial oxidative stress and display a slow defecation phenotype that is sensitive to the level of dietary cholesterol. We found that: 1) The defecation phenotype of clk-1 mutants is suppressed by mutations in tat-2 identified in a previous unbiased screen for suppressors of clk-1. TAT-2 is homologous to ATP8B1, a flippase required for normal BA secretion in mammals. 2) The phenotype is suppressed by cholestyramine, a resin that binds BAs. 3) The phenotype is suppressed by the knock-down of C. elegans homologues of BA–biosynthetic enzymes. 4) The phenotype is enhanced by treatment with BAs. 5) Lipid extracts from C. elegans contain an activity that mimics the effect of BAs on clk-1, and the activity is more abundant in clk-1 extracts. 6) clk-1 and clk-1;tat-2 double mutants show altered cholesterol content. 7) The clk-1 phenotype is enhanced by high dietary cholesterol and this requires TAT-2. 8) Suppression of clk-1 by tat-2 is rescued by BAs, and this requires dietary cholesterol. 9) The clk-1 phenotype, including the level of activity in lipid extracts, is suppressed by antioxidants and enhanced by depletion of mitochondrial superoxide dismutases. These observations suggest that C. elegans synthesizes and secretes molecules with properties and functions resembling those of BAs. These molecules act in cholesterol uptake, and their level of synthesis is up-regulated by mitochondrial oxidative stress. Future investigations should reveal whether these molecules are in fact BAs, which would suggest the unexplored possibility that the elevated oxidative stress that characterizes the metabolic syndrome might participate in disease processes by affecting the regulation of metabolism by BAs

Upregulation of Hemoglobin Expression by Oxidative Stress in Hepatocytes and Its Implication in Nonalcoholic Steatohepatitis

Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was designed to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. Analysis of microarray gene expression data revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopsies from NASH patients. Increased hemoglobin expression in NASH was validated by quantitative real time PCR. However, the expression of hematopoietic transcriptional factors and erythrocyte specific marker genes were not increased, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, increased HBA1 and HBB expression in HepG2 and HEK293 cells. Importantly, hemoglobin overexpression suppressed oxidative stress in HepG2 cells. We concluded that hemoglobin is expressed by hepatocytes and oxidative stress upregulates its expression. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage in NASH

An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Backgrounds & Aims Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC