Genistein Has Antiviral Activity against Herpes B Virus and Acts Synergistically with Antiviral Treatments to Reduce Effective Dose

Herpes B virus is a deadly zoonotic agent that can be transmitted to humans from the macaque monkey, an animal widely used in biomedical research. Currently, there is no cure for human B virus infection and treatments require a life-long daily regimen of antivirals, namely acyclovir and ganciclovir. Long-term antiviral treatments have been associated with significant debilitating side effects, thus, there is an ongoing search for alternative efficacious antiviral treatment. In this study, the antiviral activity of genistein was quantified against B virus in a primary cell culture model system. Genistein prevented plaque formation of B virus and reduced virus production with an IC50 value of 33 and 46 μM for human and macaque fibroblasts, respectively. Genistein did not interfere directly with viral entry, but instead targeted an event post-viral replication. Finally, we showed that genistein could be used at its IC50 concentration in conjunction with both acyclovir and ganciclovir to reduce their effective dose against B virus with a 93% and 99% reduction in IC50 values, respectively. The results presented here illuminate the therapeutic potential of genistein as an effective antiviral agent against B virus when used alone or in combination with current antiviral therapies

Exercise and Carotid Properties in the Young–The KiGGS-2 Study

Background: Carotid intima-media thickness (cIMT) and stiffness (cS) are predictive markers of early vascular aging and atherosclerotic risk. This study assessed, whether exercise has protective effects on carotid structure and function or on vascular risk in the young. Methods: Volume and change of exercise (recreational and organized sports participation) of German adolescents and young adults was assessed within the prospective population-study KiGGS at KiGGS-Wave-1 (2009–2012) and KiGGS-Wave-2 (2014–2017) using standardized self-reporting questionnaires. CIMT and cS were measured by real-time B-mode ultrasound sequences with semi-automated edge-detection and automatic electrocardiogram-gated quality control in 2,893 participants (14–28 years, 49.6% female). A cumulative index for atherosclerotic risk (CV-R) included z-scores of mean arterial pressure, triglycerides, total/HDL-cholesterol-ratio, body mass index, and HbA1c. Results: At KiGGS-Wave-2 cross-sectional CV-R but not cS and cIMT was lower in all exercise-groups compared to “no exercise” (B = −0.73, 95%-CI = −1.26 to 0.19, p = 0.008). Longitudinal volume of exercise was negatively associated with CV-R (B = −0.37, 95%-CI = −0.74 to 0.00, p = 0.048) but not with cS and cIMT. Cross-sectional relative risk of elevated CV-R but not cS and cIMT was lower in all exercise-groups compared to “no exercise” (RR = 0.80, 95%-CI = 0.66 to 0.98, p = 0.033). High exercise volumes were associated with lower relative risk of elevated CV-R (RR = 0.80, 95%-CI = 0.65–0.97, p = 0.021) and cS in tendency but not with cIMT. Conclusions: Increased levels of exercise are associated with a better cardiovascular risk profile in young individuals, but not with cS and cIMT. Our study confirms previous recommendations on exercise in this age group without demonstrating a clear benefit on surrogate markers of vascular health.Peer Reviewe

Expression of Xenobiotic Metabolizing Enzymes in Different Lung Compartments of Smokers and Nonsmokers

BACKGROUND: Cytochrome P450 monooxygenases (CYP) play an important role in the defense against inhaled toxicants, and expression of CYP enzymes may differ among various lung cells and tissue compartments. METHODS: We studied the effects of tobacco smoke in volunteers and investigated gene expression of 19 CYPs and 3 flavin-containing monooxygenases, as well as isoforms of gluthathione S-transferases (GST) and uridine diphosphate glucuronosyltransferases (UGT) and the microsomal epoxide hydrolase (EPHX1) in bronchoalveolar lavage cells and bronchial biopsies derived from smokers (n = 8) and nonsmokers (n = 10). We also investigated gene expression of nuclear transcription factors known to be involved in the regulation of xenobiotic metabolism enzymes. RESULTS: Gene expression of CYP1A1, CYP1B1, CYP2S1, GSTP1, and EPHX1 was induced in bronchoalveolar lavage cells of smokers, whereas expression of CYP2B6/7, CYP3A5, and UGT2A1 was repressed. In bronchial biopsies of smokers, CYP1A1, CYP1B1, CYP2C9, GSTP1, and GSTA2 were induced, but CYP2J2 and EPHX1 were repressed. Induction of CYP1A1 and CYP1B1 transcript abundance resulted in increased activity of the coded enzyme. Finally, expression of the liver X receptor and the glucocorticoid receptor was significantly up-regulated in bronchoalveolar lavage cells of smokers. CONCLUSIONS: We found gene expression of pulmonary xenobiotic metabolizing enzymes and certain key transcription factors to be regulated in bronchoalveolar lavage cells and bronchial biopsies of smokers. The observed changes demonstrate tissue specificity in xenobiotic metabolism, with likely implications for the metabolic activation of procarcinogens to ultimate carcinogens of tobacco smoke

Effects of polygenic risk for major mental disorders and cross-disorder on cortical complexity

Background MRI-derived cortical folding measures are an indicator of largely genetically driven early developmental processes. However, the effects of genetic risk for major mental disorders on early brain development are not well understood. Methods We extracted cortical complexity values from structural MRI data of 580 healthy participants using the CAT12 toolbox. Polygenic risk scores (PRS) for schizophrenia, bipolar disorder, major depression, and cross-disorder (incorporating cumulative genetic risk for depression, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit hyperactivity disorder) were computed and used in separate general linear models with cortical complexity as the regressand. In brain regions that showed a significant association between polygenic risk for mental disorders and cortical complexity, volume of interest (VOI)/region of interest (ROI) analyses were conducted to investigate additional changes in their volume and cortical thickness. Results The PRS for depression was associated with cortical complexity in the right orbitofrontal cortex (right hemisphere: p = 0.006). A subsequent VOI/ROI analysis showed no association between polygenic risk for depression and either grey matter volume or cortical thickness. We found no associations between cortical complexity and polygenic risk for either schizophrenia, bipolar disorder or psychiatric cross-disorder when correcting for multiple testing. Conclusions Changes in cortical complexity associated with polygenic risk for depression might facilitate well-established volume changes in orbitofrontal cortices in depression. Despite the absence of psychopathology, changed cortical complexity that parallels polygenic risk for depression might also change reward systems, which are also structurally affected in patients with depressive syndrome

Interaction of developmental factors and ordinary stressful life events on brain structure in adults

An interplay of early environmental and genetic risk factors with recent stressful life events (SLEs) in adulthood increases the risk for adverse mental health outcomes. The interaction of early risk and current SLEs on brain structure has hardly been investigated. Whole brain voxel-based morphometry analysis was performed in N = 786 (64.6% female, mean age = 33.39) healthy subjects to identify correlations of brain clusters with commonplace recent SLEs. Genetic and early environmental risk factors, operationalized as those for severe psychopathology (i.e., polygenic scores for neuroticism, childhood maltreatment, urban upbringing and paternal age) were assessed as modulators of the impact of SLEs on the brain. SLEs were negatively correlated with grey matter volume in the left medial orbitofrontal cortex (mOFC, FWE p = 0.003). This association was present for both, positive and negative, life events. Cognitive-emotional variables, i.e., neuroticism, perceived stress, trait anxiety, intelligence, and current depressive symptoms did not account for the SLE-mOFC association. Further, genetic and environmental risk factors were not correlated with grey matter volume in the left mOFC cluster and did not affect the association between SLEs and left mOFC grey matter volume. The orbitofrontal cortex has been implicated in stress-related psychopathology, particularly major depression in previous studies. We find that SLEs are associated with this area. Important early life risk factors do not interact with current SLEs on brain morphology in healthy subjects

Identification of transdiagnostic psychiatric disorder subtypes using unsupervised learning

Psychiatric disorders show heterogeneous symptoms and trajectories, with current nosology not accurately reflecting their molecular etiology and the variability and symptomatic overlap within and between diagnostic classes. This heterogeneity impedes timely and targeted treatment. Our study aimed to identify psychiatric patient clusters that share clinical and genetic features and may profit from similar therapies. We used high-dimensional data clustering on deep clinical data to identify transdiagnostic groups in a discovery sample (N = 1250) of healthy controls and patients diagnosed with depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other psychiatric disorders. We observed five diagnostically mixed clusters and ordered them based on severity. The least impaired cluster 0, containing most healthy controls, showed general well-being. Clusters 1-3 differed predominantly regarding levels of maltreatment, depression, daily functioning, and parental bonding. Cluster 4 contained most patients diagnosed with psychotic disorders and exhibited the highest severity in many dimensions, including medication load. Depressed patients were present in all clusters, indicating that we captured different disease stages or subtypes. We replicated all but the smallest cluster 1 in an independent sample (N = 622). Next, we analyzed genetic differences between clusters using polygenic scores (PGS) and the psychiatric family history. These genetic variables differed mainly between clusters 0 and 4 (prediction area under the receiver operating characteristic curve (AUC) = 81%;significant PGS: cross-disorder psychiatric risk, schizophrenia, and educational attainment). Our results confirm that psychiatric disorders consist of heterogeneous subtypes sharing molecular factors and symptoms. The identification of transdiagnostic clusters advances our understanding of the heterogeneity of psychiatric disorders and may support the development of personalized treatments

Latent tuberculosis among professionals from a referral hospital in oncology

Introduction: Tuberculosis (TB) is an ancient contagious disease, and continues to be the leading cause of morbidity and mortality among infectious contagious diseases. It can be considered an occupational infectious disease when it happens in health professionals. These professionals are directly exposed to TB and are considered to be a high risk population for latent tuberculosis infection (LTBI) and active TB. The primary aim of this study was to estimate the prevalence of LTBI among the clinical and administrative staff of an oncology referral hospital in Rio Grande do Sul. The secondary aim of this study was evaluate tuberculin skin test (TST) conversion rate and the risk factors for TST positivity in this population. Methods: A cross-sectional study was carried out in a retrospective cohort with data collected in March 2013 and March 2014. Data of professionals from different hospital units were included. Those with induration ≥ 10 mm were considered as reactors, and conversion rate was assessed by an increase ≥ 10 mm in induration in the second TST compared with the first one. Results: Among the 225 professionals evaluated in 2013, 135 (60%) were reactors and 90 (40%) were non-reactors. The mean age was 32.9 (± 9.55), 176 (78.22%) were female, and most of the reactors worked in the hospital for 4 years or less. Non-reactors in 2013 were recommended to repeat the test in 2014, and the conversion rate was 9.37%. There was no significant difference in prevalence among the different professional categories, and the assessed risk factors were not associated with ILTB. Conclusions: The prevalence of LTBI in the study population was high, reinforcing the need to implement effective control measures to prevent LTBI in the hospital where the study was conducted. Keywords: Latent tuberculosis; occupational risk; tuberculin test; vulnerable population

Prognostic impact of <i>CEBPA </i>mutational subgroups in adult AML

Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIP InDel), frameshift InDel or nonsense mutations inducing translational stop (bZIP STOP) or single base-pair missense alterations (bZIP ms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIP InDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIP InDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIP InDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIP InDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIP ms). (Figure presented.)</p

Diagnosis of bipolar disorders and body mass index predict clustering based on similarities in cortical thickness-ENIGMA study in 2436 individuals

AIMS: Rates of obesity have reached epidemic proportions, especially among people with psychiatric disorders. While the effects of obesity on the brain are of major interest in medicine, they remain markedly under-researched in psychiatry. METHODS: We obtained body mass index (BMI) and magnetic resonance imaging-derived regional cortical thickness, surface area from 836 bipolar disorders (BD) and 1600 control individuals from 14 sites within the ENIGMA-BD Working Group. We identified regionally specific profiles of cortical thickness using K-means clustering and studied clinical characteristics associated with individual cortical profiles. RESULTS: We detected two clusters based on similarities among participants in cortical thickness. The lower thickness cluster (46.8% of the sample) showed thinner cortex, especially in the frontal and temporal lobes and was associated with diagnosis of BD, higher BMI, and older age. BD individuals in the low thickness cluster were more likely to have the diagnosis of bipolar disorder I and less likely to be treated with lithium. In contrast, clustering based on similarities in the cortical surface area was unrelated to BD or BMI and only tracked age and sex. CONCLUSIONS: We provide evidence that both BD and obesity are associated with similar alterations in cortical thickness, but not surface area. The fact that obesity increased the chance of having low cortical thickness could explain differences in cortical measures among people with BD. The thinner cortex in individuals with higher BMI, which was additive and similar to the BD-associated alterations, may suggest that treating obesity could lower the extent of cortical thinning in BD