Abstract Perimenopause, a transition period that precedes menopause, is characterized by neuroendocrine, metabolic and behavioral changes, and is associated with increased vulnerability to affective ...disorders. The decrease in ovarian follicles during perimenopause contributes to a dynamic and complex hormonal milieu that is not yet well characterized. In rodents, 4-vinylcyclohexene diepoxide (VCD) induces a gradual depletion of ovarian follicles, modeling the transition to menopause in women. This study was aimed to investigate, in VCD-treated rats, the hormonal status and the behavior in the elevated plus-maze (EPM), a widely used test to assess anxiety-like behavior. From the postnatal day 28, rats were treated with VCD or vehicle for 15 days. At 80 ± 5 days after the beginning of treatment the experiments were performed at proestrus and diestrus. In the first experiment rats were decapitated, ovary was collected and blood samples were taken for estradiol, progesterone, follicle stimulant hormone (FSH), testosterone, dihydrotestosterone (DHT) and corticosterone measurements. In the second experiment, rats were subjected to the EPM for 5 min, and behavioral categories recorded. Administration of VCD induced follicular depletion as well as an increase of the number of atretic follicles demonstrating the treatment efficacy. The transitional follicular depletion was accompanied by lower progesterone, testosterone and DHT with no changes in the FSH, estradiol and corticosterone plasma levels. On the EPM, rats showed decreased open arm exploration and increased risk assessment behavior, indicating increased anxiety. These findings show that administration of VCD to induce ovarian failure results in endocrine and anxiety-related changes that are similar to the symptoms exhibited by women during menopause transition. Thus, this model seems to be promising in the study of perimenopause-related changes.
Suicidal ideation is common among individuals with first episode psychosis (FEP), with prevalence estimates up to 56.5 %. Despite its high prevalence, relatively little is known about how ...sociodemographic, clinical and/or developmental characteristics contribute to the experience of suicidal ideation in individuals with FEP.
In this cross-sectional study (FEP n = 551 and controls n = 857), univariate logistic regression analyses were performed to study the associations of sociodemographic, clinical, and developmental factors with suicidal ideation in individuals with FEP as well as controls. Suicidal ideation was assessed using the Community Assessment of Psychic Experiences (CAPE). In addition, multivariate logistic regression analyses were conducted based on a stepwise approach.
In FEP, only depressive symptoms remained significantly associated with suicidal ideation when all correlates were integrated into one model. In the multivariate model in controls, depressive symptoms, positive symptoms, and traumatic childhood experiences were significantly associated with suicidal ideation.
This study showed that depressive symptoms are an important factor relating to suicidal ideation in individuals with FEP, over and above other clinical, sociodemographic, and developmental factors. This underscores the relevance of screening for suicidal ideation in individuals with FEP, and highlights the need for a better understanding of the diagnostic uncertainty and course of mood symptoms in early psychosis.
Cross-sectional study design, self-reported questionnaires.
Objective
To evaluate whether colchicine treatment was associated with the inhibition of NLRP3 inflammasome activation in patients with COVID-19.
Methods
We present a post hoc analysis from a ...double-blinded placebo-controlled randomized clinical trial (RCT) on the effect of colchicine for the treatment of COVID-19. Serum levels of NOD-like receptor protein 3 (NLRP3) inflammasome products—active caspase-1 (Casp1p20), IL-1β, and IL-18—were assessed at enrollment and after 48–72 h of treatment in patients receiving standard-of-care (SOC) plus placebo vs. those receiving SOC plus colchicine. The colchicine regimen was 0.5 mg tid for 5 days, followed by 0.5 mg bid for another 5 days.
Results
Thirty-six patients received SOC plus colchicine, and thirty-six received SOC plus placebo. Colchicine reduced the need for supplemental oxygen and the length of hospitalization. On Days 2–3, colchicine lowered the serum levels of Casp1p20 and IL-18, but not IL-1β.
Conclusion
Treatment with colchicine inhibited the activation of the NLRP3 inflammasome, an event triggering the ‘cytokine storm’ in COVID-19.
Trial registration numbers
RBR-8jyhxh
Introduction
Gene-environment interactions increase psychosis risk (Gayer-Anderson
et al
. Soc Psychiatry Psychiatr Epidemiol 2020; 55(5):645-657). However, identifying the genetic variants involved ...and how they interact with environmental risk factors underlying psychosis remains challenging.
Objectives
To investigate whether there are gene-environment interactions in the relationships of childhood trauma, lifetime cannabis use, and single nucleotide variants (SNVs) of dopamine D2 receptor (D2R:
DRD2
), N-methyl-d-aspartate receptor (NMDAR:
GRIN1
,
GRIN2A
and
GRIN2B
) and cannabinoid receptor type 1 (CB1R:
CNR1
) with psychosis.
Methods
In a population-based case-control study nested in an incident study (STREAM, Brazil) (Del-Ben
et al
. Br J of Psychiatry 2019; 215(6):726-729), part of the EU-GEI consortium (Gayer-Anderson
et al
. Soc Psychiatry Psychiatr Epidemiol 2020; 55(5):645-657), 143 first-episode psychosis patients and 286 community-based controls of both sexes aged between 16 and 64 years were included over a period of 3 years. Twenty-three SNVs of D2R (rs1799978, rs7131056, rs6275), NMDAR (
GRIN1
: rs4880213, rs11146020;
GRIN2A
: rs1420040, rs11866328;
GRIN2B
: rs890, rs2098469, rs7298664), and CB1R genes (
CNR1
: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898), were genotyped from peripheral blood DNA using a custom Illumina HumanCoreExome-24 BeadChip. Environmental adversities were evaluated using the Cannabis Experience Questionnaire (Di Forti et al. The Lancet Psychiatry 2009; 6(5):427–436) and the Childhood Trauma Questionnaire (Grassi-Oliveira et al. Rev Saude Publica 2006; 40(2):249-55). Associations between SNVs and environmental risk factors were performed using the nonparametric multifactor dimensionality reduction software (version 3.0.2).
Results
Single locus analysis showed no association among the 23 SNVs with psychosis; however, gene-environment analysis was significant for the polymorphic loci rs12720071 and rs7766029 in
CNR1.
The best association models were the two-factor representing by the combination of
CNR1
rs12720071 with lifetime cannabis use (p<0.001), and
CNR1
rs12720071 with childhood trauma (p<0.05), both suggesting an increased risk of psychosis. Additionally, when considering the interaction of both environmental factors in the same model, we found
CNR1
rs7766029 to be associated with psychosis (p<0.001).
Conclusions
Our study supports the hypothesis of gene-environment interactions for psychosis involving the T allele carriers of
CNR1
SNVs (rs12720071 and rs7766029), childhood trauma and lifetime cannabis use in psychosis.
Disclosure of Interest
None Declared
N-methyl-d-aspartate receptor (NMDAR) has been largely implicated in the neurobiology of schizophrenia and other psychosis. Aiming to evaluate their potential as peripheral biomarkers for psychosis, ...we quantified the plasma concentrations of NR1 and NR2 NMDAR subunits of first-episode psychosis patients in their first contact with mental health services due to psychotic symptoms, compared with siblings and matched community-based controls.
The quantifications of NR1 and NR2 plasma concentrations were performed by ELISA. Data were analysed by nonparametric tests and Receiver Operating Curve (ROC) analysis.
We included 166 first-episode psychosis patients (mean age = 30.3 ± 12.2 years; 64% men), with the diagnosis of schizophrenia spectrum (n = 84), bipolar disorder (n = 51) and psychotic depression (n = 31), 76 siblings (mean age = 31.5 ± 11.0 years; 30.3% men) and 166 healthy community-based controls (mean age = 31.4 ± 12.0 years; 63.9% men). NMDAR subunits were significantly lower in patients compared with siblings and controls (p < 0.001), except by NR1 plasma concentrations of bipolar patients compared with siblings and controls. NR1 plasma concentrations lower than 17.65 pg/ml (AUC = 0.621) showed sensitivity of 42.8%, specificity of 84.3%, positive predictive value (PPV) of 73.2% and negative predictive value (NPV) of 59.6%. Individuals with NR2 plasma concentrations lower than 2.92 ng/ml (AUC = 0.801) presented a 10.61-fold increased risk of psychosis, with a sensibility of 71.9%, specificity of 80.6%, PPV of 79.0% and NPV of 73.9%.
This is the first study reporting the measurement and the reduction of NR1 and NR2 NMDAR subunits plasma concentrations in psychiatric disorders. In particular, the NR2 subunit may be a possible plasma biomarker for psychosis.
IntroductionNeuroanatomical abnormalities are reported in psychotic disorders compared to healthy controls; nevertheless, less is known about the role of familial liability to psychosis in ...morphological brain changes.ObjectivesUsing an exploratory voxel-based morphometry (VBM) analyses of the whole brain, we evaluated differences on GMVs across the whole brain among first-episode psychosis (FEP) patients, community-controls, and healthy siblings of patients to interrogate the role of familial liability.MethodsData were retrieved from a study (STREAM) conducted in Ribeirão Preto/SP Brazil. We included 71 first-episode psychosis patients (67.6% males, mean age±SD: 18.7±10.8), 24 unaffected siblings of patients (37.5% males, mean age±SD 30.8±10), and 36 controls (71.9% males, mean age±SD: 10±10.5). All magnetic resonance imaging (MRI) scans were acquired on a 3T Philips scanner. VBM data were processed using Statistical Parametric Mapping (SPM) software in MATLAB the MNI coordinate system. We performed exploratory voxel-wise comparisons of GMVs among the three groups using an analysis of covariance (ANCOVA) model in SPM. Results were considered significant if they retained significance after family-wise error (FWE) correction for multiple comparisons (p<0.05). All the analyses were adjusted for age, sex, education in years, and total brain GMV.ResultsThe whole-brain exploratory analyses revealed no significant findings at the p<0.05 level (FWE-corrected). However, pairwise comparisons revealed significant changes betweeen FEP patients and their unaffected siblings. In particular, FEP patients had decreased volumes in the right side of the following regions (FEW = 0.047): superior temporal cortex, Rolandic operculum, insula, Heschel’s gyrus, supramarginal gyrus, superior temporal pole, hippocampus, parahippocampal gyrus, fusiform gyrus, amydgala, olfactory, inferior frontal operculum, cerebellum, posterior and medial orbital frontal cortex, rectus, medial temporal, medial frontal, and putamen. FEP patients also showed decreased volumes on the left side of the following regions (FWE 0.049): frontal superior medial gyrus, superior frontal gyrus, frontal middle part, caudate, anterior cingulate cortex, thalamus, and pallidum. Patients also showed widespread reduced GMV in various GMVs regions compared to controls at FWE<0.05. However, no difference was found between siblings and controls (FWE: >0.05).ConclusionsThe study of healthy siblings of patients with heritable illnesses could help in the understanding of the contribution of genetic background and environmental factors to illness state and predisposition. Differences between patients and their siblings could be attributed to the disease state, considering that the unaffected sibling group and unrelated healthy control group did not differ. We will next evaluate biological and environmental contributors to the reported differences.Disclosure of InterestNone Declared
Knowledge about the needs of psychiatric patients is essential for mental health care planning. However, research on met and unmet needs is still scarce, particularly in low- and middle-income ...countries. This study aimed to describe the patients' needs (met and unmet) at least four years after their first psychiatric hospitalization and to verify the role of demographic and clinical features as possible predictors of these needs. Patients who had their first psychiatric admission between January 1, 2006 and December 31, 2007 at an inpatient unit in the city of Ribeirão Preto, Brazil, were eligible to participate in the study. Patients were contacted and face-to-face interviews were conducted by psychologists using the Camberwell Assessment of Need. Data were analyzed using zero-inflated negative binomial regression model. Of 933 eligible patients, 333 were interviewed. The highest level of needs was related to welfare benefits (32.4%, unmet=25.5%), followed by household skills (30.3%, unmet=3.0%), psychotic symptoms (29.4%, unmet=9.0%), psychological distress (27.6%, unmet=8.4%), physical health (24.3%, unmet=5.4%), daytime activities (19.5%, unmet=16.5%), and money (16.8%, unmet=9.0%). Fewer years of schooling, living with relatives, and unemployment at the moment of the first admission were significantly associated with a higher number of both met and unmet needs in the follow-up. Unmet needs were also more often reported by patients living alone. In conclusion, socioeconomic indicators were the best predictors of needs. The unmet needs related to welfare benefits point to the need for specific social and health policies.
Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle ...closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.
Abstract
Aims
Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably ...established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene
v.
environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample.
Methods
Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects (
n
= 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of ‘Genetic’ models (solely fitted with PRS-SZ), ‘Environmental’ models (solely fitted with each environmental stressor), ‘Independent’ models (with PRS-SZ and each environmental factor), and ‘Interaction’ models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models.
Results
There were no genes-environment associations. PRS-SZ was associated with positive dimensions (
β
= 0.092,
R
2
= 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension.
Conclusions
This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample.
A prospective cohort study was conducted to determine whether an increased uterine artery pulsatility index (UtA-PI) in the second trimester of pregnancy is a risk factor for neurodevelopmental ...outcomes in children 2-3 years of age. A group of pregnant women with a UtA-PI below the 90th percentile (P90) and a second group with a UtA-PI ≥ P90 in the second trimester were included in this study. The children of these women were evaluated during their second or third year of life using the Bayley III Screening Test. A total of 858 pregnancies with UtA-PI < P90 and 96 pregnancies with UtA-PI ≥ 90 were studied. The differences between the groups related to UtA-PI ≥ 90 were detected in relation to the variables of the Caucasian ethnicity, hypertension, newborn weight and stay in the intensive care unit after birth. However, adjusted neurodevelopmental outcomes did not differ between the groups: OR 0.53 (95% CI 0.27-1.04%). This study failed to demonstrate that the UtA-PI is a risk factor for adverse neurodevelopment in children.
Impact statement
What is already known on this subject? Early interventions in children at high risk for neurodevelopmental deficiency have proved to be beneficial. The complications associated with gestation and delivery negatively influence neurodevelopment. Several studies have shown that some adverse pregnancy outcomes such as preeclampsia, foetal growth restriction and foetal death can be predicted by increased resistance to flow in the uterine artery in the second trimester. However, there are no studies evaluating the association of the uterine artery with neurodevelopmental results.
What do the results of this study add? This study concludes that neurodevelopment is influenced by multiple environmental and intrinsic factors and cannot be predicted by only one variable, such as the uterine artery blood flow. The brain has repair mechanisms to attenuate insults that occur during gestation and delivery.
What are the implications of these findings for clinical practice and/or further research? This study was unable to demonstrate that blood flow in the uterine artery is a risk factor for neurodevelopment. Different, larger studies should be conducted by combining other factors with the uterine artery in an algorithm to allow the early identification of children at risk for neurodevelopmental impairment.
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