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Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations. In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire. Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery. Our findings show that 5-HT2AR activation by LSD leads to a hippocampal-prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.

Background Clinico-pathological correlation of thyroid nodules is not routinely performed as until recently there was no objective classification system for reporting thyroid nodules on ultrasound. We compared the Thyroid Imaging Reporting and Data System (TIRADS) of classifying thyroid nodules on ultrasound with the findings on fine-needle aspiration cytology (FNAC) reported using the Bethesda System. Methods A retrospective analysis of 100 consecutive cases over 1 year (Jan–Dec 2015) was performed comparing single-surgeon-performed bedside thyroid nodule ultrasound findings based on the TIRADS classification to the FNAC report based on the Bethesda Classification. TIRADS 1 (normal thyroid gland) and biopsy-proven malignancy referred by other clinicians were excluded. Benign-appearing nodules were reported as TIRADS 2 and 3. Indeterminate or suspected follicular lesions were reported as TIRADS 4, and malignant-appearing nodules were classified as TIRADS 5 during surgeon-performed bedside ultrasound. All the nodules were subjected to ultrasound-guided FNAC, and TIRADS findings were compared to Bethesda FNAC Classification. Results Of the 100 cases, 74 were considered benign or probably benign, 20 were suspicious for malignancy, and 6 were indeterminate on ultrasound. Overall concordance rate with FNAC was 83% with sensitivity and specificity of 70.6 and 90.4%, respectively. The negative predictive value was 93.8%. Conclusion It is essential for clinicians performing bedside ultrasound thyroid and guided FNAC to document their sonographic impression of the nodule in an objective fashion using the TIRADS classification and correlate with the gold standard cytology to improve their learning curve and audit their results.

Psychotic disorders develop gradually along a continuum of severity. Understanding factors associated with psychosis development, such as sleep, could aid in identification of individuals at elevated risk. This study aimed to assess (1) the dynamic relationship between psychotic experiences (PEs) and sleep quality and quantity, and (2) whether this relationship differed between different clinical stages along the psychosis continuum. We used daily diary data (90 days) of individuals ( = 96) at early stages (i.e. before a first diagnosis of psychosis) along the psychosis continuum. Multilevel models were constructed with sleep quality and sleep quantity as predictors of PEs and vice versa. Post-hoc, we constructed a multilevel model with both sleep quality and quantity as predictors of PEs. In addition, we tested whether associations differed between clinical stages. Within persons, poorer sleep predicted next day PEs ( = -0.02, = 0.01), but not vice versa. Between persons, shorter sleep over the 90-day period predicted more PEs ( = -0.04, = 0.002). Experiencing more PEs over 90-days predicted poorer ( = -0.02, = 0.02) and shorter ( = -1.06, = 0.008) sleep. We did not find any significant moderation effects for clinical stage. We found a bidirectional relationship between sleep and PEs with daily fluctuations in sleep predicting next day PEs and general patterns of more PEs predicting poorer and shorter sleep. Our results highlight the importance of assessing sleep as a risk marker in the early clinical stages for psychosis.

Lysergic acid diethylamide (LSD) induces profound changes in various mental domains, including perception, self-awareness and emotions. We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. Using a double-blind, randomised, cross-over study design, placebo or 100 μg LSD were orally administered to 20 healthy subjects before the fMRI scan, taking into account the subjective and pharmacological peak effects of LSD. The plasma levels of LSD were determined immediately before and after the scan. The study (including the a priori -defined study end point) was registered at ClinicalTrials.gov before study start (NCT02308969). The administration of LSD reduced reactivity of the left amygdala and the right medial prefrontal cortex relative to placebo during the presentation of fearful faces ( P <0.05, family-wise error). Notably, there was a significant negative correlation between LSD-induced amygdala response to fearful stimuli and the LSD-induced subjective drug effects ( P <0.05). These data suggest that acute administration of LSD modulates the engagement of brain regions that mediate emotional processing.

Background: Obesity before pregnancy is associated with impaired metabolic status of the mother and the offspring later in life. These adverse effects have been attributed to epigenetic changes in utero , but little is known about the role of placental metabolism and its contribution to fetal development. Objectives: We examined the impact of maternal pre-pregnancy obesity on the expression of genes involved in placental lipid metabolism in lean and obese women. Subjects/Methods: Seventy-three lean and obese women with healthy pregnancy were recruited at term elective cesarean delivery. Metabolic parameters were measured on maternal venous blood samples. Expression of 88 genes involved in lipid metabolism was measured in whole placenta tissue. Proteins of genes differently expressed in response to maternal obesity were quantified, correlated with maternal parameters and immunolocalized in placenta sections. Isolated primary trophoblasts were used for in vitro assays. Results: Triglyceride (TG) content was increased in placental tissue of obese (1.10, CI 1.04–1.24 mg g −1 , P <0.05) vs lean (0.84, CI 0.72–1.02 mg g −1 ) women. Among target genes examined, six showed positive correlation ( P <0.05) with maternal pre-pregnancy BMI, namely ATGL ( PNPLA2 ), FATP1 ( SLC27A1 ), FATP3 ( SLC27A3 ), PLIN2, PPARG and CGI-58 ( ABHD5 ). CGI-58 protein abundance was twofold higher ( P <0.001) in placentas of obese vs lean women. CGI-58 protein levels correlated positively with maternal insulin levels and pre-pregnancy body mass index ( R =0.63, P <0.001 and R =0.64, P <0.001, respectively). CGI-58 and PLIN2 were primarily located in the syncytiotrophoblast and, were upregulated (1.38- and 500-fold, respectively) upon oleic acid and insulin treatment of cultured trophoblast cells. Conclusion: Pre-gravid obesity significantly modifies the expression of placental genes related to transport and storage of neutral lipids. We propose that the upregulation of CGI-58, a master regulator of TG hydrolysis, contributes to the turnover of intracellular lipids in placenta of obese women, and is tightly regulated by metabolic factors of the mother.

KLF6, a ubiquitously expressed Krüppel-like transcription factor, is frequently inactivated in human cancer and has significant roles in cellular proliferation, apoptosis, differentiation and development. A key mechanism of KLF6-mediated growth suppression is through p53-independent transactivation of p21. Several cancer-derived KLF6 mutants lead to the loss of p21-mediated growth suppression through an unknown mechanism. Because several colorectal cancer and hepatocellular carcinoma-derived KLF6 mutations affect a glycogen synthase kinase 3β (GSK3β) phosphorylation consensus site, we investigated the role of GSK3β in the regulation of KLF6 function. Based on transient transfection, GSK3β augments the transactivation of a p21 promoter luciferase by KLF6. Reciprocal co-immunoprecipitation of hemagglutinin (HA)-GSK3β and Flag-KLF6 validated the interaction between these two proteins. KLF6 phosphorylation is augmented in the presence of GSK3β based on in vitro and in vivo 32 P incorporation assays. Site-directed mutagenesis of the candidate phosphorylation sites to alanines (‘KLF6-4A’ phosphomutant) eliminated a higher molecular weight phosphorylated isoform of KLF6 based on western blot. GSK3β augmented the transactivation by wild-type KLF6, but not KLF6-4A, towards the p21 promoter, and increased p21 protein. Functionally, GSK3β enhanced KLF6-mediated growth suppression, which was abrogated by the KLF6-4A phosphomutant. These data establish that GSK3β directly phosphorylates KLF6, which augments its induction of p21 and resultant growth suppression. This interaction may account for the growth-promoting effects of cancer-derived KLF6 mutants that lack tumor suppressor activity.

Impulsivity is a central symptom of borderline personality disorder (BPD) and its neural basis may be instantiated in a frontoparietal network involved in response inhibition. However, research has yet to determine whether neural activation differences in BPD associated with response inhibition are attributed to attentional saliency, which is subserved by a partially overlapping network of brain regions. Patients with BPD (n = 45) and 29 healthy controls (HCs; n = 29) underwent functional magnetic resonance imaging while completing a novel go/no-go task with infrequent odd-ball trials to control for attentional saliency. Contrasts reflecting a combination of response inhibition and attentional saliency (no-go > go), saliency processing alone (oddball > go), and response inhibition controlling for attentional saliency (no-go > oddball) were compared between BPD and HC. Compared to HC, BPD showed less activation in the combined no-go > go contrast in the right posterior inferior and middle-frontal gyri, and less activation for oddball > go in left-hemispheric inferior frontal junction, frontal pole, superior parietal lobe, and supramarginal gyri. Crucially, BPD and HC showed no activation differences for the no-go > oddball contrast. In BPD, higher vlPFC activation for no-go > go was correlated with greater self-rated BPD symptoms, whereas lower vlPFC activation for oddball > go was associated with greater self-rated attentional impulsivity. Patients with BPD show frontoparietal disruptions related to the combination of response inhibition and attentional saliency or saliency alone, but no specific response inhibition neural activation difference when attentional saliency is controlled. The findings suggest a neural dysfunction in BPD underlying attention to salient or infrequent stimuli, which is supported by a negative correlation with self-rated impulsiveness.

Employment and relationship are crucial for social integration. However, individuals with major psychiatric disorders often face challenges in these domains. We investigated employment and relationship status changes among patients across the affective and psychotic spectrum - in comparison with healthy controls, examining whether diagnostic groups or functional levels influence these transitions. The sample from the longitudinal multicentric PsyCourse Study comprised 1260 patients with affective and psychotic spectrum disorders and 441 controls (mean age ± s.d., 39.91 ± 12.65 years; 48.9% female). Multistate models (Markov) were used to analyse transitions in employment and relationship status, focusing on transition intensities. Analyses contained multiple multistate models adjusted for age, gender, job or partner, diagnostic group and Global Assessment of Functioning (GAF) in different combinations to analyse the impact of the covariates on the hazard ratio of changing employment or relationship status. The clinical group had a higher hazard ratio of losing partner (hazard ratio 1.46, < 0.001) and job (hazard ratio 4.18, < 0.001) than the control group (corrected for age/gender). Compared with controls, clinical groups had a higher hazard of losing partner (affective group, hazard ratio 2.69, = 0.003; psychotic group, hazard ratio 3.06, = 0.001) and job (affective group, hazard ratio 3.43, < 0.001; psychotic group, hazard ratio 4.11, < 0.001). Adjusting for GAF, the hazard ratio of losing partner and job decreased in both clinical groups compared with controls. Patients face an increased hazard of job loss and relationship dissolution compared with healthy controls, and this is partially conditioned by the diagnosis and functional level. These findings underscore a high demand for destigmatisation and support for individuals in managing their functional limitations.