PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to increase of LDL cholesterol in blood. Its blockers have emerged as promising therapeutics for cardiovascular diseases. Here we show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor. PCSK9 exacerbates atherosclerosis in LDL receptor knockout mice. Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9 and indispensable for the inflammatory action of PCSK9, including induction of cytokines, Toll like receptor 4, and scavenger receptors, enhancing the uptake of oxidized LDL. We find spleen tyrosine kinase (Syk) and protein kinase C delta (PKCδ) to be the key mediators of inflammation after PCSK9-CAP1 binding. In human peripheral blood mononuclear cells, serum PCSK9 levels are positively correlated with Syk, PKCδ, and p65 phosphorylation. The CAP1-fragment crystallizable region (CAP1-Fc) mitigates PCSK9-mediated inflammatory signal transduction more than the PCSK9 blocking antibody evolocumab does.

tDCS-induced modulation of GABA concentration and dopamine release in the human brain: A combination study of magnetic resonance spectroscopy and positron emission tomography.

BACKGROUND: Transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) hypothetically modulates cognitive functions by facilitating or inhibiting neuronal activities chiefly in the cerebral cortex. The effect of tDCS in the deeper brain region, the basal ganglia-cortical circuit, remains unknown. OBJECTIVE: To investigate the interaction between γ-aminobutyric acid (GABA) concentrations and dopamine release following tDCS. METHOD: This study used a randomized, placebo-controlled, double-blind, crossover design. Seventeen healthy male subjects underwent active and sham tDCS (13 min twice at an interval of 20 min) with the anode placed at the left DLPFC and the cathode at the right DLPFC, followed by examinations with [11C]-raclopride positron emission topography (PET) and GABA-magnetic resonance spectroscopy (MRS). MRS voxels were set in the left DLPFC and bilateral striata. Paired t-tests and regression analyses were performed for PET and MRS parameters. RESULTS: MRS data analyses showed elevations in GABA in the left striatum along with moderate reductions in the right striatum and the left DLPFC after active tDCS. PET data analyses showed that reductions in [11C]-raclopride binding potentials (increase in dopamine release) in the right striatum were inversely correlated with those in the left striatum after active tDCS. GABA reductions in the left DLPFC positively correlated with elevations in GABA in the left striatum and with increases in right striatal dopamine release and negatively correlated with increases in left striatal dopamine release. CONCLUSION: The present results suggest that tDCS to the DLPFC modulates dopamine-GABA functions in the basal ganglia-cortical circuit.

Different associations between intelligence and social cognition in children with and without autism spectrum disorders.

Autism spectrum disorders (ASD) are characterized by impaired social cognition and communication. In addition to social impairment, individuals with ASD often have intellectual disability. Intelligence is known to influence the phenotypic presentation of ASD. Nevertheless, the relation between intelligence and social reciprocity in people with ASD remains unclear, especially in childhood. To elucidate this relation, we analyzed 56 typically developing children (35 male, 21 female, aged 60-91 months) and 46 children with ASD (35 male, 11 female, aged 60-98 months) from university and affiliated hospitals. Their cognitive function was evaluated using the Kaufman Assessment Battery for Children. Their social cognition was assessed using the Social Responsiveness Scale. We used linear regression models to ascertain whether the associations between intelligence and social cognition of typically developing children and children with ASD are significantly different. Among the children with ASD, scores on the Kaufman Assessment Battery for Children correlated significantly with social cognition, indicating that higher intelligence is associated with better social cognition. For typically developing children, however, no significant correlation was found. One explanation might be that children with ASD fully use general intelligence for successful learning in social cognition, although extensive use of intelligence might not be necessary for TD children. Alternatively, autistic impairment in social cognition can be compensated by intelligence despite a persistent deficit in social cognition. In either case, when using the SRS as a quantitative phenotype measure for ASD, the influence of intelligence must be considered.

Depression and suicidal ideation: association of physical, mental, social, and spiritual health status.

PURPOSE: The aim of this study was to determine if multidimensional (physical, mental, social, spiritual) health status could predict the presence of depressive symptoms and suicidal ideation in the general population. METHODS: We administered a population-based, cross-sectional survey to 1200 participants from the general Korean population. The survey included the 5 Health Status Questionnaire (5HSQ) for self-rated health status, Patient Health Questionnaire-9 (PHQ-9) for depression, and a question from the PHQ-9 for suicidal ideation. Multiple logistic regression was performed to estimate the association of significant socio-demographic factors and self-rated health status with depression and suicidal ideation. RESULTS: Physical health status was associated with depression in both men and women (men: adjusted odds ratio [aOR], 4.69; 95% confidence interval [CI] 2.44-9.00; women: aOR, 2.05; 95% CI 1.13-3.72) while spiritual health status only affected men (aOR, 5.50; 95% CI 2.59-11.65) and mental health status only women (aOR, 3.92; 95% CI 2.03-7.54). Social health status was associated with suicidal ideation in men (aOR, 4.87; 95% CI 2.74-19.99) while mental health status was associated with suicidal ideation in women (aOR, 4.31; 95% CI 1.90-9.76). CONCLUSION: Physical, mental, social, and spiritual self-rated health statuses were all found to be associated with an individual's predisposition to depression and suicidal ideation with notable differences between men and women.

Endogenous dopamine release under transcranial direct-current stimulation governs enhanced attention: a study with positron emission tomography.

Transcranial direct-current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) has been established as an effective and noninvasive method to modulate cognitive function. Nevertheless, the mechanisms causing those cognitive changes under the tDCS remain largely unknown. We strove to elucidate the cognito-biological relation under the tDCS condition by examining whether the dopamine system activated by tDCS is involved in cognitive changes in human participants, or not. To evaluate the dopamine system, we used [11C]-raclopride positron emission tomography (PET) scanning: 20 healthy men underwent two [11C]-raclopride PET scans and subsequent neuropsychological tests. One scan was conducted after tDCS to the DLPFC. One was conducted after sham stimulation (control). Results of [11C]-raclopride PET measurements demonstrate that tDCS to the DLPFC caused dopamine release in the right ventral striatum. Neuropsychological tests for attentiveness revealed that tDCS to the DLPFC-enhanced participants' accuracy. Moreover, this effect was correlated significantly with dopamine release. This finding provides clinico-biological evidence, demonstrating that enhancement of dopamine signaling by tDCS in the ventral striatum is associated with attention enhancement.

Association Between Magnetoencephalographic Interictal Epileptiform Discharge and Cognitive Function in Young Children With Typical Development and With Autism Spectrum Disorders.

Electroencephalograms of individuals with autism spectrum disorders (ASD) show higher rates of interictal epileptiform discharges (IEDs), which are known to have an inverse association with cognitive function in typically developed (TD) children. Nevertheless, that phenomenon has not been investigated adequately in children with ASD. From university and affiliated hospitals, 163 TD children (84 male, 79 female, aged 32-89 months) and 107 children (85 male, 22 female, aged 36-98 months) with ASD without clinical seizure were recruited. We assessed their cognitive function using the Kaufman Assessment Battery for Children (K-ABC) and recorded 10 min of MEG. Original waveforms were visually inspected. Then a linear regression model was applied to evaluate the association between the IED frequency and level of their cognitive function. Significantly higher rates of IEDs were found in the ASD group than in the TD group. In the TD group, we found significant negative correlation between mental processing scale scores (MPS) and the IED frequency. However, for the ASD group, we found significant positive correlation between MPS scores and the IED frequency. In terms of the achievement scale, correlation was not significant in either group. Although we found a correlative rather than a causal effect, typically developed children with higher IED frequency might better be followed up carefully. Furthermore, for children with ASD without clinical seizure, clinicians might consider IEDs as less harmful than those observed in TD children.

Oxytocin effects on emotional response to others' faces via serotonin system in autism: A pilot study.

The oxytocin (OT)-related serotonergic system is thought to play an important role in the etiology and social symptoms of autism spectrum disorder (ASD). However, no evidence exists for the relation between the prosocial effect of chronic OT administration and the brain serotonergic system. Ten male subjects with ASD were administered OT for 8-10 weeks in an open-label, single-arm, non-randomized, uncontrolled manner. Before and during the OT treatment, positron emission tomography was used with the (11C)-3-amino-4-(2-[(demethylamino)methyl]phenylthio)benzonitrile(11C-DASB) radiotracer. Then binding of serotonin transporter (11C-DASB BPND) was estimated. The main outcome measures were changes in 11C-DASB BPND and changes in the emotional response to others' faces. No significant change was found in the emotional response to others' faces after the 8-10 week OT treatment. However, the increased serotonin transporter (SERT) level in the striatum after treatment was correlated significantly with increased negative emotional response to human faces. This study revealed a relation between changes in the serotonergic system and in prosociality after chronic OT administration. Additional studies must be conducted to verify the chronic OT effects on social behavior via the serotonergic system.

Ammonium acid urate urolithiasis in anorexia nervosa: a case report and literature review.

Ammonium acid urate urolithiasis is a quite rare condition. Our literature review of ammonium acid urate urolithiasis suggests that ammonium acid urate urolithiasis should be regarded as a general medical complication related to anorexia nervosa, and purging by laxative abuse might be a crucially important risk.

A pilot study of serotonergic modulation after long-term administration of oxytocin in autism spectrum disorder.

Oxytocin (OT) and the serotonergic system putatively play important roles in autism spectrum disorder (ASD) etiology and symptoms, but no direct neurobiological evidence exists for long-term OT administration effects on the brain's serotonergic system. This pilot study examined 10 male participants with ASD who were administered OT intranasally for 8-10 weeks in an open-label, single-arm, nonrandomized, and uncontrolled manner. Positron emission tomography (PET) with a radiotracer (11 C)-3-amino-4-(2-[(dimethylamino)methyl]phenylthio)benzonitrile (11 C-DASB) was used before and after OT treatment. The binding potential of serotonin transporter (11 C-DASB BPND ) was then estimated. The main outcome measures were changes in 11 C-DASB BPND and their correlation with changes in symptoms. ASD participants showed significantly elevated 11 C-DASB BPND in the left inferior frontal gyrus extending to the left middle frontal gyrus. No significant correlation was found between the change in any clinical symptom and the change in 11 C-DASB BPND . This report of a pilot study is the first describing long-term effects of OT on the brain's serotonin system in ASD. Additional randomized controlled studies must be conducted to confirm whether activation of the serotonergic system contributes to the prosocial effect of OT in people with ASD. Autism Res 2017, 10: 821-828. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Clonazepam improves dopamine supersensitivity in a schizophrenia patient: a case report.

Dopamine supersensitivity is an important consideration for assessing treatment-resistant schizophrenia. The emergence of dopamine supersensitivity might be related to upregulation of dopamine D2 receptor, which engenders tolerance to antipsychotics, rebound psychosis, and tardive dyskinesia (TD). A 24-year-old man with a history of treatment-resistant schizophrenia was hospitalized for treatment of bone fracture sustained during a suicide attempt. After the operation, his clinical symptoms implied malignant catatonia. The patient discontinued antipsychotics without rebound psychosis under clonazepam treatment. His psychotic symptoms were controlled further with 24 mg/day aripiprazole without relapse or worsening. Clonazepam might be an effective option for the management of dopamine supersensitivity psychosis (DSP).