Effect of oxytocin on lipid accumulation under inflammatory conditions in human macrophages.

INTRODUCTION AND AIMS: Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS: THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while oxLDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS: RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of oxLDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION: We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.

Activity-dependent aberrations in gene expression and alternative splicing in a mouse model of Rett syndrome.

Rett syndrome (RTT) is a severe neurodevelopmental disorder that affects about 1 in 10,000 female live births. The underlying cause of RTT is mutations in the X-linked gene, methyl-CpG-binding protein 2 (MECP2); however, the molecular mechanism by which these mutations mediate the RTT neuropathology remains enigmatic. Specifically, although MeCP2 is known to act as a transcriptional repressor, analyses of the RTT brain at steady-state conditions detected numerous differentially expressed genes, while the changes in transcript levels were mostly subtle. Here we reveal an aberrant global pattern of gene expression, characterized predominantly by higher levels of expression of activity-dependent genes, and anomalous alternative splicing events, specifically in response to neuronal activity in a mouse model for RTT. Notably, the specific splicing modalities of intron retention and exon skipping displayed a significant bias toward increased retained introns and skipped exons, respectively, in the RTT brain compared with the WT brain. Furthermore, these aberrations occur in conjunction with higher seizure susceptibility in response to neuronal activity in RTT mice. Our findings advance the concept that normal MeCP2 functioning is required for fine-tuning the robust and immediate changes in gene transcription and for proper regulation of alternative splicing induced in response to neuronal stimulation.

Acute and crucial requirement for MeCP2 function upon transition from early to late adult stages of brain maturation.

Germline mutations in the X-linked gene, methyl-CpG-binding protein 2 (MECP2), underlie most cases of Rett syndrome (RTT), an autism spectrum disorder affecting approximately one in 10 000 female live births. The disease is characterized in affected girls by a latent appearance of symptoms between 12 and 18 months of age while boys usually die before the age of two. The nature of the latency is not known, but RTT-like phenotypes are recapitulated in mouse models, even when MeCP2 is removed at different postnatal stages, including juvenile and adolescent stages. Unexpectedly, here, we show that within a very brief developmental window, between 10 (adolescent) and 15 (adult) weeks after birth, symptom initiation and progression upon removal of MeCP2 in male mice transitions from 3 to 4 months to only several days, followed by lethality. We further show that this accelerated development of RTT phenotype and lethality occur at the transition to adult stage (15 weeks of age) and persists thereafter. Importantly, within this abbreviated time frame of days, the brain acquires dramatic anatomical, cellular and molecular abnormalities, typical of classical RTT. This study reveals a new postnatal developmental stage, which coincides with full-brain maturation, where the structure/function of the brain is extremely sensitive to levels of MeCP2 and loss of MeCP2 leads to precipitous collapse of the neuronal networks and incompatibility with life within days.

Maternal Outcomes in Women with Peripartum Cardiomyopathy versus Age and Race-Matched Peers in an Urban US Community.

Peripartum cardiomyopathy (PPCM) is idiopathic systolic congestive heart failure around pregnancy. Comparisons with matched controls are lacking. We investigated maternal characteristics and outcomes up to 12 months in a cohort admitted to Montefiore Health System in Bronx, New York 1999−2015 (n = 53 cases and n = 92 age and race-matched controls, >80% Black or Hispanic/Latina). Compared to peers, women with PPCM had more chronic hypertension (24.5% vs. 8.8%, p = 0.001), prior gestational hypertension (20.8% vs. 5.4%, p = 0.001), prior preeclampsia (17.0% vs. 3.3%, p = 0.001), familial dilated cardiomyopathy (5.7% vs. 0.0%, p = 0.04), smoking (15.1% vs. 2.2%, p = 0.001), lower summary socioeconomic scores (−4.12 (IQR −6.81, −2.13) vs. −1.62 (IQR −4.20, −0.74), p < 0.001), public insurance (67.9% vs. 29.3% p = 0.001), and frequent depressive symptoms. Women with PPCM were often admitted antepartum (34.0% vs. 18.5%, p = 0.001) and underwent Cesarean section (65.4% vs. 30.4%, p = 0.001), but had less preterm labor (27.3% vs. 51.1%, p = 0.001). Women were rarely treated with bromocriptine (3.8%), frequently underwent left ventricular assist device placement (9.4% and n = 2 with menorrhagia requiring transfusion and progesterone) or heart transplantation (3.8%), but there were no in-hospital deaths. In sum, women with PPCM had worse socioeconomic disadvantage and baseline health than matched peers. Programs addressing social determinants of health may be important for women at high risk of PPCM.

Brief report: Anomalous neural deactivations and functional connectivity during receptive language in autism spectrum disorder: a functional MRI study.

Neural mechanisms that underlie language disability in autism spectrum disorder (ASD) have been associated with reduced excitatory processes observed as positive blood oxygen level dependent (BOLD) responses. However, negative BOLD responses (NBR) associated with language and inhibitory processes have been less studied in ASD. In this study, functional magnetic resonance imaging showed that the NBR in ASD participants was reduced during passive listening to spoken narratives compared to control participants. Further, functional connectivity between the superior temporal gyrus and regions that exhibited a NBR during receptive language in control participants was increased in ASD participants. These findings extend models for receptive language disability in ASD to include anomalous neural deactivations and connectivity consistent with reduced or poorly modulated inhibitory processes.

Dynamic coupling between the lateral occipital-cortex, default-mode, and frontoparietal networks during bistable perception.

The lateral occipital cortex (LOC), a visual area known to be involved in object recognition, was dynamically coupled with each of two distributed patterns of neural activity depending upon the percept (default or alternative) elicited by a bistable figure. The two distributed patterns included core nodes of the default-mode and frontoparietal networks (FPN), and they were most highly coupled to each other during the alternative percept, whereas they were less coupled during the default percept. Surprisingly, the regions associated with the nonengaged percept exhibited the highest connectivity to the LOC. Together, these findings reveal a dynamic organization between the default mode and the FPNs, and the incoming bottom-up visual stream during perceptual binding of visual images.