Ethanol upregulates the P2X7 purinergic receptor in human macrophages

Alcohol consumption is considered to be the third leading cause of death in the United States. In addition to its direct toxicity, ethanol has two contrasting effects on the immune system: the nucleotide oligomerization domain‐like receptor pyrin domain‐containing‐3 (NLRP3) inflammasome is inhibited by acute ethanol exposure but activated by chronic ethanol exposure. Purinergic receptors (especially the P2X7 receptor) are able to activate the NLRP3 inflammasome and are involved in many ethanol‐related diseases (such as gout, pulmonary fibrosis, alcoholic steatohepatitis, and certain cancers). We hypothesized that ethanol regulates purinergic receptors and thus modulates the NLRP3 inflammasome's activity. In experiments with monocyte‐derived macrophages, we found that interleukin (IL)‐1β secretion was inhibited after 7 h of exposure (but not 48 h of exposure) to ethanol. The disappearance of ethanol's inhibitory effect on IL‐1β secretion after 48 h was not mediated by the upregulated production of IL‐1β, IL‐1α, IL‐6 or the inflammasome components NLRP3, apoptosis‐associated speck‐like protein containing a caspase recruitment domain, and caspase 1. P2X7R expression was upregulated by ethanol, whereas expression of the P2X4 and P2X1 receptors was not. Taken as a whole, our results suggest that ethanol induces NLRP3 inflammasome activation by upregulating the P2X7 receptor. This observation might have revealed a new mechanism for inflammation in ethanol‐related diseases.     

Clinical Impact of Oral Anticoagulation in Patients with Atrial High-rate Episodes

Background: Atrial high-rate episodes (AHREs) are common in pacemaker patients. Our aims were to compare patients with AHREs to those without them and to assess if, in those with AHREs, the initiation of oral anticoagulation (OAC) has any clinical impact on the occurrence of ischemic and hemorrhagic events. Methods: From 2014-2017 we selected patients with pacemaker in whom AHREs were detected. AHREs were defined as episodes lasting more than 6 minutes if the electrogram was available or more than 6 hours if not. We used an age- and gender-matched population with pacemaker but no AHRE as a control group (observational study). Those with AHRE were referred to their assistant physician to decide OAC initiation, based on individual circumstances (interventional study). In interventional study, the primary outcome was a composite of systemic thromboembolism or major bleeding. Secondary outcomes were clinical relevant nonmajor bleeding, major and nonmajor bleeding, CV death, and death from all causes. Results: AHREs were detected in 86 patients: 69 patients initiated OAC and the remaining 17 patients did not. When comparing patients with and without AHRE, baseline characteristics were not different between the groups, except for indexed left atrium volume—40 mL (IQR: 34-50) in AHRE group versus 35 mL (IQR: 34-40) in control group (P?=?.014). AHREs were associated with future development of atrial fibrillation (AF) and the risk was higher if AHRE duration was superior to 6 hours. Death and cardiovascular (CV) death were not significantly different between the groups with and without AHRE. Primary outcome occurred in 4.9 per 100 person-year in OAC group versus 3.4 per 100 person-year in non-OAC group (HR 1.4, 95% CI .2-11.3, P?=?.78). Secondary outcomes were not significantly different in the groups. Conclusions: In this group of patients with pacemakers, the presence of AHREs was useful for predicting the future development of AF and the risk of AF was higher in those with a longer duration of AHRE. In the AHRE group, OAC therapy was not associated with a significant difference in the risk of thromboembolism or major bleeding.     

Effortful verb retrieval from semantic memory drives beta suppression in mesial frontal regions involved in action initiation

The contribution of the motor cortex to the semantic retrieval of verbs remains a subject of debate in neuroscience. Here, we examined whether additional engagement of the cortical motor system was required when access to verbs semantics was hindered during a verb generation task. We asked participants to produce verbs related to presented noun cues that were either strongly associated with a single verb to prompt fast and effortless verb retrieval, or were weakly associated with multiple verbs and more difficult to respond to. Using power suppression of magnetoencephalography beta oscillations (15–30 Hz) as an index of cortical activation, we performed a whole‐brain analysis in order to identify the cortical regions sensitive to the difficulty of verb semantic retrieval. Highly reliable suppression of beta oscillations occurred 250 ms after the noun cue presentation and was sustained until the onset of verbal response. This was localized to multiple cortical regions, mainly in the temporal and frontal lobes of the left hemisphere. Crucially, the only cortical regions where beta suppression was sensitive to the task difficulty, were the higher order motor areas on the medial and lateral surfaces of the frontal lobe. Stronger activation of the premotor cortex and supplementary motor area accompanied the effortful verb retrieval and preceded the preparation of verbal responses for more than 500 ms, thus, overlapping with the time window of verb retrieval from semantic memory. Our results suggest that reactivation of verb‐related motor plans in higher order motor circuitry promotes the semantic retrieval of target verbs.     

Prevalence of Key Forms of Violence Against Adolescents in the Arab Region: A Systematic Review

Purpose

This article presents a systematic review of the prevalence of violence against adolescents in the 22 countries of the Arab League.

Skin DNA methylation profile in atopic dermatitis patients: A case–control study

Atopic dermatitis (AD) is a worldwide disease with a complex aetiology. Both genetic and environmental factors cause a predisposition to AD. DNA methylation may be an additional predisposing factor. The goal of our study was to investigate genome-wide methylation profiles of skin from patients with AD and healthy persons. This case–control study included 12 AD patients and 6 healthy volunteers. DNA methylation levels in skin samples were analysed using the Illumina Infinium HumanMethylation450 BeadChip. We found that the methylation profile of skin from patients with AD was significantly different from that of healthy controls. Differential DNA methylation was observed for genes involved in a number of AD-related processes including regulation of the immune response, activation of lymphocytes, cell proliferation, apoptosis and differentiation of the epidermis. Our study indicates the involvement of epigenetic regulation in the development of atopic dermatitis.     

Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine

The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroid-stimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3′-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of T3 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB-1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.