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In the present exploratory and retrospective study, we hypothesized that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might be more abnormal in patients with epileptiform EEG activity (spike-sharp wave discharges, giant spikes) and amnesic mild cognitive impairment not due to Alzheimer's disease (noADMCI-EEA) than matched noADMCI patients without EEA (noADMCI-noEEA). Clinical, neuroimaging, neuropsychological, and rsEEG data in 32 noADMCI and 30 normal elderly (Nold) subjects were available in a national archive. Age, gender, and education were carefully matched among them. No subject had received a clinical diagnosis of epilepsy. Individual alpha frequency peak (IAF) was used to determine the delta, theta, and alpha frequency bands of rsEEG rhythms. Fixed beta and gamma bands were also considered. Regional rsEEG cortical sources were estimated by eLORETA freeware. Area under receiver operating characteristic (AUROC) curves indexed the accuracy of eLORETA solutions in the classification between noADMCI-EEA and noADMCI-noEEA individuals. As novel findings, EEA was observed in 41% of noADMCI patients. Furthermore, these noADMCI-EEA patients showed higher temporal delta source activities as compared to noADMCI-no EEA patients and Nold subjects. Those activities discriminated individuals of the two NoADMCI groups with an accuracy of about 70%. The significant percentage of noADMCI-EEA patients showing EEA and marked abnormalities in temporal rsEEG rhythms at delta frequencies suggest a substantial role of underlying neural hypersynchronization mechanisms in their brain dysfunctions.

Introduction: Despite the fact that epilepsy has been associated with cognitive decline, neuropsychological, neurobiological, and neurophysiological features in patients with late-onset epilepsy of unknown etiology (LOEU) are still unknown. This cross-sectional study aims to investigate the neuropsychological profile, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), and resting-state quantitative electroencephalographic (qEEG) cortical rhythms in LOEU patients with mild cognitive impairment (LOEU-MCI) and with normal cognition (LOEU-CN), compared to non-epileptic MCI (NE-MCI) and cognitively normal (CN) controls.Methods: Consecutive patients in two clinical Units diagnosed with LOEU-CN (19), LOEU-MCI (27), and NE-MCI (21) were enrolled, and compared to age and sex-matched cognitively normal subjects CN (11). Patients underwent standardized comprehensive neuropsychological evaluation and CSF core AD biomarkers assessment (i.e., CSF Aβ42, phospho-tau and total tau, classified through A/T/(N) system). Recordings of resting-state eyes-closed electroencephalographic (EEG) rhythms were collected and cortical source estimation of delta (30 Hz) bands with exact Low Resolution Electromagnetic Tomography (eLORETA) was performed.Results: Most LOEU patients had an MCI status at seizure onset (59%). Patients with LOEU-MCI performed significantly worse on measures of global cognition, visuo-spatial abilities, and executive functions compared to NE-MCI patients (p < 0.05). Regarding MCI subtypes, multiple-domain MCI was 3-fold more frequent in LOEU-MCI than in NE-MCI patients (OR 3.14, 95%CI 0.93–10.58, p = 0.06). CSF Aβ42 levels were lower in the LOEU-MCI compared with the LOEU-CN group. Finally, parietal and occipital sources of alpha (8–12 Hz) rhythms were less active in the LOEU-MCI than in the NE-MCI and CN groups, while the opposite was true for frontal and temporal cortical delta sources.Discussion: MCI status was relatively frequent in LOEU patients, involved multiple cognitive domains, and might have been driven by amyloidosis according to CSF biomarkers. LOEU-MCI status was associated with abnormalities in cortical sources of EEG rhythms related to quiet vigilance. Future longitudinal studies should cross-validate our findings and test the predictive value of CSF and EEG variables.

Omega-3 fatty acids have been shown to exert several beneficial effects in the prevention of cardiovascular and cerebrovascular diseases. The objective of the present study was to analyze the effects of a novel high-load omega-3 lysine complex, AvailOm®, its related constituents and a novel mixture of AvailOm® with specific vasoactive anthocyanins on vascular function in mice resistance artery. Pressure myograph was used to perform vascular reactivity studies. Nitric oxide and oxidative stress were assessed by difluorofluorescein diacetate and dihydroethidium, respectively. Increasing doses of AvailOm® exerted a dose-response vasorelaxation via AMPK-eNOS-mediated signaling. Omega-3 Ethyl Ester was identified as the main bioactive derivative of AvailOm®, being capable of inducing vasorelaxant action to the same extent of entire product. The combination of AvailOm® with a mix of potent vasoactive anthocyanins (C3-glu + DP3-glu + Mal3-glu + Mal3-gal + PEO3-gal), strongly protected mesenteric arteries from vascular dysfunction and oxidative stress evoked by oxidized-LDL. These data demonstrate for the first time the direct effects of AvailOm® on resistance arteries. The evidence that the combination of specific vasoactive anthocyanins and AvailOm® further enhanced the vasculoprotective properties of these compounds, may offer new promising perspectives for preventing the onset of cardiovascular and cerebrovascular events.

The treatment of a huge cystic lesion in the upper jaw involving the respiratory cavities may result challenging. A traditional oral approach entails patient discomfort and may have negative aesthetic implications. This treatment, particularly in case of enucleation not preceded by marsupialization for volumetric reduction of the lesion, may cause irreversible damage to important anatomical structures and the collapse of the bone architecture. The purpose of this case report is to show the benefits of an endoscopic trans-nasal approach for the definitive treatment of such a clinical situation. The surgical technique aimed to remove part of the cystic wall and to open the inner compartment of the lesion to the nasal cavity after the resection of the anterior edge of the inferior turbinate and the lateral wall of the inferior nasal meatus. After a follow-up period of 18 months, without any problem or discomfort for the patient, the cyst appeared radiologically healed without the loss of any lesion-associated tooth. The bone nasal cavity, the maxillary sinus and the anterior alveolar process architecture, noticeably modified by the expansive enlargement of the cyst, resulted completely restored with a complete recover of the respiratory and oral functions. Keywords: Endoscopy, Marsupialization, Odontogenic cysts, Maxillary sinus, Nasal cavity

The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K+ efflux as a key signaling event, suggesting that K+-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K+ channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown. Using a novel specific inhibitor of THIK-1 in combination with patch-clamp electrophysiology in slices of human neocortex, we found that THIK-1 generated the main tonic K+ conductance in microglia that sets the resting membrane potential. Extracellular ATP stimulated K+ efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demonstrated that activation of P2X7 was mandatory for ATP-evoked IL-1β release, which was strongly suppressed by blocking THIK-1. Surprisingly, THIK-1 contributed only marginally to the total K+ conductance in the presence of ATP, which was dominated by P2X7. This suggests a previously unknown, K+-independent mechanism of THIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective expression of THIK-1 in human brain microglia, while P2X7 had a much broader expression. Thus, inhibition of THIK-1 could be an effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinflammation. [ABSTRACT FROM AUTHOR]

Abstract Chronic inflammation is one of the causes of neurodegeneration in Amyotrophic lateral sclerosis (ALS). Here we examined whether circulating dendritic cells (DCs) can contribute to disease progression. We found ALS patients show a significant reduction in the number of circulating DCs. Also, patients’ DCs present an increased expression of CD62L and a tendency to overexpress CCR2 compared with healthy donors. Moreover, DCs derived from a subpopulation of ALS patients produced higher levels of IL-8 and CCL-2 upon lipopolysaccharide (LPS)-stimulation. Finally, we found a significant inverse correlation between the time from onset of the pathology to its diagnosis and the levels of IL-6 secretion induced by LPS. Our data support the hypothesis, in a subpopulation of patients, DCs recruited at the diseased tissue produce high levels of CCL-2 and IL-8 and contribute to the inflammatory process promoting the recruitment of other inflammatory cells. An increased efficiency of IL-6 production may accelerate only the initial phases of disease progression. Blood DC analysis can be used to identify ALS patients with an altered course of inflammatory cell recruitment at the diseased central nervous system (CNS). The high levels of CD62L expression suggests this molecule could be a target for treatment of CNS inflammation.

This study tested the hypothesis of cortical neural efficiency (i.e., reduced brain activation in experts) in the visuospatial information processing related to football (soccer) scenes in football players. Electroencephalographic data were recorded from 56 scalp electrodes in 13 football players and eight matched non-players during the observation of 70 videos with football actions lasting 2.5 s each. During these videos, the central fixation target changed color from red to blue or vice versa. The videos were watched two times. One time, the subjects were asked to estimate the distance between players during each action (FOOTBALL condition, visuospatial). Another time, they had to estimate if the fixation target was colored for a longer time in red or blue color (CONTROL condition, non-visuospatial). The order of the two conditions was pseudo-randomized across the subjects. Cortical activity was estimated as the percent reduction in power of scalp alpha rhythms (about 8–12 Hz) during the videos compared with a pre-video baseline (event-related desynchronization, ERD). In the FOOTBALL condition, a prominent and bilateral parietal alpha ERD (i.e., cortical activation) was greater in the football players than non-players (p < 0.05) in contrast with the neural efficiency hypothesis. In the CONTROL condition, no significant alpha ERD difference was observed. No difference in behavioral response time and accuracy was found between the two groups in any condition. In conclusion, a prominent parietal cortical activity related to visuospatial processes during football scenes was greater in the football players over controls in contrast with the neural efficiency hypothesis.

In recent years, epidemiological studies have identified a relationship between diet and cerebro–cardiovascular disease (CVD). In this regard, there is a promising dietary group for cardiovascular protection are polyphenols, especially anthocyanins. Vascular reactivity studies were performed using Healthberry 865® and constituent single anthocyanins to characterize vasomotor responses; immunofluorescence analysis with dichlorofluorescein diacetate and dihydroethidium were used to evaluate nitric oxide and oxidative stress; lucigenin assay was used to measure NADPH oxidase activity; and gel electrophoresis and immunoblotting were used to dissect the molecular mechanisms involved. We demonstrated that Healthberry 865® exerts an important vasorelaxant effect of resistance artery functions in mice. Its action is mediated by nitric oxide release through the intracellular signaling PI3K/Akt. Moreover, behind its capability of modulating vascular tone, it also exerts an important antioxidant effect though the modulation of the NADPH oxidase enzyme. Interestingly, its cardiovascular properties are mediated by the selective action of different anthocyanins. Finally, the exposure of human dysfunctional vessels to Healthberry 865® significantly reduces oxidative stress and improves NO bioavailability. Although further investigations are needed, our data demonstrate the direct role of Healthberry 865® on the modulation of vasculature, both on the vasorelaxation and on oxidative stress; thus, supporting the concept that a pure mixture of anthocyanins could be helpful in preventing the onset of vascular dysfunction associated with the development of CVD.