Partially Preserved Processing of Musical Rhythms in REM but Not in NREM Sleep.

The extent of high-level perceptual processing during sleep remains controversial. In wakefulness, perception of periodicities supports the emergence of high-order representations such as the pulse-like meter perceived while listening to music. Electroencephalography (EEG) frequency-tagged responses elicited at envelope frequencies of musical rhythms have been shown to provide a neural representation of rhythm processing. Specifically, responses at frequencies corresponding to the perceived meter are enhanced over responses at meter-unrelated frequencies. This selective enhancement must rely on higher-level perceptual processes, as it occurs even in irregular (i.e., syncopated) rhythms where meter frequencies are not prominent input features, thus ruling out acoustic confounds. We recorded EEG while presenting a regular (unsyncopated) and an irregular (syncopated) rhythm across sleep stages and wakefulness. Our results show that frequency-tagged responses at meter-related frequencies of the rhythms were selectively enhanced during wakefulness but attenuated across sleep states. Most importantly, this selective attenuation occurred even in response to the irregular rhythm, where meter-related frequencies were not prominent in the stimulus, thus suggesting that neural processes selectively enhancing meter-related frequencies during wakefulness are weakened during rapid eye movement (REM) and further suppressed in non-rapid eye movement (NREM) sleep. These results indicate preserved processing of low-level acoustic properties but limited higher-order processing of auditory rhythms during sleep.

Effects of miR-33 Deficiency on Metabolic and Cardiovascular Diseases: Implications for Therapeutic Intervention.

MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally inhibit gene expression. These small molecules are involved in several biological conditions such as inflammation, cell growth and proliferation, and regulation of energy metabolism. In the context of metabolic and cardiovascular diseases, miR-33 is of particular interest as it has been implicated in the regulation of lipid and glucose metabolism. This miRNA is located in introns harboured in the genes encoding sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, which are key transcription factors involved in lipid biosynthesis and cholesterol efflux. This review outlines the role of miR-33 in a range of metabolic and cardiovascular pathologies, such as dyslipidaemia, nonalcoholic fatty liver disease (NAFLD), obesity, diabetes, atherosclerosis, and abdominal aortic aneurysm (AAA), and it provides discussion about the effectiveness of miR-33 deficiency as a possible therapeutic strategy to prevent the development of these diseases.

Association of chemokines IP-10/CXCL10 and I-TAC/CXCL11 with insulin resistance and enhance leukocyte endothelial arrest in obesity.

BACKGROUND AND AIMS: Obesity is a key contributing factor to incidental type 2 diabetes and cardiovascular disease. CXCR3 receptor and its ligands CXCL 10 and 11 are associated with atherosclerosis and cardiovascular disease. The aim of our study was to analyse the role of the CXCR3 ligands on insulin resistance (IR) and endothelial dysfunction in human obesity. METHODS AND RESULTS: We have studied 45 obese patients (mean age 44 ± 6 years, body mass index 45 ± 9 kg/m2) who were selected for Roux-Y-gastric bypass surgery and 21 non obese control subjects with similar age and gender distribution. We measured by ELISA the circulating levels of the CXCR3 ligands interferon-γ inducible protein 10 (IP-10/CXCL10) and interferon-γ-inducible T-cell alpha chemoattractant (I-TAC/CXCL11). Using an ex vivo procedure with the flow chamber assay, we have investigated the effect of such chemokines on endothelial leukocytes arrest under dynamic conditions. Peripheral blood levels of CXCL10 and CXCL11 were significantly higher in obese subjects than in controls (p < 0.001) and significantly correlated with BMI, waist circunference and HOMA-IR. Obese patients with HOMA-IR index above 75th percentile showed highest increase of circulating CXCL10 and CXCL11 values. Under dynamic flow conditions, the enhanced adhesion of patient leukocytes to TNFα-induced human arterial endothelial cells was partly dependent on CXCR3. CONCLUSIONS: The study demonstrates that CXCL10 and CXCL11 are associated with IR and enhance leukocyte endothelial arrest in obese subjects. Blockade of CXCR3 signaling might be a new therapeutic approach for the prevention of obesity-associated cardiovascular co-morbidities.

The nuclear retinoid-related orphan receptor RORα controls adipose tissue inflammation in patients with morbid obesity and diabetes.

BACKGROUND/AIMS: Inflammation governs adipose tissue (AT) dysfunction in obesity. Retinoic acid receptor-related orphan receptor alpha (RORα) is associated with inflammation and insulin resistance in animal studies, but its role in human obesity remains elusive. We investigated the expression and function of RORα on AT inflammation in patients with morbid obesity with/without diabetes. SUBJECTS/METHODS: We assessed RORα expression in paired biopsies of subcutaneous and omental AT from 41 patients (body mass index (BMI) 43.3 ± 0.8 kg/m2) during Roux-en-Y-gastric surgery and explored the functional consequences of pharmacological RORα blockade in AT ex vivo. RESULTS: RORα expression was significantly higher in omental AT than in subcutaneous AT (p = 0.03) and was positively associated with BMI (r = 0.344, p = 0.027) and homeostasis model assessment of insulin resistance (r = 0.319, p = 0.041). In ex vivo assays, IL-8/CXCL8 and MCP-1/CCL2 chemokine release was significantly higher in omental fat explants from diabetic patients than from non-diabetics and was significantly diminished by RORα blockade (p < 0.05). Inhibition of RORα improved protein kinase B signaling and decreased NF-κB activity in omental AT from patients with diabetes (p < 0.05). Under dynamic flow conditions, RORα blockade prevented mononuclear cell attachment to human dysfunctional endothelial cells. CONCLUSIONS: RORα blockade represents a potential therapy to prevent AT dysfunction and inflammation associated with insulin resistance in human obesity.

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium.

Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can affect this response and the underlying mechanisms involved. Under physiological flow conditions, TNFα-induced endothelial adhesion of human leukocyte cells was concentration-dependently inhibited by preincubation of human umbilical arterial endothelial cells with the selective human CAR ligand CITCO. CAR agonism also prevented TNFα induced VCAM-1 expression, as well as MCP-1/CCL-2 and RANTES/CCL-5 release in endothelial cells. Suppression of CAR expression with a small interfering RNA abrogated the inhibitory effects of CITCO on these responses. Furthermore, CITCO increased interaction of CAR with Retinoid X Receptor (RXR) and reduced TNFα-induced p38-MAPK/NF-κB activation. In vivo, using intravital microscopy in the mouse cremasteric microcirculation treatment with the selective mouse CAR ligand TCPOBOP inhibited TNFα-induced leukocyte rolling flux, adhesion, and emigration and decreased VCAM-1 in endothelium. These results reveal that CAR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps in the leukocyte recruitment cascade. Therefore, CAR agonists may constitute a new therapeutic tool in controlling cardiovascular disease-associated inflammatory processes.

SGLT-2 (Sodium-Glucose Cotransporter 2) Inhibition Reduces Ang II (Angiotensin II)-Induced Dissecting Abdominal Aortic Aneurysm in ApoE (Apolipoprotein E) Knockout Mice.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a pathological condition of permanent vessel dilatation that predisposes to the potentially fatal consequence of aortic rupture. SGLT-2 (sodium-glucose cotransporter 2) inhibitors have emerged as powerful pharmacological tools for type 2 diabetes mellitus treatment. Beyond their glucose-lowering effects, recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events and have beneficial effects on several vascular diseases such as atherosclerosis; however, the potential effects of SGLT-2 inhibition on AAA remain unknown. This study evaluates the effect of oral chronic treatment with empagliflozin-an SGLT-2 inhibitor-on dissecting AAA induced by Ang II (angiotensin II) infusion in apoE (apolipoprotein E)-/- mice. Approach and Results: Empagliflozin treatment significantly reduced the Ang II-induced increase in maximal suprarenal aortic diameter in apoE-/- mice independently of blood pressure effects. Immunohistochemistry analysis revealed that empagliflozin diminished Ang II-induced elastin degradation, neovessel formation, and macrophage infiltration at the AAA lesion. Furthermore, Ang II infusion resulted in a marked increase in the expression of chemokines (CCL-2 [chemokine (C-C motif) ligand 2] and CCL-5 [chemokine (C-C motif) ligand 5]), VEGF (vascular endothelial growth factor), and MMP (matrix metalloproteinase)-2 and MMP-9 in suprarenal aortic walls of apoE-/- mice, and all were reduced by empagliflozin cotreatment. Western blot analysis revealed that p38 MAPK (p38 mitogen-activated protein kinase) and NF-κB (nuclear factor-κB) activation was also reduced in the suprarenal aortas of apoE-/- mice cotreated with empagliflozin. Finally, in vitro studies in human aortic endothelial cells and macrophages showed that empagliflozin inhibited leukocyte-endothelial cell interactions and release of proinflammatory chemokines. CONCLUSIONS: Pharmacological inhibition of SGLT-2 by empagliflozin inhibits AAA formation. SGLT-2 inhibition might represent a novel promising therapeutic strategy to prevent AAA progression.

Deferasirox reduces oxidative DNA damage in bone marrow cells from myelodysplastic patients and improves their differentiation capacity.

Patients with low-risk myelodysplastic syndromes (MDS) usually develop iron overload. This leads to a high level of oxidative stress in the bone marrow (BM) and increases haematopoietic cell dysfunction. Our objective was to analyse whether chelation with deferasirox (DFX) alleviates the consequences of oxidative stress and improves BM cell functionality. We analysed 13 iron-overloaded MDS patients' samples before and 4-10 months after treatment with DFX. Using multiparametric flow cytometry analysis, we measured intracellular reactive oxygen species (ROS), DNA oxidation and double strand breaks. Haematopoietic differentiation capacity was analysed by colony-forming unit (CFU) assays. Compared to healthy donors, MDS showed a higher level of intracellular ROS and DNA oxidative damage in BM cells. DNA oxidative damage decreased following DFX treatment. Furthermore, the clonogenic assays carried out before treatment suggest an impaired haematopoietic differentiation. DFX seems to improve this capacity, as illustrated by a decreased cluster/CFU ratio, which reached values similar to controls. We conclude that BM cells from MDS are subject to higher oxidative stress conditions and show an impaired haematopoietic differentiation. These adverse features seem to be partially rectified after DFX treatment.

Mesenchymal Stromal Cell Irradiation Interferes with the Adipogenic/Osteogenic Differentiation Balance and Improves Their Hematopoietic-Supporting Ability.

Bone marrow mesenchymal stromal cells (MSCs) are precursors of adipocytes and osteoblasts and key regulators of hematopoiesis. Irradiation is widely used in conditioning regimens. Although MSCs are radio-resistant, the effects of low-dose irradiation on their behavior have not been extensively explored. Our aim was to evaluate the effect of 2.5 Gy on MSCs. Cells from 25 healthy donors were either irradiated or not (the latter were used as controls). Cells were characterized following International Society for Cellular Therapy criteria, including in vitro differentiation assays. Apoptosis was evaluated by annexin V/7-amino-actinomycin staining. Gene expression profiling and reverse transcriptase (RT)-PCR of relevant genes was also performed. Finally, long-term bone marrow cultures were performed to test the hematopoietic-supporting ability. Our results showed that immunophenotypic characterization and viability of irradiated cells was comparable with that of control cells. Gene expression profiling showed 50 genes differentially expressed. By RT-PCR, SDF-1 and ANGPT were overexpressed, whereas COL1A1 was downregulated in irradiated cells (P = .015, P = .007, and P = .031, respectively). Interestingly, differentiation of irradiated cells was skewed toward osteogenesis, whereas adipogenesis was impaired. Higher expression of genes involved in osteogenesis as SPP1 (P = .039) and lower of genes involved in adipogenesis, CEBPA and PPARG (P = .003 and P = .019), together with an increase in the mineralization capacity (Alizarin Red) was observed in irradiated cells. After differentiation, adipocyte counts were decreased in irradiated cells at days 7, 14, and 21 (P = .018 P = .046, and P = .018, respectively). Also, colony-forming unit granulocyte macrophage number in long-term bone marrow cultures was significantly higher in irradiated cells after 4 and 5 weeks (P = .046 and P = .007). In summary, the irradiation of MSCs with 2.5 Gy improves their hematopoietic-supporting ability by increasing osteogenic differentiation and decreasing adipogenesis.

Upregulation of angiostatic chemokines IP-10/CXCL10 and I-TAC/CXCL11 in human obesity and their implication for adipose tissue angiogenesis.

BACKGROUND/AIMS: Impaired angiogenesis is linked to adipose tissue (AT) dysfunction, inflammation, and insulin resistance in human obesity. Chemokine (C-X-C motif) receptor. (CXCR3) ligands are important regulators of angiogenesis in different disease contexts such as cancer; however, their role in human morbid obesity is unknown. We investigated the role of the CXCR3 axis in AT angiogenesis in morbidly obese patients. SUBJECTS/METHODS: The study group comprised 50 morbidly obese patients (mean age 44 ± 1 years, body mass index 44 ± 1 kg/m2) who had undergone laparoscopic Roux-Y-gastric bypass surgery, and 25 age-matched non-obese control subjects. We measured the circulating levels of the CXCR3 ligands monokine induced by interferon-γ (MIG/CXCL9), interferon-γ inducible protein 10 (IP-10/CXCL10), and interferon-γ-inducible T-cell alpha chemoattractant (I-TAC/CXCL11) in all studied subjects. Additionally, the expression of CXCR3 ligands was analyzed in paired biopsies of subcutaneous and visceral AT obtained during the laparoscopic procedure in morbidly obese patients. Additionally, we explored the functional role of CXCR3 ligands on angiogenesis in AT from morbidly obese patients using an ex vivo assay. RESULTS: Plasma levels of CXCL10 and CXCL11 were significantly higher in morbidly obese patients than in controls (p < 0.01). In ex vivo assays, angiogenic growth was markedly lower in visceral AT than in subcutaneous AT (p < 0.05), which was related to significant tissue upregulation of CXCL10, CXCL11 and CXCR3 (p < 0.05). CXCL10 or CXCL11 inhibited AT angiogenesis (p < 0.05), and blockade of CXCR3 function significantly increased capillary sprouting in visceral fat deposits (p < 0.05). Western blot analysis showed that the p38 mitogen-activated protein kinase signaling pathway was implicated in the angiostatic effects of CXCR3 in AT. CONCLUSIONS: CXCL10 and CXCL11 may play. deleterious role in obesity as potential inhibitors of AT angiogenesis. Accordingly, pharmacological blockade of CXCR3 could represent. therapy to prevent AT dysfunction in obesity.

MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry.

BACKGROUND: Human mesenchymal stromal cells (hMSC) are multipotent cells with both regenerative and immunomodulatory activities making them an attractive tool for cellular therapy. In the last few years it has been shown that the beneficial effects of hMSC may be due to paracrine effects and, at least in part, mediated by extracellular vesicles (EV). EV have emerged as important mediators of cell-to-cell communication. Flow cytometry (FCM) is a routine technology used in most clinical laboratories and could be used as a methodology for hMSC-EV characterization. Although several reports have characterized EV by FCM, a specific panel and protocol for hMSC-derived EV is lacking. The main objective of our study was the characterization of hMSC-EV using a standard flow cytometer. METHODS: Human MSC from bone marrow of healthy donors, mesenchymal cell lines (HS-5 and hTERT) and a leukemic cell line (K562 cells) were used to obtain EV for FCM characterization. EV released from the different cell lines were isolated by ultracentrifugation and were characterized, using a multi-parametric analysis, in a conventional flow cytometer. EV characterization by transmission electron microscopy (TEM), western blot (WB) and Nano-particle tracking analysis (NTA) was also performed. RESULTS: EV membranes are constituted by the combination of specific cell surface molecules depending on their cell of origin, together with specific proteins like tetraspanins (e.g. CD63). We have characterized by FCM the EV released from BM-hMSC, that were defined as particles less than 0.9 µm, positive for the hMSC markers (CD90, CD44 and CD73) and negative for CD34 and CD45 (hematopoietic markers). In addition, hMSC-derived EV were also positive for CD63 and CD81, the two characteristic markers of EV. To validate our characterization strategy, EV from mesenchymal cell lines (hTERT/HS-5) were also studied, using the leukemia cell line (K562) as a negative control. EV released from mesenchymal cell lines displayed the same immunophenotypic profile as the EV from primary BM-hMSC, while the EV derived from K562 cells did not show hMSC markers. We further validated the panel using EV from hMSC transduced with GFP. Finally, EV derived from the different sources (hMSC, hTERT/HS-5 and K562) were also characterized by WB, TEM and NTA, demonstrating the expression by WB of the exosomal markers CD63 and CD81, as well as CD73 in those from MSC origin. EV morphology and size/concentration was confirmed by TEM and NTA, respectively. CONCLUSION: We described a strategy that allows the identification and characterization by flow cytometry of hMSC-derived EV that can be routinely used in most laboratories with a standard flow cytometry facility.

Does Targeted Memory Reactivation during SWS and REM sleep have differential effects on mnemonic discrimination and generalization?

Targeted memory reactivation (TMR), or the presentation of learning-related cues during sleep, has been shown to benefit memory consolidation for specific memory traces when applied during non-rapid eye movement (NREM) sleep. Prior studies suggest that TMR during REM sleep may play a role in memory generalization processes, but evidence remains scarce. We tested the hypothesis that TMR exerts a differential effect on distinct mnemonic processes as a function of the sleep state (REM vs. NREM) in which TMR is delivered. Mnemonic discrimination and generalization of semantic categories were investigated using an adapted version of the Mnemonic Similarity Task, before and after sleep. Forty-eight participants encoded pictures from eight semantic categories, each associated with a sound. In the pre-sleep immediate test, they had to discriminate "old" (targets) from "similar" (lures) or "new" (foils) pictures. During sleep, half of the sounds were replayed in slow wave sleep (SWS) or REM sleep. Recognition, discrimination, and generalization memory indices were tested in the morning. These indices did not differ between SWS and REM TMR groups or reactivated and non-reactivated item categories. Additional results suggest a positive effect of TMR on performance for highly similar items mostly relying on mnemonic discrimination processes. During sleep, EEG activity after cue presentation increased in the delta-theta and sigma band in the SWS group, and in the beta band in the REM TMR group. These results do not support the hypothesis of a differential processing of novel memory traces when TMR is administered in distinctive physiological sleep states.

Reduced REM and N2 sleep, and lower dream intensity predict increased mind-wandering.

Mind-wandering is a mental state in which attention shifts from the present environment or current task to internally driven, self-referent mental content. Homeostatic sleep pressure seems to facilitate mind-wandering as indicated by studies observing links between increased mind-wandering and impaired sleep. Nevertheless, previous studies mostly relied on cross-sectional measurements and self-reports. We aimed to combine the accuracy of objective sleep measures with the use of self-reports in a naturalistic setting in order to examine if objective sleep parameters predict the tendency for increased mind-wandering on the following day. We used mobile sleep electroencephalographic (EEG) headbands and self-report scales over 7 consecutive nights in a group of 67 healthy participants yielding ~400 analyzable nights. Nights with more wakefulness and shorter REM and slow wave sleep were associated with poorer subjective sleep quality at the intraindividual level. Reduced REM and N2 sleep, as well as less intense dream experiences, predicted more mind-wandering the following day. Our micro-longitudinal study indicates that intraindividual fluctuations in the duration of specific sleep stages predict the perception of sleep quality as assessed in the morning, as well as the intensity of daytime mind-wandering the following hours. The combined application of sleep EEG assessments and self-reports over repeated assessments provides new insights into the subtle intraindividual, night-to-day associations between nighttime sleep and the next day's subjective experiences.

Lateralized tactile stimulation during NREM sleep globally increases both slow and fast frequency activities.

Slow frequency activity during non-rapid eye movement (NREM) sleep emerges from synchronized activity of widely distributed thalamo-cortical and cortico-cortical networks, reflecting homeostatic and restorative properties of sleep. Slow frequency activity exhibits a reactive nature, and can be increased by acoustic stimulation. Although non-invasive brain stimulation is a promising technique in basic and clinical sleep research, sensory stimulation studies focusing on modalities other than the acoustic are scarce. We explored here the potential of lateralized vibro-tactile stimulation (VTS) of the finger to locally modify electroencephalographic activity during nocturnal NREM sleep. Eight seconds-long sequences of vibro-tactile pulses were delivered at a rate of 1 Hz either to the left or to the right index finger, in addition to a sham condition, in fourteen healthy participants. VTS markedly increased slow frequency activity that peaked between 1-4 Hz but extended to higher (~13 Hz) frequencies, with fronto-central dominance. Enhanced slow frequency activity was accompanied by increased (14-22 Hz) fast frequency power peaking over central and posterior locations. VTS increased the amplitude of slow waves, especially during the first 3-4 s of stimulation. Noticeably, we did not observe local-hemispheric effects, that is, VTS resulted in a global cortical response regardless of stimulation laterality. VTS moderately increased slow and fast frequency activities in resting wakefulness, to a much lower extent compared to NREM sleep. The concomitant increase in slow and fast frequency activities in response to VTS indicates an instant homeostatic response coupled with wake-like, high-frequency activity potentially reflecting transient periods of increased environmental processing.

Impact of electric vechicles on power transmission grids.

This paper presents a methodology for assessing the impact of electric vehicles (EVs) on the power transmission grid of the Costa Rica Power System. The methodology considers penetration scenarios, user preferences, charging habits, and expected fleet growth. Using ETAP software, the study simulates power flow, demand behavior, and voltage levels in the presence of high penetration of electric vehicles. The analysis covers a 15-year horizon and focuses on voltage and demand profiles in 2025, 2030, and 2040. The results indicate a decline in voltage profiles that reaches dangerous levels after 2030, primarily in the distribution grid, and an increase in demand by Image 1 for 2040 in the most severe scenario. The analysis also reveals several key findings (a) the identification of problems in the electrical infrastructure starting in 2030 and a major insufficiency in accommodating the increase in EVs by 2040; (b) the need to evaluate stability in transmission grids considering loadability and voltage; (c) the necessity of investing in electrical infrastructure, driven by public policies, to meet future energy requirements and strengthen transmission networks; (d) the significance of accounting for both EV growth and electric infrastructure improvements in system analysis; and (e) the anticipation that the system's performance will fall within the extreme demand values presented in the analysis. The study emphasizes the importance of considering a broader range of scenarios and variability in parameters, especially user charging behaviors, to enable decision-makers to plan for the challenges and opportunities associated with the widespread adoption of EVs in a country's power grid.

A Pilot Study of Neurobiological Mechanisms of Stress and Cardiovascular Risk.

Objective: Coronary heart disease is a leading cause of death and disability. Although psychological stress has been identified as an important potential contributor, mechanisms by which stress increases risk of heart disease and mortality are not fully understood. The purpose of this study was to assess mechanisms by which stress acts through the brain and heart to confer increased CHD risk. Methods: Coronary Heart Disease patients (N=10) underwent cardiac imaging with [Tc-99m] sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of [18F]2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress. Patients with (N=4) and without (N=6) mental stress-induced myocardial ischemia were compared for glucose uptake in brain, heart, adipose tissue and aorta with mental stress. Results: Patients with mental stress-induced ischemia showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group as a whole, activity increase with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (r=0.69, p=0.038; and r=0.69, p=0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (r=0.71, p=0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Activity in other brain areas not implicated in stress did not show similar correlations. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (r=0.85, p=0.004). Conclusions: These findings suggest a link between brain response to stress in key areas mediating emotion and peripheral organs involved in inflammation and hematopoietic activity, as well as myocardial ischemia, in Coronary Heart Disease patients.

Leveraging Accelerometry as a Prognostic Indicator for Increase in Opioid Withdrawal Symptoms.

Treating opioid use disorder (OUD) is a significant healthcare challenge in the United States. Remaining abstinent from opioids is challenging for individuals with OUD due to withdrawal symptoms that include restlessness. However, to our knowledge, studies of acute withdrawal have not quantified restlessness using involuntary movements. We hypothesized that wearable accelerometry placed mid-sternum could be used to detect withdrawal-related restlessness in patients with OUD. To study this, 23 patients with OUD undergoing active withdrawal participated in a protocol involving wearable accelerometry, opioid cues to elicit craving, and non-invasive Vagal Nerve Stimulation (nVNS) to dampen withdrawal symptoms. Using accelerometry signals, we analyzed how movements correlated with changes in acute withdrawal severity, measured by the Clinical Opioid Withdrawal Scale (COWS). Our results revealed that patients demonstrating sinusoidal-i.e., predominantly single-frequency oscillation patterns in their motion almost exclusively demonstrated an increase in the COWS, and a strong relationship between the maximum power spectral density and increased withdrawal over time, measured by the COWS (R = 0.92, p = 0.029). Accelerometry may be used in an ambulatory setting to indicate the increased intensity of a patient's withdrawal symptoms, providing an objective, readily-measurable marker that may be captured ubiquitously.

Transcutaneous cervical vagus nerve stimulation reduces behavioral and physiological manifestations of withdrawal in patients with opioid use disorder: A double-blind, randomized, sham-controlled pilot study.

BACKGROUND: Opioid Use Disorder (OUD) is a serious public health problem, and the behavioral and physiological effects of opioid withdrawal can be a major impediment to recovery. Medication for OUD is currently the mainstay of treatment; however, it has limitations and alternative approaches are needed. OBJECTIVE: The purpose of this study was to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on behavioral and physiological manifestations of acute opioid withdrawal. METHODS: Patients with OUD undergoing acute opioid withdrawal were randomly assigned to receive double blind active tcVNS (N = 10) or sham stimulation (N = 11) while watching neutral and opioid cue videos. Subjective opioid withdrawal, opioid craving, and anxiety were measured using a Visual Analogue Scale (VAS). Distress was measured using the Subjective Units of Distress Scale (SUDS), and pain was measured using the Numerical Rating Scale (NRS) for pain. Electrocardiogram signals were measured to compute heart rate. The primary outcomes of this initial phase of the clinical trial (ClinicalTrials.gov NCT04556552) were heart rate and craving. RESULTS: tcVNS compared to sham resulted in statistically significant reductions in subjective opioid withdrawal (p = .047), pain (p = .045), and distress (p = .004). In addition, tcVNS was associated with lower heart rate compared to sham (p = .026). Craving did not significantly differ between groups (p = .11). CONCLUSIONS: tcVNS reduces behavioral and physiological manifestations of opioid withdrawal, and should be evaluated in future studies as a possible non-pharmacologic, easily implemented approach for adjunctive OUD treatment.

Home confinement during the COVID-19: day-to-day associations of sleep quality with rumination, psychotic-like experiences, and somatic symptoms.

Due to the coronavirus disease 2019 (COVID-19) pandemic, populations from many countries have been confined at home for extended periods of time in stressful environmental and media conditions. Cross-sectional studies already evidence deleterious psychological consequences, with poor sleep as a risk factor for impaired mental health. However, limitations of cross-sectional assessments are response bias tendencies and the inability to track daily fluctuations in specific subjective experiences in extended confinement conditions. In a prospective study conducted across three European countries, we queried participants (N = 166) twice a day through an online interface about their sleep quality and their negative psychological experiences for two consecutive weeks. The focus was set on between- and within-person associations of subjective sleep quality with daytime experiences, such as rumination, psychotic-like experiences, and somatic complaints about the typical symptoms of the coronavirus. The results show that daily reports of country-specific COVID-19 deaths predicted increased negative mood, psychotic-like experiences, and somatic complaints during the same day and decreased subjective sleep quality the following night. Disrupted sleep was globally associated with negative psychological outcomes during the study period, and a relatively poorer night of sleep predicted increased rumination, psychotic-like experiences, and somatic complaints the following day. This temporal association was not paralleled by daytime mental complaints predicting relatively poorer sleep quality on the following night. Our findings show that night-to-night changes in sleep quality predict how individuals cope the next day with daily challenges induced by home confinement.

CX3CR1/CX3CL1 Axis Mediates Platelet-Leukocyte Adhesion to Arterial Endothelium in Younger Patients with a History of Idiopathic Deep Vein Thrombosis.

Mechanisms linking deep vein thrombosis (DVT) and subclinical atherosclerosis and risk of cardiovascular events are poorly understood. The aim of this study was to investigate the potential impact of CX3CR1/CX3CL1 axis in DVT-associated endothelial dysfunction. The study included 22 patients (age: 37.5 ± 8.2 years) with a history of idiopathic DVT and without known cardiovascular risk factors and 23 aged-matched control subjects (age: 34 ± 7.8 years). Flow cytometry was used to evaluate peripheral markers of platelet activation, leukocyte immunophenotypes and CX3CR1/CX3CL1 expression in both groups. A flow chamber assay was employed to measure leukocyte arrest under dynamic conditions. Platelet activation and the percentage of circulating CX3CR1-expressing platelets, CX3CR1-expressing platelet-bound monocytes and CD8+ lymphocytes were higher in patients with DVT than in controls. Additionally, patients with DVT had increased plasma levels of CX3CL1, soluble P-selectin and platelet factor 4/CXCL4. Interestingly, this correlated with enhanced platelet-leukocyte interaction and leukocyte adhesion to TNFα-stimulated arterial endothelial cells, which was partly dependent on endothelial CX3CL1 upregulation and increased CX3CR1 expression on platelets, monocytes and lymphocytes. In conclusion, increased CX3CR1 expression on circulating platelets may constitute a prognostic marker for long-term adverse cardiovascular events in patients with DVT. Blockade of CX3CL1/CX3CR1 axis may represent a new therapeutic strategy for the prevention of cardiovascular comorbidities associated with DVT.

HDAC8 overexpression in mesenchymal stromal cells from JAK2+ myeloproliferative neoplasms: a new therapeutic target?

Histone deacetylases (HDACs) are involved in epigenetic modulation and their aberrant expression has been demonstrated in myeloproliferative neoplasms (MPN). HDAC8 inhibition has been shown to inhibit JAK2/STAT5 signaling in hematopoietic cells from MPN. Nevertheless, the role of HDAC8 expression in bone marrow-mesenchymal stromal cells (BM-MSC) has not been assessed. In the current work we describe that HDAC8 is significantly over-expressed in MSC from in JAK-2 positive MPN compared to those from healthy-donors (HD-MSC). Using a selective HDAC8 inhibitor (PCI34051), we verified that the subsequent decrease in the protein and mRNA expression of HDAC8 is linked with an increased apoptosis of malignant MSC whereas it has no effects on normal MSC. In addition, HDAC8 inhibition in MPN-MSC also decreased their capacity to maintain neoplastic hematopoiesis, by increasing the apoptosis, cell-cycle arrest and colony formation of JAK2+-hematopoietic cells. Mechanistic studies using different MPN cell lines revealed that PCI34051 induced their apoptosis, which is enhanced when were co-cultured with JAK2V617F-MSC, decreased their colony formation and the phosphorylation of STAT3 and STAT5. In summary, we show for the first time that the inhibition of HDAC8 in MSC from JAK2+ MPN patients selectively decreases their hematopoietic-supporting ability, suggesting that HDAC8 may be a potential therapeutic target in this setting by acting not only on hematopoietic cells but also on the malignant microenvironment.