Male violence disrupts estrogen receptor ß signaling in the female hippocampus.

Women are the main target of intimate partner violence (IPV), which is escalating worldwide. Mechanisms subtending IPV-related disorders, such as anxiety, depression and PTSD, remain unclear. We employed a mouse model molded on an IPV scenario (male vs. female prolonged violent interaction) to unearth the neuroendocrine alterations triggered by an aggressive male mouse on the female murine brain. Experimental IPV (EIPV) prompted marked anxiety-like behavior in young female mice, coincident with high circulating/cerebral corticosterone levels. The hippocampus of EIPV-inflicted female animals displayed neuronal loss, reduced BrdU-DCX-positive nuclei, decreased mature DCX-positive cells, and diminished dendritic arborization level in the dentate gyrus (DG), features denoting impaired neurogenesis and neuronal differentiation. These hallmarks were associated with marked down-regulation of estrogen receptor ß (ERß) density in the hippocampus, especially in the DG and dependent prosurvival ERK signaling. Conversely, ERα expression was unchanged. After EIPV, the DG harbored lowered local BDNF pools, diminished TrkB phosphorylation, and elevated glucocorticoid receptor phosphorylation. In unison, ERß KO mice had heightened anxiety-like behavior and curtailed BDNF levels at baseline, despite enhanced circulating estradiol levels, while dying prematurely during EIPV. Thus, reiterated male-to-female violence jeopardizes hippocampal homeostasis in the female brain, perturbing ERß/BDNF signaling, thus instigating anxiety and chronic stress.

Hyperbaric Oxygen Therapy Counters Oxidative Stress/Inflammation-Driven Symptoms in Long COVID-19 Patients: Preliminary Outcomes.

Long COVID-19 patients show systemic inflammation and persistent symptoms such as fatigue and malaise, profoundly affecting their quality of life. Since improving oxygenation can oppose inflammation at multiple tissue levels, we hypothesized that hyperbaric oxygen therapy (HBOT) could arrest inflammation progression and thus relieve symptoms of COVID-19. We evaluated oxy-inflammation biomarkers in long COVID-19 subjects treated with HBOT and monitored with non-invasive methods. Five subjects (two athletes and three patients with other comorbidities) were assigned to receive HBOT: 100% inspired O2 at 2.4 ATA in a multiplace hyperbaric chamber for 90 min (three athletes: 15 HBOT × 5 days/wk for 3 weeks; two patients affected by Idiopathic Sudden Sensorineural Hearing Loss: 30 HBOT × 5 days/wk for 6 weeks; and one patient with osteomyelitis: 30 HBOT × 5 days/wk for week for 6 weeks and, after a 30-day break, followed by a second cycle of 20 HBOT). Using saliva and/or urine samples, reactive oxygen species (ROS), antioxidant capacity, cytokines, lipids peroxidation, DNA damage, and renal status were assessed at T1_pre (basal level) and at T2_pre (basal level after treatment), and the results showed attenuated ROS production, lipid peroxidation, DNA damage, NO metabolites, and inflammation biomarker levels, especially in the athletes post-treatment. Thus, HBOT may represent an alternative non-invasive method for treating long COVID-19-induced long-lasting manifestations of oxy-inflammation.

Enhanced Myocardial Adenylyl Cyclase Activity Alters Heart-Brain Communication.

BACKGROUND: The central nervous system's influence on cardiac function is well described; however, direct evidence for signaling from heart to brain remains sparse. Mice with cardiac-selective overexpression of adenylyl cyclase type 8 (TGAC8) display elevated heart rate/contractility and altered neuroautonomic surveillance. OBJECTIVES: In this study the authors tested whether elevated adenylyl cyclase type 8-dependent signaling at the cardiac cell level affects brain activity and behavior. METHODS: A telemetry system was used to record electrocardiogram (ECG) and electroencephalogram (EEG) in TGAC8 and wild-type mice simultaneously. The Granger causality statistical approach evaluated variations in the ECG/EEG relationship. Mouse behavior was assessed via elevated plus maze, open field, light-dark box, and fear conditioning tests. Transcriptomic and proteomic analyses were performed on brain tissue lysates. RESULTS: Behavioral testing revealed increased locomotor activity in TGAC8 that included a greater total distance traveled (+43%; P < 0.01), a higher average speed (+38%; P < 0.01), and a reduced freezing time (-45%; P < 0.01). Dual-lead telemetry recording confirmed a persistent heart rate elevation with a corresponding reduction in ECG-R-waves interval variability and revealed increased EEG-gamma activity in TGAC8 vs wild-type. Bioinformatic assessment of hippocampal tissue indicated upregulation of dopamine 5, gamma-aminobutyric acid A, and metabotropic glutamate 1/5 receptors, major players in gamma activity generation. Granger causality analyses of ECG and EEG recordings showed a marked increase in informational flow between the TGAC8 heart and brain. CONCLUSIONS: Perturbed signals arising from the heart cause changes in brain activity, altering mouse behavior. More specifically, the brain interprets augmented myocardial humoral/functional output as a "sustained exercise-like" situation and responds by activating central nervous system output controlling locomotion.

ß3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure.

BACKGROUND: Loss of brain-derived neurotrophic factor (BDNF)/TrkB (tropomyosin kinase receptor B) signaling accounts for brain and cardiac disorders. In neurons, ß-adrenergic receptor stimulation enhances local BDNF expression. It is unclear if this occurs in a pathophysiological relevant manner in the heart, especially in the ß-adrenergic receptor-desensitized postischemic myocardium. Nor is it fully understood whether and how TrkB agonists counter chronic postischemic left ventricle (LV) decompensation, a significant unmet clinical milestone. METHODS: We conducted in vitro studies using neonatal rat and adult murine cardiomyocytes, SH-SY5Y neuronal cells, and umbilical vein endothelial cells. We assessed myocardial ischemia (MI) impact in wild type, ß3AR knockout, or myocyte-selective BDNF knockout (myoBDNF KO) mice in vivo (via coronary ligation [MI]) or in isolated hearts with global ischemia-reperfusion (I/R). RESULTS: In wild type hearts, BDNF levels rose early after MI (<24 hours), plummeting at 4 weeks when LV dysfunction, adrenergic denervation, and impaired angiogenesis ensued. The TrkB agonist, LM22A-4, countered all these adverse effects. Compared with wild type, isolated myoBDNF KO hearts displayed worse infarct size/LV dysfunction after I/R injury and modest benefits from LM22A-4. In vitro, LM22A-4 promoted neurite outgrowth and neovascularization, boosting myocyte function, effects reproduced by 7,8-dihydroxyflavone, a chemically unrelated TrkB agonist. Superfusing myocytes with the ß3AR-agonist, BRL-37344, increased myocyte BDNF content, while ß3AR signaling underscored BDNF generation/protection in post-MI hearts. Accordingly, the ß1AR blocker, metoprolol, via upregulated ß3ARs, improved chronic post-MI LV dysfunction, enriching the myocardium with BDNF. Last, BRL-37344-imparted benefits were nearly abolished in isolated I/R injured myoBDNF KO hearts. CONCLUSIONS: BDNF loss underscores chronic postischemic heart failure. TrkB agonists can improve ischemic LV dysfunction via replenished myocardial BDNF content. Direct cardiac ß3AR stimulation, or ß-blockers (via upregulated ß3AR), is another BDNF-based means to fend off chronic postischemic heart failure.

Dopamine/BDNF loss underscores narcosis cognitive impairment in divers: a proof of concept in a dry condition.

PURPOSE: Divers can experience cognitive impairment due to inert gas narcosis (IGN) at depth. Brain-derived neurotrophic factor (BDNF) rules neuronal connectivity/metabolism to maintain cognitive function and protect tissues against oxidative stress (OxS). Dopamine and glutamate enhance BDNF bioavailability. Thus, we hypothesized that lower circulating BDNF levels (via lessened dopamine and/or glutamate release) underpin IGN in divers, while testing if BDNF loss is associated with increased OxS. METHODS: To mimic IGN, we administered a deep narcosis test via a dry dive test (DDT) at 48 msw in a multiplace hyperbaric chamber to six well-trained divers. We collected: (1) saliva samples before DDT (T0), 25 msw (descending, T1), 48 msw (depth, T2), 25 msw (ascending, T3), 10 min after decompression (T4) to dopamine and/or reactive oxygen species (ROS) levels; (2) blood and urine samples at T0 and T4 for OxS too. We administered cognitive tests at T0, T2, and re-evaluated the divers at T4. RESULTS: At 48 msw, all subjects experienced IGN, as revealed by the cognitive test failure. Dopamine and total antioxidant capacity (TAC) reached a nadir at T2 when ROS emission was maximal. At decompression (T4), a marked drop of BDNF/glutamate content was evidenced, coinciding with a persisting decline in dopamine and cognitive capacity. CONCLUSIONS: Divers encounter IGN at - 48 msw, exhibiting a marked loss in circulating dopamine levels, likely accounting for BDNF-dependent impairment of mental capacity and heightened OxS. The decline in dopamine and BDNF appears to persist at decompression; thus, boosting dopamine/BDNF signaling via pharmacological or other intervention types might attenuate IGN in deep dives.

Intimate partner violence: psycho-physio-pathological sequelae for defining a holistic enriched treatment.

Intimate partner violence (IPV) is a health priority, which worldwide, mainly affects women. The consequences of IPV include several psychophysiological effects. These range from altered levels of hormones and neurotrophins to difficulties in emotion regulation and cognitive impairment. Mounting evidence from preclinical studies has shown that environmental enrichment, a form of sensory-motor, cognitive, and social stimulation, can induce a wide range of neuroplastic processes in the brain which consistently improve recovery from a wide variety of somatic and psychiatric diseases. To support IPV survivors, it is essential to ensure a safe housing environment, which can serve as a foundation for environmental enrichment-based interventions. However, some concerns have been raised when supportive housing interventions focus on the economic aspects of survivors' lives instead of the emotional ones. We thus propose a holistic intervention in which supportive housing is integrated with evidenced-based psychotherapies which could constitute an enriched therapeutic approach for IPV survivors.

Cognitive decline in heart failure: Biomolecular mechanisms and benefits of exercise.

By definition, heart failure (HF) is a pathological condition affecting the structure and function of all organs in the body, and the brain is not an exception to that. Failure of the heart to pump enough blood centrally and peripherally is at the foundation of HF patients' inability to attend even the most ordinary daily activities and progressive deterioration of their cognitive capacity. What is more, between heart and brain exists a bidirectional relationship that goes well beyond hemodynamics and concerns bioelectric and endocrine signaling. This increasingly consolidated evidence makes the scenario even more complex. Studies have mainly chased how HF impairs cognition without focusing much on preventive measures, notably cardio-cerebral health proxies. Here, we aim to provide a brief account of known and hypothetical factors that may explain how exercise can help obviate cognitive dysfunction associated with HF in its different forms. As we shall see, there is a stringent need for a deeper grasp of such mechanisms. Indeed, gaining this new knowledge will automatically shed new light on the inner workings of HF itself, thus resulting in more effective prevention and treatment of this escalating syndrome.

Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.

BACKGROUND: Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. We tested the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF. METHODS: First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice. RESULTS: In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling. CONCLUSIONS: In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.

Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy.

Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2 mut/mut), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca2+) overload in Dsg2 mut/mut hearts, which induced calpain-1 (CAPN1) activation, association of CAPN1 with mitochondria, and CAPN1-induced cleavage of mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocated to the myocyte nucleus triggering large-scale DNA fragmentation and cell death, an effect potentiated by mitochondrial-driven AIF oxidation. Posttranslational oxidation of AIF cysteine residues was due, in part, to a depleted mitochondrial thioredoxin-2 redox system. Hearts from exercised Dsg2 mut/mut mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca2+ overload-induced necrosis. When cardiomyocytes differentiated from Dsg2 mut/mut embryonic stem cells (ES-CMs) were challenged with ß-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2 mut/mut ES-CMs with an AIF-mimetic peptide, mirroring the cyclophilin-A (PPIA) binding site of AIF, blocked PPIA-mediated AIF-nuclear translocation, and reduced both apoptosis and necrosis. Thus, preventing CAPN1-induced AIF-truncation or barring binding of AIF to the nuclear chaperone, PPIA, may avert myocyte death and, ultimately, disease progression to heart failure in ACM and likely other forms of cardiomyopathies.

Psychosocial Stress Hastens Disease Progression and Sudden Death in Mice with Arrhythmogenic Cardiomyopathy.

Physiological stressors, such as exercise, can precipitate sudden cardiac death or heart failure progression in patients with arrhythmogenic cardiomyopathy (ACM). Yet, whether and to what extent a highly prevalent and more elusive environmental factor, such as psychosocial stress (PSS), can also increase ACM disease progression is unexplored. Here, we first quantified perceived stress levels in patients with ACM and found these levels correlated with the extent of arrhythmias and cardiac dysfunction. To determine whether the observed correlation is due to causation, we inflicted PSS-via the resident-intruder (RI) paradigm-upon Desmoglein-2 mutant mice, a vigorously used mammalian model of ACM. We found that ACM mice succumbed to abnormally high in-trial, PSS mortality. Conversely, no sudden deaths occurred in wildtype (WT) counterparts. Desmoglein-2 mice that survived RI challenge manifested markedly worse cardiac dysfunction and remodeling, namely apoptosis and fibrosis. Furthermore, WT and ACM mice displayed similar behavior at baseline, but Desmoglein-2 mice exhibited heightened anxiety following RI-induced PSS. This outcome correlated with the worsening of cardiac phenotypes. Our mouse model demonstrates that in ACM-like subjects, PSS is incisive enough to deteriorate cardiac structure and function per se, i.e., in the absence of any pre-existing anxious behavior. Hence, PSS may represent a previously underappreciated risk factor in ACM disease penetrance.

Potential Bidirectional Relationship Between Periodontitis and Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population, representing a global public health priority. Despite a large improvement in understanding the pathogenesis of AD, the etiology of this disorder remains still unclear, and no current treatment is able to prevent, slow, or stop its progression. Thus, there is a keen interest in the identification and modification of the risk factors and novel molecular mechanisms associated with the development and progression of AD. In this context, it is worth noting that several findings support the existence of a direct link between neuronal and non-neuronal inflammation/infection and AD progression. Importantly, recent studies are now supporting the existence of a direct relationship between periodontitis, a chronic inflammatory oral disease, and AD. The mechanisms underlying the association remain to be fully elucidated, however, it is generally accepted, although not confirmed, that oral pathogens can penetrate the bloodstream, inducing a low-grade systemic inflammation that negatively affects brain function. Indeed, a recent report demonstrated that oral pathogens and their toxic proteins infect the brain of AD patients. For instance, when AD progresses from the early to the more advanced stages, patients could no longer be able to adequately adhere to proper oral hygiene practices, thus leading to oral dysbiosis that, in turn, fuels infection, such as periodontitis. Therefore, in this review, we will provide an update on the emerging (preclinical and clinical) evidence that supports the relationship existing between periodontitis and AD. More in detail, we will discuss data attesting that periodontitis and AD share common risk factors and a similar hyper-inflammatory phenotype.

Sleep slow oscillations favour local cortical plasticity underlying the consolidation of reinforced procedural learning in human sleep.

We investigated changes of slow-wave activity and sleep slow oscillations in the night following procedural learning boosted by reinforcement learning, and how these changes correlate with behavioural output. In the Task session, participants had to reach a visual target adapting cursor's movements to compensate an angular deviation introduced experimentally, while in the Control session no deviation was applied. The task was repeated at 13:00 hours, 17:00 hours and 23:00 hours before sleep, and at 08:00 hours after sleep. The deviation angle was set at 15° (13:00 hours and 17:00 hours) and increased to 45° (reinforcement) at 23:00 hours and 08:00 hours. Both for Task and Control nights, high-density electroencephalogram sleep recordings were carried out (23:30-19:30 hours). The Task night as compared with the Control night showed increases of: (a) slow-wave activity (absolute power) over the whole scalp; (b) slow-wave activity (relative power) in left centro-parietal areas; (c) sleep slow oscillations rate in sensorimotor and premotor areas; (d) amplitude of pre-down and up states in premotor regions, left sensorimotor and right parietal regions; (e) sigma crowning the up state in right parietal regions. After Task night, we found an improvement of task performance showing correlations with sleep slow oscillations rate in right premotor, sensorimotor and parietal regions. These findings suggest a key role of sleep slow oscillations in procedural memories consolidation. The diverse components of sleep slow oscillations selectively reflect the network activations related to the reinforced learning of a procedural visuomotor task. Indeed, areas specifically involved in the task stand out as those with a significant association between sleep slow oscillations rate and overnight improvement in task performance.

Perioperative Heart-Brain Axis Protection in Obese Surgical Patients: The Nutrigenomic Approach.

The number of obese patients undergoing cardiac and noncardiac surgery is rapidly increasing because they are more prone to concomitant diseases, such as diabetes, thrombosis, sleep-disordered breathing, cardiovascular and cerebrovascular disorders. Even if guidelines are already available to manage anesthesia and surgery of obese patients, the assessment of the perioperative morbidity and mortality from heart and brain disorders in morbidly obese surgical patients will be challenging in the next years. The present review will recapitulate the new mechanisms underlying the Heart-brain Axis (HBA) vulnerability during the perioperative period in healthy and morbidly obese patients. Finally, we will describe the nutrigenomics approach, an emerging noninvasive dietary tool, to maintain a healthy body weight and to minimize the HBA propensity to injury in obese individuals undergoing all types of surgery by personalized intake of plant compounds that may regulate the switch from health to disease in an epigenetic manner. Our review provides current insights into the mechanisms underlying HBA response in obese surgical patients and how they are modulated by epigenetically active food constituents.

Anesthetic Agents Isoflurane and Propofol Decrease Maximal Ca2+-Activated Force and Thus Contractility in the Failing Myocardium.

In the normal heart, frequently used anesthetics such as isoflurane and propofol can reduce inotropy. However, the impact of these agents on the failing myocardium is unclear. Here, we examined whether and how isoflurane and propofol influence cardiac contractility in intact cardiac muscles from rats treated with monocrotaline to induce heart failure. We measured force and intracellular Ca2+ ([Ca2 +]i) in trabeculae from the right ventricles of the rats in the absence or presence of propofol or isoflurane. At low to moderate concentrations, both propofol and isoflurane dose-dependently depressed cardiac force generation in failing trabeculae without altering [Ca2+]i At high doses, propofol (but not isoflurane) also decreased amplitude of [Ca2+]i transients. During steady-state activation, both propofol and isoflurane impaired maximal Ca2+-activated force (Fmax) while increasing the amount of [Ca2+]i required for 50% of maximal activation (Ca50). These events occurred without apparent change in the Hill coefficient, suggesting no impairment of cooperativity. Exposing these same muscles to the anesthetics after fiber skinning resulted in a similar decrement in Fmax and rise in Ca50 but no change in the myofibrillar ATPase-Ca2+ relationship. Thus, our study demonstrates that challenging the failing myocardium with commonly used anesthetic agents such as propofol and isoflurane leads to reduced force development as a result of lowered myofilament responsiveness to Ca2+ SIGNIFICANCE STATEMENT: Commonly used anesthetics such as isoflurane and propofol can impair myocardial contractility in subjects with heart failure by lowering myofilament responsiveness to Ca2+. High doses of propofol can also reduce the overall amplitude of the intracellular Ca2+ transient. These findings may have important implications for the safety and quality of intra- and perioperative care of patients with heart failure and other cardiac disorders.

Obese mice exposed to psychosocial stress display cardiac and hippocampal dysfunction associated with local brain-derived neurotrophic factor depletion.

INTRODUCTION: Obesity and psychosocial stress (PS) co-exist in individuals of Western society. Nevertheless, how PS impacts cardiac and hippocampal phenotype in obese subjects is still unknown. Nor is it clear whether changes in local brain-derived neurotrophic factor (BDNF) account, at least in part, for myocardial and behavioral abnormalities in obese experiencing PS. METHODS: In adult male WT mice, obesity was induced via a high-fat diet (HFD). The resident-intruder paradigm was superimposed to trigger PS. In vivo left ventricular (LV) performance was evaluated by echocardiography and pressure-volume loops. Behaviour was indagated by elevated plus maze (EPM) and Y-maze. LV myocardium was assayed for apoptosis, fibrosis, vessel density and oxidative stress. Hippocampus was analyzed for volume, neurogenesis, GABAergic markers and astrogliosis. Cardiac and hippocampal BDNF and TrkB levels were measured by ELISA and WB. We investigated the pathogenetic role played by BDNF signaling in additional cardiac-selective TrkB (cTrkB) KO mice. FINDINGS: When combined, obesity and PS jeopardized LV performance, causing prominent apoptosis, fibrosis, oxidative stress and remodeling of the larger coronary branches, along with lower BDNF and TrkB levels. HFD/PS weakened LV function similarly in WT and cTrkB KO mice. The latter exhibited elevated LV ROS emission already at baseline. Obesity/PS augmented anxiety-like behaviour and impaired spatial memory. These changes were coupled to reduced hippocampal volume, neurogenesis, local BDNF and TrkB content and augmented astrogliosis. INTERPRETATION: PS and obesity synergistically deteriorate myocardial structure and function by depleting cardiac BDNF/TrkB content, leading to augmented oxidative stress. This comorbidity triggers behavioral deficits and induces hippocampal remodeling, potentially via lower BDNF and TrkB levels. FUND: J.A. was in part supported by Rotary Foundation Global Study Scholarship. G.K. was supported by T32 National Institute of Health (NIH) training grant under award number 1T32AG058527. S.C. was funded by American Heart Association Career Development Award (19CDA34760185). G.A.R.C. was funded by NIH (K01HL133368-01). APB was funded by a Grant from the Friuli Venezia Giulia Region entitled: "Heart failure as the Alzheimer disease of the heart; therapeutic and diagnostic opportunities". M.C. was supported by PRONAT project (CNR). N.P. was funded by NIH (R01 HL136918) and by the Magic-That-Matters fund (JHU). V.L. was in part supported by institutional funds from Scuola Superiore Sant'Anna (Pisa, Italy), by the TIM-Telecom Italia (WHITE Lab, Pisa, Italy), by a research grant from Pastificio Attilio Mastromauro Granoro s.r.l. (Corato, Italy) and in part by ETHERNA project (Prog. n. 161/16, Fondazione Pisa, Italy). Funding source had no such involvement in study design, in the collection, analysis, interpretation of data, in the writing of the report; and in the decision to submit the paper for publication.

Postoperative cognitive dysfunction and short-term neuroprotection from blueberries: a pilot study.

BACKGROUND: General anesthesia may be a risk factor for post-operative cognitive impairment, which could be counteracted by neuroprotective compounds. The aims of this study were to determine cognitive functions impaired by general anesthesia and to test blueberry juice as a neuroprotective agent against neuropsychological dysfunctions induced by general anesthesia. METHODS: Twenty-six patients undergoing elective major surgery were randomized into two groups, receiving either 500 mL/day of blueberry juice within 14 preoperative days (G1) or to a control group (G0). Neuropsychological tests were performed around 20 days before surgery (T0), as well as both three hours (T1) and 24 hours (T2) after surgery. All the scores were statistically analyzed to find significant differences between groups and within the three times. RESULTS: The control (G0) group showed a significant decrease in the performance in the Prose Memory Test (P<0.001), the Attentional Matrices Test (P<0.01), and the Trail Making Test Part B (P<0.01) after general anesthesia. Significant differences were reported in the Prose Memory test, T0 versus T1 (P<0.01), T0 versus T2 (P<0.001); in the Trail Making Test Part B, T0 versus T2 (P<0.01); and the Attentional Matrices test, and T0 versus T2 (P<0.001). The G1 group did not show any decrease in the performance of the three tests. CONCLUSIONS: General anesthesia induces a short-term impairment of verbal memory and selective and divided attention. Blueberry compounds may prevent these neuropsychological deficits through a neuroprotective action in patients undergoing general anesthesia.

Pattern recognition with adaptive-thresholds for sleep spindle in high density EEG signals.

Medicine and Surgery, University of Pisa, via Savi 10, 56126, Pisa, Italy Sleep spindles are electroencephalographic oscillations peculiar of non-REM sleep, related to neuronal mechanisms underlying sleep restoration and learning consolidation. Based on their very singular morphology, sleep spindles can be visually recognized and detected, even though this approach can lead to significant mis-detections. For this reason, many efforts have been put in developing a reliable algorithm for spindle automatic detection, and a number of methods, based on different techniques, have been tested via visual validation. This work aims at improving current pattern recognition procedures for sleep spindles detection by taking into account their physiological sources of variability. We provide a method as a synthesis of the current state of art that, improving dynamic threshold adaptation, is able to follow modification of spindle characteristics as a function of sleep depth and inter-subjects variability. The algorithm has been applied to physiological data recorded by a high density EEG in order to perform a validation based on visual inspection and on evaluation of expected results from normal night sleep in healthy subjects.