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Manuela Thienel,1,&ast; Magda Haum,1,&ast; Sebastian Sadoni,2 Julia Novotny,1 Heidi L Estner,1 Stephanie Fichtner,1 Korbinian Lackermair1 1Department of Medicine I, Munich University Hospital, Ludwig-Maximilian-University, Munich, Germany; 2Department of Cardiac Surgery, Munich University Hospital, Ludwig-Maximilian-University, Munich, Germany&ast;These authors contributed equally to this workCorrespondence: Korbinian Lackermair, Department of Medicine I, Munich University Hospital, Ludwig-Maximilian-University, Marchioninistr. 15, Munich, 81377, Germany, Email Korbinian.lackermair@med.uni-muenchen.deBackground: The subcutaneous cardioverter defibrillator (S-ICD) has been shown to be a viable alternative to transvenous ICDs (TV-ICD) in all patients at risk of sudden cardiac death (SCD) but without pacing indication.Aim: The aim of this study was to examine the impact of therapy with current S-ICD devices on quality of life (QoL) in comparison to patients with TV-ICD devices.Methods: In our single-centre study, 52 consecutive patients with S-ICD and 52 matched patients with TV-ICD were analysed. QoL has been assessed by a standardized questionnaire (EQ-5D-3L, modified). Additionally, clinical baseline and follow-up data were evaluated.Results: Two-thirds of the total study population reported restrictions in daily routine compared to their life before ICD implantation. A total of 27.7% of S-ICD patients stated to expect an improvement of QoL by deactivation or explantation of their defibrillator compared to only 6.4% of patients with TV-ICD (p=0.006), which was mainly caused by discomfort and pain from the S-ICD pocket (relevant discomfort and pain in 32.6% vs 11.5%; p< 0.01).Limitations: Main limitation of the study is that quality of life was assessed for one single time point only and time since implantation differed significantly between S-ICD and TV-ICD. Furthermore our collective is younger, and, due to the high proportion of patients without cardiomyopathy, the mean EF is better than usual ICD collective. The absence of heart failure in about the half of our patients might have relevant impact on our QoL analysis.Conclusion: A relevant proportion of S-ICD patients expects an improvement of QoL by explantation of the device. Of note, this impression was not driven by the fear of receiving shocks but mainly by discomfort and pain caused by the pulse generator.Keywords: subcutaneous cardioverter defibrillator, S-ICD, transvenous cardioverter defibrillator, quality of life

Abstract: Platelets are key players in cardiovascular disease, and platelet aggregation represents a central pharmacologic target, particularly in secondary prevention. However, inhibition of adenosine diphosphate and thromboxane signaling has low efficacy in preventing venous thromboembolism, necessitating the inhibition of the plasmatic coagulation cascade in this disease entity. Anticoagulation carries a significantly higher risk of bleeding complications, highlighting the need of alternative therapeutic approaches. We hypothesized that procoagulant activation (PA) of platelets promotes venous thrombus formation and that targeting PA could alleviate venous thrombosis. Here, we found elevated levels of procoagulant platelets in the circulation and in thrombi of patients with deep vein thrombosis (DVT) and pulmonary embolism, and in mice developing DVT following inferior vena cava stenosis. Furthermore, we detected PA of recruited platelets within murine venous thrombi and human pulmonary emboli. Mice with platelet-specific deficiency in central pathways of PA-cyclophilin D and transmembrane protein 16F-were more resistant toward low flow-induced venous thrombosis. Finally, we found that a clinically approved carbonic anhydrase inhibitor, methazolamide, reduced platelet procoagulant activity and alleviated murine thrombus formation without affecting trauma-associated hemostasis. These findings identify an essential role of platelet procoagulant function in venous thrombosis and delineate novel pharmacologic strategies targeting platelets in the prevention of venous thromboembolism., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Immediate activated factor (F)X (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases., Objectives: Therefore, we analyzed platelet-derived effects of long-term FXa inhibition in the setting of acute myocardial infarction (AMI) and stroke., Methods: We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following AMI and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa nonvitamin K antagonist oral anticoagulant treatment and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of patients with AMI, we determined cardiovascular magnetic resonance based cardiac endpoints under FXa nonvitamin K antagonist oral anticoagulant effects on clinical endpoints in a cohort of patients with AMI., Results: Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24 hours after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced neutrophil extracellular trap formation in mice and patient samples. Proteome and RNA expression analysis of FXa inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet α and dense granule release. Subsequent, thromboinflammatory neutrophil extracellular trap density in thrombi isolated from stroke and myocardial infarction patients was reduced. Patients with AMI treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment., Conclusion: Long-term FXa inhibition induces antithromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke., Competing Interests: Declaration of Competing Interests There are no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a major cause of morbidity and mortality. Short-term immobility-related conditions are a major risk factor for the development of VTE. Paradoxically, long-term immobilized free-ranging hibernating brown bears and paralyzed spinal cord injury (SCI) patients are protected from VTE. We aimed to identify mechanisms of immobility-associated VTE protection in a cross-species approach. Mass spectrometry-based proteomics revealed an antithrombotic signature in platelets of hibernating brown bears with heat shock protein 47 (HSP47) as the most substantially reduced protein. HSP47 down-regulation or ablation attenuated immune cell activation and neutrophil extracellular trap formation, contributing to thromboprotection in bears, SCI patients, and mice. This cross-species conserved platelet signature may give rise to antithrombotic therapeutics and prognostic markers beyond immobility-associated VTE.

Cardiac arrhythmias are a common and potentially serious cardiovascular disorders that affect both men and women. However, there is evidence to suggest that there may be sex-related differences in the prevalence, clinical presentation, and management of cardiac arrhythmias. Hormonal and cellular factors may play a role in these sex-specific differences. In addition, there are differences in the types of arrhythmias that men and women experience, with men more likely to experience ventricular arrhythmias and women more likely to experience supraventricular arrhythmias. The management of cardiac arrhythmias also differs between men and women. For example, some studies have found that women are less likely to receive appropriate treatment for arrhythmias and are more likely to have adverse outcomes following treatment. Despite these sex-related differences, the majority of research on cardiac arrhythmias has been conducted in men, and there is a need for more research to specifically examine the differences between men and women. This is especially important given that the prevalence of cardiac arrhythmia is increasing, and it is essential to understand how to effectively diagnose and treat these conditions in both men and women. In this review, we examine the current understanding of sex-related differences in cardiac arrhythmias. We also review the available data on sex-specific management strategies for cardiac arrhythmias and highlight areas of future research., Competing Interests: Declaration of Competing Interest M.T. and K.L. received lecture fees from AstraZeneca GmbH. M.H. and A.K. have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Heparin-induced thrombocytopenia (HIT) is a serious, immune-mediated adverse drug reaction to unfractionated heparin (UFH) affecting also patients undergoing venoarterial extracorporeal membrane oxygenation (VA-ECMO). Although the association between VA-ECMO support and the development of thrombocytopenia has long been known and discussed, HIT as one underlying cause is still insufficiently understood. Therefore, the purpose of this study was to further investigate the epidemiology, mortality, diagnosis, and clinical management of HIT occurring in VA-ECMO patients treated with UFH. Methods: We conducted a retrospective single-center study including adult patients (≥18 years) with VA-ECMO support in the cardiac intensive care unit (ICU) of the University Hospital of Munich (LMU) between January 2013 and May 2022, excluding patients with a known history of HIT upon admission. Differences in baseline characteristics and clinical outcome between excluded HIT (positive anti-platelet factor 4 (PF4)/heparin antibody test but negative functional assay) and confirmed HIT (positive anti-PF4/heparin antibody test and positive functional assay) VA-ECMO patients as well as diagnosis and clinical management of HIT were analysed. Results: Among the 373 patients included, anti-PF4/heparin antibodies were detected in 53/373 (14.2%) patients. Functional HIT testing confirmed HIT in 13 cases (3.5%) and excluded HIT in 40 cases (10.7%), corresponding to a prevalence of confirmed HIT of 13/373 (3.5%) [1.6, 5.3] and a positive predictive value (PPV) of 24.5% for the antibody screening test. The platelet course including platelet recovery following argatroban initiation was similar between all groups. One-month mortality in patients with excluded HIT was 14/40 (35%) and 3-month mortality 17/40 (43%), compared to 5/13 (38%) (p > 0.999), and 6/13 (46%) (p > 0.999) in patients with confirmed HIT. Neurological outcome in both groups measured by the cerebral performance category of survivors on hospital discharge was similar, as well as adverse events during VA-ECMO therapy. Conclusions: With a prevalence of 3.5%, HIT is a non-frequent complication in patients on VA-ECMO and was not associated with a higher mortality rate. HIT was ultimately excluded by functional essay in 75% of VA-ECMO patients with clinical suspicion of HIT and positive anti-PF4/heparin antibody test. Argatroban seems to be an appropriate and safe therapeutic option for confirmed HIT-positive patients on VA-ECMO support.

Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered myosin light chain and extracellular-signal-regulated kinase activation through reactive oxygen species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Benzodiazepines are recommended as first line sedative agent in ventilated cardiogenic shock patients, although data regarding the optimal sedation strategy are sparse. The aim of this study was to investigate the hemodynamic effects of propofol versus midazolam sedation in our cardiogenic shock registry., Materials and Methods: Mechanically ventilated patients suffering from cardiogenic shock were retrospectively enrolled from the cardiogenic shock registry of the university hospital of Munich. 174 patients treated predominantly with propofol were matched by propensity-score to 174 patients treated predominantly with midazolam., Results: Catecholamine doses were similar on admission but significantly lower in the propofol group on days 1-4 of ICU stay. Mortality rate was 38% in the propofol and 52% in the midazolam group after 30 days (p = 0.002). Rate of ≥BARC3 bleeding was significantly lower in the propofol group compared to the midazolam group (p = 0.008). Sedation with midazolam was significantly associated with ICU mortality., Conclusion: In this observational cohort study, sedation with propofol in comparison to midazolam was linked to a reduced dose of catecholamines, decreased mortality and bleeding rates for patients with cardiogenic shock. Based on this study and in contrast to current recommendations, propofol should be given consideration for sedation in cardiogenic shock patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Nonvitamin K oral anticoagulants (NOACs) or direct oral anticoagulants comprise inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban) or factor IIa (dabigatran). Both classes efficiently interfere with the final or penultimate step of the coagulation cascade and showed superior net clinical benefit compared with vitamin K antagonists for prevention of thromboembolic events in patients with AF and for prevention and therapy of deep vein thrombosis and pulmonary embolism. None the less, accumulating data suggested, that there may be differences regarding the frequency of atherothrombotic cardiovascular events between NOACs. Thus, the optimal individualized NOAC for each patient remains a matter of debate. Against this background, some basic and translational analyses emphasized NOAC effects that impact on platelet activity and arterial thrombus formation beyond inhibition of plasmatic coagulation. In this review, we will provide an overview of the available clinical and translational evidence for so-called noncanonical NOAC effects on platelet activation and arterial thrombosis., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Even among biomarker-negative patients undergoing elective percutaneous coronary intervention (PCI), periprocedural thrombotic and bleeding complications can lead to increased morbidity and mortality. Whether stronger platelet inhibition by an intensified oral loading strategy (ILS) before PCI impacts on outcomes among these patients in contemporary practice remains unclear., Methods: This multicenter, randomized, assessor-blinded trial tested the hypothesis that in elective PCI prasugrel 60 mg (ILS) is superior to standard loading strategy with clopidogrel 600 mg regarding a composite primary end point of all-cause death, any myocardial infarction, definite/probable stent thrombosis, stroke, or urgent vessel revascularization. After PCI, all patients were on clopidogrel 75 mg/day and aspirin. The trial was terminated prematurely because of slower-than-expected recruitment and funding discontinuation., Results: Of 781 patients included in the final analysis, 382 were assigned to ILS and 399 to standard loading strategy. At 30 days, the primary end point occurred in 66 patients (17.3%) assigned to ILS and 74 patients (18.6%) assigned to standard loading strategy (odds ratio, 0.92 [95% CI, 0.63-1.32]; P =0.64). Any myocardial infarction and Bleeding Academic Research Consortium ≥2 bleeding rates were similar among ILS and standard loading strategy groups 16.2% versus 17.5%, odds ratio, 0.91 (95% CI, 0.62-1.32), P =0.62 and 4.2% versus 4.8%, odds ratio 0.87 (95% CI, 0.44-1.73), P =0.70, respectively., Conclusions: In biomarker-negative stable and unstable angina patients undergoing elective PCI, the trial did not find a conclusive difference in efficacy or safety. This observation should be interpreted in the context of wide CIs and premature termination of the trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02548611.

Assessing the platelets' functional status during surgery on cardiopulmonary bypass is challenging. This study used multiple electrode impedance aggregometry (Multiplate ® ) to create a timeline of platelet aggregation changes as induced by cardiopulmonary bypass in antiplatelet-naive patients undergoing elective surgery for mitral valve regurgitation. We performed six consecutive measurements (T1: pre-operatively, T2: after heparinization, T3: 3 min after establishment of cardiopulmonary bypass, T4: immediately after administration of cardioplegia, T5: 5 min after administration of cardioplegia, and T6: 45 min after administration of cardioplegia). Platelet aggregation was determined after stimulation with 3.2-μg/mL collagen, 6.4-μM adenosine diphosphate, and 32-μM thrombin receptor activating peptide. Five patients were included (age: 64 ± 10 years, one female). We observed a decrease in hematocrit levels by -17.1% ± 3.7% (T1 vs T6) with a drop after establishment of cardiopulmonary bypass (T2 vs T3) and slightly decreasing platelet counts by -6.2% ± 7.7% (T1 vs T6). Immediately after establishment of cardiopulmonary bypass (T2 vs T3), we observed reduced platelet aggregation responses for stimulation with adenosine diphosphate (-19.7% ± 12.8%) and thrombin receptor activating peptide (-19.3% ± 6.3%). Interestingly, we found augmented platelet aggregation for all stimuli 45 min after administration of cardioplegia (T5 vs T6) with the strongest increase for collagen (+83.4% ± 42.8%; adenosine diphosphate: +39.0% ± 37.2%; thrombin receptor activating peptide: +34.5% ± 18.5%). Thus, after an initial drop due to hemodilution upon establishment of cardiopulmonary bypass, platelet reactivity increased over time which was not outweighed by decreasing platelet counts due to mechanical platelet destruction and absorption. These findings have implications for rational transfusion, peri-operative antiplatelet therapy, and for the management of patients on other extracorporeal support, such as extracorporeal life support or extracorporeal membrane oxygenation.

Rationale: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown., Objective: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis., Methods and Results: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity., Conclusions: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

A patient with a history of colon cancer was admitted to our emergency department due to progressive dyspnea, chest pain, and swelling of the upper limbs and face. A central venous port device had been implanted into the right subclavian vein for administration of systemic chemotherapy several months prior. Thoracic computed tomography scan revealed a 2.8 cm-long thrombus arising from the tip of the venous catheter, which completely occluded the superior vena cava in close proximity to the right atrium.

Aim and Objective: We sought to investigate and compare outcomes 2 years after Hybrid-stenting with bioresorbable vascular scaffolds (BVS) and contemporary metallic drug-eluting stents (DES) within the same coronary lesion versus BVS alone., Methods: Between 11/2012 and 7/2015 at our institution, 134 (33.2%) were treated with Hybrid-stenting for complex or long coronary lesions, 270 patients were treated by BVS alone. The primary outcome of interest was target lesion failure (TLF) at 2-years of follow-up., Results: Patients treated by Hybrid-stenting were more frequently men (80% vs. 70%, p = 0.04) had extensive multivessel disease (84% vs. 71%, p < 0.01) including more complex (89% vs. 52%, p < 0.01) and longer lesions (28.9 mm vs 16.4 ± mm, p < 0.01) resulting in longer treated segments (47.3 mm vs 21.5 mm, p < 0.01) and more residual in-segment stenosis (12.3% vs 8.5%, p < 0.01) compared to BVS alone patients. At 2 years, cumulative incidence of TLF was 9.7% of Hybrid-stenting patients and 11.5% of BVS alone patients (p = 0.62), myocardial infarction (3.0% vs 4.1%, p = 0.59) and mortality (1.5% vs 4.1%, p = 0.17), respectively. Target lesion revascularization occurred in 9 Hybrid-stenting patients (2 located in DES) and in 20 BVS alone patients, cumulative incidence 6.7% vs. 7.4% (p = 0.80). Chronic kidney disease and residual in-segment stenosis >30% were identified as independent predictors of TLF at 2-years., Conclusion: Despite differences in clinical and angiographic profile, Hybrid-stenting performed similar to BVS alone at 2 years after percutaneous coronary intervention., (© 2018 Wiley Periodicals, Inc.)

Background: The Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX)-score is a validated tool for risk stratification and revascularization strategy selection in patients with complex coronary artery disease. The aim of this study was to analyse its age-related prognostic value., Methods: SYNTAX-score was calculated in 1331 all-comer patients undergoing percutaneous coronary intervention (PCI): 463 patients ≥ 75 years and 868 patients < 75 years. Outcomes of interest were all-cause mortality at one and two years., Results: A significant interaction of age and SYNTAX-score for mortality was observed at two-year ( P interaction = 0.019) but not at one-year follow-up ( P interaction = 0.594). In multivariable analysis, SYNTAX-score independently predicted 1-year mortality in both age groups (< 75 years, hazard ratio (HR): 1.43, 95% confidence intervals (CI): 1.03-2.00, P = 0.034; and ≥ 75 years, HR: 1.37, 95% CI: 1.01-1.85, P = 0.042), but only two-year mortality among younger patients (< 75 years, HR: 1.33, 95% CI: 1.01-1.76, P = 0.041; and ≥ 75 years, HR: 1.11, 95% CI: 0.87-1.41, P = 0.394). SYNTAX-score tertiles were useful to stratify 1-year mortality in both, patients < 75 years (SYNTAX-score < 9, 3.8%; 9-20, 5.3%; ≥ 20, 10.3%; P = 0.004) and ≥ 75 years (SYNTAX-score < 11, 5.7%; 11-22.5, 16.1%; ≥ 22.5, 18.7%; P = 0.003), but two-year mortality only among patients < 75 years (SYNTAX-score < 9, 6.5%; 9-20, 7.6%; ≥ 20, 15%; P < 0.001) and not among ≥ 75 years old patients (SYNTAX-score < 11, 19.4%; 11-22.5, 26.3%; ≥ 22.5, 27.9%; P = 0.138)., Conclusions: Age modifies the impact of the SYNTAX-score on longer-term mortality after PCI. Among patients < 75 years, the SYNTAX-score independently predicts the risk of death at one and two years after PCI, while among patients ≥ 75 years its predictive role is limited to the first year after PCI. Further studies are needed to evaluate the value of SYNTAX-score for selecting the most appropriate revascularization strategy among elderly patients.

The hypothalamic neurohormone oxytocin decreases food intake via largely unexplored mechanisms. We investigated the central nervous mediation of oxytocin's hypophagic effect in comparison to its impact on the processing of generalized rewards. Fifteen fasted normal-weight, young men received intranasal oxytocin (24 IU) or placebo before functional magnetic resonance imaging (fMRI) measurements of brain activity during exposure to food stimuli and a monetary incentive delay task (MID). Subsequently, ad-libitum breakfast intake was assessed. Oxytocin compared to placebo increased activity in the ventromedial prefrontal cortex, supplementary motor area, anterior cingulate, and ventrolateral prefrontal cortices in response to high- vs. low-calorie food images in the fasted state, and reduced calorie intake by 12%. During anticipation of monetary rewards, oxytocin compared to placebo augmented striatal, orbitofrontal and insular activity without altering MID performance. We conclude that during the anticipation of generalized rewards, oxytocin stimulates dopaminergic reward-processing circuits. In contrast, oxytocin restrains food intake by enhancing the activity of brain regions that exert cognitive control, while concomitantly increasing the activity of structures that process food reward value. This pattern points towards a specific role of oxytocin in the regulation of eating behaviour in humans that might be of relevance for potential clinical applications.

Aging is associated with increases in hypothalamic-pituitary-adrenal (HPA) axis activity that can predispose to metabolic and cognitive impairments. We investigated in elderly and young subjects whether intranasal insulin administration to the human brain reduces early-sleep nadir concentrations of adrenocorticotropin and cortisol, that is, indicators of baseline HPA axis activity. In within-subject comparisons, intranasal insulin (160 IU) or placebo was administered to 14 elderly (mean age 70.0 years) and 30 young (23.6 years) healthy subjects before bedtime. Sleep was polysomnographically assessed and blood samples were repeatedly collected. Elderly compared with young participants displayed increased early-sleep cortisol concentrations (p < 0.04) and reductions in slow wave and REM sleep (p < 0.001). Insulin administration reduced cortisol levels between 2300 hours and 0020 hours in the elderly (p = 0.03) but not young participants (p = 0.56; p = 0.003 for interaction). Findings indicate that central nervous insulin acts as an inhibitory signal in basal HPA axis activity regulation and suggest that intranasal insulin may normalize sleep-associated stress axis activity in older age., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

In patients with atrial fibrillation, oral anticoagulation with oral thrombin inhibitors (OTIs), in contrast to vitamin K antagonists (VKAs), associates with a modest increase in acute coronary syndromes (ACSs). Whether this observation is causatively linked to OTI treatment and, if so, whether OTI action is the result of a lower antithrombotic efficacy of OTI compared to VKA or reflects a yet undefined prothrombotic activity of OTI remain unclear. We analyzed platelet function in patients receiving OTI or dose-adapted VKA under static and flow conditions. In vivo, we studied arterial thrombosis in OTI-, VKA-, and vehicle-treated mice using carotid ligation and wire injury models. Further, we examined thrombus formation on human atherosclerotic plaque homogenates under arterial shear to address the relevance to human pathology. Under static conditions, aggregation in the presence of ristocetin was increased in OTI-treated blood, whereas platelet reactivity and aggregation to other agonists were only marginally affected. Under flow conditions, firm platelet adhesion and thrombus formation on von Willebrand factor, collagen, and human atherosclerotic plaque were increased in the presence of OTI in comparison to VKA. OTI treatment was associated with increased thrombus formation in injured carotid arteries of mice. Inhibition or ablation of GPIbα-thrombin interactions abolished the effect of OTI on thrombus formation, suggesting a mechanistic role of the platelet receptor GPIbα and its thrombin-binding site. The effect of OTI was also abrogated in the presence of aspirin. In summary, OTI treatment has prothrombotic activity that might contribute to the increase in ACS observed clinically in patients., (Copyright © 2016, American Association for the Advancement of Science.)

Insects exhibit three patterns of gas exchange: continuous (CoGE), cyclic (CGE) and discontinuous (DGE). In this work, we present the first record of a DGE in Phasmatodea and its transition to CGE and to CoGE through a thermal gradient. The rate of CO2 production (VCO2) at 10, 20 and 30°C was examined in adults of Agathemera crassa, a high-Andean phasmid of central Chile. Carbon dioxide release was recorded during 24 h with L:D cycle of 12:12 h in order to record both rest and activity periods. At rest, A. crassa showed three patterns of gas exchange, highlighting the use of DGE preferably at 10°C. As the temperature increased, the CoGE pattern was more frequent being the only pattern observed in all individuals at 30°C. During activity, patterns changed to CoGE with a significant increase in VCO2. Our results support the idea that gas exchange patterns in insects are not distinct but correspond to a continuum of responses addressed by metabolic demand and where DGE can be expressed only under an absolute state of rest. Our results support the idea that the presence of the DGE may be underestimated in other insect taxa because they may have been measured under conditions where this pattern not necessarily can be expressed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Oxytocin is an evolutionarily highly preserved neuropeptide that contributes to the regulation of social interactions including the processing of facial stimuli. We hypothesized that its improving effect on social approach behavior depends on perceived sexual features and, consequently, on sexual orientation. In 19 homosexual and 18 heterosexual healthy young men, we investigated the acute effect of intranasal oxytocin (24IU) and placebo, respectively, on the processing of social stimuli as assessed by ratings of trustworthiness, attractiveness and approachability for male and female faces. Faces were each presented with a neutral, a happy, and an angry expression, respectively. In heterosexual subjects, the effect of oxytocin administration was restricted to a decrease in ratings of trustworthiness for angry female faces (p<0.02). In contrast, in homosexual men oxytocin administration robustly increased ratings of attractiveness and approachability for male faces regardless of the facial expression (all p ≤ 0.05), as well as ratings of approachability for happy female faces (p<0.01). Results indicate that homosexual in comparison to heterosexual men display higher sensitivity to oxytocin's enhancing impact on social approach tendencies, suggesting that differences in sexual orientation imply differential oxytocinergic signaling., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The role of brain insulin signaling in the control of food intake in humans has not been thoroughly defined. We hypothesized that the hormone contributes to the postprandial regulation of appetite for palatable food, and assessed the effects on appetite and snack intake of postprandial versus fasted intranasal insulin administration to the brain in healthy women. Two groups of subjects were intranasally administered 160 IU insulin or vehicle after lunch. Two hours later, consumption of cookies of varying palatability was measured under the pretext of a taste test. In a control study, the effects of intranasal insulin administered to fasted female subjects were assessed. Compared with placebo, insulin administration in the postprandial but not in the fasted state decreased appetite as well as intake and rated palatability of chocolate chip cookies (the most palatable snack offered). In both experiments, intranasal insulin induced a slight decrease in plasma glucose but did not affect serum insulin concentrations. Data indicate that brain insulin acts as a relevant satiety signal during the postprandial period, in particular reducing the intake of highly palatable food, and impacts peripheral glucose homeostasis. Postprandial intranasal insulin administration might be useful in curtailing overconsumption of snacks with accentuated rewarding value.