Connecting the dots in the zona incerta: A study of neural assemblies and motifs of inter-area coordination in mice.

The zona incerta (ZI), a subthalamic area connected to numerous brain regions, has raised clinical interest because its stimulation alleviates the motor symptoms of Parkinson's disease. To explore its coordinative nature, we studied the assembly formation in a dataset of neural recordings in mice and quantified the degree of functional coordination of ZI with other 24 brain areas. We found that the ZI is a highly integrative area. The analysis in terms of "loop-like" motifs, directional assemblies composed of three neurons spanning two areas, has revealed reciprocal functional interactions with reentrant signals that, in most cases, start and end with the activation of ZI units. In support of its proposed integrative role, we found that almost one-third of the ZI's neurons formed assemblies with more than half of the other recorded areas and that loop-like assemblies may stand out as hyper-integrative motifs compared to other types of activation patterns.

Disentangling the identity of the zona incerta: a review of the known connections and latest implications.

The zona incerta (ZI) is a subthalamic region composed by loosely packed neurochemically mixed neurons, juxtaposed to the main ascending and descending bundles. The extreme neurochemical diversity that characterizes this area, together with the diffuseness of its connections with the entire neuraxis and its hard-to-reach positioning in the brain caused the ZI to keep its halo of mystery for over a century. However, in the last decades, a rich albeit fragmentary body of knowledge regarding both the incertal anatomical connections and functional implications has been built mostly based on rodent studies and its lack of cohesion makes difficult to depict an integrated, exhaustive picture regarding the ZI and its roles. This review aims to provide a unified resource that summarizes the current knowledge regarding the anatomical profile of interactions of the ZI in rodents and non-human primates and the functional significance of its connections, highlighting the aspects still unbeknown to research.

Massive cerebral venous sinus thrombosis in vaccine-induced immune thrombotic thrombocytopenia after ChAdOx1 nCoV-19 serum: case report of a successful multidisciplinary approach.

We report a case of massive cerebral venous sinus thrombosis in the contest of vaccine-induced immune thrombotic thrombocytopenia that required the rapid coordination of many specialists from different departments, notably emergency, neurology, neuroradiology, hematology, and neurosurgery. The patient was rapidly treated with steroids, immunoglobulin, and fondaparinux. She underwent within 6 h after hospital admission a mechanical thrombectomy in order to allow flow restoration in cerebral venous systems. Neuroendovascular treatment in cerebral venous thrombosis related to VITT has never been described before. It can represent a complementary tool along with the other therapies and a multidisciplinary approach.

Oxidized low-density lipoproteins induce tissue factor expression in T-lymphocytes via activation of lectin-like oxidized low-density lipoprotein receptor-1.

AIMS: T-lymphocytes plays an important role in the pathophysiology of acute coronary syndromes. T-cell activation in vitro by pro-inflammatory cytokines may lead to functional tissue factor (TF) expression, indicating a possible contribution of immunity to thrombosis. Oxidized low-density lipoproteins (oxLDLs) are found abundantly in atherosclerotic plaques. We aimed at evaluating the effects of oxLDLs on TF expression in T cells and the role of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). METHODS AND RESULTS: CD3+ cells were isolated from healthy volunteers. Gene, protein, and surface expression of TF, as well as of LOX-1, were assessed at different time-points after oxLDL stimulation. To determine whether oxLDL-induced TF was LOX-1 dependent, T cells were pre-incubated with an LOX-1 inhibiting peptide (L-RBP) or with an anti-LOX-1 blocking antibody. To exclude that TF expression was mediated by reactive oxygen species (ROS) generation, oxLDL-stimulated T cells were pre-incubated with superoxide dismutase + catalase or with 4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), an intracellular free radical scavenger. Finally, to determine if the observed findings in vitro may have a biological relevance, the presence of CD3+/TF+/LOX-1+ cells was evaluated by immunofluorescence in human carotid atherosclerotic lesions. oxLDLs induced functionally active TF expression in T cells in a dose- and time-dependent manner, independently on ROS generation. No effect was observed in native LDL-treated T cells. LOX-1 expression was also induced by oxLDLs in a time- and dose-dependent manner. Pre-incubation with L-RBP or anti-LOX-1 antibody almost completely inhibited oxLDL-mediated TF expression. Interestingly, human carotid plaques showed significant infiltration of CD3+ cells (mainly CD8+ cells), some of which were positive for both TF and LOX-1. CONCLUSION: oxLDLs induce functional TF expression in T-lymphocytes in vitro via interaction of oxLDLs with LOX-1. Human carotid atherosclerotic plaques contain CD3+/CD8+cells that express both TF and LOX-1, indicating that also in patients these mechanisms may play an important role.

Clinical Performance of Apixaban vs. Vitamin K Antagonists in Patients with Atrial Fibrillation Undergoing Direct Electrical Current Cardioversion: A Prospective Propensity Score-Matched Cohort Study.

INTRODUCTION: Atrial fibrillation (AF) is associated with an increased risk of thromboembolic events. OBJECTIVES: This study compared the long-term efficacy and safety of apixaban with that of uninterrupted vitamin K antagonist (VKA) therapy in patients with AF scheduled for transesophageal echocardiogram (TEE)-guided direct current cardioversion (DCC) from June 2014 to September 2016. METHODS: We enrolled consecutive patients with persistent nonvalvular AF scheduled to undergo DCC. Patients received apixaban 5 mg or 2.5 mg twice daily (bid) or VKA at therapeutic doses for at least 3 weeks before and 4 weeks after DCC. All patients underwent anamnestic, clinical, electrocardiographic, and echocardiographic evaluation at each follow-up visit and were followed-up for 12 months. The primary efficacy endpoint was the composite of stroke/transient ischemic attack and systemic embolism. The primary safety endpoint was major bleeding. RESULTS: After propensity score matching, comparative treatment groups comprised 182 (75.8%) patients receiving apixaban 5 mg bid and 182 receiving VKA. A low incidence of atrial thrombus (0.5%) at TEE was found in both groups. The acute cardioversion success rate was 86.1% in the apixaban group (156/181) and 83.9% in the VKA group (152/181). During the follow-up period, a similarly low incidence of thromboembolic events (1.1%) was reported in both groups; the bleeding safety profile tended to favor apixaban over VKA (1.1 vs. 1.6%; p = 0.3). CONCLUSIONS: Newly initiated anticoagulation with apixaban in patients with nonvalvular AF scheduled for TEE-guided DCC seems to be as effective and safe as uninterrupted VKA therapy during 12 months of follow-up.

Bachmann bundle pacing reduces atrial electromechanical delay in type 1 myotonic dystrophy patients.

BACKGROUND: Atrial electromechanical delay (AEMD) is an echocardiographic parameter correlated with the onset of supraventricular arrhythmias in several clinical conditions. Inter-atrial septal pacing in the region of Bachmann's bundle (BB) has been shown to be safe and feasible in myotonic dystrophy type 1 (DM1) patients, with a low rate of sensing and pacing defects. The aim of this study was to assess the impact of temporary BB pacing compared with right atrial appendage (RAA) pacing on AEMD in DM1 patients undergoing pacemaker (PM) implantation for cardiac rhythm abnormalities. METHODS: The study enrolled 70 consecutive DM1 patients undergoing PM implantation for cardiac rhythm abnormalities in accordance with the current guidelines. Seventy age- and sex-matched non-DM1 patients undergoing dual-chamber PM implantation for cardiac rhythm abnormalities were used as controls. The atrial pacing lead was temporarily positioned in the RAA and on the right side of the inter-atrial septum in the region of Bachmann's bundle. For each site (BB and RAA), temporary atrial pacing in the AAI mode was established at 10 beats per minute above the sinus rate and a detailed trans-thoracic echocardiogram with tissue Doppler (TDI) analysis was recorded after at least 10 min of atrial pacing to evaluate AEMD. RESULTS: Temporary RAA pacing did not show statistically significant differences in inter-AEMD (48.2 ± 17.8 vs 50.5 ± 16.5 ms; P = 0.8), intra-left AEMD (43.3 ± 15.5 vs 44.6 ± 15.8 ms; P = 0.1), or intra-right-AEMD (14.1 ± 4.2 vs 15.4 ± 5.8 ms; P = 0.9), in comparison with sinus rhythm. Temporary BB pacing determined a significantly lower inter-AEMD (36.1 ± 17.1 vs 50.5 ± 16.5 ms; P = 0.001) and intra-left AEMD (32.5 ± 15.2 vs 44.6 ± 15.8 ms; P = 0.001) values in comparison with temporary RAA pacing. No statistically significant difference was found in intra-right AEMD (12.2 ± 4.6 vs 15.4 ± 5.8 ms; P = 0.2). In the control group, neither temporary RAA pacing nor temporary BB pacing showed statistically significant differences in inter-AEMD, intra-left AEMD, or intra-right AEMD values in comparison with sinus rhythm. CONCLUSIONS: In DM1 patients undergoing dual-chamber PM implantation, atrial pacing in the Bachmann bundle region is associated with significantly lower echocardiographic indices of atrial electromechanical delay (inter-AEMD and intra-left AEMD) in comparison with RAA pacing.

Complete resolution of left atrial appendage thrombosis with oral dabigatran etexilate in a patient with Myotonic Dystrophy type 1 and atrial fibrillation.

Myotonic Dystrophy type 1 (DM1) is the most common muscular dystrophy in adult life characterized by muscle dysfunction and cardiac conduction abnormalities. Atrial fibrillation frequently occurs in DM1 patients. It's related to the discontinuous and inhomogeneous propagation of sinus impulses and to the prolongation of atrial conduction time, caused by progressive fibrosis and fatty replacement of the myocardium. AF predisposes to a hyper-coagulable state and to an increased risk of thromboembolism. We report the first case of complete resolution of left atrial appendage thrombosis with oral dabigatran etexilate in a myotonic dystrophy type I patient with atrial fibrillation scheduled for transesophageal echocardiogram-guided direct current cardioversion.

The main determinant of hypotension in nitroglycerine tilt-induced vasovagal syncope.

BACKGROUND: The aim of the study was to assess the main determinant of the fall in blood pressure (BP) responsible for the head-up tilt testing-induced syncope. METHODS AND RESULTS: The study involved 200 patients (mean age 42 ± 3; 81 male) with syncope of unknown origin after the first evaluation. According to the response to the diagnostic tilt test, the population study was divided into four groups: Group I with mixed vasovagal syncope; Group II with cardioinhibitory syncope; Group III with vasodepressive syncope; Group IV: 40 patients with clinical syncope but no tilt-induced syncope. Finger arterial BP (Portapres, TNO, Amsterdam, the Netherlands) was recorded during tilt testing. Left ventricular stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were computed from the pressure pulsations (Modelflow, TNO, Amsterdam, the Netherlands). During syncopal phase, the TPR decreased significantly in Group III, and increased in Group I and in Group II. CO decreased in Group I and in Group II and did not change significantly in Group III. SV decreased significantly in all groups. CONCLUSIONS: Our data showed that the arterial system appears to be the main determinant of the BP fall in vasodepressive vasovagal syncope; while the impaired constrictive response of the venous system, leading to reduced venous return to the heart, appears to be the main determinant of BP fall in mixed and cardioinhibitory vasovagal syncope.

Does Bachmann's bundle pacing prevent atrial fibrillation in myotonic dystrophy type 1 patients? A 12 months follow-up study.

AIMS: Paroxysmal atrial arrhythmias occur in myotonic dystrophy type 1 (MD1) patients frequently. Pacemaker (PM) including detailed diagnostic functions may facilitate the diagnosis and management of frequent paroxysmal atrial tachyarrhythmias that may remain undetected during conventional clinical follow-up. Aim of our study was to evaluate the preventive effects of interatrial septum pacing in the Bachmann's Bundle region on atrial fibrillation (AF) in MD1 patients during 12 months follow up period. METHODS AND RESULTS: Thirty MD1 patients (age 50.3 +/- 7.3; 11 F) who underwent dual chamber PM implantation were randomized at implantation to receive right atrial appendage pacing (16 patients) or Bachmann's bundle pacing (14 patients). No statistically significant difference in the electrical parameters (P wave amplitude, pacing threshold and lead impedance) was found between the two groups at implantation. Patients were followed at 1 month, 3 months, and every 6 months thereafter. They underwent clinical assessment, a standard 12-lead ECG and assessment of device performance at every visit. We counted the number of episodes of atrial arrhythmia occurred during the collection period and the duration of each episode. At 12 months of follow-up, no statistically significant differences in the number of AF episodes or in AF duration were found. Lead parameters remained stable over time and there were no displacements of the electrodes after implantation. CONCLUSION: Implantation of an atrial-active fixation lead on the atrial septum is safe and feasible. However, this study showed no significant difference between septal pacing and high atrial pacing, using the endpoints of AF duration and number of AF episodes.

Right atrial appendage versus Bachmann's bundle stimulation: a two-year comparative study of electrical parameters in myotonic dystrophy type-1 patients.

AIM: We performed a two-year follow-up comparative study of long-term electrical parameters between the right atrial appendage (RAA) and Bachmann's Bundle (BB) stimulation in myotonic dystrophy type 1 (MD1) patients. METHODS: Twenty-five MD1 patients (18 men; age: 54 +/- 13 years) with no difference in the electrical parameters between the RAA site and the BB region at implantation were randomized into two groups: in group I (13 patients; age: 52 +/- 14 years; four women) the atrial lead was placed in the RAA and in group II (12 patients, age: 56 +/- 12 years, three women) the lead was placed in the BB region. Measurements of electrical parameters were recorded at follow-up intervals of 6 weeks and then 12 and 24 months postimplant. RESULTS: There was no statistically significant different in P-wave amplitude, pacing threshold, and impedance values between the two groups at 6 weeks. At 24 months follow-up, the intrinsic P-wave amplitude was 2.05 +/- 1.45 mV in the RAA group versus 3.28 +/- 1.09 mV in the BB group (P < 0.05); the pacing threshold was 1.85 +/- 1.8 V in the RAA group versus 0.50 +/- 0.39 V in the BB group (P = 0.03); there were no differences in the atrial impedance between the two groups during the follow-up period. CONCLUSIONS: In a direct two-year follow-up comparison between the RAA and BB atrial pacing sites, we showed a statistically significant increased pacing threshold and decreased intrinsic P-wave amplitude during RAA stimulation in MD1 patients.