Clinical correlates and prognostic impact of neurologic disorders in Takotsubo syndrome

Cardiac alterations are frequently observed after acute neurological disorders. Takotsubo syndrome (TTS) represents an acute heart failure syndrome and is increasingly recognized as part of the spectrum of cardiac complications observed after neurological disorders. A systematic investigation of TTS patients with neurological disorders has not been conducted yet. The aim of the study was to expand insights regarding neurological disease entities triggering TTS and to investigate the clinical profile and outcomes of TTS patients after primary neurological disorders. The International Takotsubo Registry is an observational multicenter collaborative effort of 45 centers in 14 countries (ClinicalTrials.gov, identifier NCT01947621). All patients in the registry fulfilled International Takotsubo Diagnostic Criteria. For the present study, patients were included if complete information on acute neurological disorders were available. 2402 patients in whom complete information on acute neurological status were available were analyzed. In 161 patients (6.7%) an acute neurological disorder was identified as the preceding triggering factor. The most common neurological disorders were seizures, intracranial hemorrhage, and ischemic stroke. Time from neurological symptoms to TTS diagnosis was <= 2 days in 87.3% of cases. TTS patients with neurological disorders were younger, had a lower female predominance, fewer cardiac symptoms, lower left ventricular ejection fraction, and higher levels of cardiac biomarkers. TTS patients with neurological disorders had a 3.2-fold increased odds of in-hospital mortality compared to TTS patients without neurological disorders. In this large-scale study, 1 out of 15 TTS patients had an acute neurological condition as the underlying triggering factor. Our data emphasize that a wide spectrum of neurological diseases ranging from benign to life-threatening encompass TTS. The high rates of adverse events highlight the need for clinical awareness

Synthesis of titanate nanostructures using amorphous precursor material and their adsorption/photocatalytic properties

This paper reports on a new and swift hydrothermal chemical route to prepare titanate nanostructures (TNS) avoiding the use of crystalline TiO2 as starting material. The synthesis approach uses a commercial solution of TiCl3 as titanium source to prepare an amorphous precursor, circumventing the use of hazardous chemical compounds. The influence of the reaction temperature and dwell autoclave time on the structure and morphology of the synthesised materials was studied. Homogeneous titanate nanotubes with a high length/diameter aspect ratio were synthesised at 160^{\circ}C and 24 h. A band gap of 3.06\pm0.03 eV was determined for the TNS samples prepared in these experimental conditions. This value is red shifted by 0.14 eV compared to the band gap value usually reported for the TiO2 anatase. Moreover, such samples show better adsorption capacity and photocatalytic performance on the dye rhodamine 6G (R6G) photodegradation process than TiO2 nanoparticles. A 98% reduction of the R6G concentration was achieved after 45 minutes of irradiation of a 10 ppm dye aqueous solution and 1 g/L of TNS catalyst.Comment: 29 pages, 10 figures, accepted for publication in Journal of Materials Scienc

Circadian pacemaker coupling by multi-peptidergic neurons in the cockroach Leucophaea maderae

Lesion and transplantation studies in the cockroach, Leucophaea maderae, have located its bilaterally symmetric circadian pacemakers necessary for driving circadian locomotor activity rhythms to the accessory medulla of the optic lobes. The accessory medulla comprises a network of peptidergic neurons, including pigment-dispersing factor (PDF)-expressing presumptive circadian pacemaker cells. At least three of the PDF-expressing neurons directly connect the two accessory medullae, apparently as a circadian coupling pathway. Here, the PDF-expressing circadian coupling pathways were examined for peptide colocalization by tracer experiments and double-label immunohistochemistry with antisera against PDF, FMRFamide, and Asn13-orcokinin. A fourth group of contralaterally projecting medulla neurons was identified, additional to the three known groups. Group one of the contralaterally projecting medulla neurons contained up to four PDF-expressing cells. Of these, three medium-sized PDF-immunoreactive neurons coexpressed FMRFamide and Asn13-orcokinin immunoreactivity. However, the contralaterally projecting largest PDF neuron showed no further peptide colocalization, as was also the case for the other large PDF-expressing medulla cells, allowing the easy identification of this cell group. Although two-thirds of all PDF-expressing medulla neurons coexpressed FMRFamide and orcokinin immunoreactivity in their somata, colocalization of PDF and FMRFamide immunoreactivity was observed in only a few termination sites. Colocalization of PDF and orcokinin immunoreactivity was never observed in any of the terminals or optic commissures. We suggest that circadian pacemaker cells employ axonal peptide sorting to phase-control physiological processes at specific times of the day

Cardiomyocyte injury following acute ischemic stroke: protocol for a prospective observational cohort study

BACKGROUND: Elevated cardiac troponin, which indicates cardiomyocyte injury, is common after acute ischemic stroke and is associated with poor functional outcome. Myocardial injury is part of a broad spectrum of cardiac complications that may occur after acute ischemic stroke. Previous studies have shown that in most patients, the underlying mechanism of stroke-associated myocardial injury may not be a concomitant acute coronary syndrome. Evidence from animal research and clinical and neuroimaging studies suggest that functional and structural alterations in the central autonomic network leading to stress-mediated neurocardiogenic injury may be a key underlying mechanism (ie, stroke-heart syndrome). However, the exact pathophysiological cascade remains unclear, and the diagnostic and therapeutic implications are unknown. OBJECTIVE: The aim of this CORONA-IS (Cardiomyocyte injury following Acute Ischemic Stroke) study is to quantify autonomic dysfunction and to decipher downstream cardiac mechanisms leading to myocardial injury after acute ischemic stroke. METHODS: In this prospective, observational, single-center cohort study, 300 patients with acute ischemic stroke, confirmed via cerebral magnetic resonance imaging (MRI) and presenting within 48 hours of symptom onset, will be recruited during in-hospital stay. On the basis of high-sensitivity cardiac troponin levels and corresponding to the fourth universal definition of myocardial infarction, 3 groups are defined (ie, no myocardial injury [no cardiac troponin elevation], chronic myocardial injury [stable elevation], and acute myocardial injury [dynamic rise/fall pattern]). Each group will include approximately 100 patients. Study patients will receive routine diagnostic care. In addition, they will receive 3 Tesla cardiovascular MRI and transthoracic echocardiography within 5 days of symptom onset to provide myocardial tissue characterization and assess cardiac function, 20-min high-resolution electrocardiogram for analysis of cardiac autonomic function, and extensive biobanking. A follow-up for cardiovascular events will be conducted 3 and 12 months after inclusion. RESULTS: After a 4-month pilot phase, recruitment began in April 2019. We estimate a recruitment period of approximately 3 years to include 300 patients with a complete cardiovascular MRI protocol. CONCLUSIONS: Stroke-associated myocardial injury is a common and relevant complication. Our study has the potential to provide a better mechanistic understanding of heart and brain interactions in the setting of acute stroke. Thus, it is essential to develop algorithms for recognizing patients at risk and to refine diagnostic and therapeutic procedures. TRIAL REGISTRATION: Clinicaltrials.gov NCT03892226; https://www.clinicaltrials.gov/ct2/show/NCT03892226. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/2418

WldS requires Nmnat1 enzymatic activity and N16–VCP interactions to suppress Wallerian degeneration

Slow Wallerian degeneration (WldS) encodes a chimeric Ube4b/nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) fusion protein that potently suppresses Wallerian degeneration, but the mechanistic action of WldS remains controversial. In this study, we characterize WldS-mediated axon protection in vivo using Drosophila melanogaster. We show that Nmnat1 can protect severed axons from autodestruction but at levels significantly lower than WldS, and enzyme-dead versions of Nmnat1 and WldS exhibit severely reduced axon-protective function. Interestingly, a 16–amino acid N-terminal domain of WldS (termed N16) accounts for the differences in axon-sparing activity between WldS and Nmnat1, and N16-dependent enhancement of Nmnat1-protective activity in WldS requires the N16-binding protein valosin-containing protein (VCP)/TER94. Thus, WldS-mediated suppression of Wallerian degeneration results from VCP–N16 interactions and Nmnat1 activity converging in vivo. Surprisingly, mouse Nmnat3, a mitochondrial Nmnat enzyme that localizes to the cytoplasm in Drosophila cells, protects severed axons at levels indistinguishable from WldS. Thus, nuclear Nmnat activity does not appear to be essential for WldS-like axon protection

Myocardial injury in patients with acute ischemic stroke detected by cardiovascular magnetic resonance imaging

BACKGROUND: Patients with acute ischemic stroke (AIS) are at high risk of adverse cardiovascular events. Until now, the burden of myocardial injury derived from cardiovascular magnetic resonance imaging (CMR) has not been established in this population. METHODS: Patients with AIS underwent CMR at 3 Tesla within 120 h after the index stroke as part of a prospective, single-center study. Patients with persistent atrial fibrillation were excluded. Morphology and function of both cardiac chambers and atria were assessed applying SSFP cine. Myocardial tissue differentiation was based on native and contrast-enhanced imaging including late gadolinium enhancement (LGE) after 0.15 mmol/kg gadobutrol for focal fibrosis and parametric T2- and T1-mapping for diffuse findings. To detect myocardial deformation global longitudinal (GLS), circumferential (GCS) and radial (GRS) strain was measured applying feature tracking. Cardiac troponin was measured using a high-sensitivity assay (99th percentile upper reference limit 14 ng/L). T2 mapping values were compared with 20 healthy volunteers. RESULTS: CMR with contrast media was successfully performed in 92 of 115 patients (mean age 74 years, 40% female, known myocardial infarction 6%). Focal myocardial fibrosis (LGE) was detected in 31 of 92 patients (34%) of whom 23/31 (74%) showed an ischemic pattern. Patients with LGE were more likely to have diabetes, prior myocardial infarction, prior ischemic stroke, and to have elevated troponin levels compared to those without. Presence of LGE was accompanied by diffuse fibrosis (increased T1 native values) even in remote cardiac areas as well as reduced global radial, circumferential and longitudinal strain values. In 14/31 (45%) of all patients with LGE increased T2-mapping values were detectable. CONCLUSIONS: More than one-third of patients with AIS have evidence of focal myocardial fibrosis on CMR. Nearly half of these changes may have acute or subacute onset. These findings are accompanied by diffuse myocardial changes and reduced myocardial deformation. Further studies, ideally with serial CMR measurements during follow-up, are required to establish the impact of these findings on long-term prognosis after AIS

Hungarian Marfan family with large FBN1 deletion calls attention to copy number variation detection in the current NGS era

Copy number variations (CNVs) comprise about 10% of reported disease-causing mutations in Mendelian disorders. Nevertheless, pathogenic CNVs may have been under-detected due to the lack or insufficient use of appropriate detection methods. In this report, on the example of the diagnostic odyssey of a patient with Marfan syndrome (MFS) harboring a hitherto unreported 32-kb FBN1 deletion, we highlight the need for and the feasibility of testing for CNVs (>1 kb) in Mendelian disorders in the current next-generation sequencing (NGS) era

Computational Model of the Insect Pheromone Transduction Cascade

A biophysical model of receptor potential generation in the male moth olfactory receptor neuron is presented. It takes into account all pre-effector processes—the translocation of pheromone molecules from air to sensillum lymph, their deactivation and interaction with the receptors, and the G-protein and effector enzyme activation—and focuses on the main post-effector processes. These processes involve the production and degradation of second messengers (IP3 and DAG), the opening and closing of a series of ionic channels (IP3-gated Ca2+ channel, DAG-gated cationic channel, Ca2+-gated Cl− channel, and Ca2+- and voltage-gated K+ channel), and Ca2+ extrusion mechanisms. The whole network is regulated by modulators (protein kinase C and Ca2+-calmodulin) that exert feedback inhibition on the effector and channels. The evolution in time of these linked chemical species and currents and the resulting membrane potentials in response to single pulse stimulation of various intensities were simulated. The unknown parameter values were fitted by comparison to the amplitude and temporal characteristics (rising and falling times) of the experimentally measured receptor potential at various pheromone doses. The model obtained captures the main features of the dose–response curves: the wide dynamic range of six decades with the same amplitudes as the experimental data, the short rising time, and the long falling time. It also reproduces the second messenger kinetics. It suggests that the two main types of depolarizing ionic channels play different roles at low and high pheromone concentrations; the DAG-gated cationic channel plays the major role for depolarization at low concentrations, and the Ca2+-gated Cl− channel plays the major role for depolarization at middle and high concentrations. Several testable predictions are proposed, and future developments are discussed

Ultrahigh-Field MRI in Human Ischemic Stroke – a 7 Tesla Study

INTRODUCTION: Magnetic resonance imaging (MRI) using field strengths up to 3 Tesla (T) has proven to be a powerful tool for stroke diagnosis. Recently, ultrahigh-field (UHF) MRI at 7 T has shown relevant diagnostic benefits in imaging of neurological diseases, but its value for stroke imaging has not been investigated yet. We present the first evaluation of a clinically feasible stroke imaging protocol at 7 T. For comparison an established stroke imaging protocol was applied at 3 T. METHODS: In a prospective imaging study seven patients with subacute and chronic stroke were included. Imaging at 3 T was immediately followed by 7 T imaging. Both protocols included T1-weighted 3D Magnetization-Prepared Rapid-Acquired Gradient-Echo (3D-MPRAGE), T2-weighted 2D Fluid Attenuated Inversion Recovery (2D-FLAIR), T2-weighted 2D Fluid Attenuated Inversion Recovery (2D-T2-TSE), T2* weighted 2D Fast Low Angle Shot Gradient Echo (2D-HemoFLASH) and 3D Time-of-Flight angiography (3D-TOF). RESULTS: The diagnostic information relevant for clinical stroke imaging obtained at 3 T was equally available at 7 T. Higher spatial resolution at 7 T revealed more anatomical details precisely depicting ischemic lesions and periinfarct alterations. A clear benefit in anatomical resolution was also demonstrated for vessel imaging at 7 T. RF power deposition constraints induced scan time prolongation and reduced brain coverage for 2D-FLAIR, 2D-T2-TSE and 3D-TOF at 7 T versus 3 T. CONCLUSIONS: The potential of 7 T MRI for human stroke imaging is shown. Our pilot study encourages a further evaluation of the diagnostic benefit of stroke imaging at 7 T in a larger study

Towards plant-odor-related olfactory neuroethology in Drosophila

Drosophila melanogaster is today one of the three foremost models in olfactory research, paralleled only by the mouse and the nematode. In the last years, immense progress has been achieved by combining neurogenetic tools with neurophysiology, anatomy, chemistry, and behavioral assays. One of the most important tasks for a fruit fly is to find a substrate for eating and laying eggs. To perform this task the fly is dependent on olfactory cues emitted by suitable substrates as e.g. decaying fruit. In addition, in this area, considerable progress has been made during the last years, and more and more natural and behaviorally active ligands have been identified. The future challenge is to tie the progress in different fields together to give us a better understanding of how a fly really behaves. Not in a test tube, but in nature. Here, we review our present state of knowledge regarding Drosophila plant-odor-related olfactory neuroethology to provide a basis for new progress