Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells.

BACKGROUND: Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA's role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. METHODS: We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. RESULTS: The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. CONCLUSIONS: AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe condition with a high mortality rate despite advances in diagnostic and therapeutic strategies. In recent years, significant scientific progress has been made in the understanding of the underlying pathobiological mechanisms. Since current available treatments mainly target pulmonary vasodilation, but lack an effect on the pathological changes that develop in the pulmonary vasculature, there is need to develop novel therapeutic compounds aimed at antagonizing the pulmonary vascular remodeling. This review presents the main molecular mechanisms involved in the pathobiology of PAH, discusses the new molecular compounds currently being developed for the medical treatment of PAH and assesses their potential future role in the therapeutic algorithms of PAH.

Dysregulated lipid metabolism in hepatocellular carcinoma cancer stem cells.

According to the stem cell theory for cancer, hepatocellular carcinomas are sustained by a group of cancer stem cells (CSCs) which are responsible for resistance to chemotherapy. In the present study we aimed to examine lipid metabolism in cancer stem cells induced by long-term treatment with sorafenib and its relationship with acquisition of a CSC-like phenotype. Two cell lines (HepG2SF1 and Huh7SF1) were generated by incubation with a step-wise increase of sorafenib concentrations for 10 months. These cell lines displayed stem-like characteristics like increase in the expression of ABCB1A, Nanog and Oct4 as well as an E-cadherin/N-cadherin switch. HepG2SF1 and Huh7SF1 cells showed intracellular accumulation of neutral lipids, assessed by flow cytometry and confocal microscopy. The exam of lipid metabolism revealed that HepG2SF1 and Huh7SF1 cells increased the expression of the enzymes involved in de novo lipid synthesis ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) and that of the fatty acid transporter CD36. In addition, these CSC-like cells had enhanced expression of the lipogenic transcription factor SREBP1c. Analysis of the key metabolic sensor AMP-activated kinase (AMPK) demonstrated that both AMPK phosphorylation and levels were decreased in the CSC-like cells compared to their parental cells. Interestingly, transfection of HepG2SF1 and Huh7SF1 cells with AMPK, restored the levels of the lipogenic enzymes and SREBP1c and decreased the intracellular lipid accumulation. Furthermore, AMPK transfection decreased the stemness markers and inhibited the E-cadherin/N-cadherin switch. Targeting AMPK and lipid metabolism of hepatocellular cancer stem cells is a promising strategy to face stemness and chemotherapy resistance.

Targeting the anion exchanger 2 with specific peptides as a new therapeutic approach in B lymphoid neoplasms.

Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears to be a promising therapeutic approach in cancer patients. Mice with targeted deletion of the gene encoding the Cl-/HCO3- anion exchanger AE2 (also termed SLC4A2), a membrane-bound carrier involved in intracellular pH regulation, showed a progressive decrease in the number of Treg cells. We therefore challenged AE2 as a potential target for tumor therapy, and generated linear peptides designed to bind the third extracellular loop of AE2, which is crucial for its exchange activity. Peptide p17AE2 exhibited optimal interaction ability and indeed promoted apoptosis in mouse and human Treg cells, while activating effector T-cell function. Interestingly, this linear peptide also induced apoptosis in different types of human leukemia, lymphoma and multiple myeloma cell lines and primary malignant samples, while it showed only moderate effects on normal B lymphocytes. Finally, a macrocyclic AE2 targeting peptide exhibiting increased stability in vivo was effective in mice xenografted with B-cell lymphoma. These data suggest that targeting the anion exchanger AE2 with specific peptides may represent an effective therapeutic approach in B-cell malignancies.

Two Affinity Sites of the Cannabinoid Subtype 2 Receptor Identified by a Novel Homogeneous Binding Assay.

Endocannabinoids act on G protein-coupled receptors that are considered potential targets for a variety of diseases. There are two different cannabinoid receptor types: ligands for cannabinoid type 2 receptors (CB2Rs) show more promise than those for cannabinoid type 1 receptors (CB1Rs) because they lack psychotropic actions. However, the complex pharmacology of these receptors, coupled with the lipophilic nature of ligands, is delaying the translational success of medications targeting the endocannabinoid system. We here report the discovery and synthesis of a fluorophore-conjugated CB2R-selective compound, CM-157 (3-[[4-[2-tert-butyl-1-(tetrahydropyran-4-ylmethyl)benzimidazol-5-yl]sulfonyl-2-pyridyl]oxy]propan-1-amine), which was useful for pharmacological characterization of CB2R by using a time-resolved fluorescence resonance energy transfer assay. This methodology does not require radiolabeled compounds and may be undertaken in homogeneous conditions and in living cells (i.e., without the need to isolate receptor-containing membranes). The affinity of the labeled compound was similar to that of the unlabeled molecule. Time-resolved fluorescence resonance energy transfer assays disclosed a previously unreported second affinity site and showed conformational changes in CB2R forming receptor heteromers with G protein-coupled receptor GPR55, a receptor for l-α-lysophosphatidylinositol. The populations displaying subnanomolar and nanomolar affinities were undisclosed in competitive assays using a well known cannabinoid receptor ligand, AM630 (1-[2-(morpholin-4-yl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-6-iodoindole), and TH-chrysenediol, not previously tested on binding to cannabinoid receptors. Variations in binding parameters upon formation of dimers with GPR55 may reflect decreases in binding sites or alterations of the quaternary structure of the macromolecular G protein-coupled receptor complexes. In summary, the homogeneous binding assay described here may serve to better characterize agonist binding to CB2R and to identify specific properties of CB2R on living cells.

Harnessing quinone methides: total synthesis of (±)-vaticanol†A.

Although quinone methides are often postulated as intermediates in the biosynthesis of many polyphenolic natural products, deploying their power in a laboratory setting to achieve similar bond constructions has sometimes proven challenging. Herein, a total synthesis of the resveratrol trimer vaticanol A has been achieved through three instances of quinone methide chemistry. These operations, one of which succeeded only under very specific conditions, expediently generated its [7,5]-carbocyclic core, afforded a unique sequence for dihydrobenzofuran formation, and concurrently generated, in addition to the target molecule, a series of diastereomers reflective of many other isolates.

Triple vasodilator therapy in pulmonary arterial hypertension associated with congenital heart disease.

OBJECTIVE: This study assessed the long-term effects of triple therapy with prostanoids on patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), as there is limited information on the safety and efficacy of this treatment approach. METHODS: A retrospective cohort study was conducted on patients with PAH-CHD who were actively followed up at our centre. All patients were already receiving dual combination therapy at maximum doses. Clinical characteristics, including functional class (FC), 6-minute walking test distance (6MWTD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, were documented before initiating triple therapy and annually for a 2-year follow-up period. RESULTS: A total of 60 patients were included in the study, with a median age of 41 years and 68% being women. Of these, 32 had Eisenmenger syndrome, 9 had coincidental shunts, 18 had postoperative PAH and 1 had a significant left-to-right shunt. After 1 year of triple combination initiation, a significant improvement in 6MWTD was observed (406 vs 450; p=0.0027), which was maintained at the 2-year follow-up. FC improved in 79% of patients at 1 year and remained stable in 76% at 2 years. NT-proBNP levels decreased significantly by 2 years, with an average reduction of 199 ng/L. Side effects were experienced by 33.3% of patients but were mostly mild and manageable. Subgroup analysis showed greater benefits in patients without Eisenmenger syndrome and those with pre-tricuspid defects. CONCLUSIONS: Triple therapy with prostanoids is safe and effective for patients with PAH-CHD, improving FC, 6MWTD and NT-proBNP levels over 2 years. The treatment is particularly beneficial for patients with pre-tricuspid defects and non-Eisenmenger PAH-CHD.

One-year longitudinal changes of peripheral CD4+ T-lymphocyte counts, gut microbiome, and plaque vulnerability after an acute coronary syndrome.

Background: Longitudinal changes in gut microbiome and inflammation may be involved in the evolution of atherosclerosis after an acute coronary syndrome (ACS). We aimed to characterize repeated profiles of gut microbiota and peripheral CD4+ T lymphocytes during the first year after an ACS, and to address their relationship with atherosclerotic plaque changes. Methods: Over one year we measured the microbiome, peripheral counts of CD4+ T populations and cytokines in 67 patients shortly after a first ACS. We compared baseline measurements to those of a matched population of 40 chronic patients. A subgroup of 20 ACS patients underwent repeated assessment of fibrous cap thickness (FCT) of a non-culprit lesion. Results: At admission, ACS patients showed gut dysbiosis compared with the chronic group, which was rapidly reduced and remained low at 1-year. Also, their Th1 and Th2 CD4+ T counts were increased but decreased over time. The CD4+ T counts were related to ongoing changes in gut microbiome. Unsupervised clustering of repeated CD4+ Th0, Th1, Th2, Th17 and Treg counts in ACS patients identified two different cell trajectory patterns, related to cytokines. The group of patients following a high-CD4+ T cell trajectory showed a one-year reduction in their FCT [net effect = -24.2 µm; p = 0.016]. Conclusions: Patients suffering an ACS show altered profiles of microbiome and systemic inflammation that tend to mimic values of chronic patients after 1-year. However, in one-third of patients, this inflammatory state remains particularly dysregulated. This persistent inflammation is likely related to plaque vulnerability as evident by fibrous cap thinning (Clinical Trial NCT03434483).

Prognostic implications of atrial fibrillation in adults with Ebstein anomaly.

OBJECTIVE: Supraventricular arrhythmias are common in adults with Ebstein anomaly (EA). However, there are limited data about prognostic implications of atrial fibrillation (AF) in this population. Accordingly, our aim was to assess the clinical profile and burden of AF in adults with EA, and the relationship between AF and outcomes. METHODS AND RESULTS: Six hundred eighty-two consecutive adults with a median age of 36 (24-49) years from Mayo Clinic, Minnesota, USA, between 2003 and 2020 were included. Sustained episodes of AF, clinical, echocardiographic, rhythm and surgical data were collected. Prevalence of AF at baseline was 18% (126 patients); the first episode occurred at a mean age of 43±17 years. Patients with AF were older, were more likely men, and had hypertension, renal dysfunction, cardiac devices, and more advanced right-sided and left-sided remodelling. During a median follow-up of 156 (81-240) months, 62 patients (11%) developed incident AF. At the last encounter, prevalence of AF was 28% (188 patients); of those, 63 (34%) had recurrent AF. Hospitalisation for heart failure (HF) occurred in 51 patients (7%). AF (HR 2.32, 95% CI 1.18 to 4.47; p=0.01) was independently associated with hospitalisation for HF. All-cause death occurred in 53 patients (8%); it was more frequent in those with AF in the univariable analysis, although it did not remain significant in the multivariable analysis. CONCLUSIONS: AF in EA develops at relatively young ages with one-third of the cohort exhibiting a recurrent pattern. Patients with AF had a higher prevalence of comorbidities and worse right-sided and left-sided cardiac remodelling. AF was independently associated with HF hospitalisation.

Haemodynamic and prognostic associations of liver fibrosis scores in Fontan-associated liver disease.

OBJECTIVES: Fontan-associated liver disease (FALD) is universal post-Fontan palliation; however, its impact on survival remains controversial and current diagnostic tools have limitations. We aimed to assess the prognostic role of liver fibrosis scores (aminotransferase to platelet ratio [APRI] and fibrosis-4 [FIB-4]) and their association with haemodynamics and other markers of liver disease. METHODS: 159 adults (age ≥18 years) post-Fontan undergoing catheterisation at Mayo Clinic, Minnesota, between 1999 and 2017 were included. Invasive haemodynamics and FALD-related laboratory, imaging and pathology data were documented. RESULTS: Mean age was 31.5±9.3 years, while median age at Fontan procedure was 7.5 years (4-14). Median APRI score (n=159) was 0.49 (0.33-0.61) and median FIB-4 score (n=94) was 1.12 (0.71-1.65). Correlations between APRI and FIB-4 scores and Fontan pressures (r=0.30, p=0.0002; r=0.34, p=0.0008, respectively) and pulmonary arterial wedge pressure (r=0.25, p=0.002; r=0.30, p=0.005, respectively) were weak. Median average hepatic stiffness by magnetic resonance elastography was 4.9 kPa (4.3-6.0; n=26) and 24 (77.4%) showed stage 3 or 4 liver fibrosis on biopsy; these variables were not associated with APRI/FIB-4 scores. On multivariable analyses, APRI and FIB-4 scores were independently associated with overall mortality (HR 1.31 [1.07-1.55] per unit increase, p=0.003; HR 2.15 [1.31-3.54] per unit increase, p=0.003, respectively). CONCLUSIONS: APRI and FIB-4 scores were associated with long-term all-cause mortality in Fontan patients independent of other prognostic markers. Correlations between haemodynamic status and liver scores were weak; furthermore, most markers of liver fibrosis failed to correlate with non-invasive indices, underscoring the complexity of FALD.

Takotsubo Syndrome, Stressful Triggers, and Risk of Recurrence.

The risk of recurrence in takotsubo syndrome (TTS) appears to be low, although previous studies have shown conflicting results and factors associated with recurrences are unclear. The aim of this study is to evaluate the incidence and predictors of TTS recurrences. Adult patients included in the Spanish Multicenter REgistry of TAKOtsubo syndrome (RETAKO) between January 2003 and September 2019 were identified. Patients were categorized based on recurrences during follow-up and a multivariate logistic regression model was used to identify factors associated with recurrences. A total of 1097 patients (mean age 71.0±11.9 years, 87% females) were included, repeated TTS events were documented in 44 patients (4.0%), including 13 patients with prior TTS and 31 patients with recurrent TTS during a median follow-up of 279 days. Two patients (0.02%) had two episodes of recurrence. Compared to patients who had no recurrence of TTS, those with recurrent TTS more frequently had no identifiable stressful trigger in the index admission (20 [64.5%] vs 352 [33.0%], p <0.001). Primary TTS, defined as TTS without physical trigger, was also more common in the recurrence group (93.5% vs 68.3%, p <0.001). The only factor independently associated with recurrences was the absence of an identifiable trigger (odds ratio 3.7 [95% confidence interval 1.8-7.8], p=0.001). In conclusion, our data indicate that for patients presenting with TTS, the rate of early recurrent TTS is approximately 4% per year. Among TTS patients, those who have no identifiable trigger events appear to have a higher rate of recurrence.

Surgical Repair of Truncus Arteriosus: A Long-Term Hemodynamic Assessment.

Background: Unrepaired truncus arteriosus (TA) carries poor prognosis due to complications of unrestricted pulmonary flow, truncal valve insufficiency, and pulmonary vascular disease. Currently, the hemodynamic profile of adults late after TA repair is unknown. We reviewed the hemodynamics, prevalence, and pathophysiology of pulmonary hypertension (PH) in this population. Methods: Eighteen adult patients with repaired TA who underwent cardiac catheterization at Mayo Clinic, MN, between 1997 and 2021 were identified. PH was defined as either precapillary (mean pulmonary artery pressure [mPAP] ≥25 mm Hg, pulmonary artery wedge pressure [PAWP] ≤15 mm Hg, and pulmonary vascular resistance [PVR] >3 Wood units), isolated postcapillary (mPAP ≥25, PAWP >15, PVR ≤3), or combined (mPAP ≥25, PAWP >15, and PVR >3). Diastolic pressure and transpulmonary gradients were used as ancillary data for classification. Results: Mean age at catheterization was 34 ± 10 years. Mean right ventricular (RV) systolic pressure was 82 ± 22.6 mm Hg, mean right and left mPAPs 28.1 ± 16.2 and 27.9 ± 11.9 mm Hg, respectively. Seven patients (41.2%) had PAWP >15 mm Hg and, among those undergoing arterial catheterization, 7 (53.8%) had a left ventricular (LV) end-diastolic pressure >15 mm Hg. PH was diagnosed in 13 patients (72.2%): 6 (33.3%) precapillary, 4 (22.2%) isolated postcapillary, and 3 (16.7%) combined. PAWP >15 mm Hg was associated with male sex (P = .049),

Risk Factors for Atrial Arrhythmias in Adults With Ebstein Anomaly.

Background: Atrial arrhythmias (AA) are common in Ebstein anomaly (EA), but risk factors associated with AA are not well understood. Objectives: The purpose of this study was to determine the prevalence and risk factors for AA at baseline, incidence, and risk factors for AA during follow-up. Methods: Adults with EA receiving care at Mayo Clinic, MN, between 2003 and 2020 were included. AA was defined as atrial fibrillation (AF) or atrial flutter/tachycardia (AFL). Clinical, echocardiographic, rhythm, surgical data were collected. Results: Of 682 patients (aged 36 [24-49] years), 235 (34%) had AA at baseline (126 [18%] AF and 144 [21%] AFL), and the risk factors for AA were age, left and right atrial volume indexes, and reservoir strain. Among 447 patients without AA, 10-year cumulative incidence of AF and AFL was 16% and 22%, respectively. The risk factors for incident AF were older age and right atrial reservoir strain. The risk factors for incident AFL were atrial septal defect, left atrial volume index, and male sex. Among patients with baseline AA, 129 (40%) had recurrent episodes (AF 63 [20%], AFL 78 [24%]). The 5-year recurrence rate of AA was 34%, without significant difference for AF vs AFL (46% vs 27%, P = 0.081). Older age and right atrial reservoir strain were associated with recurrent AF. Conclusions: Patients with EA are at risk for incident and recurrent AA. AF was almost as common as AFL despite relatively young ages. Echocardiographic indexes of atrial function can identify at-risk patients, hence be used to improve risk stratification and guide therapy.

Antiplatelet therapy at discharge and long-term prognosis in Takotsubo syndrome: Insights from the Spanish National Registry (RETAKO).

INTRODUCTION: Endothelial dysfunction and platelet activation have been highlighted as possible mediators in Takotsubo syndrome (TTS). Nevertheless, to date, evidence on the usefulness of antiplatelet therapy in TTS remains controversial. The aim of our study is to evaluate long-term prognosis in TTS patients treated with antiplatelet therapy (APT) at hospitalization discharge. MATERIAL AND METHODS: An ambispective cohort study from the Spanish National Takotsubo Registry database was performed (June 2002 to March 2017). Patients were divided into two groups: those who received APT at hospital discharge (APT cohort) and those who did not (non-APT cohort). Primary endpoint was all-cause death. Secondary endpoints included the composite of recurrence or readmission and a composite of death, recurrence or readmission. RESULTS: From a total of 741 patients, 728 patients were alive at discharge. Follow-up was performed in 544 patients, who were included in the final analysis: 321 patients (59.0%) in the APT cohort and 223 patients (41.0%) in the non-APT cohort. The APT cohort had a better clinical presentation and received more heart failure and acute coronary syndrome-like therapies (angiotensin converting enzyme inhibitors/angiotensin receptor blockers: 75.1% vs. 51.1%; p<0.001, betablockers: 71.3% vs. 50.7%; p<0.001, statins: 67.9% vs. 33.2%; p<0.001). After adjusting for confounder factors, APT at discharge was a protective factor for all-cause death (adjusted hazard ratio (HR) 0.315, 95% confidence interval (CI): 0.106-0.943; p=0.039) and the composite endpoint of all-cause death, recurrence or readmission (adjusted HR 0.318, 95% CI: 0.164-0.619; p=0.001) at month 25 of follow-up. CONCLUSION: Patients with TTS receiving APT at discharge presented better prognosis up to two-years of follow-up compared with their counterparts not receiving APT.

Differences Between Takotsubo and the Working Diagnosis of Myocardial Infarction With Nonobstructive Coronary Arteries.

Aim: Whether Takotsubo syndrome (TTS) should be classified within myocardial infarction with non-obstructive coronary arteries (MINOCAs) is still controversial. The aim of this work was to evaluate the main differences between TTS and non-TTS MINOCAs. Methods and Results: A cohort study based on two prospective registries: TTS from the RETAKO registry (N:1,015) and patients with non-TTS MINOCAs from contemporary records of acute myocardial infarction from five 5 national centers (N:1,080). Definitions and management recommended by the ESC were used. Survival analysis was based on the Cox regression analysis; propensity score matching (PS) was created to adjust prognostic variables. Takotsubo syndrome were more often women (85.9 vs. 51.9%; p < 0.001) and older (69.4 ± 12.5 vs. 64.5 ± 14.1 years; p < 0.001). Atrial fibrillation (AF) was more frequent in non-TTS MINOCAs (10.4 vs. 14.4%; p = 0.007). Psychiatric disorders were more prevalent in TTS (15.5 vs. 10.2%, p < 0.001). In-hospital mortality and complications were higher in TTS: 3.4 vs. 1.8%, (p = 0.015), and 25.8 vs. 11.5%, (p < 0.001). Global mortality before PS matching was 16.1% in non-TTS MINOCAs and 8.1% in TTS. Median follow-up was 32.4 months; after PS matching, TTS had fewer major adverse cardiovascular events (MACEs): hazard ratio (HR) 0.59; 95% CI 0.42-0.83. There were no differences in global mortality (HR 0.87; CI: 0.64-1.19), but TTS had lower cardiovascular mortality (HR 0.58; CI: 0.35-0.98). Conclusion: Compared to the rest of MINOCAs, TTS presents a different patient profile and a more aggressive acute phase. However, its long-term cardiovascular prognosis is better. These results support that TTS should be considered a separate entity with unique characteristics and prognosis.

Sexual dimorphism in the hoverfly motion vision pathway.

Many insects perform high-speed aerial maneuvers in which they navigate through visually complex surrounds. Among insects, hoverflies stand out, with males switching from stationary hovering to high-speed pursuit at extreme angular velocities [1]. In dipterans, 50-60 large interneurons -- the lobula-plate tangential cells (LPTCs) -- detect changes in optic flow experienced during flight [2-5]. It has been predicted that large LPTC receptive fields are a requirement of accurate "matched filters" of optic flow [6]. Whereas many fly taxa have three horizontal system (HS) LPTC neurons in each hemisphere, hoverflies have four [7], possibly reflecting the more sophisticated flight behavior. We here show that the most dorsal hoverfly neuron (HS north [HSN]) is sexually dimorphic, with the male receptive field substantially smaller than in females or in either sex of blowflies. The (hoverfly-specific) HSN equatorial (HSNE) is, however, sexually isomorphic. Using complex optic flow, we show that HSN, despite its smaller receptive field, codes yaw velocity as well as HSNE. Responses to a target moving against a plain or textured background suggest that the male HSN could potentially play a role in target pursuit under some conditions.

Rapid contrast gain reduction following motion adaptation.

Neural and sensory systems adapt to prolonged stimulation to allow signaling across broader input ranges than otherwise possible with the limited bandwidth of single neurons and receptors. In the visual system, adaptation takes place at every stage of processing, from the photoreceptors that adapt to prevailing luminance conditions, to higher-order motion-sensitive neurons that adapt to prolonged exposure to motion. Recent experiments using dynamic, fluctuating visual stimuli indicate that adaptation operates on a time scale similar to that of the response itself. Further work from our own laboratory has highlighted the role for rapid motion adaptation in reliable encoding of natural image motion. Physiologically, motion adaptation can be broken down into four separate components. It is not clear from the previous studies which of these motion adaptation components are involved in the fast and dynamic response changes. To investigate the adapted response in more detail, we therefore analyzed the effect of motion adaptation using a test-adapt-test protocol with adapting durations ranging from 20 ms to 20 s. Our results underscore the very rapid rate of motion adaptation, suggesting that under free flight, visual motion-sensitive neurons continuously adapt to the changing scenery. This might help explain recent observations of strong invariance in the response to natural scenes with highly variable contrast and image structure.

Atrial Fibrillation in Congenital Heart Disease.

The increasing prevalence of AF in a growing population of adults with congenital heart disease (CHD) poses new challenges to clinicians involved in the management of these patients. Distinctive underlying anatomies, unique physiological aspects, a high diversity of corrective surgeries and associated comorbidities can complicate clinical decision-making. In this review, the authors provide an overview of the current knowledge on epidemiology and pathophysiology, with a special focus on the differences to the non-CHD population and the clinical impact of AF in adults with CHD. Acute and long-term management strategies are summarised, including the use of antiarrhythmic drugs, catheter or surgical ablation and prophylaxis of thromboembolism. Finally, gaps of knowledge and potential areas of future research are highlighted.

Electrocardiographic Characteristics and Associated Outcomes in Patients with Takotsubo Syndrome. Insights from the RETAKO Registry.

Electrocardiographic disturbances in Takotsubo syndrome have been previously partially described but their consequences remain mostly unknown. Our aim was to describe the prevalence and prognostic significance of different electrocardiographic features in patients with Takotsubo syndrome. Our data come from the Spanish multicenter REgistry of TAKOtsubo syndrome (RETAKO). All patients with an available 12-lead surface electrocardiogram at admission and 48 hours post-admission were included. A total of 246 patients were studied, mean age was 71.3 ± 11.5 and 215 (87.4%) were women. ST-segment elevation was seen in 143 patients (59.1%) and was present in ≥2 wall leads in 97 (39.8%). Exclusive elevation in inferior leads was infrequent (5% - 2.0%). After 48 hours, 198 patients (88.0%) developed negative T waves in a median of 8 leads with a mean amplitude of 0.7 ± 0.5 mV and 137 (60.9%) had pathological Q waves. The mean corrected QT interval was 520 ± 72 ms. Corrected QT interval was independently associated with the primary endpoint of all-cause death and nonfatal cardiovascular events (P = 0.002) and all-cause death (P = 0.008). A higher heart rate at admission was an independent predictor of the primary endpoint (P = 0.001) and of acute pulmonary edema (P = 0.04). ST-segment elevation with reciprocal depression was an independent predictor of all-cause death (P = 0.04). Absence of ST-segment deviation was a protective factor (P = 0.005) for the primary endpoint. Tachyarrhythmias were independently associated with cardiogenic shock (P< 0.001). Takotsubo syndrome patients present with distinct electrocardiographic features. Prolonged corrected QT interval, tachyarrhythmias, heart rate at admission, and more extensive repolarization alterations are associated with poor outcomes.