Extracellular Kir2.1C122Y Mutant Upsets Kir2.1-PIP2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.

MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM).

The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT-deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy.

Extracellular cysteine disulfide bond break at Cys122 disrupts PIP2-dependent Kir2.1 channel function and leads to arrhythmias in Andersen-Tawil Syndrome.

Background: Andersen-Tawil Syndrome Type 1 (ATS1) is a rare heritable disease caused by mutations in the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys122-to-Cys154 disulfide bond in the Kir2.1 channel structure is crucial for proper folding, but has not been associated with correct channel function at the membrane. We tested whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing the open state of the channel. Methods and Results: We identified a Kir2.1 loss-of-function mutation in Cys122 (c.366 A>T; p.Cys122Tyr) in a family with ATS1. To study the consequences of this mutation on Kir2.1 function we generated a cardiac specific mouse model expressing the Kir2.1C122Y mutation. Kir2.1C122Y animals recapitulated the abnormal ECG features of ATS1, like QT prolongation, conduction defects, and increased arrhythmia susceptibility. Kir2.1C122Y mouse cardiomyocytes showed significantly reduced inward rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking ability and localization at the sarcolemma and the sarcoplasmic reticulum. Kir2.1C122Y formed heterotetramers with wildtype (WT) subunits. However, molecular dynamic modeling predicted that the Cys122-to-Cys154 disulfide-bond break induced by the C122Y mutation provoked a conformational change over the 2000 ns simulation, characterized by larger loss of the hydrogen bonds between Kir2.1 and phosphatidylinositol-4,5-bisphosphate (PIP2) than WT. Therefore, consistent with the inability of Kir2.1C122Y channels to bind directly to PIP2 in bioluminescence resonance energy transfer experiments, the PIP2 binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch-clamping the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing PIP2 concentrations. Conclusion: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential to channel function. We demonstrated that ATS1 mutations that break disulfide bonds in the extracellular domain disrupt PIP2-dependent regulation, leading to channel dysfunction and life-threatening arrhythmias.

Análisis de la adherencia a medio plazo tras la realización de un programa de rehabilitación cardiaca / Analysis of medium-term adherence after the implementation of a cardiac rehabilitation program

Resumen Objetivo: Los programas de rehabilitación cardiaca (PRC) son una excelente herramienta para lograr adherencia al cumplimiento terapéutico. El objetivo fue analizar la adherencia a medio plazo e identificar predictores de mala adherencia al cumplimiento farmacológico y a los cambios en el estilo de vida. Material y métodos: Estudio retrospectivo de 100 pacientes remitidos a un PRC en 2018 tras un síndrome coronario agudo (SCA). En la revisión al año se analizó la adherencia a la dieta, al ejercicio físico y la deshabituación tabáquica. Se consideró adherencia óptima si se cumplían los tres ítems. Se estudió el cumplimiento farmacológico empleando el test de Morisky-Green. Se analizaron los predictores de mala adherencia mediante análisis de regresión lineal/logística. Resultados: El 98% de los pacientes presentaron adherencia aceptable a la dieta mediterránea, el 83% buena adherencia al ejercicio físico y el 79% de los fumadores consiguieron dejar de fumar. Respecto a la adherencia farmacológica, el 97% de los pacientes la cumplió de forma correcta. En conjunto consiguieron una adherencia óptima el 68% de los pacientes. La nacionalidad de Europa del este, el sedentarismo y los programas no presenciales fueron predictores de mala adherencia. Los pacientes más jóvenes y la profesión de «cuello azul¼ mostraron tendencia a mala adherencia, aunque no de forma significativa. Conclusiones: En nuestro entorno existe una buena adherencia a los cambios de estilo de vida y al cumplimiento farmacológico en pacientes que tras un SCA completan un PRC. La nacionalidad Europea del este, el sedentarismo y los programas no presenciales se asociaron con mala adherencia.

Abstract Objectives: Cardiac Rehabilitation Programs (CRP) are an excellent tool to achieve adherence to therapeutic. The aim of our study was analyzing at the medium-term adherence, as well as identifying low adherence predictors to pharmacological therapeutic compliance and changes in lifestyle. Methods: Retrospective study of 100 patients referred to a CRP in 2018 after presenting ACS. At the one-year review adherence to diet, physical exercise, and smoking cessation were analyzed. Optimal adherence was considered if all three items were met. Compliance with taking medication was also studied using the Morisky-Green test. Finally, low adherence predictors were analyzed by lineal/logistic regression analysis. Results: 98% of the patients presented acceptable adherence to the Mediterranean diet, 83% good adherence to physical exercise, and 79% of the smokers achieved the cessation of smoking. Regarding drug adherence, 97% of the patients complied correctly. 68% of the patients achieved good overall adherence. Eastern European nationality, sedentary lifestyle, and home-based CRP were predictors of low adherence. The youngest patients and the "blue collar" occupation showed a tendency to poor adherence, although not significantly. Conclusions: In our environment there is good medium-term adherence to lifestyle changes and pharmacological compliance in patients who complete CRP after ACS. Eastern European nationality, sedentary lifestyle, and home-based programs were associated with poor adherence.

Analysis of medium-term adherence after the implementation of a cardiac rehabilitation program.

OBJECTIVES: Cardiac Rehabilitation Programs (CRP) are an excellent tool to achieve adherence to therapeutic. The aim of our study was analyzing at the medium-term adherence, as well as identifying low adherence predictors to pharmacological therapeutic compliance and changes in lifestyle. METHODS: Retrospective study of 100 patients referred to a CRP in 2018 after presenting ACS. At the one-year review adherence to diet, physical exercise, and smoking cessation were analyzed. Optimal adherence was considered if all three items were met. Compliance with taking medication was also studied using the Morisky-Green test. Finally, low adherence predictors were analyzed by lineal/logistic regression analysis. RESULTS: 98% of the patients presented acceptable adherence to the Mediterranean diet, 83% good adherence to physical exercise, and 79% of the smokers achieved the cessation of smoking. Regarding drug adherence, 97% of the patients complied correctly. 68% of the patients achieved good overall adherence. Eastern European nationality, sedentary lifestyle, and home-based CRP were predictors of low adherence. The youngest patients and the "blue collar" occupation showed a tendency to poor adherence, although not significantly. CONCLUSIONS: In our environment there is good medium-term adherence to lifestyle changes and pharmacological compliance in patients who complete CRP after ACS. Eastern European nationality, sedentary lifestyle, and home-based programs were associated with poor adherence.

OBJETIVO: Los programas de rehabilitación cardiaca (PRC) son una excelente herramienta para lograr adherencia al cumplimiento terapéutico. El objetivo fue analizar la adherencia a medio plazo e identificar predictores de mala adherencia al cumplimiento farmacológico y a los cambios en el estilo de vida. MATERIAL Y MÉTODOS: Estudio retrospectivo de 100 pacientes remitidos a un PRC en 2018 tras un síndrome coronario agudo (SCA). En la revisión al año se analizó la adherencia a la dieta, al ejercicio físico y la deshabituación tabáquica. Se consideró adherencia óptima si se cumplían los tres ítems. Se estudió el cumplimiento farmacológico empleando el test de Morisky-Green. Se analizaron los predictores de mala adherencia mediante análisis de regresión lineal/logística. RESULTADOS: El 98% de los pacientes presentaron adherencia aceptable a la dieta mediterránea, el 83% buena adherencia al ejercicio físico y el 79% de los fumadores consiguieron dejar de fumar. Respecto a la adherencia farmacológica, el 97% de los pacientes la cumplió de forma correcta. En conjunto consiguieron una adherencia óptima el 68% de los pacientes. La nacionalidad de Europa del este, el sedentarismo y los programas no presenciales fueron predictores de mala adherencia. Los pacientes más jóvenes y la profesión de «cuello azul¼ mostraron tendencia a mala adherencia, aunque no de forma significativa. CONCLUSIONES: En nuestro entorno existe una buena adherencia a los cambios de estilo de vida y al cumplimiento farmacológico en pacientes que tras un SCA completan un PRC. La nacionalidad Europea del este, el sedentarismo y los programas no presenciales se asociaron con mala adherencia.

Caveolin-1 dolines form a distinct and rapid caveolae-independent mechanoadaptation system.

In response to different types and intensities of mechanical force, cells modulate their physical properties and adapt their plasma membrane (PM). Caveolae are PM nano-invaginations that contribute to mechanoadaptation, buffering tension changes. However, whether core caveolar proteins contribute to PM tension accommodation independently from the caveolar assembly is unknown. Here we provide experimental and computational evidence supporting that caveolin-1 confers deformability and mechanoprotection independently from caveolae, through modulation of PM curvature. Freeze-fracture electron microscopy reveals that caveolin-1 stabilizes non-caveolar invaginations-dolines-capable of responding to low-medium mechanical forces, impacting downstream mechanotransduction and conferring mechanoprotection to cells devoid of caveolae. Upon cavin-1/PTRF binding, doline size is restricted and membrane buffering is limited to relatively high forces, capable of flattening caveolae. Thus, caveolae and dolines constitute two distinct albeit complementary components of a buffering system that allows cells to adapt efficiently to a broad range of mechanical stimuli.

3-Step didactic white matter dissection of human cerebellum: Micro-neuroanatomical training.

OBJECTIVES: A thorough understanding of cerebellum anatomy is essential in 4th ventricle approaches (more frequent in pediatric neurosurgery), avoiding relevant complications such as cerebellar mutism. The aim of the present work is to show the feasibility of a didactic dissection of human cerebellum focusing on cerebellar peduncles and dentate nucleus (DN), which are structures at high risk during these surgical procedures. MATERIAL AND METHODS: The cerebellum was dissected according to the Klingler method for white matter, using standard and specific microsurgery tools. Surgical microscope magnification (×6-×40) provided by a D.F. Vasconcellos M900 was required. A Canon EOS T7 18-55 mm digital camera was used and Adobe Lightroom Classic CC and Keynote were selected as photo enhancing software. Special methods such as LED light endoscopic transillumination were used for photographical reasons. RESULTS: DN dissection was successfully achieved and the relations between these nucleus and the cerebellar peduncles, inferior vermis and medullary velums were described. Through this three steps dissection guide (1. tentorial surface; 2. suboccipital surface; 3. 4th ventricle structures), the most relevant anatomical structures were shown and its implications in different 4th ventricle approaches were characterised. CONCLUSION: 3 D perspective provided by real specimen anatomical dissection is critical for learning neuroanatomy. LED transillumination was shown as a useful technique for the 4th ventricle structures photographic documentation which improves spatial recognition. This benefit can be applied for the study of the relations between the medullary velums and the rhomboid fossa foramina, which are permeable to light. The proposed three-steps dissection guide helps to a better understanding of human cerebellum and to gain self-confidence, allowing safer practice for neurosurgeons in all stages of their career.

Case report: A third variant in the 5' UTR of TWIST1 creates a novel upstream translation initiation site in a child with Saethre-Chotzen syndrome.

Introduction: Saethre-Chotzen syndrome, a craniosynostosis syndrome characterized by the premature closure of the coronal sutures, dysmorphic facial features and limb anomalies, is caused by haploinsufficiency of TWIST1. Although the majority of variants localize in the coding region of the gene, two variants in the 5' UTR have been recently reported to generate novel upstream initiation codons. Methods: Skeletal dysplasia Next-generation sequencing (NGS) panel was used for genetic analysis in a patient with bicoronal synostosis, facial dysmorphisms and limb anomalies. The variant pathogenicity was assessed by a luciferase reporter promoter assay. Results: Here, we describe the identification of a third ATG-creating de novo variant, c.-18C>T, in the 5' UTR of TWIST1 in the patient with a clinical diagnosis of Saethre-Chotzen syndrome. It was predicted to create an out-of-frame new upstream translation initiation codon resulting in a 40 amino acid larger functionally inactive protein. We performed luciferase reporter promoter assays to demonstrate that the variant does indeed reduce translation from the main open reading frame. Conclusion: This is the third variant identified in this region and confirms the introduction of upstream ATGs in the 5' UTR of TWIST1 as a pathogenic mechanism in Saethre-Chotzen syndrome. This case report shows the necessity for performing functional characterization of variants of unknown significance within national health services.

The hippocampus as the switchboard between perception and memory.

Adaptive memory recall requires a rapid and flexible switch from external perceptual reminders to internal mnemonic representations. However, owing to the limited temporal or spatial resolution of brain imaging modalities used in isolation, the hippocampal-cortical dynamics supporting this process remain unknown. We thus employed an object-scene cued recall paradigm across two studies, including intracranial electroencephalography (iEEG) and high-density scalp EEG. First, a sustained increase in hippocampal high gamma power (55 to 110 Hz) emerged 500 ms after cue onset and distinguished successful vs. unsuccessful recall. This increase in gamma power for successful recall was followed by a decrease in hippocampal alpha power (8 to 12 Hz). Intriguingly, the hippocampal gamma power increase marked the moment at which extrahippocampal activation patterns shifted from perceptual cue toward mnemonic target representations. In parallel, source-localized EEG alpha power revealed that the recall signal progresses from hippocampus to posterior parietal cortex and then to medial prefrontal cortex. Together, these results identify the hippocampus as the switchboard between perception and memory and elucidate the ensuing hippocampal-cortical dynamics supporting the recall process.

Factibilidad y resultados de un programa de rehabilitación cardiaca intensiva. Perspectiva del estudio aleatorizado MxM (Más por Menos) / Feasibility and results of an intensive cardiac rehabilitation program. Insights from the MxM (Más por Menos) randomized trial

Introducción y objetivos: Los programas de rehabilitación cardiaca (PRC) engloban intervenciones encaminadas a mejorar el pronóstico de la enfermedad cardiovascular influyendo en la condición física, mental y social de los pacientes, pero no se conoce su duración óptima. Nuestro objetivo es comparar los resultados de un PRC estándar frente a otro intensivo más breve tras un síndrome coronario agudo, mediante el estudio Más por Menos. Métodos: Diseño prospectivo, aleatorizado, abierto, enmascarado a los evaluadores de eventos y multicéntrico (PROBE). Se aleatorizó a los pacientes al PRC estándar de 8 semanas u otro intensivo de 2 semanas con sesiones de refuerzo. Se realizó una visita final 12 meses después, tras la finalización del programa. Se evaluó: adherencia a la dieta, esfera psicológica, hábito tabáquico, tratamiento farmacológico, capacidad funcional, calidad de vida, parámetros cardiometabólicos y antropométricos, eventos cardiovasculares y mortalidad por cualquier causa durante el seguimiento. Resultados: Se analizó a 497 pacientes (media de edad, 57,8±10,0 años; el 87,3% varones; programa intensivo, n=262; estándar, n=235). Las características basales de ambos grupos eran similares. Al año, más del 93% había mejorado en al menos 1 MET el resultado de la ergometría. Además, la adherencia a la dieta mediterránea y la calidad de vida mejoraron significativamente con el PRC, sin diferencias significativas entre grupos. Los eventos cardiovasculares ocurrieron de manera similar en ambos grupos. Conclusiones: La PRC intensiva podría ser tan efectiva como la PRC estándar en lograr la adherencia a las medidas de prevención secundaria y ser una alternativa para algunos pacientes y centros. (AU)

Introduction and objectives: Cardiac rehabilitation programs (CRP) are a set of interventions to improve the prognosis of cardiovascular disease by influencing patients’ physical, mental, and social conditions. However, there are no studies evaluating the optimal duration of these programs. We aimed to compare the results of a standard vs a brief intensive CRP in patients after ST-segment elevation and non–ST-segment elevation acute coronary syndrome through the Más por Menos study (More Intensive Cardiac Rehabilitation Programs in Less Time). Methods: In this prospective, randomized, open, evaluator-blind for end-point, and multicenter trial (PROBE design), patients were randomly allocated to either standard 8-week CRP or intensive 2-week CRP with booster sessions. A final visit was performed 12 months later, after completion of the program. We assessed adherence to the Mediterranean diet, psychological status, smoking, drug therapy, functional capacity, quality of life, cardiometabolic and anthropometric parameters, cardiovascular events, and all-cause mortality during follow-up. Results: A total of 497 patients (mean age, 57.8±10.0 years; 87.3% men) were finally assessed (intensive: n=262; standard: n=235). Baseline characteristics were similar between the 2 groups. At 12 months, the results of treadmill ergometry improved by ≥ 1 MET in ≥ 93% of the patients. In addition, adherence to the Mediterranean diet and quality of life were significantly improved by CRP, with no significant differences between the groups. The occurrence of cardiovascular events was similar in the 2 groups. Conclusions: Intensive CRP could be as effective as standard CRP in achieving adherence to recommended secondary prevention measures after acute coronary syndrome and could be an alternative for some patients and centers. (AU)

Seven Microaneurysms: Description of an Experimental Rodent Model for Neurovascular Training.

AIM: To demonstrate the microsurgical procedures, and to evaluate the feasibility of living models of experimental neurovascular training by developing new complex vascular exercises mimicking the most common intracranial aneurysms. MATERIAL AND METHODS: The procedures were performed under a Zeiss (OPMI pico f170) microscope using basic microsurgery instruments, 10/0 Nylon and blue Polypropylene micro-sutures. We selected adult albino Wistar rats weighing between 258 and 471g each. Seven different aneurysm types were created using carotid, jugular, cava, aorta and femoral vessels. RESULTS: Seven types of aneurysm were designed and created in the rat with a high-medium successful rate. There are differences in terms of realism and the difficulty of performance, according to the different types: lateral wall, bifurcation, top of the basilar, fusiform, fusiform + involved branch, Anterior Communicating Artery (ACoA) and giant. The steps and technical issues to produce these exercises are described. CONCLUSION: We show the feasibility of creating several types of aneurysm using different vessels in a rodent model. Training on these models help to improve microsurgical skills, allowing safe practice for neurosurgeons in all stages of their career.

3-Step didactic white matter dissection of human cerebellum: Micro-neuroanatomical training. / Disección didáctica de fibra blanca en cerebelo humano en tres pasos: entrenamiento microneuroanatómico.

OBJECTIVES: A thorough understanding of cerebellum anatomy is essential in 4th ventricle approaches (more frequent in pediatric neurosurgery), avoiding relevant complications such as cerebellar mutism. The aim of the present work is to show the feasibility of a didactic dissection of human cerebellum focusing on cerebellar peduncles and dentate nucleus (DN), which are structures at high risk during these surgical procedures. MATERIAL AND METHODS: The cerebellum was dissected according to the Klingler method for white matter, using standard and specific microsurgery tools. Surgical microscope magnification (x6-x40) provided by a D.F. Vasconcellos M900 was required. A Canon EOS T7 18-55 mm digital camera was used and Adobe Lightroom Classic CC and Keynote were selected as photo enhancing software. Special methods such as LED light endoscopic transillumination were used for photographical reasons. RESULTS: DN dissection was successfully achieved and the relations between these nucleus and the cerebellar peduncles, inferior vermis and medullary velums were described. Through this three steps dissection guide (1. tentorial surface; 2. suboccipital surface; 3. 4th ventricle structures), the most relevant anatomical structures were shown and its implications in different 4th ventricle approaches were characterised. CONCLUSION: 3 D perspective provided by real specimen anatomical dissection is critical for learning neuroanatomy. LED transillumination was shown as a useful technique for the 4th ventricle structures photographic documentation which improves spatial recognition. This benefit can be applied for the study of the relations between the medullary velums and the rhomboid fossa foramina, which are permeable to light. The proposed three-steps dissection guide helps to a better understanding of human cerebellum and to gain self-confidence, allowing safer practice for neurosurgeons in all stages of their career.

Management of a ruptured intraventricular aneurysm arising from distal anterior choroidal artery (AChA): pediatric case report.

Intracranial aneurysms arising from the distal anterior choroidal artery (AChA) are uncommon entities, with less than 30 cases reported. A 4-year-old boy was admitted to the Emergency Department with a sudden onset of severe headache and vomiting. CT scan of the head showed signs of intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Cerebral angiography revealed a right AChA aneurysm arising from a distal intraventricular branch with an associated microarteriovenous malformation (microAVM). Following a multidisciplinary assessment, the patient underwent surgical clipping. An ipsilateral transcortical transparietal approach was utilized. Early postoperative deficits were not found, and good clinical and radiological outcomes were assessed at long-term follow-up. Postoperative cerebral angiography showed complete exclusion and resection of both aneurysm and AVM. Surgery for intracranial aneurysms in this location can be challenging; however, good surgical and neurological outcomes can be achieved. The present work highlights the value of multidisciplinary assessment in the decision-making process in complex pediatric neurovascular pathology, especially when facing rare cases like this one, which represents the youngest case of a ruptured distal AChA aneurysm reported in the literature.

Diffuse leptomeningeal glioneuronal tumour: where to biopsy? Case report and literature review.

PURPOSE: Diffuse leptomeningeal glioneuronal tumour (DLGT) is an infrequent entity. Diagnosis is made with biopsy but with so few cases described management, prognosis remains undefined. There are not currently any articles regarding most effective place to biopsy. METHODS: Current literature review and introduction of the case of a 3-year-old male presenting at the emergency room with irritability, vomiting and nuchal rigidity. A head CT was made showing tetraventricular enlargement and a posterior fossa cyst. RESULTS: Patient underwent urgent ventriculoperitoneal shunting surgery with complete symptomp resolution. Brain MRI showed diffuse leptomeningeal enhancing, predominantly in basal cisterns, and multiple cystic-solid lesions along the neural axis. After ruling other conditions, a biopsy among intraoperative samples, was obtained of a PET positive gadolinium spinal enhancing lesion at D8 level, with the final diagnosis of DLGT. CONCLUSION: DLGT can present as acute hydrocephalus. Biopsy stablishes the diagnosis but the place to take the sample can be difficult to select. Our experience suggests that PET-CT and intraoperative biopsy analysis can improve the effectivity of a representative sample.

Feasibility and results of an intensive cardiac rehabilitation program. Insights from the MxM (Más por Menos) randomized trial.

INTRODUCTION AND OBJECTIVES: Cardiac rehabilitation programs (CRP) are a set of interventions to improve the prognosis of cardiovascular disease by influencing patients' physical, mental, and social conditions. However, there are no studies evaluating the optimal duration of these programs. We aimed to compare the results of a standard vs a brief intensive CRP in patients after ST-segment elevation and non-ST-segment elevation acute coronary syndrome through the Más por Menos study (More Intensive Cardiac Rehabilitation Programs in Less Time). METHODS: In this prospective, randomized, open, evaluator-blind for end-point, and multicenter trial (PROBE design), patients were randomly allocated to either standard 8-week CRP or intensive 2-week CRP with booster sessions. A final visit was performed 12 months later, after completion of the program. We assessed adherence to the Mediterranean diet, psychological status, smoking, drug therapy, functional capacity, quality of life, cardiometabolic and anthropometric parameters, cardiovascular events, and all-cause mortality during follow-up. RESULTS: A total of 497 patients (mean age, 57.8±10.0 years; 87.3% men) were finally assessed (intensive: n=262; standard: n=235). Baseline characteristics were similar between the 2 groups. At 12 months, the results of treadmill ergometry improved by ≥ 1 MET in ≥ 93% of the patients. In addition, adherence to the Mediterranean diet and quality of life were significantly improved by CRP, with no significant differences between the groups. The occurrence of cardiovascular events was similar in the 2 groups. CONCLUSIONS: Intensive CRP could be as effective as standard CRP in achieving adherence to recommended secondary prevention measures after acute coronary syndrome and could be an alternative for some patients and centers. Registered at ClinicalTrials.gov (Identifier: NCT02619422).

Machine Learning Improves Cardiovascular Risk Definition for Young, Asymptomatic Individuals.

BACKGROUND: Clinical practice guidelines recommend assessment of subclinical atherosclerosis using imaging techniques in individuals with intermediate atherosclerotic cardiovascular risk according to standard risk prediction tools. OBJECTIVES: The purpose of this study was to develop a machine-learning model based on routine, quantitative, and easily measured variables to predict the presence and extent of subclinical atherosclerosis (SA) in young, asymptomatic individuals. The risk of having SA estimated by this model could be used to refine risk estimation and optimize the use of imaging for risk assessment. METHODS: The Elastic Net (EN) model was built to predict SA extent, defined by a combined metric of the coronary artery calcification score and 2-dimensional vascular ultrasound. The performance of the model for the prediction of SA extension and progression was compared with traditional risk scores of cardiovascular disease (CVD). An external independent cohort was used for validation. RESULTS: EN-PESA (Progression of Early Subclinical Atherosclerosis) yielded a c-statistic of 0.88 for the prediction of generalized subclinical atherosclerosis. Moreover, EN-PESA was found to be a predictor of 3-year progression independent of the baseline extension of SA. EN-PESA assigned an intermediate to high cardiovascular risk to 40.1% (n = 1,411) of the PESA individuals, a significantly larger number than atherosclerotic CVD (n = 267) and SCORE (Systematic Coronary Risk Evaluation) (n = 507) risk scores. In total, 86.8% of the individuals with an increased risk based on EN-PESA presented signs of SA at baseline or a significant progression of SA over 3 years. CONCLUSIONS: The EN-PESA model uses age, systolic blood pressure, and 10 commonly used blood/urine tests and dietary intake values to identify young, asymptomatic individuals with an increased risk of CVD based on their extension and progression of SA. These individuals are likely to benefit from imaging tests or pharmacological treatment. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Risk factors associated with conversion of an Ommaya reservoir to a permanent cerebrospinal fluid shunt in preterm posthemorrhagic hydrocephalus.

OBJECTIVE: A considerable percentage of preterm infants with posthemorrhagic hydrocephalus initially managed with an Ommaya reservoir require a permanent CSF shunt. The objective of the study was to analyze possible risk factors associated with the need for converting an Ommaya reservoir to a permanent shunt. METHODS: The authors retrospectively reviewed the clinical records of premature infants weighing 1500 g or less with posthemorrhagic hydrocephalus (Papile grades III and IV) managed with an Ommaya reservoir at their institution between 2002 and 2017. RESULTS: Forty-six patients received an Ommaya reservoir. Five patients (10.9%) were excluded due to intraventricular infection during management with an Ommaya reservoir. Average gestational age and weight for the remaining 41 patients was 27 ± 1.8 weeks and 987 ± 209 grams, respectively. Thirty patients required a permanent shunt and 11 patients did not require a permanent shunt. The conversion rate from an Ommaya reservoir to a permanent shunt was 76.1%. Symptomatic persistent ductus arteriosus (PDA) was more frequent in the nonpermanent shunt group than in the shunt group (88.9% vs 50%, p = 0.04). The need for extraction of more than 10 ml/kg per day of CSF through the Ommaya reservoir was lower in the nonpermanent shunt group than in the shunt group (9.1% vs 51.7%, p = 0.015). CSF lactate was lower in the nonpermanent group than in the shunt group (mean 2.48 mg/dl vs 3.19 mg/dl; p = 0.004). A cutoff value of ≥ 2.8 mg/dl CSF lactate predicted the need for a permanent shunt with sensitivity and specificity of 82.4% and 80%, respectively. There were no significant differences in gestational age, sex, weight, Papile grade, ventricular index, or other biochemical markers. After the multivariate analysis, only CSF lactate ≥ 2.8 mg/dl was associated with a higher conversion rate to a permanent shunt. CONCLUSIONS: This study showed that a high level of CSF lactate, absence of symptomatic PDA, and a higher CSF extraction requirement were associated with a higher likelihood of implanting a permanent CSF shunt. The authors believe these findings should be considered in future studies.

Prevención secundaria tras un síndrome coronario agudo. Resultados a medio plazo de un programa de rehabilitación cardiaca / Secondary prevention after an acute coronary syndrome: medium-term results of a cardiac rehabilitation programme

Resumen Introducción: Los Programas de Rehabilitación Cardiaca han adquirido gran relevancia como herramienta para mejorar el pronóstico y la calidad de vida de pacientes que han presentado un síndrome coronario agudo. Objetivo: Evaluar los resultados de un programa de rehabilitación cardiaca a medio plazo. Materiales y métodos: Estudio descriptivo retrospectivo de 121 pacientes que presentaron un síndrome coronario agudo y fueron incluidos en el programa de rehabilitación cardiaca. Se analizaron las características demográficas, antropométricas, analíticas y de capacidad funcional a la inclusión, tras finalizar el programa presencial y a los 12 meses. Resultados: La edad media fue 54±7 años. El factor de riesgo cardiovascular más prevalente fue el sobrepeso/obesidad (88,4%). Tras la finalización del programa de rehabilitación cardiaca disminuyeron significativamente los valores de colesterol LDL (81,1±28,7 vs. 76,5±31,5 mg/dl; p 0,03). Un porcentaje significativo de diabéticos alcanzaron objetivos de Hb A1c <7% (50% vs. 68,5%; p 0,01). El perímetro abdominal mostró una disminución estadísticamente significativa (100,8±12,8 vs. 99,5±12,3 cm; p 0,004). El 89,3% de los pacientes mejoraron su capacidad funcional. En la revisión anual la mayoría de los parámetros estudiados mostraron una discreta tendencia negativa. Un 47,36% de los fumadores a la inclusión mantenían el hábito tabáquico al año. Conclusiones: Los programas de rehabilitación cardiaca mejoran el control de los factores de riesgo cardiovascular, cambios de estilo de vida y capacidad funcional en los pacientes que han sufrido un síndrome coronario agudo. Es preciso reforzar las estrategias de control para mantener estos beneficios a medio-largo plazo.

Abstract Introduction: Cardiac rehabilitation programmes have become a very important tool for improving the prognosis and quality of life of patients that have suffered an acute coronary syndrome. Objective: To evaluate the medium-term results of a cardiac rehabilitation programme. Materials and methods: A descriptive study of 121 patients that presented with an acute coronary syndrome and were included in a cardiac rehabilitation programme. An analysis was performed on the demographic and anthropometric characteristics, as well as laboratory tests and functional capacity on inclusion, after finishing the programme, and at 12 months. Results: The mean age of the patients was 54±7 years. The most prevalent cardiovascular risk factor was overweight / obesity (88.4%). After finishing the cardiac rehabilitation programmes, the LDL Cholesterol values significantly decreased (81.1±28.7 vs. 76.5±31.5 mg/dl; P=.03). A significant percentage of diabetics reached objectives of an Hb A1c <7% (50% vs. 68.5%; P=.01). The abdominal circumference showed a statistically significant decrease (100.8±12.8 vs. 99.5±12.3 cm; P=.004). An improvement in functional capacity was observed in 89.3% of the patients. In the annual review, the majority of the parameters studied showed a slight negative trend. Just under half (47.36%) of smokers at inclusion maintained the tobacco habit at one year. Conclusions: Cardiac rehabilitation programmes improve the control of cardiovascular risk factors, changes in life style and functional capacity in patients that had suffered an acute coronary syndrome. Control strategies need to be enforced in order to maintain these benefits in the medium-long term.

Intelligibility in speech maskers with a binaural cochlear implant sound coding strategy inspired by the contralateral medial olivocochlear reflex.

We have recently proposed a binaural cochlear implant (CI) sound processing strategy inspired by the contralateral medial olivocochlear reflex (the MOC strategy) and shown that it improves intelligibility in steady-state noise (Lopez-Poveda et al., 2016, Ear Hear 37:e138-e148). The aim here was to evaluate possible speech-reception benefits of the MOC strategy for speech maskers, a more natural type of interferer. Speech reception thresholds (SRTs) were measured in six bilateral and two single-sided deaf CI users with the MOC strategy and with a standard (STD) strategy. SRTs were measured in unilateral and bilateral listening conditions, and for target and masker stimuli located at azimuthal angles of (0°, 0°), (-15°, +15°), and (-90°, +90°). Mean SRTs were 2-5 dB better with the MOC than with the STD strategy for spatially separated target and masker sources. For bilateral CI users, the MOC strategy (1) facilitated the intelligibility of speech in competition with spatially separated speech maskers in both unilateral and bilateral listening conditions; and (2) led to an overall improvement in spatial release from masking in the two listening conditions. Insofar as speech is a more natural type of interferer than steady-state noise, the present results suggest that the MOC strategy holds potential for promising outcomes for CI users.

Atypical clinical presentation and long-term survival in a patient with optic nerve medulloepithelioma: a case report.

INTRODUCTION: Medulloepithelioma is a rare congenital tumor of the primitive medullary neuroepithelium. A significant proportion of patients with medulloepithelioma arising from the optic nerve die from intracranial spread or cerebral metastasis. Because it has no known distinct clinical features and because of its low frequency, this tumor presents within the first two to six years of life and is usually misdiagnosed clinically as a different type of optic nerve tumor. Here, we describe a new and atypical case of medulloepithelioma of the optic nerve in a 12-year-old boy. To the best of our knowledge, he is the oldest reported patient to present with this disease and, now as an adult, has the longest documented period of disease-free survival. CASE PRESENTATION: A 12-year-old Caucasian boy with headache and unilateral amaurosis was referred for a presumed optic nerve glioma to our hospital. A computed tomography scan showed optic nerve enlargement, and fundoscopy showed a whitish mass at the optic disc. Our patient had been followed at his local hospital for four years for an 'optic disc cyst' with no change or progression. He experienced mild progressive visual impairment during that period. He was admitted for resection, and a histopathological analysis revealed a medulloepithelioma of the optic nerve. Supplemental orbital radiotherapy was performed. He remained disease-free for 25 years. CONCLUSIONS: Medulloepithelioma of the optic nerve can clinically mimic more common pediatric tumors, such as optic glioma, meningioma, or retinoblastoma. Thus, medulloepithelioma should be included in the differential diagnoses of pediatric optic nerve lesions. Fundoscopy in these patients may provide relevant information for diagnosis. Anterior optic nerve medulloepitheliomas may behave differently from and have a better prognosis than medulloepitheliomas that have a more posterior location. Our case report illustrates that long-term survival can be achieved in patients with this malignant tumor.