Mecanismes neuronals de la facilitació de l'aprenentatge i la memoria per autoestimulació eléctrica intracranial en rates: espines dendrítiques

La potenciación de procesos de aprendizaje y memoria por autoestimación eléctrica intracraneal (AEIC) se ha observado principalmente en tareas de aprendizaje de tipo implícito, caracterizado por necesitar de múltiples ensayos y por dar lugar a una respuesta conductual rígida. Los efectos de la AEIC sobre formas de aprendizaje consideradas más complejas, como la memoria de navegación espacial, son menos conocidos. En nuestro laboratorio hemos observado recientemente que el tratamiento de AEIC es también capaz de facilitar tanto la adquisición como la retención de una tarea relacional, en el laberinto acuático de Morris (MWM) (Ruiz-Medina et al., 2008). El proyecto de investigación objeto de esta memoria continúa el estudio de este efecto potenciador yendo un paso más allá al profundizar en los mecanismos neurales de este efecto. Lo relativo a las espinas dendríticas, su tamaño, forma y aparición es uno de los campos más actuales en el estudio de las bases neurales de la memoria. Trabajos previos apuntan a un incremento en la densidad de espinas inmaduras -las consideradas de aprendizaje- como efecto tanto del entrenamiento en el MWM como de la AEIC. Relacionar la potenciación de memoria en el MWM resultado de la AEIC con cambios significativos en la población de espinas dendríticas hipocampales sería uno de los principales objetivos del presente trabajo, que se realizará en colaboración con el Instituto Ramón y Cajal de Madrid.

The role of computational fluid dynamics in the management of unruptured intracranial aneurysms: a clinicians' view

Objective: The importance of hemodynamics in the etiopathogenesis of intracranial aneurysms (IAs) is widely accepted.Computational fluid dynamics (CFD) is being used increasingly for hemodynamic predictions. However, alogn with thecontinuing development and validation of these tools, it is imperative to collect the opinion of the clinicians. Methods: A workshopon CFD was conducted during the European Society of Minimally Invasive Neurological Therapy (ESMINT) Teaching Course,Lisbon, Portugal. 36 delegates, mostly clinicians, performed supervised CFD analysis for an IA, using the @neuFuse softwaredeveloped within the European project @neurIST. Feedback on the workshop was collected and analyzed. The performancewas assessed on a scale of 1 to 4 and, compared with experts’ performance. Results: Current dilemmas in the management ofunruptured IAs remained the most important motivating factor to attend the workshop and majority of participants showedinterest in participating in a multicentric trial. The participants achieved an average score of 2.52 (range 0–4) which was 63% (range 0–100%) of an expert user. Conclusions: Although participants showed a manifest interest in CFD, there was a clear lack ofawareness concerning the role of hemodynamics in the etiopathogenesis of IAs and the use of CFD in this context. More effortstherefore are required to enhance understanding of the clinicians in the subject.

Patient-specific computational hemodynamics of intracranial aneurysms from 3D rotational angiography and CT angiography: an in vivo reproducibility study

Patient-specific simulations of the hemodynamics in intracranial aneurysms can be constructed by using image-based vascular models and CFD techniques. This work evaluates the impact of the choice of imaging technique on these simulations

Biomechanical wall properties of human intracranial aneurysms resected following surgical clipping (IRRAs Project)

Background and purpose: Individual rupture risk assessment of intracranial aneurysms is a major issue in the clinical management of asymptomatic aneurysms. Aneurysm rupture occurs when wall tension exceeds the strength limit of the wall tissue. At present, aneurysmal wall mechanics are poorly understood and thus, risk assessment involving mechanical properties is inexistent. Aneurysm computational hemodynamics studies make the assumption of rigid walls, an arguable simplification. We therefore aim to assess mechanical properties of ruptured and unruptured intracranial aneurysms in order to provide the foundation for future patient-specific aneurysmal risk assessment. This work also challenges some of the currently held hypotheses in computational flow hemodynamics research. Methods: A specific conservation protocol was applied to aneurysmal tissues following clipping and resection in order to preserve their mechanical properties. Sixteen intracranial aneurysms (11 female, 5 male) underwent mechanical uniaxial stress tests under physiological conditions, temperature, and saline isotonic solution. These represented 11 unruptured and 5 ruptured aneurysms. Stress/strain curves were then obtained for each sample, and a fitting algorithm was applied following a 3-parameter (C(10), C(01), C(11)) Mooney-Rivlin hyperelastic model. Each aneurysm was classified according to its biomechanical properties and (un)rupture status.Results: Tissue testing demonstrated three main tissue classes: Soft, Rigid, and Intermediate. All unruptured aneurysms presented a more Rigid tissue than ruptured or pre-ruptured aneurysms within each gender subgroup. Wall thickness was not correlated to aneurysmal status (ruptured/unruptured). An Intermediate subgroup of unruptured aneurysms with softer tissue characteristic was identified and correlated with multiple documented risk factors of rupture. Conclusion: There is a significant modification in biomechanical properties between ruptured aneurysm, presenting a soft tissue and unruptured aneurysms, presenting a rigid material. This finding strongly supports the idea that a biomechanical risk factor based assessment should be utilized in the to improve the therapeutic decision making.

Wall motion estimation in intracranial aneurysms

The quantification of wall motion in cerebral aneurysms is becoming important owing to its potential connection to rupture, and as a way to incorporate the effects of vascular compliance in computational fluid dynamics (CFD) simulations.Most of papers report values obtained with experimental phantoms, simulated images, or animal models, but the information for real patients is limited. In this paper, we have combined non-rigid registration (IR) with signal processing techniques to measure pulsation in real patients from high frame rate digital subtraction angiography (DSA). We have obtained physiological meaningful waveforms with amplitudes in therange 0mm-0.3mm for a population of 18 patients including ruptured and unruptured aneurysms. Statistically significant differences in pulsation were found according to the rupture status, in agreement with differences in biomechanical properties reported in the literature.

Three-dimensional morphological analysis of intracranial aneurysms: a fully automated method for aneurysm sac isolation and quantification

Morphological descriptors are practical and essential biomarkers for diagnosis andtreatment selection for intracranial aneurysm management according to the current guidelinesin use. Nevertheless, relatively little work has been dedicated to improve the three-dimensionalquanti cation of aneurysmal morphology, automate the analysis, and hence reduce the inherentintra- and inter-observer variability of manual analysis. In this paper we propose a methodologyfor the automated isolation and morphological quanti cation of saccular intracranial aneurysmsbased on a 3D representation of the vascular anatomy.

Craniectomía descompresiva frente la hipertensión intracraneal

La craniectomia descompressiva es presenta com una estratègia terapèutica davant la hipertensió intracranial refractària al tractament mèdic. L’objectiu és avaluar els efectes de la CD en el resultat funcional dels pacients en els quals les mesures terapèutiques convencionals no aconsegueixen un control òptim de la pressió intracranial. Els resultats mostren que probablement la CD modifica l’evolució natural de la HTIC refractària disminuint la mortalitat, sense augmentar la morbiditat dels pacients, aconseguint un bon resultat funcional a l’any en més de la meitat dels pacients estudiats.

Influencia del tratamiento previo con antiagregantes en el riesgo de crecimiento del hematoma y el pronóstico en pacientes con Hemorragia Intracerebral Aguda.

Realizamos un estudio prospectivo sobre la influencia del tratamiento previo con antiagregación plaquetaria en pacientes que sufren una hemorragia intracerebral espontánea. Se realizó un anàlisis de 90 pacientes recogidos consecutivamente y se estudió la influencia del tratamiento previo con antiagregación sobre el crecimiento del hematoma, la evolución clínica, la mortalidad y el pronóstico funcional a los tres meses en comparación con pacientes sin tratamiento previo con antiagregación. Tras el anàlisis podemos concluir que el tratamiento previo con antiagregación en la hemorragia intracraneal espontánea no influye sobre el crecimiento del hematoma, la evolución clínica, la mortalidad ni el pronóstico funcional.

Aterosclerosis cérvico-cerebral subclínica: evaluación del índice REGICOR, el grosor íntima-media y el índice tobillo-brazo en la detección de sujetos en riesgo en la población

La aterosclerosis cérvico-cerebral es una de las principales causas de ictus isquémico, y por tanto, de morbimortalidad en nuestro medio. La detección de la misma en su fase asintomática mediante instrumentos como la función REGICOR, el grosor íntima-media y el índice tobillo-brazo podría mejorar las estrategias de prevención primaria. Comprobamos que, en nuestra cohorte de 933 sujetos sin antecedentes cardiovasculares, los tres factores (REGICOR≥10, GIM≥0.9, ITB≤ 0.9) se asociaron de forma independiente con la presencia de aterosclerosis cérvico-cerebral y de cualquier localización (extracraneal-intracraneal-combinada). La utilización conjunta de REGICOR e ITB podría facilitar el diagnóstico precoz de la aterosclerosis cérvico-cerebral subclínica.

OSIRISv1.2: a named entity recognition system for sequence variants of genes in biomedical literature

Background: Single Nucleotide Polymorphisms, among other type of sequence variants, constitute key elements in genetic epidemiology and pharmacogenomics. While sequence data about genetic variation is found at databases such as dbSNP, clues about the functional and phenotypic consequences of the variations are generally found in biomedical literature. The identification of the relevant documents and the extraction of the information from them are hampered by the large size of literature databases and the lack of widely accepted standard notation for biomedical entities. Thus, automatic systems for the identification of citations of allelic variants of genes in biomedical texts are required. Results: Our group has previously reported the development of OSIRIS, a system aimed at the retrieval of literature about allelic variants of genes http://ibi.imim.es/osirisform.html. Here we describe the development of a new version of OSIRIS (OSIRISv1.2, http://ibi.imim.es/OSIRISv1.2.html webcite) which incorporates a new entity recognition module and is built on top of a local mirror of the MEDLINE collection and HgenetInfoDB: a database that collects data on human gene sequence variations. The new entity recognition module is based on a pattern-based search algorithm for the identification of variation terms in the texts and their mapping to dbSNP identifiers. The performance of OSIRISv1.2 was evaluated on a manually annotated corpus, resulting in 99% precision, 82% recall, and an F-score of 0.89. As an example, the application of the system for collecting literature citations for the allelic variants of genes related to the diseases intracranial aneurysm and breast cancer is presented. Conclusion: OSIRISv1.2 can be used to link literature references to dbSNP database entries with high accuracy, and therefore is suitable for collecting current knowledge on gene sequence variations and supporting the functional annotation of variation databases. The application of OSIRISv1.2 in combination with controlled vocabularies like MeSH provides a way to identify associations of biomedical interest, such as those that relate SNPs with diseases.

How do coil configuration and packing density influence intra-aneurysmal hemodynamics?

Endovascular coiling is a well-established therapy for treating intracranial aneurysms. Nonetheless, postoperative hemodynamic changes induced by this therapy remain not fully understood. The purpose of this work is to assess the influence of coil configuration and packing density on intra-aneurysmal hemodynamics

Toward integrated management of cerebral aneurysms

In the last few years, some of the visionary concepts behind the virtual physiological human began to be demonstrated on various clinical domains, showing great promise for improving healthcare management. In the current work, we provide an overview of image- and biomechanics-based techniques that, when put together, provide a patient-specific pipeline for the management of intracranial aneurysms. The derivation and subsequent integration of morphological, morphodynamic, haemodynamic and structural analyses allow us to extract patient-specific models and information from which diagnostic and prognostic descriptors can be obtained. Linking such new indices with relevant clinical events should bring new insights into the processes behind aneurysm genesis, growth and rupture. The development of techniques for modelling endovascular devices such as stents and coils allows the evaluation of alternative treatment scenarios before the intervention takes place and could also contribute to the understanding and improved design of more effective devices. A key element to facilitate the clinical take-up of all these developments is their comprehensive validation. Although a number of previously published results have shown the accuracy and robustness of individual components, further efforts should be directed to demonstrate the diagnostic and prognostic efficacy of these advanced tools through large-scale clinical trials.

Automated Segmentation of Cerebral Vasculature with Aneurysms in 3DRA and TOF-MRA using Geodesic Active Regions: an Evaluation Study

Purpose: To evaluate the suitability of an improved version of an automatic segmentation method based on geodesic active regions (GAR) for segmenting cerebral vasculature with aneurysms from 3D X-ray reconstruc-tion angiography (3DRA) and time of °ight magnetic resonance angiography (TOF-MRA) images available in the clinical routine.Methods: Three aspects of the GAR method have been improved: execution time, robustness to variability in imaging protocols and robustness to variability in image spatial resolutions. The improved GAR was retrospectively evaluated on images from patients containing intracranial aneurysms in the area of the Circle of Willis and imaged with two modalities: 3DRA and TOF-MRA. Images were obtained from two clinical centers, each using di®erent imaging equipment. Evaluation included qualitative and quantitative analyses ofthe segmentation results on 20 images from 10 patients. The gold standard was built from 660 cross-sections (33 per image) of vessels and aneurysms, manually measured by interventional neuroradiologists. GAR has also been compared to an interactive segmentation method: iso-intensity surface extraction (ISE). In addition, since patients had been imaged with the two modalities, we performed an inter-modality agreement analysis with respect to both the manual measurements and each of the two segmentation methods. Results: Both GAR and ISE di®ered from the gold standard within acceptable limits compared to the imaging resolution. GAR (ISE, respectively) had an average accuracy of 0.20 (0.24) mm for 3DRA and 0.27 (0.30) mm for TOF-MRA, and had a repeatability of 0.05 (0.20) mm. Compared to ISE, GAR had a lower qualitative error in the vessel region and a lower quantitative error in the aneurysm region. The repeatabilityof GAR was superior to manual measurements and ISE. The inter-modality agreement was similar between GAR and the manual measurements. Conclusions: The improved GAR method outperformed ISE qualitatively as well as quantitatively and is suitable for segmenting 3DRA and TOF-MRA images from clinical routine.

Estudio prospectivo de la cefalea en pacientes con hemopatías malignas

Objetivo: describir las cefaleas en pacientes ingresados con neoplasias hematológicas, identificar los factores asociados a cefaleas secundarias graves. Estudio observacional prospectivo. Se incluyen 30 casos de cefalea correspondientes a 23 pacientes. Ocho cefaleas son primarias y 22 secundarias. Diez de estas, son secundarias a patología grave o potencialmente grave: encefalopatía hipertensiva, neoplasia intracraneal, hemorragia intracraneal, infección cefálica, trombosis venosa, fiebre tumoral e hipertensión sin encefalopatía. El riesgo de que una cefalea sea secundaria a patología grave es mayor en los casos que presentan esa cefalea por primera vez y en los que coincide con el debut de la enfermedad hematológica.

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

Background: Vorapaxar is a new oral protease-activatedreceptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. Methods: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (KaplanMeier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P = 0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P = 0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. Conclusions: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.)