Evolutionary analysis of genes of two pathways involved in placental malaria infection

Placental malaria is a special form of malaria that causes up to 200,000 maternal and infant deaths every year. Previous studies show that two receptor molecules, hyaluronic acid and chondroitin sulphate A, are mediating the adhesion of parasite-infected erythrocytes in the placenta of patients, which is believed to be a key step in the pathogenesis of the disease. In this study, we aimed at identifying sites of malaria-induced adaptation by scanning for signatures of natural selection in 24 genes in the complete biosynthesis pathway of these two receptor molecules. We analyzed a total of 24 Mb of publicly available polymorphism data from the International HapMap project for three human populations with European, Asian and African ancestry, with the African population from a region of presently and historically high malaria prevalence. Using the methods based on allele frequency distributions, genetic differentiation between populations, and on long-range haplotype structure, we found only limited evidence for malaria-induced genetic adaptation in this set of genes in the African population; however, we identified one candidate gene with clear evidence of selection in the Asian population. Although historical exposure to malaria in this population cannot be ruled out, we speculate that it might be caused by other pathogens, as there is growing evidence that these molecules are important receptors in a variety of host-pathogen interactions. We propose to use the present methods in a systematic way to help identify candidate regions under positive selection as a consequence of malaria.

A targeted association study of immunity genes and networks suggests novel associations with placental malaria infection

A large proportion of the death toll associated with malaria is a consequence of malaria infection during pregnancy, causing up to 200,000 infant deaths annually. We previously published the first extensive genetic association study of placental malaria infection, and here we extend this analysis considerably, investigating genetic variation in over 9,000 SNPs in more than 1,000 genes involved in immunity and inflammation for their involvement in susceptibility to placental malaria infection. We applied a new approach incorporating results from both single gene analysis as well as gene-gene interactionson a protein-protein interaction network. We found suggestive associations of variants in the gene KLRK1 in the single geneanalysis, as well as evidence for associations of multiple members of the IL-7/IL-7R signalling cascade in the combined analysis. To our knowledge, this is the first large-scale genetic study on placental malaria infection to date, opening the door for follow-up studies trying to elucidate the genetic basis of this neglected form of malaria.

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.

Deployment of self-expandable stents in aneurysmatic cerebral vessels: comparison of different computational approaches for interventional planning

In the last few years, there has been a growing focus on faster computational methods to support clinicians in planning stenting procedures. This study investigates the possibility of introducing computational approximations in modelling stent deployment in aneurysmatic cerebral vessels to achieve simulations compatible with the constraints of real clinical workflows. The release of a self-expandable stent in a simplified aneurysmatic vessel was modelled in four different initial positions. Six progressively simplified modelling approaches (based on Finite Element method and Fast Virtual Stenting – FVS) have been used. Comparing accuracy of the results, the final configuration of the stent is more affected by neglecting mechanical properties of materials (FVS) than by adopting 1D instead of 3D stent models. Nevertheless, the differencesshowed are acceptable compared to those achieved by considering different stent initial positions. Regarding computationalcosts, simulations involving 1D stent features are the only ones feasible in clinical context.

Morphodynamic analysis of cerebral aneurysm pulsation from time-resolved rotational angiography

This paper presents a technique to estimate and model patient-specific pulsatility of cerebral aneurysms over onecardiac cycle, using 3D rotational X-ray angiography (3DRA) acquisitions. Aneurysm pulsation is modeled as a time varying-spline tensor field representing the deformation applied to a reference volume image, thus producing the instantaneousmorphology at each time point in the cardiac cycle. The estimated deformation is obtained by matching multiple simulated projections of the deforming volume to their corresponding original projections. A weighting scheme is introduced to account for the relevance of each original projection for the selected time point. The wide coverage of the projections, together with the weighting scheme, ensures motion consistency in all directions. The technique has been tested on digital and physical phantoms that are realistic and clinically relevant in terms of geometry, pulsation and imaging conditions. Results from digital phantomexperiments demonstrate that the proposed technique is able to recover subvoxel pulsation with an error lower than 10% of the maximum pulsation in most cases. The experiments with the physical phantom allowed demonstrating the feasibility of pulsation estimation as well as identifying different pulsation regions under clinical conditions.

Detecció automàtica de punts facials característics mitjançant un algoritme inspirat en el còrtex cerebral

En aquest article presentem l'aplicació d'un algoritme inspirat en el còrtex cerebral anomenat HMAX com a part central d'un procés de detecció automàtica de punts facials característics en imatges.

Fighting against Malaria: Prevent wars while waiting for the "miraculous" vaccine

The World Health Organization estimates that 300 million clinical cases of malaria occur annually and observed that during the 80's and part of the 90's its incidence increased. In this paper we explore the influence of refugees from civil wars on the incidence of malaria in the refugee-receiving countries. Using civil wars as an instrumental variable we show that for each 1,000 refugees there are between 2,000 and 2,700 cases of malaria in the refugee receiving country. On average 13% of the cases of malaria reported by the WHO are caused by forced migration as a consequence of civil wars.

Glibenclamide enhances neurogenesis and improves long-term functional recovery after transient focal cerebral ischemia

Glibenclamide is neuroprotective against cerebral ischemia in rats. We studied whether glibenclamide enhances long-term brain repair and improves behavioral recovery after stroke. Adult male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 90 minutes. A low dose of glibenclamide (total 0.6mg) was administered intravenously 6, 12, and 24 hours after reperfusion. We assessed behavioral outcome during a 30-day follow-up and animals were perfused for histological evaluation. In vitro specific binding of glibenclamide to microglia increased after pro-inflammatory stimuli. In vivo glibenclamide was associated with increased migration of doublecortin-positive cells in the striatum toward the ischemic lesion 72 hours after MCAO, and reactive microglia expressed sulfonylurea receptor 1 (SUR1) and Kir6.2 in the medial striatum. One month after MCAO, glibenclamide was also associated with increased number of NeuN-positive and 5-bromo-2-deoxyuridine-positive neurons in the cortex and hippocampus, and enhanced angiogenesis in the hippocampus. Consequently, glibenclamide-treated MCAO rats showed improved performance in the limb-placing test on postoperative days 22 to 29, and in the cylinder and water-maze test on postoperative day 29. Therefore, acute blockade of SUR1 by glibenclamide enhanced long-term brain repair in MCAO rats, which was associated with improved behavioral outcome.

Evaluación económica de la determinación del propéptido natriurético cerebral N-terminal (NT-proBNP) en pacientes con disnea en los servicios de urgencias españoles

Introducción: Analizar la eficiencia de añadir la determinación NT-proBNP al examen clínico convencional (ECC) para el diagnóstico de insuficiencia cardíaca (IC) en pacientes con disnea que acuden a servicios de urgencias (SU) españoles. Material y métodos: Se desarrolló un árbol de decisión para evaluar los resultados clínicos y económicos de ambas alternativas durante 60 días de seguimiento desde la visita al SU en pacientes hospitalizados y no hospitalizados. Los parámetros clínicos fueron principalmente obtenidos del estudio PRIDE y validados por médicos de SU y cardiólogos. El punto de corte de la determinación NT-proBNP fue de 900 pg/mL (sensibilidad del 90% y especificidad del 85%). En base a datos espa noles publicados, se asumió que el 65% de pacientes con disnea sufrían IC. El uso de recursos fue identificado mediante opinión de expertos y evaluado desde la perspectiva del Sistema Nacional de Salud (SNS). El análisis comparó el diagnóstico final del paciente con el diagnóstico realizado en el SU. Se realizaron diversos análisis de sensibilidad para evaluar la incertidumbre del modelo. Resultados: El diagnóstico incorporando la determinación NT-proBNP fue correcto en el 91,96% de los pacientes (59,09% verdaderos positivos y 32,87% verdaderos negativos) frente al 85,53% mediante ECC (50,79% verdaderos positivos y 34,74% verdaderos negativos). La incorporación de la determinación NT-proBNP resultó tener un coste menor (3.720 versus 5.188 ). Los análisis de sensibilidad realizados confirmaron los resultados.

Cerebral infarction in diabetes: Clinical pattern, stroke subtypes,and predictors of in-hospital mortality

Background: To compare the characteristics and prognostic features of ischemic stroke in patients with diabetes and without diabetes, and to determine the independent predictors of in-hospital mortality in people with diabetes and ischemic stroke.Methods: Diabetes was diagnosed in 393 (21.3%) of 1,840 consecutive patients with cerebral infarction included in a prospective stroke registry over a 12-year period. Demographic characteristics, cardiovascular risk factors, clinical events, stroke subtypes, neuroimaging data, and outcome in ischemic stroke patients with and without diabetes were compared. Predictors of in-hospital mortality in diabetic patients with ischemic stroke were assessed by multivariate analysis. Results: People with diabetes compared to people without diabetes presented more frequently atherothrombotic stroke (41.2% vs 27%) and lacunar infarction (35.1% vs 23.9%) (P < 0.01). The in-hospital mortality in ischemic stroke patients with diabetes was 12.5% and 14.6% in those without (P = NS). Ischemic heart disease, hyperlipidemia, subacute onset, 85 years old or more, atherothrombotic and lacunar infarcts, and thalamic topography were independently associated with ischemic stroke in patients with diabetes, whereas predictors of in-hospital mortality included the patient's age, decreased consciousness, chronic nephropathy, congestive heart failure and atrial fibrillation. Conclusion: Ischemic stroke in people with diabetes showed a different clinical pattern from those without diabetes, with atherothrombotic stroke and lacunar infarcts being more frequent. Clinical factors indicative of the severity of ischemic stroke available at onset have a predominant influence upon in-hospital mortality and may help clinicians to assess prognosis more accurately.

RTS,S/AS02A malaria vaccine does not induce parasite CSP T cell epitope selection and reduces multiplicity of infection

Objective: The candidate malaria vaccine RTS,S/AS02A is a recombinant protein containing part of the circumsporozoite protein (CSP) sequence of Plasmodium falciparum, linked to the hepatitis B surface antigen and formulated in the proprietary adjuvant system AS02A. In a recent trial conducted in children younger than age five in southern Mozambique, the vaccinedemonstrated significant and sustained efficacy against both infection and clinical disease. In a follow-up study to the main trial, breakthrough infections identified in the trial were examined to determine whether the distribution of csp sequences was affected by the vaccine and to measure the multiplicity of infecting parasite genotypes. Design: P. falciparum DNA from isolates collected during the trial was used for genotype studies. Setting: The main trial was carried out in the Manhiça district, Maputo province, Mozambique, between April 2003 and May 2004. Participants: Children from the two cohorts of the main trial provided parasite isolates as follows: children from Cohort 1 who were admitted to hospital with clinical malaria; children from Cohort 1 who were parasite-positive in a cross-sectional survey at study month 8.5; children from Cohort 2 identified as parasite-positive during follow-up by active detection of infection. Outcome: Divergence of DNA sequence encoding the CSP T cell-epitope region sequence from that of the vaccine sequence was measured in 521 isolates. The number of distinct P. falciparum genotypes was also determined. Results: We found no evidence that parasite genotypes from children in the RTS,S/AS02A arm were more divergent than those receiving control vaccines. For Cohort 1 (survey at studymonth 8.5) and Cohort 2, infections in the vaccine group contained significantly fewer genotypes than those in the control group, (p 1/4 0.035, p 1/4 0.006), respectively, for the two cohorts. This was not the case for children in Cohort 1 who were admitted to hospital (p 1/4 0.478). Conclusions: RTS,S/AS02A did not select for genotypes encoding divergent T cell epitopes in the C-terminal region of CSP in this trial. In both cohorts, there was a modest reduction in the mean number of parasite genotypes harboured by vaccinated children compared with controls, but only among those with asymptomatic infections.

Parálisis cerebral. Tratamiento ortopodológico

Después de varios años de experiencia en la aplicación de las férulas estabilizadoras del sistema aquileocalcáneo plantar FESAP) en pacientes con parálisis cerebral, creemos que deberían ser el tratamiento ortopodológico de elección del pie equino en niños con miopatías y lesiones neurológlcas de la unidad motora, del sistema piramidal o extrapiramidal, tanto por su perfecta adaptación a la morfología de la extremidad inferior como por sus caracteristicas funcionales y sus acciones fisio1ógicas y terapéuticas.

El paciente con parálisis cerebral y su tratamiento odontoestomatológico

En el presente trabajo, se explican las características generales y odontoestomatológicas así como los tratamientos necesarios de los pacientes afectos de parálisis cerebral

Memòria, reorganització cerebral evidenciada amb fMRI i hipocamp

Aquesta pretén ser una revisió general dels processos cognitius normals i de la capacitat de reorganització cerebral en cas de dany cerebral adquirit (lesions i malalties neurodegeneratives).