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The phospholipase A2 (PLA2) superfamily consists of lipolytic enzymes that hydrolyze specific cell membrane phospholipids and have long been considered a central hub of biosynthetic pathways, where their lipid metabolites exert a variety of physiological roles. A misregulated PLA2 activity is associated with mainly inflammatory-derived pathologies and thus has shown relevant therapeutic potential. Many natural and synthetic anti-inflammatory drugs (AIDs) have been proposed as direct modulators of PLA2 activity. However, despite the specific chemical properties that these drugs share in common, little is known about the indirect modulation able to finely tune membrane structural changes at the precise lipid-binding site. Here, we use a novel experimental strategy based on differential scanning calorimetry to systematically study the structural properties of lipid membrane systems during PLA2 cleavage and under the influence of several AIDs. For a better understanding of the AIDs-membrane interaction, we present a comprehensive and comparative set of molecular dynamics (MD) simulations. Our thermodynamic results clearly demonstrate that PLA2 cleavage is hindered by those AIDs that significantly reduce the lipid membrane cooperativity, while the rest of the AIDs oppositely tend to catalyze PLA2 activity to different extents. On the other hand, our MD simulations support experimental results by providing atomistic details on the binding, insertion, and dynamics of each AID on a pure lipid system; the drug efficacy to impact membrane cooperativity is related to the lipid order perturbation. This work suggests a membrane-based mechanism of action for diverse AIDs against PLA2 activity and provides relevant clues that must be considered in its modulation.
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Simulação de Dinâmica Molecular , Fosfolipídeos , Fosfolipases A2/química , Fosfolipídeos/química , Membrana Celular/metabolismo , Fenômenos BiofísicosRESUMO
BACKGROUND: Nanomedicine and the pharmaceutical industry demand the investigation of new biomaterials to improve drug therapies. Combinations of lipids, proteins, and polymers represent innovative platforms for drug delivery. However, little is known about the interactions between such compounds and this knowledge is key to prepare successful drug delivery systems. METHODS: Biophysical properties of biohybrid vesicles (BhVs) composed of phospholipids, proteins, and amphiphilic block copolymers, assembled without using organic solvents, were investigated by differential scanning calorimetry and dynamic light scattering. We studied four biohybrid systems; two of them included the effect of incorporating tetracaine. Thermal changes of phospholipids and proteins when interacting with the amphiphilic block copolymers and tetracaine were analyzed. RESULTS: Lysozyme and the copolymers adsorb onto the lipid bilayer modifying the phase transition temperature, enthalpy change, and cooperativity. Dynamic light scattering investigations revealed relevant changes in the size and zeta potential of the BhVs. Interestingly, tetracaine, a membrane-active drug, can fluidize or rigidize BhVs. CONCLUSIONS: We conclude that positively charged regions of lysozyme are necessary to incorporate the block copolymer chains into the lipid membrane, turning the bilayer into a more rigid system. Electrostatic properties and the hydrophilic-lipophilic balance are determinant for the stability of biohybrid membranes. GENERAL SIGNIFICANCE: This investigation provides fundamental information associated with the performance of biohybrid drug delivery systems and can be of practical significance for designing more efficient drug nanocarriers.
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Lipossomos , Polímeros , Lipossomos/química , Polímeros/química , Tetracaína , Muramidase , Bicamadas Lipídicas/química , Fosfolipídeos/química , ProteínasRESUMO
We demonstrate, experimentally and by molecular dynamics simulations, that krypton and xenon form nanostructured water-gas domains. High pressure was applied to force the inert gases to dissolve in water following Henry's law, then the liquid was depressurized, centrifuged, and inspected by dynamic light scattering. The observed objects have similar sizes and electrical properties to nanobubbles, but we found that they have fairly neutral buoyancy even at high gravitational fields. We posit that the formed nano objects are not bubbles but blobs, unique structures conceived as clathrate-hydrate precursors, thus resolving the so-called Laplace pressure bubble catastrophe.
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Phase transitions of liposomes are normally studied by differential scanning calorimetry. A suspension of liposomes is subjected to an increase (decrease) of temperature and when heat is absorbed (released), the liposomes transit from a gel (liquid) to a liquid (gel) phase. This endothermic (exothermic) process takes place at a temperature called the melting temperatureTm, which is distinctive of the type of lipids forming the vesicles. The vesicles, though, also modify their size in the transition. Indeed, the thickness of the membranes decreases (increases) because carbon tails misalign (align). Concomitant with the modifications in the membrane thickness, the diameter (D) of the liposomes changes too. Therefore, when they are inspected by light, the scattered signal carries information from such dilatation (contraction) process. We performed careful experiments using dynamic light scattering as a function of temperature to detect the size changes of different liposomes. Gaussian fits of the derivatives of theDvsTcurves coincide within 1% with thermograms, which hints to the possibility of performing thermodynamic studies of lipid systems employing light.
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Lipossomos , Fosfatidilcolinas , Varredura Diferencial de Calorimetria , Temperatura Alta , Luz , Lipossomos/química , Fosfatidilcolinas/química , Temperatura , TermodinâmicaRESUMO
After exciting scientific debates about its nature, the development of the exclusion zone, a region near hydrophilic surfaces from which charged colloidal particles are strongly expelled, has been finally traced back to the diffusiophoresis produced by unbalanced ion gradients. This was done by numerically solving the coupled Poisson equation for electrostatics, the two stationary Stokes equations for low Reynolds numbers in incompressible fluids, and the Nernst-Planck equation for mass transport. Recently, it has also been claimed that the leading mechanism behind the diffusiophoretic phenomenon is electrophoresis [Esplandiu et al., Soft Matter 16, 3717 (2020)]. In this paper, we analyze the evolution of the exclusion zone based on a one-component interaction model at the Langevin equation level, which leads to simple analytical expressions instead of the complex numerical scheme of previous works, yet being consistent with it. We manage to reproduce the evolution of the exclusion zone width and the mean-square displacements of colloidal particles we measure near Nafion, a perfluorinated polymer membrane material, along with all characteristic time regimes, in a unified way. Our findings are also strongly supported by complementary experiments using two parallel planar conductors kept at a fixed voltage, mimicking the hydrophilic surfaces, and some computer simulations.
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INTRODUCTION: In primary hip replacement, different materials are used for bearing surfaces. In our medium metal or ceramic heads with highly crossed-linked polyethylene (PA) are the most used. These combinations have good results, but it is not clear which is clinically superior. The objective of this study is to determine whether there is any clinically significant difference based on a systematic review of the literature and national registries of arthroplasty. MATERIAL AND METHODS: We conduct a systematic review of the literature and national registries of arthroplasty and we were looking for studies comparing bearing surfaces: ceramic-highly cross-linked polyethylene (CP) and metal-highly cross-linked polyethylene (MP); describing the revision rate according to the surface type with a minimum 10-year follow-up. The outcome evaluated was: review rate for any cause depending on surface type. RESULTS: Two out of fifteen national registries were included. The Australian registry shows a difference in the 15-year revision rate: CP: 6.3 (IC 5.8, 6.7) vs MP: 5.1 (IC 4.6, 5.7). The New Zealand registry shows no differences in revision rate/100 components/year: CP 0.54 (0.48-0.61) vs MP 0.61 (0.57-0.66). We do not find clinical studies with inclusion criteria that answer the research question. CONCLUSION: The results of this review show a high survival rate with the use of highly cross-linked polyethylene, the results are similar when using ceramic or metal heads.
INTRODUCCIÓN: En un reemplazo total de cadera primario (RTC), diferentes materiales son los que se usan para las superficies de apoyo. En nuestro medio, las cabezas de metal o cerámica con polietileno altamente entrecruzado (PA) son los más utilizados. Estas combinaciones tienen buenos resultados, pero no es claro cuál es superior clínicamente. Basados en una revisión sistemática de la literatura y de los registros nacionales de artroplastía, el objetivo de este estudio es determinar si existe alguna diferencia significativa desde el punto de vista clínico. MATERIAL Y MÉTODOS: Realizamos una revisión sistemática de la literatura y de los registros nacionales de artroplastía. Buscamos estudios en los que se compararan los tipos de superficie de contacto: cerámica-polietileno altamente entrecruzado (CP) y metal-polietileno altamente entrecruzado (MP), además de los registros nacionales de artroplastía que describieran, con un seguimiento mínimo de 10 años, la tasa de revisión según el tipo de superficie. El desenlace evaluado fue: tasa de revisión por cualquier causa según el tipo de superficie. RESULTADOS: Dos de quince registros nacionales fueron incluidos: el registro australiano muestra una diferencia en la tasa de revisión a 15 años, comparando CP: 6.3 (IC 5.8, 6.7) contra MP: 5.1 (IC 4.6, 5.7). El registro de Nueva Zelanda no muestra diferencias en la tasa de revisión/100 componentes/año: CP de 0.54 (0.48-0.61) en comparación con MP de 0.61 (0.57-0.66). No encontramos estudios clínicos con los criterios de inclusión que respondan la pregunta de investigación. CONCLUSIÓN: Los resultados de esta revisión muestran una alta supervivencia cuando se usa polietileno altamente entrecruzado; asimismo, los resultados son similares cuando se utilizan cabezas de cerámica o metálicas.
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Artroplastia de Quadril , Prótese de Quadril , Austrália , Cerâmica , Humanos , Polietileno , Desenho de Prótese , Falha de Prótese , ReoperaçãoRESUMO
Combined coarse-grained (CG) and atomistic molecular dynamics (MD) simulations were performed to study the interactions of xenon with model lipid rafts consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) and cholesterol (Chol). At a concentration of 2 Xe/lipid we observed an unexpected result: spontaneous nucleation of Xe nano bubbles which rapidly plunged into the bilayer. In this process Chol, essential for raft stabilization, was pulled out from the raft into the hydrophobic zone. When concentration was further increased (3 Xe/lipid), the bubbles increase in size and disrupted both the membrane and raft. We computed the radial distribution functions, pair-wise potentials, second virial coefficients and Schlitter entropy to scrutinize the nature of the interactions. Our findings, concurring with a recent report on the origin of general anaesthesia (M. A. Pavel, E. N. Petersen, H. Wang, R. A. Lerner and S. B. Hansen, Proc. Natl. Acad. Sci. U. S. A., 2020, 117(24), 13757-13766), suggest that the well-known anaesthetic effect of Xe could be mediated by sequestration of Chol, which, in turn, compromises the stability of rafts where specialized proteins needed to produce the nervous signal are anchored.
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Bicamadas Lipídicas , Fosfatidilcolinas , Colesterol , Microdomínios da Membrana , XenônioRESUMO
n-Aliphatic alcohols act as anesthetics only up to a certain chain length, beyond which its biological activity disappears. This is known as the 'cut-off' phenomenon. Although the most accepted explanation is based on action sites in membrane proteins, it is not well understood why alcohols alter their functions. The structural dependence of these protein receptors to lipid domains known as 'lipid rafts', suggests a new approach to tackle the puzzling phenomenon. In this work, by performing molecular dynamic simulations (MDS) to explore the lipid role, we provide relevant molecular details about the membrane-alcohol interaction at the cut-off point regime. Since the high variability of the cut-off points found on protein receptors in neurons may be a consequence of differences in the lipid composition surrounding such proteins, our results could have a clear-cut importance.
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Álcoois , Anestésicos , Lipídeos , Microdomínios da Membrana , Simulação de Dinâmica MolecularRESUMO
Despite decades of intense research to understand the phenomenon of anesthesia and its membrane-related changes in neural transmission, where lipids and proteins have been proposed as primary targets of anesthetics, the involved action mechanisms remain unclear. Based on the overall agreement that anesthetics and neurotransmitters induce particular modifications in the plasma membrane of neurons, triggering specific responses and changes in their energetic states, we present here a thermal study to investigate membrane effects in a lipid-protein model made of 1,2-dimyristoyl-sn-glycero-3-phosphocholine and albumin from chicken egg white under the influence of neurotransmitters and anesthetics. First, we observe how ovalbumin, ovotransferrin, and lysozyme (main albumin constituents from chicken egg white) interact with the lipid membrane enhancing their lipophilic character while exposing their hydrophobic domains. This produces a lipid separation and a more ordered hybrid lipid-protein assembly. Second, we measured the thermotropic changes of this assembly induced by acetylcholine, γ-aminobutiric acid, tetracaine, and pentobarbital. Although the protein in our study is not a receptor, our results are striking, for they give evidence of the great importance of non-specific interactions in the anesthesia mechanism.
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Anestésicos/farmacologia , Membranas Artificiais , Modelos Biológicos , Neurotransmissores/farmacologia , Temperatura , Albuminas , Animais , Galinhas , Dimiristoilfosfatidilcolina , Proteínas do Ovo , Interações Hidrofóbicas e Hidrofílicas , Lipídeos de Membrana , Proteínas de MembranaRESUMO
Photo-modulation with visible light has been used to induce gains in the motility of the sperms of rabbits, boars, buffalo, bulls, fish, and humans. Although different hypotheses have been proposed to explain such an effect, the origin and mechanisms by which visible light affects sperm motility are still far from being completely understood. Several groups have observed changes in the intracellular Ca2+ concentration and significant differences in the production of ROS, which are attributed to specific photosensitizers. Also, it has been reported that blue light induces nitric oxide production in sperm cells, which plays a vital role in acrosome reaction and capacitation leading to an augmentation in the fertilisation probability. In the present work, we study the effects of green light (490-540 nm) on the sperm motility of mice. Firstly, we carried out experiments at 37 °C to confirm what previous researchers have observed before using red and blue light: that the overall sperm motility increases. Secondly, we studied the effects of green light at 10 °C and found that the motility drastically diminishes. In order to understand this opposing outcome, we carried out fluorescence measurements to evaluate reactive oxygen species production induced by green light at both temperatures. Our results suggest that the balance between the use and generation of ROS at 37 °C is favorable to the cells, while at 10 °C it is harmful.
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Luz , Motilidade dos Espermatozoides/efeitos da radiação , Espermatozoides/metabolismo , Animais , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Espermatozoides/efeitos da radiação , TemperaturaRESUMO
Local anaesthetics are among the most used drugs in clinical practice, but once they are released to the environment, the effects on the aquatic fauna remain uncertain. This study evaluates, for the first time, the impact of tetracaine, lidocaine and bupivacaine on the survival rate and physiological effects of cladocera Daphnia magna. Video-tracking and image processing allowed us to obtain changes in behaviour parameters like swimming average velocity and mean square displacement. We found that tetracaine shows the most severe effect. A high-speed microscopy system was also used to determine the response of D. magna heart to these drugs. Our results show that tetracaine presents dose-dependent area reduction during all cardiac cycle, while bupivacaine and lidocaine did not present significative effects on heart size. The tested drugs, at environmental high concentrations, altered behaviour, heart function and survival of D. magna.
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Anestésicos Locais/toxicidade , Daphnia/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Microscopia , NataçãoRESUMO
We study how cell motility affects the stains left by the evaporation of droplets of a biofluid suspension containing mouse spermatozoa. The suspension, which contains also a high concentration of salts usually needed by motile cells, forms, upon drying, a crystallized pattern. We examine the structural characteristics of such patterns by optical microscopy. The analysis reveals that cell motility affects the formation of elongated crystals with lateral tips, as well as the creation of interlocked aggregates. We prove that a lacunarity algorithm based on polar symmetry, distinguishes among deposits generated by motile and non-motile cells with an accuracy greater than 95%.
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Corantes/química , Espermatozoides/citologia , Algoritmos , Animais , Corantes/síntese química , Epididimo/citologia , Masculino , Camundongos , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
The propagation of sound waves on lipid monolayers supported on water has been previously studied during the melting transition. Since changes in volume, area, and compressibility in lipid membranes have biological relevance, the observed sound propagation is of paramount importance. However, it is unknown what would occur on a lipid bilayer, which is a more approximate model of a cell membrane. With the aim to answer this relevant question, we built an experimental setup to assemble long artificial lipid membranes. We found that if these membranes are heated in order to force local melting, a thermo-mechanical perturbation propagates a long distance. Our findings may support the existence of solitary waves, postulated to explain the propagation of isentropic signals together with the action potential in neurons.
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Membrana Celular/metabolismo , Fenômenos Mecânicos , Temperatura , Fenômenos Biomecânicos , Neurônios/citologiaRESUMO
Chromatography is, at present, the most used technique to determine the purity of alcoholic drinks. This involves a careful separation of the components of the liquid elements. However, since this technique requires sophisticated instrumentation, there are alternative techniques such as conductivity measurements and UV-Vis and infrared spectrometries. We report here a method based on salt-induced crystallization patterns formed during the evaporation of alcoholic drops. We found that droplets of different samples form different structures upon drying, which we characterize by their radial density profiles. We prove that using the dried deposit of a spirit as a control sample, our method allows us to differentiate between pure and adulterated drinks. As a proof of concept, we study tequila.
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The evaporation of liquid droplets deposited on a substrate is a very complex phenomenon. Driven by capillary and Marangoni flows, particle-particle and particle-substrate interactions, the deposits they leave are vestiges of such complexity. We study the formation of patterns during the evaporation of liposome suspension droplets deposited on a hydrophobic substrate at different temperatures. We observed that as we change the temperature of the substrate, a morphological phase transition occurs at a given temperature Tm. This temperature corresponds to the gel-fluid lipid melting transition of the liposome suspension. Optical microscopy and atomic force microscopy are used to study the morphology of the patterns. Based on the radial density profiles we found that all structures can be classified into two groups: patterns composed by nearly uniform deposition (below Tm) and prominent structures containing randomly distributed voids (above Tm).
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1,2-Dipalmitoilfosfatidilcolina/química , Gotículas Lipídicas/química , Lipossomos/química , Fosfatidilgliceróis/química , Calorimetria , Interações Hidrofóbicas e Hidrofílicas , Gotículas Lipídicas/ultraestrutura , Lipossomos/ultraestrutura , Tamanho da Partícula , Transição de Fase , Propriedades de Superfície , TemperaturaRESUMO
Few years ago an article addressing the physics behind aaabstract paintings was published by Herczynski et al. (Phys. Today 64, 31 (2011) issue No. 6). The authors aimed to understand how artists like Jackson Pollock manipulated paints to create pieces of art where the theory of fluid dynamics had a clear and perceivable role. Scaling laws were found to explain the plasticity observed in the artists's traces that we admire in worldwide museums. Because sand drawings are not only wonderful artistic expressions but also intangible cultural heritages of humanity, we wonder if they could be analyzed in a similar fashion. Our goal is to explore the physics behind the formation of such drawings. In order to do so, we carry out experimental studies on the formation of sand cavities, furrows and piles, which individually or interconnected, give rise to artistic patterns. Moreover, in order to manipulate such three observables, some control parameters are needed. Altogether, they conform into simple exponential and power laws that collapse when a scaling is performed.
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Recent studies have shown that anesthetic agents alter the physical properties of lipid rafts on model membranes. However, if this destabilization occurs in brain membranes, altering the lipid raft-protein interaction, remains unknown. We analyzed the effects produced by pentobarbital (PB) on brain plasma membranes and lipid rafts in vivo. We characterized for the first time the thermotropic behavior of plasma membranes, synaptosomes, and lipid rafts from rat brain. We found that the transition temperature from the ordered gel to disordered liquid phase of lipids is close to physiological temperature. We then studied the effect of PB on protein composition of lipid rafts. Our results show a reduction of the total protein associated to rafts, with a higher reduction of the NMDAR compared to the GABAA receptor. Both receptors are considered the main targets of PB. In general, our results suggest that lipid rafts could be plausible mediators in anesthetic action.
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Encéfalo/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Pentobarbital/farmacologia , Receptores de GABA-A/genética , Receptores de N-Metil-D-Aspartato/genética , Anestesia , Animais , Encéfalo/metabolismo , Expressão Gênica , Hipnóticos e Sedativos/metabolismo , Masculino , Microdomínios da Membrana/química , Microdomínios da Membrana/metabolismo , Pentobarbital/metabolismo , Ratos , Ratos Wistar , Receptores de GABA-A/biossíntese , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/biossíntese , Sinaptossomos/química , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Temperatura de TransiçãoRESUMO
We study how a magnetic bead bounces onto a horizontal diamagnetic conducting plane. The bead, falling down by gravity from a certain height, produces an Eddy current that creates a repelling force. For low velocities the bead is trapped by the surface, for intermediate ones it escapes. In such a case the induced current changes its sign, and so does the force. The balance between diamagnetic and viscoelastic interactions determines the bouncing dynamics. We find experimentally the restitution coefficient as a function of the impact speed of the bead and develop, taking into account simple energetic considerations, a model able to reproduce our findings.
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Magnetismo , Microesferas , Elasticidade , Gravitação , ViscosidadeRESUMO
Granular self-assembly of confined non-Brownian spheres under gravity is studied by molecular dynamics simulations. Starting from a disordered phase, dry or cohesive spheres organize, by vibrational annealing, into body-centered-tetragonal or face-centered-cubic structures, respectively. During the self-assembling process, isothermal and isodense points are observed. The existence of such points indicates that both granular temperature and packing fraction undergo an inversion process that may be in the core of crystal nucleation. Around the isothermal point, a sudden growth of granular clusters having the maximum coordination number takes place, indicating the outcome of a first-order phase transition. We propose a heuristic equation that successfully describes the dynamic evolution of the local packing fraction in terms of the local granular temperature, along the entire crystallization process.
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OBJETIVO: Presentar nuestra experiencia en el manejo de los cavernomas de tronco cerebral, de tálamo y de ganglios basales. MATERIAL Y MÉTODO: Analizamos una serie de 16 pacientes asistidos en nuestra Institución, entre enero de 1990 y diciembre del año 2013. De ellos, 9 fueron varones y 7 mujeres. El rango de edad osciló entre 3 y 61 años. RESULTADOS: Siete debutaron con hemorragia cerebral, de ellos 4 se localizaban en protuberancia y 3 en el bulbo raquídeo. Siete pacientes tuvieron cavernomas múltiples, de ellos 3 tenían familiares con la misma enfermedad. El procedimiento diagnóstico de elección fue la resonancia nuclear magnética de cerebro en todos, y en los pacientes con cavernomas múltiples se completó el estudio con resonancia nuclear magnética de médula espinal. El tratamiento fue conservador en 9 enfermos, quirúrgico en 6 y radiocirugía estereotáctica en 1 enfermo; a éste paciente hubo necesidad de operarlo 6 meses después del tratamiento radiante por un resangrado voluminoso en la protuberancia. DISCUSIÓN: La cirugía es exitosa cuando el cavernoma se ubica a 2 mm de la piamadre, o del epéndimo. La radiocirugía puede ser causante de resangrado y de mayor volumen que las hemorragias previas. Por último, el tratamiento conservador sigue teniendo vigencia en los pacientes que se recuperaron neurológicamente y cuando se ubican en la profundidad del tronco cerebral, tálamo óptico o ganglios basales. CONCLUSIÓN: Cada paciente debe evaluarse individualmente para decidir el tipo de tratamiento, teniendo en cuenta la edad, la recuperación de los signos neurológicos, el volumen y la localización precisa del cavernoma
Objective: To present our experience in the management of brainstem, thalamus and basal ganglia cavernous malformations. Material and Method: We analyzed a series of 16 patients admitted to our Institution between January 1990 and December 2013. Nine of them were male and 7 female. Age ranged between 3 and 61. Results: Seven patients presented brainstem hemorrhage, 4 being pontine and the remaining 3 were medullary. Seven patients had multiple cavernomas, and 3 of them had a family background with the disease. The chosen diagnostic procedure was brain MRI in all patients; in patients with multiple cavernomas spine MRI was also requested. Nine patients received conservative treatment, 6 patients underwent surgery and one was treated with stereotactic radiosurgery but had to be operated on six months after radiation treatment due to voluminous re-bleeding at protuberance. Discussion: Surgery is successful when the cavernous malformation is placed 2 mm away from pia mater or ependyma. Radiosurgery can cause re-bleeding and of a greater volume than previous hemorrhages. Finally, conservative treatment is useful in patients who get neurologically recovered and when malformations are placed deep in brainstem, optic thalamus or basal ganglia. Conclusion: Each patient has to be individually assessed to individually assessed to make a decision regarding the type of treatment, taking into account age, recovery of neurological signs, volume, and precise location of cavernous malformation