Understanding the Differences of Danusertib's Residence Time in Aurora Kinases A/B: Dissociation Paths and Key Residues Identified using Conventional and Enhanced Molecular Dynamics Simulations.

The accurate experimental estimation of protein-ligand systems' residence time (τ) has become very relevant in drug design projects due to its importance in the last stages of refinement of the drug's pharmacodynamics and pharmacokinetics. It is now well-known that it is not sufficient to estimate the affinity of a protein-drug complex in the thermodynamic equilibrium process in in vitro experiments (closed systems), where the concentrations of the drug and protein remain constant. On the contrary, it is mandatory to consider the conformational dynamics of the system in terms of the binding and unbinding processes between protein and drugs in in vivo experiments (open systems), where their concentrations are in constant flux. This last model has been proven to dictate much of several drugs' pharmacological activities in vivo. At the atomistic level, molecular dynamics simulations can explain why some drugs are more effective than others or unveil the molecular aspects that make some drugs work better in one molecular target. Here, the protein kinases Aurora A/B, complexed with its inhibitor Danusertib, were studied using conventional and enhanced molecular dynamics (MD) simulations to estimate the dissociation paths and, therefore, the computational τ values and their comparison with experimental ones. Using classical molecular dynamics (cMD), three differential residues within the Aurora A/B active site, which seems to play an essential role in the observed experimental Danusertib's residence time against these kinases, were characterized. Then, using WT-MetaD, the relative Danusertib's residence times against Aurora A/B kinases were measured in a nanosecond time scale and were compared to those τ values observed experimentally. In addition, the potential dissociation paths of Danusertib in Aurora A and B were characterized, and differences that might be explained by the differential residues in the enzyme's active sites were found. In perspective, it is expected that this computational protocol can be applied to other protein-ligand complexes to understand, at the molecular level, the differences in residence times and amino acids that may contribute to it.

Crystal structure, quantum chemical insights, and molecular docking studies of Naryl-2-(N-disubstituted) acetamide compounds: potential inhibitors for neurodegenerative enzymes.

The increase in and concern about neurodegenerative diseases continue to grow in an increasingly long-lived world population. Therefore, the search for new drugs continues to be a priority for medicinal chemistry. We present here the synthesis of a series of compounds with acetamide nuclei. Their structures were established using UV-Visible, NMR, HRMS and IR techniques. Furthermore, we report the crystal structures that were obtained from compounds 5a-5d by X-ray diffraction. The compounds were evaluated as potential inhibitors of the monoxidase enzymes; A (MAO-A) and B (MAO-B), and cholinesterases; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) through in silico studies using the induced fit docking (IFD) method and binding free energy (ΔGbind) calculations by the MMGBSA method. Interestingly, compounds 5b, 5c and 5d showed much better ΔGbind than the reference drug Zonisamide. Compound 5c is the best in the series, which indicates a potential selective affinity of our compounds against MAO-B, which could be a promising finding in the search for new drugs for Parkinson's disease treatment. The acetamide crystal exhibits moderate NLO properties suggesting that it could be considered a potential candidate for application in nonlinear optical devices.

Selective TASK-1 Inhibitor with a Defined Structure-Activity Relationship Reduces Cancer Cell Proliferation and Viability.

Chemical structures of selective blockers of TASK channels contain aromatic groups and amide bonds. Using this rationale, we designed and synthesized a series of compounds based on 3-benzamidobenzoic acid. These compounds block TASK-1 channels by binding to the central cavity. The most active compound is 3-benzoylamino-N-(2-ethyl-phenyl)-benzamide or F3, blocking TASK-1 with an IC50 of 148 nM, showing a reduced inhibition of TASK-3 channels and not a significant effect on different K+ channels. We identified putative F3-binding sites in the TASK-1 channel by molecular modeling studies. Mutation of seven residues to A (I118A, L122A, F125A, Q126A, L232A, I235A, and L239A) markedly decreased the F3-induced inhibition of TASK-1 channels, consistent with the molecular modeling predictions. F3 blocks cell proliferation and viability in the MCF-7 cancer cell line but not in TASK-1 knockdown MCF-7 cells, indicating that it is acting in TASK-1 channels. These results indicated that TASK-1 is necessary to drive proliferation in the MCF-7 cancer cell line.

Identification of a critical binding site for local anaesthetics in the side pockets of Kv 1 channels.

BACKGROUND AND PURPOSE: Local anaesthetics block sodium and a variety of potassium channels. Although previous studies identified a residue in the pore signature sequence together with three residues in the S6 segment as a putative binding site, the precise molecular basis of inhibition of Kv channels by local anaesthetics remained unknown. Crystal structures of Kv channels predict that some of these residues point away from the central cavity and face into a drug binding site called side pockets. Thus, the question arises whether the binding site of local anaesthetics is exclusively located in the central cavity or also involves the side pockets. EXPERIMENTAL APPROACH: A systematic functional alanine mutagenesis approach, scanning 58 mutants, together with in silico docking experiments and molecular dynamics simulations was utilized to elucidate the binding site of bupivacaine and ropivacaine. KEY RESULTS: Inhibition of Kv 1.5 channels by local anaesthetics requires binding to the central cavity and the side pockets, and the latter requires interactions with residues of the S5 and the back of the S6 segments. Mutations in the side pockets remove stereoselectivity of inhibition of Kv 1.5 channels by bupivacaine. Although binding to the side pockets is conserved for different local anaesthetics, the binding mode in the central cavity and the side pockets shows considerable variations. CONCLUSION AND IMPLICATIONS: Local anaesthetics bind to the central cavity and the side pockets, which provide a crucial key to the molecular understanding of their Kv channel affinity and stereoselectivity, as well as their spectrum of side effects.

Molecular Pharmacology of K2P Potassium Channels.

Potassium channels of the tandem of two-pore-domain (K2P) family were among the last potassium channels cloned. However, recent progress in understanding their physiological relevance and molecular pharmacology revealed their therapeutic potential and thus these channels evolved as major drug targets against a large variety of diseases. However, after the initial cloning of the fifteen family members there was a lack of potent and/or selective modulators. By now a large variety of K2P channel modulators (activators and blockers) have been described, especially for TASK-1, TASK-3, TREK-1, TREK2, TRAAK and TRESK channels. Recently obtained crystal structures of K2P channels, alanine scanning approaches to map drug binding sites, in silico experiments with molecular dynamics simulations (MDs) combined with electrophysiological studies to reveal the mechanism of channel inhibition/activation, yielded a good understanding of the molecular pharmacology of these channels. Besides summarizing drugs that were identified to modulate K2P channels, the main focus of this article is on describing the differential binding sites and mechanisms of channel modulation that are utilized by the different K2P channel blockers and activators.

Elucidating the Structural Basis of the Intracellular pH Sensing Mechanism of TASK-2 K2P Channels.

Two-pore domain potassium (K2P) channels maintain the cell's background conductance by stabilizing the resting membrane potential. They assemble as dimers possessing four transmembrane helices in each subunit. K2P channels were crystallized in "up" and "down" states. The movements of the pore-lining transmembrane TM4 helix produce the aperture or closure of side fenestrations that connect the lipid membrane with the central cavity. When the TM4 helix is in the up-state, the fenestrations are closed, while they are open in the down-state. It is thought that the fenestration states are related to the activity of K2P channels and the opening of the channels preferentially occurs from the up-state. TASK-2, a member of the TALK subfamily of K2P channels, is opened by intracellular alkalization leading the deprotonation of the K245 residue at the end of the TM4 helix. This charge neutralization of K245 could be sensitive or coupled to the fenestration state. Here, we describe the relationship between the states of the intramembrane fenestrations and K245 residue in TASK-2 channel. By using molecular modeling and simulations, we show that the protonated state of K245 (K245+) favors the open fenestration state and, symmetrically, that the open fenestration state favors the protonated state of the lysine residue. We show that the channel can be completely blocked by Prozac, which is known to induce fenestration opening in TREK-2. K245 protonation and fenestration aperture have an additive effect on the conductance of the channel. The opening of the fenestrations with K245+ increases the entrance of lipids into the selectivity filter, blocking the channel. At the same time, the protonation of K245 introduces electrostatic potential energy barriers to ion entrance. We computed the free energy profiles of ion penetration into the channel in different fenestration and K245 protonation states, to show that the effects of the two transformations are summed up, leading to maximum channel blocking. Estimated rates of ion transport are in qualitative agreement with experimental results and support the hypothesis that the most important barrier for ion transport under K245+ and open fenestration conditions is the entrance of the ions into the channel.

TASK Channels Pharmacology: New Challenges in Drug Design.

Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the wild chemical space and unravel the molecular basis of the ion channels modulators binding mechanisms. TASK channels belong to the two-pore domain potassium channel family and are modulated by extracellular acidosis. They are extensively distributed along the cardiovascular and central nervous systems, and their expression is up- and downregulated in different cancer types, which makes them an attractive therapeutic target. However, TASK channels remain unexplored, and drugs designed to target these channels are poorly selective. Here, we review TASK channels properties and their known blockers and activators, considering the new challenges in ion channels drug design and focusing on the implementation of computational methodologies in the drug discovery process.

Structure/Activity Analysis of TASK-3 Channel Antagonists Based on a 5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine.

TASK-3 potassium (K+) channels are highly expressed in the central nervous system, regulating the membrane potential of excitable cells. TASK-3 is involved in neurotransmitter action and has been identified as an oncogenic K+ channel. For this reason, the understanding of the action mechanism of pharmacological modulators of these channels is essential to obtain new therapeutic strategies. In this study we describe the binding mode of the potent antagonist PK-THPP into the TASK-3 channel. PK-THPP blocks TASK-1, the closest relative channel of TASK-3, with almost nine-times less potency. Our results confirm that the binding is influenced by the fenestrations state of TASK-3 channels and occurs when they are open. The binding is mainly governed by hydrophobic contacts between the blocker and the residues of the binding site. These interactions occur not only for PK-THPP, but also for the antagonist series based on 5,6,7,8 tetrahydropyrido[4,3-d]pyrimidine scaffold (THPP series). However, the marked difference in the potency of THPP series compounds such as 20b, 21, 22 and 23 (PK-THPP) respect to compounds such as 17b, inhibiting TASK-3 channels in the micromolar range is due to the presence of a hydrogen bond acceptor group that can establish interactions with the threonines of the selectivity filter.

Identification of the A293 (AVE1231) Binding Site in the Cardiac Two-Pore-Domain Potassium Channel TASK-1: a Common Low Affinity Antiarrhythmic Drug Binding Site.

BACKGROUND/AIMS: The two-pore-domain potassium channel TASK-1 regulates atrial action potential duration. Due to the atrium-specific expression of TASK-1 in the human heart and the functional upregulation of TASK-1 currents in atrial fibrillation (AF), TASK-1 represents a promising target for the treatment of AF. Therefore, detailed knowledge of the molecular determinants of TASK-1 inhibition may help to identify new drugs for the future therapy of AF. In the current study, the molecular determinants of TASK-1 inhibition by the potent and antiarrhythmic compound A293 (AVE1231) were studied in detail. METHODS: Alanine-scanning mutagenesis together with two-electrode voltage-clamp recordings were combined with in silico docking experiments. RESULTS: Here, we have identified Q126 located in the M2 segment together with L239 and N240 of the M4 segment as amino acids essential for the A293-mediated inhibition of TASK-1. These data indicate a binding site which is different to that of A1899 for which also residues of the pore signature sequence and the late M4 segments are essential. Using in silico docking experiments, we propose a binding site at the lower end of the cytosolic pore, located at the entry to lateral side fenestrations of TASK-1. Strikingly, TASK-1 inhibition by the low affinity antiarrhythmic TASK-1 blockers propafenone, amiodarone and carvedilol was also strongly diminished by mutations at this novel binding site. CONCLUSION: We have identified the A293 binding site in the central cavity of TASK-1 and propose that this site might represent a conserved site of action for many low affinity antiarrhythmic TASK-1 blockers.

The molecular basis for an allosteric inhibition of K+-flux gating in K2P channels.

Two-pore-domain potassium (K2P) channels are key regulators of many physiological and pathophysiological processes and thus emerged as promising drug targets. As for other potassium channels, there is a lack of selective blockers, since drugs preferentially bind to a conserved binding site located in the central cavity. Thus, there is a high medical need to identify novel drug-binding sites outside the conserved lipophilic central cavity and to identify new allosteric mechanisms of channel inhibition. Here, we identified a novel binding site and allosteric inhibition mechanism, disrupting the recently proposed K+-flux gating mechanism of K2P channels, which results in an unusual voltage-dependent block of leak channels belonging to the TASK subfamily. The new binding site and allosteric mechanism of inhibition provide structural and mechanistic insights into the gating of TASK channels and the basis for the drug design of a new class of potent blockers targeting specific types of K2P channels.

Carcinomas sarcomatoides pulmonares primarios / Primary Pulmonary Sarcomatoid Carcinomas

Objetivo: Describir las características y el resultado del tratamiento quirúrgico de una serie de pacientes con carcinomas sarcomatoides pulmonares primarios (CSPP). Metodología: Estudio descriptivo de 11 pacientes con CSPP operados en el Servicio de Cirugía Torácica del Hospital Universitario 12 de Octubre de Madrid entre 2005 a 2009. Se analizó: edad, género, tipo histológico, estadio patológico, tipo de cirugía y supervivencia en meses. Resultados: Diez pacientes eran varones y 11 eran fumadores, con una edad media de 55 años. Los estadios patológicos fueron 4 estadios IIA, 3 estadios IIB, 2 estadios IB y 2 estadios IA. El tipo histológico más frecuente fue el carcinoma pleomórfico, con 5 casos. Se realizó resección completa en 10 casos, y 7 recibieron terapia adyuvante. Siete de ellos se encuentran libres de enfermedad en un periodo de seguimiento con una media de 49 meses. Conclusiones: La cirugía completa en estadios iniciales de los CSPP puede mejorar la supervivencia (AU)

Objective: To describe the characteristics and the result of surgical treatment in a series of patients with primary pulmonary sarcomatoid carcinoma (PSC). Methodology: A descriptive study of 11 patients with primary PSC who were treated by the Thoracic Surgery Department at the Hospital Universitario 12 de Octubre in Madrid (Spain) between 2005 and 2009. We analyzed age, gender, histologic type, pathological stage, type of surgery and survival (in months). Results: Ten patients were male and 11 were smokers; mean age of was 55. The pathologic stages were: 4 stage IIA, 3 stage IIB, 2 stage IB and 2 stage IA. The most frequent histologic type was pleomorphic carcinoma, which was found in 5 cases. Complete resection was performed in 10 cases, and 7 received adjuvant therapy. Seven are disease-free after a mean follow-up period of 49 months. Conclusions: Complete surgery in the initial stages of primary PSC can improve survival (AU)

Evolución y complicaciones del traumatismo torácico / Evolution and Complications of Chest Trauma

Objetivo: Describir las características clínicas y los factores de riesgo de los pacientes con traumatismo torácico, y evaluar su relación en el desarrollo de complicaciones. Metodología: Estudio de tipo descriptivo, prospectivo y analítico de una cohorte de pacientes con traumatismo torácico a los que se les hizo seguimiento durante un periodo de 30días. Se excluyeron pacientes con traumatismo craneoencefálico moderado a severo, fracturas de huesos largos, traumatismo abdominal, y pacientes que requirieron ventilación mecánica. Resultados: Un total 376 pacientes cumplieron criterios de inclusión, y de ellos 220 eran varones (58,5%). Las causas más frecuentes de traumatismo fueron las caídas (218 casos; 57,9%) y los accidentes de tráfico (57 casos; 15,1%). El tipo de traumatismo más frecuente fue la contusión costal (248 casos; 65,9%) y la fractura de un arco costal (61casos; 16,2%). Se observaron complicaciones en 43pacientes (11,4%), principalmente por hemotórax (13casos), neumotórax (9casos), neumonía (6casos) e insuficiencia renal aguda (4casos). De estos pacientes, 4fallecieron por neumonía y hemotórax. Treinta y tres pacientes (8,7%) fueron ingresados y 10 (2,6%) requirieron reingreso hospitalario. El riesgo de complicaciones aumenta significativamente en pacientes con más de 2 fracturas costales, en mayores de 85 años y en presencia de algunas comorbilidades como la EPOC y patologías que requieren anticoagulación. El riesgo de reingreso es mayor en pacientes con más de 60 años. Conclusiones: Los pacientes con traumatismo torácico que presentan algunas comorbilidades, son mayores de 85 años y tienen más de2 fracturas costales pueden presentar más complicaciones, y se deben considerar estos factores en su evaluación, manejo y seguimiento (AU)

Objective: To describe the clinical characteristics and risk factors of patients with chest trauma, and to evaluate their correlation with the development of complications. Methods: Descriptive, prospective and analytical study of a patient cohort with chest trauma who underwent follow-up for a period of 30days. Excluded from the study were those patients with moderate to severe traumatic brain injury, long-bone fractures, abdominal trauma and patients requiring mechanical ventilation. Results: A total of 376 patients met the inclusion criteria, 220 of whom were males (58.5%). The most frequent causes of trauma were falls (218 cases; 57.9%) and motor vehicle accidents (57 cases; 15.1%). The most frequent type of trauma was rib contusion (248 cases; 65.9%) and rib fractures (61 cases; 16.2%). Complications were observed in 43 patients (11.4%), mainly hemothorax (13 cases), pneumothorax (9 cases), pneumonia (6 cases) and acute renal failure (4 cases). Four patients died due to pneumonia and hemothorax. Thirty-three patients were hospitalized (8.7%) and 10 (2.6%) required later re-admittance. The risk for complications increased significantly in patients with more than 2 rib fractures, in those over the age of 85 and in the presence of certain comorbidities, such as COPD and pathologies requiring anticoagulation therapy. The risk for re-admittance is higher in patients over the age of 60. Conclusions: Patients with chest trauma who present certain comorbidities, are over the age of 85 and have more than 2 rib fractures may present more complications. These factors should be contemplated in the evaluation, management and follow-up of these subjects (AU)

Evolution and complications of chest trauma.

OBJECTIVE: To describe the clinical characteristics and risk factors of patients with chest trauma, and to evaluate their correlation with the development of complications. METHODS: Descriptive, prospective and analytical study of a patient cohort with chest trauma who underwent follow-up for a period of 30 days. Excluded from the study were those patients with moderate to severe traumatic brain injury, long-bone fractures, abdominal trauma and patients requiring mechanical ventilation. RESULTS: A total of 376 patients met the inclusion criteria, 220 of whom were males (58.5%). The most frequent causes of trauma were falls (218 cases; 57.9%) and motor vehicle accidents (57 cases; 15.1%). The most frequent type of trauma was rib contusion (248 cases; 65.9%) and rib fractures (61 cases; 16.2%). Complications were observed in 43 patients (11.4%), mainly hemothorax (13 cases), pneumothorax (9 cases), pneumonia (6 cases) and acute renal failure (4 cases). Four patients died due to pneumonia and hemothorax. Thirty-three patients were hospitalized (8.7%) and 10 (2.6%) required later re-admittance. The risk for complications increased significantly in patients with more than 2 rib fractures, in those over the age of 85 and in the presence of certain comorbidities, such as COPD and pathologies requiring anticoagulation therapy. The risk for re-admittance is higher in patients over the age of 60. CONCLUSIONS: Patients with chest trauma who present certain comorbidities, are over the age of 85 and have more than 2 rib fractures may present more complications. These factors should be contemplated in the evaluation, management and follow-up of these subjects.

Primary pulmonary sarcomatoid carcinomas.

OBJECTIVE: To describe the characteristics and the result of surgical treatment in a series of patients with primary pulmonary sarcomatoid carcinoma (PSC). METHODOLOGY: A descriptive study of 11 patients with primary PSC who were treated by the Thoracic Surgery Department at the Hospital Universitario 12 de Octubre in Madrid (Spain) between 2005 and 2009. We analyzed age, gender, histologic type, pathological stage, type of surgery and survival (in months). RESULTS: Ten patients were male and 11 were smokers; mean age of was 55. The pathologic stages were: 4 stage IIA, 3 stage IIB, 2 stage IB and 2 stage IA. The most frequent histologic type was pleomorphic carcinoma, which was found in 5 cases. Complete resection was performed in 10 cases, and 7 received adjuvant therapy. Seven are disease-free after a mean follow-up period of 49 months. CONCLUSIONS: Complete surgery in the initial stages of primary PSC can improve survival.

Vivir la violencia materna: la voz de los niños y las niñas / Viver a violência materna: as vozes dos meninos e das meninas / Experiencing maternal violence: the voice of children

El presente artículo informa acerca del significado que un grupo de hijos e hijas de madres que se nombran como maltratadoras le atribuyen a este vínculo afectivo. Método: fenomenológico-hermenéutico del enfoque comprensivo-cualitativo con muestra multinivel. Técnicas de Producción de Información para el estudio general: entrevistas en profundidad con madres, grupos focales con sus hijos e hijas y con padres y madres de tres instituciones educativas. Aquí se desarrollan los hallazgos de los grupos focales con los hijos e hijas. Conclusiones: la violencia materna genera un estilo comunicacional fundamento en el desencuentro vincular; los niños y niñas que creen poder “torcer el destino”, tienen unas estrategias de resistencia contra la violencia materna; el sentirse reconocido y captado en una trama vincular hace resilientes a los niños y niñas y, finalmente, se ratifica la importancia de un tercero que regule la violencia materna.

O presente artigo informa a respeito do significado que um grupo de filhos e filhas de mães que se nomeiam como maltratadoras lhe atribuem a este vínculo afectivo. Método: fenomenológico-hermenêutico do enfoque compreensivo qualitativo com uma amostra multi-nível. Têcnicas de Produção de Informação: entrevistas emprofundidadecom as mães, grupos focales comseusfilhos e filhas e compais e mães de trêsinstituições educativas. Aqui desenvolvem-se os achados dos grupos focales com os filhos e filhas. Conclusões: a violência materna geraum estilo comunicacional baseado no desencontro vincular; os meninos e as meninas que acreditam poder “torcer o destino”têmestratégias de resistência contra a violência materna; sentir-se reconhecido e captado numa trama vincular faz resilientesaos meninos e meninas e, finalmente, a importância de umterceiro para regular a violência materna é confirmada.

This article provides information regarding the meaning that a group of sons and daughters place in their affective bonding with their mothers, who consider themselves mistreating mothers. Method: a phenomenologicalhermeneutic method following a qualitative-comprehensive approach with multilevel sampling. Data generation techniques for the general study: in-depth interviews with mothers, and focus groups with their children. We also used focus groups with parents from three different educational institutions. It was there where we developed the findings obtained from using the focal groups technique with the children. Conclusions: we conclude that (1) maternal violence creates a communication style based on a disagreement of bonds; (2) children who believe they can “bend destiny” have some strategies for withstanding maternal violence; (3) the feeling of recognition and belonging to a weave of bonds builds resilience in children; and (4) this study confirms the importance of a third party that regulates maternal violence.

Condiciones de favorabilidad al maternaje y violencia materna / Condições de favorabilidade à maternagem e violência materna / Maternal violence in childhood and the conditions that bring about mothering

Realizamos un acercamiento al problema de las prácticas de violencia materna hacialos niños y niñas y su impacto en el vínculo materno-filial. Objetivo: reconocer en madres que se nombrancomo maltratadoras, y en sus hijos e hijas maltratados, el significado dado a su vínculo afectivo. Método:fenomenológico-hermenéutico del enfoque cualitativo con muestra multinivel. Técnicas de Producción deInformación: entrevistas en profundidad con madres, grupos focales con sus hijos e hijas y con madres y padres detres instituciones educativas. Conclusiones: las madres explican la violencia hacia sus hijos e hijas acudiendo auna cadena vincular generacional con su propia madre; las condiciones de favorabilidad al maternaje adversaspredicen tal violencia; no todo niño o niña violentado será padre violento o madre violenta y, finalmente,postulamos que existe una tipología de madre violenta.

Realizamos uma aproximação ao problema das práticas da violência materna contra as criançase seu impacto no vínculo materno-filial. Objetivo: reconhecer em mães que se nomeiam como maltratadoras, e emseus filhos e filhas maltratados, o significado dado ao seu vínculo afetivo. Método: fenomenológico-hermenêuticode abordagem qualitativa com amostra multinível. Técnicas de Produção de Informação: entrevistas emprofundidade com mães, grupos focais com seus filhos e filhas e com mães e pais de três instituições educativas.Conclusões: as mães explicam a violência contra seus filhos e filhas acudindo a uma cadeia vincular com suaprópria mãe; as condições de favorabilidade à maternagem adversas predizem tal violência; nem toda criançaviolentada será pai ou mãe violenta e, finalmente, postulamos que existe uma tipología de mãe violenta.

This paper is the result of a study that approaches the issue of maternal violence towardschildren and its influence in the mother-child bond. Objective of the study: to analyze the narratives of bothself-recognized mistreating mothers and their children, in order to identify the meaning given to their bonding.Method: a phenomenological-hermeneutic method from the qualitative comprehensive approach, with multilevelsampling. Data Generation Techniques: in-depth interviews with mothers, and focus groups with children and parents from three educational institutions. Conclusions: mothers explain the violence towards their children byresorting to a generational chain of bonds with their own mother; the conditions that have an adverse effect onmothering predict the appearance of maternal violence; and, not every mistreated child will be a mistreatingparent. Finally, the existence of a typology of the mother who mistreats her children is proposed.• Keywords: mother-child bond, maternal violence, individuation, mothering, care.

El acto médico como ética de la relación / Medical action as the ethics of relationships

El presente trabajo, de carácter documental, aborda el problema de las éticas posibles en la vivencia del acto médico, el cual es concebido no solamente como acto terapéutico sino también ético llevado a cabo por el profesional de la salud. Se concluye que el acto médico puede ser vivido como expresión de dos grandes posiciones éticas: una de ellas ha sido denominada ética instrumental, en la que la palabra desplegada en el acto que realiza el profesional tiene un valor instrumental; la otra se ha llamado ética intersubjetiva, en la que la palabra ocupa un lugar privilegiado como posibilidad de restitución de la subjetividad del paciente y de construcción de un tejido relacional médicopaciente en el que acontezca la acción curativa. Se concluye, acorde con esta segunda posición ética, que la vocación médica implica que el médico cultive para sí y para sus pacientes una vida buena, virtuosa y estética, que promueva el bien pleno como criterio ético fundamental.

This documentary paper approaches the issue of the possible types of ethics that can be used in the medical practice, conceived as both therapeutic and ethical actions carried out by health professionals. It is concluded that medical action can be carried out as the expression of two main ethical approaches, namely: The instrumental ethics in which the discourse used by the professional during medical actions has an instrumental value. The second one is called intersubjective ethics, which considers that the aforementioned discourse has a special role, since it may restore the patient’s subjectivity and build a relational weave between the patient and the physician in which healing action can take place. It is concluded, in accordance with the second ethical approach, that medical vocation implies that physicians should develop a good, virtuous, and aesthetic life for themselves and for their patients.

Clínica Psicológica: una tercera vía a la centenaria discusión acerca de la crisis de la psicología y sus implicaciones para la psicología actual / Psychological Clinic: a third way to the centennial discussion about the crisis of psychology and its implications for current psychology

El presente artículo aborda el problema de la crisis de la psicología desde una perspectiva histórica, aludiendo a la visión particular que de ella poseen tres autores, a saber, Kurt Koffka (2001) con su artículo La introspección y el método de la psicología (1924), Liev Semiónovich Vigotsky (1997), quien escribe el texto El significado histórico de la crisis de la psicología. Una investigación metodológica ( 1927) y K. Koffka con su artículo La introspección y el método de la psicología . Los autores en mención realizan una caracterización de la crisis, intentando ofrecer algunos aportes para su comprensión e interpretación y plantean su opinión en lo que a la manera de resolver la crisis se refiere. Todos proponen una tercera vía.

This article addresses the problem of the crisis of psychology from a historical perspective, referring to the particular vision that three authors possess of it, namely, Kurt Koffka (2001) with his article The introspection and the method of psychology (1924 ), Liev Semiónovich Vigotsky (1997), who writes the text The historical significance of the crisis of psychology. A methodological investigation (1927) and K. Koffka with his article The introspection and the method of psychology. The authors in question make a characterization of the crisis, trying to offer some contributions for their understanding and interpretation and raise their opinion as to how the crisis is resolved. All propose a third way.

Aportes de Liev Semiónovich Vigotsky para una psicología de la postmodernidad / Contributions of Liev Semiónovich Vigotsky for a postmodern psychology

Se realiza un acercamiento a las obras de Liev Semiónovich Vigotsky El significado histórico de la crisis de la psicología. Una investigación metodológica (1927) y sobre el artículo de K. Koffka: "la introspección y el método de la psicología". A manera de introducción (1926) , extrayendo de ellas lo que el autor considera ha de ser el método indirecto de la psicología, a saber, la interpretación.

An approach is made to the works of Liev Semiónovich Vigotsky The historical significance of the crisis of psychology. A methodological investigation (1927) and on the article by K. Koffka: "introspection and the method of psychology". By way of introduction (1926), extracting from them what the author considers should be the indirect method of psychology, namely, interpretation.