Morphological differentiation of peritumoral brain zone microglia.

The Peritumoral Brain Zone (PBZ) contributes to Glioblastoma (GBM) relapse months after the resection of the original tumor, which is influenced by a variety of pathological factors. Among those, microglia are recognized as one of the main regulators of GBM progression and probably relapse. Although microglial morphology has been analyzed inside GBM and its immediate surroundings, it has not been objectively characterized throughout the PBZ. Thus, we aimed to perform a thorough characterization of microglial morphology in the PBZ and its likely differentiation not just from the tumor-associated microglia but from control tissue microglia. For this purpose, Sprague Dawley rats were intrastriatally implanted with C6 cells to induce a GBM formation. Gadolinium-based magnetic resonance imaging (MRI) was performed to locate the tumor and to define the PBZ (2 mm beyond the tumor border), thus delimitating the different regions of interest (ROIs: core tumoral zone and immediate interface; contralateral striatum as control). Brain slices were obtained and immunolabeled with the microglia marker Iba-1. Sixteen morphological parameters were measured for each cell, significative differences were found in all parameters when comparing the four ROIs. To determine if PBZ microglia could be morphologically differentiated from microglia in other ROIs, hierarchical clustering analysis was performed, revealing that microglia can be separated into four morphologically differentiated clusters, each of them mostly integrated by cells sampled in each ROI. Furthermore, a classifier based on linear discriminant analysis, including only three morphological parameters, categorized microglial cells across the studied ROIs and showed a gradual transition between them. The robustness of this classification was assessed through principal component analysis with the remaining 13 morphological parameters, corroborating the obtained results. Thus, in this study we provided objective and quantitative evidence that PBZ microglia represent a differentiable microglial morphotype that could contribute to the recurrence of GBM in this area.

N-(levodopa) chitosan derivative based on click chemistry shows biological functionality in brain cells.

OBJECTIVE: To develop N-(levodopa) chitosan derivatives through click chemistry to study their effect in brain cells.Significance: This study presents a proof-of-concept that macromolecules such as N-(Levodopa) chitosan derivatives traverse brain cell membranes and induce biomedical functionalities. METHODS: Through click chemistry, we developed N-(levodopa) chitosan derivatives. They were physically and chemically characterized by FT-IR, 1H-NMR, TGA and Dynamic Light Scattering analyses. Solution and nanoparticles of N-(levodopa) chitosan derivatives were tested in primary cell cultures from the postnatal rat olfactory bulb, substantia nigra and corpus callosum. Ca2+ imaging and UPLC experiments were used to investigate if the biomaterial modulated the brain cell physiology. RESULTS: N-(levodopa) chitosan derivatives induced intracellular Ca2+ responses in primary cell cultures of the rat brain. UPLC experiments indicated that levodopa attached to chitosan was converted into dopamine by brain cells. CONCLUSION: The present study shows that N-(levodopa) chitosan may be useful to develop new treatment strategies, which could serve as molecular reservoirs of biomedical drugs to treat degenerative disorders of the nervous system.

Differentiation of circulating monocytes into macrophages with metabolically activated phenotype regulates inflammation in dyslipidemia patients.

Macrophages are mediators of inflammation having an important role in the pathogenesis of cardiovascular diseases. Recently, a pro-inflammatory subpopulation, known as metabolically activated macrophages (MMe), has been described in conditions of obesity and metabolic syndrome where they are known to release cytokines that can promote insulin resistance. Dyslipidemia represents an important feature in metabolic syndrome and corresponds to one of the main modifiable risk factors for the development of cardiovascular diseases. Circulating monocytes can differentiate into macrophages under certain conditions. They correspond to a heterogeneous population, which include inflammatory and anti-inflammatory subsets; however, there is a wide spectrum of phenotypes. Therefore, we decided to investigate whether the metabolic activated monocyte (MoMe) subpopulation is already present under dyslipidemia conditions. Secondly, we assessed whether different levels of cholesterol and triglycerides play a role in the polarization towards the metabolic phenotype (MMe) of macrophages. Our results indicate that MoMe cells are found in both healthy and dyslipidemia patients, with cells displaying the following metabolic phenotype: CD14varCD36+ABCA1+PLIN2+. Furthermore, the percentages of CD14++CD68+CD80+ pro-inflammatory monocytes are higher in dyslipidemia than in healthy subjects. When analysing macrophage differentiation, we observed that MMe percentages were higher in the dyslipidemia group than in healthy subjects. These MMe have the ability to produce high levels of IL-6 and the anti-inflammatory cytokine IL-10. Furthermore, ABCA1 expression in MMe correlates with LDL serum levels. Our study highlights the dynamic contributions of metabolically activated macrophages in dyslipidemia, which may have a complex participation in low-grade inflammation due to their pro- and anti-inflammatory function.

Masculinidade hegemônica e violência em casais gays: uma leitura psicanalítica / Hegemonic masculinity and violence in gay couples: a psychoanalytic reading

ABSTRACT: The initial purpose of this paper is to analyze the literature on hegemonic masculinity and its intersection with violence in intimate gay couples. As a result, it is identified that hegemonic masculinity is a historical, social and cultural construction that, in order to perpetuate its power over other masculinities "contaminated by the feminine", employs diverse mechanisms of violence, sometimes imperceptible to those who experience it. Psychoanalytically oriented, a case is analyzed to obtain empirical information and to situate the reality of the phenomenon beyond heteronormative parameters, while offering a methodology to investigate the problem.

Resumo: O presente trabalho tem como objetivo inicial uma análise da literatura sobre masculinidade hegemônica e sua interseção com a violência em casais gays íntimos. Como resultado, identifica-se que a masculinidade hegemônica é uma construção histórica, social e cultural que, para perpetuar seu poder sobre outras masculinidades "contaminadas pelo feminino", utiliza vários mecanismos de violência às vezes imperceptíveis por quem a vive. De orientação psicanalítica, analisamos um caso que nos permite obter informações empíricas e colocar a realidade do fenômeno além dos parâmetros heteronormativos, oferecendo um método metodológico para investigar o problema.

Intervención fonoaudiológica para la feminización de la voz en una persona transgénero MTF: estudio de caso / Phoniatric intervention for voice feminization in a transgender person MTF: a case study

El término transgénero hace referencia a aquellas personas cuya identidad de género (masculino -femenino) difiere del sexo (hombre ­mujer). La persona transgénero presenta un conflicto entre la identidad sexual y su condición biológica, debido a que esta última, ya está ajustada a unas características que están dadas desde el nacimiento. Una de las mayores dificultades que presentan es en la feminización de voz, debido a que esta es percibida como la del género opuesto. Por ello, usualmente realizan cambios vocales sin una técnica adecuada, recurriendo principalmente a tratamientos quirúrgicos u hormonales, desconociendo la terapia fonoaudiológica como una alternativa para mejorar su calidad vocal e interacción social. Dado lo anterior, el objetivo de este trabajo fue determinar la efectividad de la intervención fonoaudiológica para la feminización de la voz en una persona Transgénero MTF (Male to Female). Se utilizó un diseño descriptivo, cuantitativo, usando un diseño longitudinal de serie de estudio de caso de reversión ABA. La intervención se estructuró, principalmente, en tres apartados: evaluación inicial, intervención y reevaluación final. Los resultados mostraron una variación significativa en las cualidades acústico-perceptuales de la voz, la que presentó mayores características de una voz femenina, con modificaciones en el patrón fonorespiratorio y en la postura. En conclusión, la intervención fonoaudiológica fue efectiva debido a que se lograron cambios que permitieron lograr una voz más femenina en la persona tratada.

The term transgender denotes a person whose gender identity (male-female) is different from their sex (men-women). A transgender person presents a contradiction between sexual identity and biological condition, because the latter is determined by certain given characteristics since birth. One of the most difficult issues is the feminization of the person's voice (in the case if male to female), since it is perceived as being in the opposite end of gender. For this reason, usually male to female transgenders engage in vocal changes without appropriate techniques, resorting mostly to surgical procedures or hormonal treatments and ignoring speech and language therapy as an alternative to improve their vocal quality and social interaction. Therefore, the main goal of this work was to determine the effectiveness of the phoniatric intervention in order to produce the feminization of the voice in a transgender individual MTF. The methodology used is a quantitative, descriptive, using a longitudinal design of ABA reversion case study series. The intervention was structured in three main sections: initial evaluation, intervention and final re-evaluation. The results showed a significant variation in the acoustic perceptual qualities of the voice, with a more feminine voice involving modifications in the phonorespiratory pattern and in the posture. In conclusion, the phoniatric intervention was effective because achieved changes led to a more feminine voice.

DNA damage in different wildlife species exposed to persistent organic pollutants (POPs) from the delta of the Coatzacoalcos river, Mexico.

The delta of the Coatzacoalcos river is a priority region for the biological conservation in the Gulf of Mexico. Environmental studies in the area have detected a complex mixture of contaminants where the presence of Persistent organic compounds (POPs) is highlighted. Deoxyribonucleic acid (DNA) integrity of biological populations are global concerns due to their ecological implications. The purpose of this study was to measure the exposure to POPs and DNA damage in nine species residing in the Coatzacoalcos river classified by taxonomic group, type of habitat and feeding habits. Total POPs concentrations (minimum and maximum) detected for all species were from 22.7 to 24,662.1 ng/g l.w; and the values of DNA damage (minimum and maximum) varied from 0.7 to 20.5 and from 6.5 to 56.8 µm (Olive tail moment and tail length respectively). Broadly speaking, reptiles, species residing in the wetland and the ones with a carnivorous diet showed higher levels of POPs and DNA damage. This study provides us with a baseline of the state of POPs contamination and shows the degree of environmental stress to which the different components of the ecosystem of the Coatzacoalcos river delta are subject to.

Efficacy and safety of oral baclofen in the management of spasticity: A rationale for intrathecal baclofen.

Oral baclofen has long been a mainstay in the management of spasticity. This review looks at the clinical evidence for the efficacy and safety of oral baclofen in patients with spasticity of any origin or severity, to determine whether there is a rationale for the use of intrathecal baclofen. Results suggest that oral baclofen may be effective in many patients with spasticity, regardless of the underlying disease or severity, and that it is at least comparable with other antispasmodic agents. However, adverse effects, such as muscle weakness, nausea, somnolence and paraesthesia, are common with oral baclofen, affecting between 25% and 75% of patients, and limiting its usefulness. Intrathecal baclofen may be an effective alternative as the drug is delivered directly into the cerebrospinal fluid, thus bypassing the blood-brain barrier and thereby optimizing the efficacy of baclofen while minimizing drug-related side-effects. Intrathecal baclofen is a viable option in patients who experience intolerable side-effects or who fail to respond to the maximum recommended dose of oral baclofen.

Reversed T Cell Receptor Docking on a Major Histocompatibility Class I Complex Limits Involvement in the Immune Response.

The anti-viral T cell response is drawn from the naive T cell repertoire. During influenza infection, the CD8+ T cell response to an H-2Db-restricted nucleoprotein epitope (NP366) is characterized by preferential expansion of T cells bearing TRBV13+ T cell receptors (TCRs) and avoidance of TRBV17+ T cells, despite the latter dominating the naive precursor repertoire. We found two TRBV17+ TCRs that bound H-2Db-NP366 with a 180° reversed polarity compared to the canonical TCR-pMHC-I docking. The TRBV17 ß-chain dominated the interaction and, whereas the complementarity determining region-3 (CDR3) loops exclusively mediated contacts with the MHC-I, peptide specificity was attributable to germline-encoded recognition. Nevertheless, the TRBV17+ TCR exhibited moderate affinity toward H-2Db-NP366 and was capable of signal transduction. Thus, the naive CD8+ T cell pool can comprise TCRs adopting reversed pMHC-I docking modes that limit their involvement in the immune response.

[Modulation of apoptosis by cytomegalovirus, from the perspective of the central nervous system]. / Modulación de la apoptosis por cytomegalovirus en la perspectiva del sistema nervioso central.

Apoptosis is one of the most effective mechanisms against the spread of pathogens such as viruses. However, viruses have developed measures to counter the protective role of apoptosis in infected cells. Cytomegalovirus (CMV) represents the major cause of congenital infection worldwide triggering important damage in the developing central nervous system (CNS). Several mechanisms of apoptosis prevention during CMV infection have been described, among them, viral proteins and RNAs are capable of prevent apoptosis by the intrinsic and extrinsic pathways as well as the one mediated by stress in the endoplasmic reticulum. Nevertheless, the CMV pro-apoptotic effect remains enigmatic and it has been suggested as a bystander effect in non-infected cells. This review summarizes the mechanisms by which CMV modulates the signaling pathways involved in apoptosis. It also includes a brief description of the permissiveness of the CNS to CMV infection and the generated cell death after infection, which may relate to the observed damage during a congenital infection.

Modulación de la apoptosis por cytomegalovirus en la perspectiva del sistema nervioso central / Modulation of apoptosis by cytomegalovirus, from the perspective of the central nervous system

Apoptosis is one of the most effective mechanisms against the spread of pathogens such as viruses. However, viruses have developed measures to counter the protective role of apoptosis in infected cells. Cytomegalovirus (CMV) represents the major cause of congenital infection worldwide triggering important damage in the developing central nervous system (CNS). Several mechanisms of apoptosis prevention during CMV infection have been described, among them, viral proteins and RNAs are capable of prevent apoptosis by the intrinsic and extrinsic pathways as well as the one mediated by stress in the endoplasmic reticulum. Nevertheless, the CMV pro-apoptotic effect remains enigmatic and it has been suggested as a bystander effect in non-infected cells. This review summarizes the mechanisms by which CMV modulates the signaling pathways involved in apoptosis. It also includes a brief description of the permissiveness of the CNS to CMV infection and the generated cell death after infection, which may relate to the observed damage during a congenital infection.

La apoptosis representa uno de los mecanismos de defensa más eficaces frente a la propagación de patógenos como lo son los virus. No obstante, éstos han desarrollado medidas para contrarrestar el papel protector de la apoptosis en las células infectadas. Citomegalovirus (CMV) es considerado la principal causa de infecciones congénitas a nivel mundial, afectando de forma importante el sistema nervioso central (SNC) en desarrollo. Diversos mecanismos de prevención de apoptosis durante la infección por CMV han sido descritos, entre los cuales, se encuentran proteínas y ARNs virales capaces de evitar la apoptosis por las vías intrínseca, extrínseca y la mediada por estrés del retículo endoplásmico. Sin embargo, aún representa un enigma el efecto pro-apoptótico de CMV que se sugiere actúe como un efecto espectador sobre las células no infectadas. En el presente trabajo se ofrece una revisión de los mecanismos mediante los cuales CMV modula las vías de señalización involucradas en la apoptosis. Asimismo se incluye una breve descripción de la permisividad del SNC a la infección por CMV y sobre la muerte celular generada tras la infección, que pueden relacionarse con el daño observado durante una infección congénita.

Women with nonischemic cardiomyopathy have a favorable prognosis and a better left ventricular remodeling than men after cardiac resynchronization therapy.

AIMS: Cardiac resynchronization therapy (CRT) is a well established therapy in heart failure patients who are on optimal medical therapy and have reduced left ventricular ejection fraction (LVEF) and wide QRS complexes. Although women and patients with nonischemic cardiomyopathy are under-represented in CRT trials and registries, there is evidence that these two groups of patients can benefit more from CRT. The aim of our analysis was to investigate the impact of female sex on mortality in a population that included a high percentage of patients (61%) with nonischemic cardiomyopathy. METHODS: We analyzed data on 507 consecutive patients (20% women) who received CRT at two Italian Heart Transplant centers and were followed up for a maximum of 48 months. RESULTS: After multivariate adjustment, women showed a trend toward better survival with regard to all-cause mortality [hazard ratio (HR) 0.32, confidence interval (CI) 0.10-1.04; P = 0.059]. However, this benefit was limited to nonischemic patients with regard to all-cause mortality (HR 0.20, CI 0.05-0.87, P = 0.032) and cardiovascular mortality (HR 0.14, CI 0.02-1.05, P = 0.056). CONCLUSION: Female CRT recipients, at mid-term, have a favorable prognosis than male patients and this benefit appears to be more evident in nonischemic patients. Thus, we strongly believe that the apparent under-utilization of CRT in females is an anomaly that should be corrected.

Algunas conclusiones provisorias sobre las posibilidades de simbolizar las experiencias emocionales vinculadas al climaterio en un grupo de mujeres de San Luis / Some tentative conclusions about the possibilities of symbolizing emotional experiences linked to menopause in a group of women in San Luis

Esta comunicación deriva de una investigación más amplia de la Facultad de Psicología de la Universidad Nacional de San Luis, que indaga la problemática del climaterio femenino desde una perspectiva psicoanalítica. El objetivo de este trabajo es en primer lugar, explorar las modalidades y cualidades que adquiere el vínculo con la madre, en un grupo de mujeres que transitan el climaterio. Se conjetura que haber podido internalizar una madre continente, posibilitaría el desarrollo de un equipo mental que permita afrontar las distintas vicisitudes en la construcción de la femineidad, en particular las transformaciones involucradas en el climaterio. Se analiza además la incidencia que tienen en la modalidad en que se transita esta crisis vital, la elaboración de las etapas previas de la construcción de la femineidad. Se infiere que la perturbación en la simbolización de estas experiencias emocionales afectaría el estado mental de las mujeres en la actualidad. Por último, se indaga la capacidad de dar sentido a las múltiples pérdidas inherentes al pasaje por este período, ya que se considera que la modalidad en que cada una de ellas elabore los duelos específicos de este momento, dependerá del equipo mental con el que cuentan.(AU)

Algunas conclusiones provisorias sobre las posibilidades de simbolizar las experiencias emocionales vinculadas al climaterio en un grupo de mujeres de San Luis / Some tentative conclusions about the possibilities of symbolizing emotional experiences linked to menopause in a group of women in San Luis

Esta comunicación deriva de una investigación más amplia de la Facultad de Psicología de la Universidad Nacional de San Luis, que indaga la problemática del climaterio femenino desde una perspectiva psicoanalítica. El objetivo de este trabajo es en primer lugar, explorar las modalidades y cualidades que adquiere el vínculo con la madre, en un grupo de mujeres que transitan el climaterio. Se conjetura que haber podido internalizar una madre continente, posibilitaría el desarrollo de un equipo mental que permita afrontar las distintas vicisitudes en la construcción de la femineidad, en particular las transformaciones involucradas en el climaterio. Se analiza además la incidencia que tienen en la modalidad en que se transita esta crisis vital, la elaboración de las etapas previas de la construcción de la femineidad. Se infiere que la perturbación en la simbolización de estas experiencias emocionales afectaría el estado mental de las mujeres en la actualidad. Por último, se indaga la capacidad de dar sentido a las múltiples pérdidas inherentes al pasaje por este período, ya que se considera que la modalidad en que cada una de ellas elabore los duelos específicos de este momento, dependerá del equipo mental con el que cuentan.

Structural basis for PI(4)P-specific membrane recruitment of the Legionella pneumophila effector DrrA/SidM.

Recruitment of the Legionella pneumophila effector DrrA to the Legionella-containing vacuole, where it activates and AMPylates Rab1, is mediated by a P4M domain that binds phosphatidylinositol 4-phosphate [PI(4)P] with high affinity and specificity. Despite the importance of PI(4)P in Golgi trafficking and its manipulation by pathogens, the structural bases for PI(4)P-dependent membrane recruitment remain poorly defined. Here, we determined the crystal structure of a DrrA fragment including the P4M domain in complex with dibutyl PI(4)P and investigated the determinants of phosphoinositide recognition and membrane targeting. Headgroup recognition involves an elaborate network of direct and water-mediated interactions with basic and polar residues in the context of a deep, constrictive binding pocket. An adjacent hydrophobic helical element packs against the acyl chains and inserts robustly into PI(4)P-containing monolayers. The structural, biochemical, and biophysical data reported here support a detailed structural mechanism for PI(4)P-dependent membrane targeting by DrrA.

Left ventricular ejection fraction overcrossing 35% after one year of cardiac resynchronization therapy predicts long term survival and freedom from sudden cardiac death: single center observational experience.

BACKGROUND: Reverse remodeling and increased LVEF after CRT correlate with survival and heart failure hospitalizations, but their relationship with the risk of SCD is unclear. We aimed to evaluate whether exceeding a threshold value of 35% for left ventricular ejection fraction (LVEF) 1 year after cardiac resynchronization therapy (CRT) predicts survival and freedom from sudden cardiac death (SCD). METHODS: 330 patients who survived ≥ 6 months after CRT (males 80%, age 62 ± 11 years) were grouped according to 1-year LVEF ≤ 35% (Group 1, n=187, 57%) or >35% (Group 2, n=143, 43%). According to changes vs. baseline (reduction of left end-systolic volume [LVESV] ≥ 10% or increase of LVEF% > 10 units), patients were also classified as echocardiographic (Echo) non-responders (Group A, n=152, 46%) or responders (Group B, n=178, 54%). RESULTS: At baseline, LVESV volume was larger and LVEF was lower in Group 1 vs. Group 2 (p<0.001). After 1 year, echocardiographic improvement was greater in Group 2 vs. Group 1 (p<0.001 for changes in both LVESV and LVEF). Over a median follow-up of 49 months, 47 patients (14%) died, 36 in Group 1 vs. 11 in Group 2 (19% vs. 8%, p=0.004). A significantly higher rate of freedom from all-cause mortality (p=0.002), cardiovascular mortality (p<0.001) and SCD (p<0.001) was observed in Group 2. Multivariate analysis demonstrated that only 1-year LVEF >35% was associated with freedom from SCD/VF. CONCLUSIONS: LVEF >35% after 1 year of CRT characterizes a favorable long-term outcome, with a very low risk for SCD.

The Legionella pneumophila GTPase activating protein LepB accelerates Rab1 deactivation by a non-canonical hydrolytic mechanism.

GTPase activating proteins (GAPs) from pathogenic bacteria and eukaryotic host organisms deactivate Rab GTPases by supplying catalytic arginine and glutamine fingers in trans and utilizing the cis-glutamine in the DXXGQ motif of the GTPase for binding rather than catalysis. Here, we report the transition state mimetic structure of the Legionella pneumophila GAP LepB in complex with Rab1 and describe a comprehensive structure-based mutational analysis of potential catalytic and recognition determinants. The results demonstrate that LepB does not simply mimic other GAPs but instead deploys an expected arginine finger in conjunction with a novel glutamic acid finger, which forms a salt bridge with an indispensible switch II arginine that effectively locks the cis-glutamine in the DXXGQ motif of Rab1 in a catalytically competent though unprecedented transition state configuration. Surprisingly, a heretofore universal transition state interaction with the cis-glutamine is supplanted by an elaborate polar network involving critical P-loop and switch I serines. LepB further employs an unusual tandem domain architecture to clamp a switch I tyrosine in an open conformation that facilitates access of the arginine finger to the hydrolytic site. Intriguingly, the critical P-loop serine corresponds to an oncogenic substitution in Ras and replaces a conserved glycine essential for the canonical transition state stereochemistry. In addition to expanding GTP hydrolytic paradigms, these observations reveal the unconventional dual finger and non-canonical catalytic network mechanisms of Rab GAPs as necessary alternative solutions to a major impediment imposed by substitution of the conserved P-loop glycine.

Clinical outcomes in patients with implantable cardioverter defibrillators and Sprint Fidelis leads.

OBJECTIVE: The performances of implantable cardioverter defibrillators and leads are important issues for healthcare providers and patients. In 2007 Sprint Fidelis leads were found to be associated with an increased failure rate and so the purpose of the study was to evaluate long-term mortality and clinical outcomes in patients implanted with Sprint Fidelis leads compared with Sprint Quattro leads. DESIGN, SETTING, PATIENTS: 508 patients with Sprint Fidelis leads and 468 with Sprint Quattro leads were prospectively followed in 12 Italian cardiology centres. MAIN OUTCOME MEASURES: Information on hospitalisations and other clinical events were collected during scheduled and unscheduled hospital visits. Deaths were identified from medical records or via phone contacts with patients' family members or through the National Office of Vital Statistics. RESULTS: Over a mean follow-up of 27±18 months 141 deaths occurred in the overall population. No death was observed in patients with diagnosed failing lead. Kaplan-Meier patient survival differed between the two lead groups (80±2% in Fidelis leads vs 70±4% in the Sprint Quattro leads at 4 years, p=0.002). Multivariate analyses showed that mortality was neither associated with lead type nor with diagnosed failed lead. The annual rate of lead failure was 1.8% patient-year for Fidelis leads and 0.2% for the Sprint Quattro leads. CONCLUSIONS: In our multicentre research, the clinical outcomes of patients with Fidelis leads differed from those of patients with Sprint Quattro leads. Nevertheless, neither mortality nor the combined endpoint of mortality and heart failure hospitalisations was associated with the lead type. http://clinicaltrials.gov/ct2/show/NCT01007474.

[Cardiac resynchronization therapy in women]. / La terapia di resincronizzazione cardiaca nella donna.

Cardiac resynchronization therapy (CRT) is a well established option in patients with moderate to severe heart failure on optimal medical therapy, NYHA functional class Ill-IV, reduced systolic function (left ventricular ejection fraction < or =35%), broad QRS complex (>120 ms), but data addressing sex differences in response to CRT are lacking. Women are underrepresented in clinical and observational trials on CRT (<30%) but, when examining response across recent studies, there is evidence of a more positive effect of CRT in women. Also our data show that females seem to achieve a greater survival benefit with CRT than male recipients. While larger trials remain the ideal way to specifically address the question of a gender effect, with some uncertainties on the understanding of the greater benefit still present (specific factors intrinsic to women are responsible for this difference? pre-CRT clinical characteristics, prevalence of nonischemic cardiomyopathy and left bundle branch block, other than female gender itself?), current evidence supports the notion of increasing access to CRT for women with the appropriate indication, to allow them to exploit the distinctive benefits associated with this treatment strategy.

A novel pleckstrin homology domain-containing protein enhances insulin-stimulated Akt phosphorylation and GLUT4 translocation in adipocytes.

Protein kinase B/Akt protein kinases control an array of diverse functions, including cell growth, survival, proliferation, and metabolism. We report here the identification of pleckstrin homology-like domain family B member 1 (PHLDB1) as an insulin-responsive protein that enhances Akt activation. PHLDB1 contains a pleckstrin homology domain, which we show binds phosphatidylinositol PI(3,4)P(2), PI(3,5)P(2), and PI(3,4,5)P(3), as well as a Forkhead-associated domain and coiled coil regions. PHLDB1 expression is increased during adipocyte differentiation, and it is abundant in many mouse tissues. Both endogenous and HA- or GFP-tagged PHLDB1 displayed a cytoplasmic disposition in unstimulated cultured adipocytes but translocated to the plasma membrane in response to insulin. Depletion of PHLDB1 by siRNA inhibited insulin stimulation of Akt phosphorylation but not tyrosine phosphorylation of IRS-1. RNAi-based silencing of PHLDB1 in cultured adipocytes also attenuated insulin-stimulated deoxyglucose transport and Myc-GLUT4-EGFP translocation to the plasma membrane, whereas knockdown of the PHLDB1 isoform PHLDB2 failed to attenuate insulin-stimulated deoxyglucose transport. Furthermore, adenovirus-mediated expression of PHLDB1 in adipocytes enhanced insulin-stimulated Akt and p70 S6 kinase phosphorylation, as well as GLUT4 translocation. These results indicate that PHLDB1 is a novel modulator of Akt protein kinase activation by insulin.

Una indagación psicoanalítica de las perturbaciones del crecimiento mental en pacientes no neuróticos / Mental growth disturbances in non-neurotic patients from a psychoanalytical perspectiva

Este trabajo deriva del Proyecto de Investigación Nº 4-2-0303 22/H635: El proceso de simbolización de las experiencias emocionales. Una indagación psicoanalítica de la incidencia de sus perturbaciones en el crecimiento mental de la Facultad de Ciencias Humanas de la Universidad Nacional de San Luis. Uno de