The autophagy protein RUBCNL/PACER represses RIPK1 kinase-dependent apoptosis and necroptosis.

Mesenchymal stem cells (MSCs) are used in cell therapy; nonetheless, their application is limited by their poor survival after transplantation in a proinflammatory microenvironment. Macroautophagy/autophagy activation in MSCs constitutes a stress adaptation pathway, promoting cellular homeostasis. Our proteomics data indicate that RUBCNL/PACER (RUN and cysteine rich domain containing beclin 1 interacting protein like), a positive regulator of autophagy, is also involved in cell death. Hence, we screened MSC survival upon various cell death stimuli under loss or gain of function of RUBCNL. MSCs were protected from TNF (tumor necrosis factor)-induced regulated cell death when RUBCNL was expressed. TNF promotes inflammation by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We determine that MSCs succumb to RIPK1 kinase-dependent apoptosis upon TNF sensing and necroptosis when caspases are inactivated. We show that RUBCNL is a negative regulator of both RIPK1-dependent apoptosis and necroptosis. Furthermore, RUBCNL mutants that lose the ability to regulate autophagy, retain their function in negatively regulating cell death. We also found that RUBCNL forms a complex with RIPK1, which disassembles in response to TNF. In line with this finding, RUBCNL expression limits assembly of RIPK1-TNFRSF1A/TNFR1 complex I, suggesting that complex formation between RUBCNL and RIPK1 represses TNF signaling. These results provide new insights into the crosstalk between the RIPK1-mediated cell death and autophagy machineries and suggest that RUBCNL, due to its functional duality in autophagy and apoptosis/necroptosis, could be targeted to improve the therapeutic efficacy of MSCs. Abbreviations: BAF: bafilomycin A1; CASP3: caspase 3; Caspases: cysteine-aspartic proteases; cCASP3: cleaved CASP3; CQ: chloroquine; CHX: cycloheximide; cPARP: cleaved poly (ADP-ribose) polymerase; DEPs: differential expressed proteins; ETO: etoposide; MEF: mouse embryonic fibroblast; MLKL: mixed lineage kinase domain-like; MSC: mesenchymal stem cell; MTORC1: mechanistic target of rapamycin kinase complex 1; Nec1s: necrostatin 1s; NFKB/NF-kB: nuclear factor of kappa light polypeptide gene enhancer in B cells; PLA: proximity ligation assay; RCD: regulated cell death; RIPK1: receptor (TNFRSF)-interacting serine-threonine kinase 1; RIPK3: receptor-interacting serine-threonine kinase 3; RUBCNL/PACER: RUN and cysteine rich domain containing beclin 1 interacting protein like; siCtrl: small interfering RNA nonsense; siRNA: small interfering RNA; TdT: terminal deoxynucleotidyl transferase; Tm: tunicamycin; TNF: tumor necrosis factor; TNFRSF1A/TNFR1: tumor necrosis factor receptor superfamily, member 1a.

Trends in primary percutaneous coronary intervention for the treatment of acute coronary ST-elevation myocardial infarction in Latin American countries: insights from the CECI consortium.

Background: ST-elevation myocardial infarction (STEMI) requires revascularization treatment, preferably via primary percutaneous coronary interventions (pPCI). There is a lack of data about contemporary management of STEMI in Latin America. Methods: This was a multicenter, multinational, prospective, and dynamic registry of patients undergoing pPCI in Latin America for STEMI (STEMI/LATAMI Registry) that was carried out in nine centers from five countries (Argentina, Ecuador, Venezuela, Bolivia, and the Dominican Republic) between June 2021 and June 2023. All interventionalists involved in the study were originally trained at the same institution (Centro de Estudios en Cardiología Intervencionista, Buenos Aires, Argentina). The primary objective was to evaluate procedural and in-hospital outcomes of pPCI in STEMI and in-hospital outcome in the Latin America (LATAM) region; as secondary endpoints, we analyzed the following subgroups: differences between pPCI vs. pharmaco-invasive or late presenters, gender, elderly and very elderly patients, cardiogenic shock outcomes, and causes of STEMI. Results: In total, 744 STEMI patients who underwent PCI between June 2021 and June 2023 in five countries (nine centers) in our continent were included; 76.3% had a pPCI, 8.1% pharmaco-invasive PCI, and 15.6% had late STEMI PCI. There were no differences in region or center when we evaluated in-hospital and 30 days of death. The rate of procedural success was 96.2%, and the overall in-hospital mortality rate was 2.2%. In the subgroup of pPCI, mean symptom onset-to-balloon time was 295.3 ± 246 min, and mean door-to-balloon time was 55.8 ± 49.9 min. The femoral approach was chosen in 60.5%. In 3.0% of patients, the left main disease was the culprit artery, with 1.63 ± 1.00 stents per patient (564 drug-eluting stents and 652 bare metal stents), with 34 patients receiving only plain optimal balloon angioplasty. Definitive stent thrombosis was related to the infarct artery as the primary cause of STEMI in 7.5% of patients. The use of assistant mechanical devices was low, at 2.1% in the pPCI group. Women were older, with large numbers in very elderly age (≥90 years), greater mortality, and incidence of spontaneous coronary dissection as a cause of STEMI (p < 0.001, p < 0.001, p < 0.001, and p < 0.003, respectively). Conclusion: In suitable LATAM Centers from low/medium-income countries, this prospective registry in patients with STEMI, PCI performed by well-trained operators has comparable results to those reported in well-developed countries.

The autophagy protein Def8 is altered in Alzheimer's disease and Aß42-expressing Drosophila brains.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by protein accumulation in the brain as a main neuropathological hallmark. Among them, Aß42 peptides tend to aggregate and create oligomers and plaques. Macroautophagy, a form of autophagy characterized by a double-membrane vesicle, plays a crucial role in maintaining neuronal homeostasis by degrading protein aggregates and dysfunctional organelles as a quality control process. Recently, DEF8, a relatively uncharacterized protein, has been proposed as a participant in vesicular traffic and autophagy pathways. We have reported increased DEF8 levels in lymphocytes from mild cognitive impairment (MCI) and early-stage AD patients and a neuronal profile in a murine transgenic AD model. Here, we analyzed DEF8 localization and levels in the postmortem frontal cortex of AD patients, finding increased levels compared to healthy controls. To evaluate the potential function of DEF8 in the nervous system, we performed an in silico assessment of its expression and network profiles, followed by an in vivo evaluation of a neuronal Def8 deficient model using a Drosophila melanogaster model of AD based on Aß42 expression. Our findings show that DEF8 is an essential protein for maintaining cellular homeostasis in the nervous system, and it is upregulated under stress conditions generated by Aß42 aggregation. This study suggests DEF8 as a novel actor in the physiopathology of AD, and its exploration may lead to new treatment avenues.

Características y evolución clínica de pacientes con infarto agudo de miocardio y elevación del segmento ST con y sin bloqueo interauricular

Fundamento resulta novedoso establecer la relación entre bloqueo interauricular e infarto agudo de miocardio con elevación del segmento ST debido a los pocos estudios que abordan el tema. Objetivo evaluar las características y evolución clínica de pacientes con infarto agudo de miocardio con elevación del segmento ST con y sin bloqueo interauricular. Métodos: se realizó un estudio descriptivo y correlacional en unidades de cuidados progresivos del Hospital General Universitario Dr. Gustavo Aldereguía Lima de Cienfuegos. Se seleccionaron 169 sujetos con diagnóstico de infarto agudo de miocardio con elevación del segmento ST divididos en dos grupos con y sin bloqueo interauricular. Se analizaron como variables demográficas: edad, sexo, color de la piel y entre las clínicas hábitos tóxicos (fumador, exfumador); antecedentes patológicos (infarto de miocardio, angina, enfermedad arterial periférica, hipertensión arterial, diabetes mellitus tipo 2, enfermedad renal crónica; localización del infarto (anterior, inferior, bloqueo de rama izquierda); complicaciones: insuficiencia cardíaca, fibrilación auricular, taquicardia ventricular/fibrilación ventricular, trastornos de conducción aurículo ventricular, complicación mecánica, angina postinfarto, embolismo arterial) y estado al egreso (vivo o fallecido). Resultados el 52,17 % de los pacientes con infarto agudo de miocardio con elevación del segmento ST con bloqueo interauricular desarrollaron insuficiencia cardíaca, vs el 29,45 % de los pacientes sin bloqueo con significación estadística (p = 0.03). La relación entre la ocurrencia o no de complicaciones (así como el estado al egreso) y la presencia o no de bloqueo resultó muy significativa (p=0.01). Conclusiones el análisis minucioso en este contexto, de otros aspectos no habituales como la onda p, debe ser también rutinario, pues la documentación de bloqueo interauricular pudiera relacionarse con el curso clínico de los pacientes.

Foundation: it is novel to establish the relationship between interatrial block and acute myocardial infarction with ST-segment elevation due to the few studies that address the subject. Objective: to evaluate the characteristics and clinical evolution of patients with ST-segment elevation acute myocardial infarction with and without interatrial block. Methods: a descriptive and correlational study was carried out in progressive care units of the Dr. Gustavo Aldereguía Lima University General Hospital in Cienfuegos. 169 subjects with a diagnosis of ST-segment elevation myocardial infarction divided into two groups with and without interatrial block were selected. Demographic variables were analyzed: age, sex, skin color and between clinics: toxic habits (smoker, ex-smoker); medical history (myocardial infarction, angina, peripheral arterial disease, arterial hypertension, type 2 diabetes mellitus, chronic kidney disease; infarct location (anterior, inferior, left bundle branch block); complications: heart failure, atrial fibrillation, ventricular tachycardia/ventricular fibrillation, atrioventricular conduction disorders, mechanical complication, post infarction angina, arterial embolism) and discharge status (alive or deceased). Results: 52.17 % of patients with ST-segment elevation myocardial infarction with interatrial block developed heart failure, vs 29.45 % among patients without block with statistical significance (p = 0.03). The relationship between the occurrence or not of complications (as well as the state at discharge) and the presence or not of blockade was highly significant (p=0.01). Conclusions: the detailed analysis, in this context, of the p wave of the electrocardiogram should be routine, since the documentation of interatrial block could be related to the clinical course of the patients.

Structural Behavior of Amphiphilic Triblock Copolymer P104/Water System.

A detailed study of the different structural transitions of the triblock copolymer PEO27-PPO61-PEO27 (P104) in water, in the dilute and semi-dilute regions, is addressed here as a function of temperature and P104 concentration (CP104) by mean of complimentary methods: viscosimetry, densimetry, dynamic light scattering, turbidimetry, polarized microscopy, and rheometry. The hydration profile was calculated through density and sound velocity measurements. It was possible to identify the regions where monomers exist, spherical micelle formation, elongated cylindrical micelles formation, clouding points, and liquid crystalline behavior. We report a partial phase diagram including information for P104 concentrations from 1 × 10-4 to 90 wt.% and temperatures from 20 to 75 °C that will be helpful for further interaction studies with hydrophobic molecules or active principles for drug delivery.

Caracterización de pacientes con infarto agudo de miocardio atendidos en el Hospital General Universitario Dr. Gustavo Aldereguía Lima

Fundamento: el infarto agudo de miocardio con elevación del segmento ST impone un gran desafío a los sistemas de salud, por tanto, su diagnóstico y manejo son importantes. Objetivo: determinar las principales características clínico-epidemiológicas de pacientes con diagnóstico de infarto agudo de miocardio con elevación del segmento ST. Métodos: se realizó un estudio descriptivo y transversal sobre una serie de pacientes atendidos en el Hospital General Universitario Dr. Gustavo Aldereguía Lima de Cienfuegos, en el periodo de enero a junio de 2021. El universo estuvo constituido por 77 pacientes. Se estudiaron variables como: edad, sexo, color de la piel, procedencia, comorbilidades, hábitos tóxicos, manifestaciones clínicas, trombolisis, lugar donde se trombolizaron, causas de no trombolisis, topografía del infarto agudo de miocardio, estado al egreso, complicaciones del infarto y del tratamiento trombolítico. Para el procesamiento y análisis de la información se creó una base de datos en el paquete estadístico SPSS versión 21.0 que permitió el cálculo de las frecuencias absolutas y los porcentajes. Resultados: la media de edad fue 66,08 (±9,43). Hubo un predominio del sexo masculino (64,7 %); el 59,7 % de los pacientes fueron trombolizados; el dolor torácico típico fue la principal manifestación clínica con un 71,4 %; fallecieron 12 pacientes, de ellos el 10,4 % no recibió tratamiento trombolítico. Conclusiones: el principal motivo de consulta sigue siendo el dolor torácico. La edad y las comorbilidades son factores de riesgo a tener en cuenta a la hora de prevenir esta entidad. La trombolisis es una medida terapéutica que tiene repercusión directa en el estado al egreso de los pacientes, este procedimiento se realiza en su mayoría en el hospital.

Background: ST-segment elevation acute myocardial infarction poses a great challenge to health systems, therefore its diagnosis and management are important. Objective: to determine the main clinical-epidemiological characteristics of patients diagnosed with ST-segment elevation acute myocardial infarction. Methods: a descriptive and cross-sectional study was carried out on a series of patients treated at the Dr. Gustavo Aldereguía Lima University General Hospital in Cienfuegos, from January to June 2021. The universe consisted of 77 patients. Variables such as: age, sex, skin color, origin, comorbidities, toxic habits, clinical manifestations, thrombolysis, place where they were thrombolyzed, causes of non-thrombolysis, topography of acute myocardial infarction, discharge status, infarction complications and of thrombolytic treatment. For the processing and analysis of the information, a database was created in the statistical package SPSS version 21.0 that allowed the calculation of the absolute frequencies and the percentages. Results: the mean age was 66.08 (±9.43). There was a predominance of the male sex (64.7 %); 59.7 % of the patients were thrombolyzed; typical chest pain was the main clinical manifestation with 71.4 %; 12 patients died, of which 10.4 % did not receive thrombolytic treatment. Conclusions: the main reason for consultation continues to be chest pain. Age and comorbidities are risk factors to take into account when preventing this entity. Thrombolysis is a therapeutic measure that has a direct impact on the state at discharge of patients, this procedure is performed mostly in the hospital.

Ten-year outcomes of pseudophakic mini-monovision correction of hyperopic presbyopia.

PURPOSE: To evaluate long-term efficacy, safety, and spectacle independence after the treatment of hyperopic presbyopia with pseudophakic mini-monovision using standard monofocal intraocular lenses (IOLs) after bilateral cataract surgery. SETTING: Private practice in Barcelona, Spain. DESIGN: Retrospective, noncomparative case series. METHODS: Patients with hyperopic presbyopia underwent bilateral cataract surgery with pseudophakic mini-monovision using standard monofocal IOLs between 2008 and 2018. Main outcomes analyzed were uncorrected distance visual acuity (UDVA), uncorrected near distance visual acuity (UNVA), and rates of spectacle independence at postoperative day 1 (POD1), months 1, 6 and 12, and at 5 and 10 years (Y10) postoperatively. RESULTS: The study enrolled 463 patients. Both UDVA and UNVA significantly improved postoperatively ( P < .05). The mean binocular UDVA improved from 0.47 ± 0.3 logMAR preoperatively to 0.096 ± 0.14 at POD1 to 0.16 ± 0.2 at Y10 ( P = .0033). The binocular UNVA was 0.05 logMAR at Y10, whereas in preoperative visits, all patients needed spectacles. The mean UDVA for the dominant eye ≤0.20 logMAR was achieved in 84.29% at the Y10. Self-reported and measured complete spectacle independence for near vision was achieved in 79.61% of patients at POD1 and 71.92% at Y10 postoperatively. For distance, respectively, in 86.29% of patients at POD1 and 78.43% at Y10. The achieved results were stable. No serious events were reported, as well as no photic phenomena. CONCLUSIONS: Pseudophakic mini-monovision in hyperopic presbyopes is a safe, effective, and low-cost approach for the long-term correction of presbyopia. It significantly reduces spectacle dependence and fulfils patients' expectations after bilateral cataract surgery.

Infarto agudo de miocardio con elevacion del segmento ST. Guía de Práctica Clínica

RESUMEN La implementación de las Guías de Práctica Clínica, con intervenciones eficaces basadas en la evidencia, ha mejorado los resultados del manejo de pacientes con infarto agudo de miocardio con elevación del segmento ST en países de altos ingresos, sin embargo, no ocurre lo mismo en países con medianos y bajos ingresos, donde existen grandes brechas en su implementación, debido a múltiples factores. La presente Guía de Práctica Clínica se refiere a los pacientes que presentan síntomas isquémicos o sus equivalentes y una elevación persistente del segmento ST en el electrocardiograma. Esta guía no aborda los elementos relacionados directamente con los procedimientos de intervencionismo coronario percutáneo ni la revascularización miocárdica quirúrgica.

ABSTRACT The implementation of Clinical Practice Guidelines, with effective evidence-based interventions, has improved the results of managing patients with ST-segment elevation acute myocardial infarction in high-income countries, however, the same is not true in countries with medium and low incomes, where there are large gaps in its implementation, due to multiple factors. This Clinical Practice Guideline refers to patients presenting with ischemic symptoms or their equivalents and persistent ST-segment elevation on the electrocardiogram. This guideline does not address elements directly related to percutaneous coronary intervention procedures or surgical myocardial revascularization.

A FRET-Based Biosensor for the Src N-Terminal Regulatory Element.

In signaling proteins, intrinsically disordered regions often represent regulatory elements, which are sensitive to environmental effects, ligand binding, and post-translational modifications. The conformational space sampled by disordered regions can be affected by environmental stimuli and these changes trigger, vis a vis effector domain, downstream processes. The disordered nature of these regulatory elements enables signal integration and graded responses but prevents the application of classical approaches for drug screening based on the existence of a fixed three-dimensional structure. We have designed a genetically encodable biosensor for the N-terminal regulatory element of the c-Src kinase, the first discovered protooncogene and lead representative of the Src family of kinases. The biosensor is formed by two fluorescent proteins forming a FRET pair fused at the two extremes of a construct including the SH4, unique and SH3 domains of Src. An internal control is provided by an engineered proteolytic site allowing the generation of an identical mixture of the disconnected fluorophores. We show FRET variations induced by ligand binding. The biosensor has been used for a high-throughput screening of a library of 1669 compounds with seven hits confirmed by NMR.

Astroglial gliotransmitters released via Cx43 hemichannels regulate NMDAR-dependent transmission and short-term fear memory in the basolateral amygdala.

Astrocytes release gliotransmitters via connexin 43 (Cx43) hemichannels into neighboring synapses, which can modulate synaptic activity and are necessary for fear memory consolidation. However, the gliotransmitters released, and their mechanisms of action remain elusive. Here, we report that fear conditioning training elevated Cx43 hemichannel activity in astrocytes from the basolateral amygdala (BLA). The selective blockade of Cx43 hemichannels by microinfusion of TAT-Cx43L2 peptide into the BLA induced memory deficits 1 and 24 h after training, without affecting learning. The memory impairments were prevented by the co-injection of glutamate and D-serine, but not by the injection of either alone, suggesting a role for NMDA receptors (NMDAR). The incubation with TAT-Cx43L2 decreased NMDAR-mediated currents in BLA slices, effect that was also prevented by the addition of glutamate and D-serine. NMDARs in primary neuronal cultures were unaffected by TAT-Cx43L2, ruling out direct effects of the peptide on NMDARs. Finally, we show that D-serine permeates through purified Cx43 hemichannels reconstituted in liposomes. We propose that the release of glutamate and D-serine from astrocytes through Cx43 hemichannels is necessary for the activation of post-synaptic NMDARs during training, to allow for the formation of short-term and subsequent long-term memory, but not for learning per se.

Regulation of Phosphorylated State of NMDA Receptor by STEP61 Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress.

Traumatic Brain Injury (TBI) mediates neuronal death through several events involving many molecular pathways, including the glutamate-mediated excitotoxicity for excessive stimulation of N-methyl-D-aspartate receptors (NMDARs), producing activation of death signaling pathways. However, the contribution of NMDARs (distribution and signaling-associated to the distribution) remains incompletely understood. We propose a critical role of STEP61 (Striatal-Enriched protein tyrosine phosphatase) in TBI; this phosphatase regulates the dephosphorylated state of the GluN2B subunit through two pathways: by direct dephosphorylation of tyrosine-1472 and indirectly via dephosphorylation and inactivation of Fyn kinase. We previously demonstrated oxidative stress's contribution to NMDAR signaling and distribution using SOD2+/- mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2+/- animals. After TBI, we found alterations in cognitive performance, NMDAR-dependent synaptic function (decreased synaptic form of NMDARs and decreased synaptic current NMDAR-dependent), and increased STEP61 activity. These changes are reduced partially with the STEP61-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP61 in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.

Adult gonococcal conjunctivitis: Prevalence, clinical features and complications.

Introduction. Gonorrhoea is a sexually transmitted disease whose incidence has increased in recent years and adult gonococcal conjunctivitis (AGC) is a relatively uncommon complication.Hypothesis/Gap Statement. AGC is associated with increased incidence of genital gonorrhoea and must be treated correctly to avoid serious corneal complications.Aims. To report the prevalence, clinical features, and complications of AGC in a tertiary ophthalmology centre in Barcelona, Spain. Present epidemiological data, clinical features, ocular complications, and antibiotic susceptibility. Design: Single-centre, descriptive, retrospective case series.Methodology. Systematic case-defined search in medical records and further retrospective chart review study of microbiologically confirmed AGC attending outpatient clinic and/or emergency room from 2012 to 2020. We analysed the clinical presentation, treatments, antibiotic susceptibility, complications and ocular sequelae.Results. Thirteen patients were diagnosed of AGC. Eleven patients had unilateral presentation. Two patients had bilateral presentation. In ten cases there was abundant mucopurulent discharge, three cases presented periocular pain and periocular inflammation requiring a CT scan to rule out post-septal cellulitis. The diagnosis was confirmed by culture. In total, 100 % of strains were susceptible to ceftriaxone, 58 % were ciprofloxacin resistant and no beta-lactamase production was detected. Three patients required hospital admission. One patient developed a complication presenting with ptosis caused by superior symblepharon.Conclusion. AGC is a rare disease which is difficult to diagnose as it requires a high index of suspicion to prevent corneal perforation but in an important number of cases it may mimic orbital cellulitis. It is crucial that treatment starts as soon as possible to avoid serious corneal damage. Patients should promptly receive complete and correct treatment when admitted to the emergency room since an elevated number of patients do not attend their medical follow-up visit. Azithromycin or aminoglycoside eye drops are probably the best option to complete the treatment, due to high quinolone resistance.

Near-infrared transmitting occlusive intraocular lens implantation for intractable diplopia: Report of two cases.

OBJECTIVE: The objective of this article is to report two cases of black occlusive intraocular lens and implantation for treating intractable diplopia. CASE DESCRIPTIONS: Two patients with intractable diplopia after orbitofacial, trauma, and surgical removal of pituitary adenoma failed to conservative management. After uneventful cataract, phacoemulsification, a black intraocular lens was implanted in every case. In both cases, a complete degree of satisfaction was achieved, with no symptoms of diplopia, and no complications have been observed in their follow-up. The use of optical coherence tomography has been possible in both cases to assess the macula and optic nerve, since a fundoscopy is not possible in such cases. CONCLUSION: Implantation of a near-infrared transmitting occlusive intraocular lens for treating intractable diplopia provided a complete resolution of symptoms without eliminating the possibility of examining macula and optic nerve using optical coherence tomography.

Guía de práctica clínica para el tratamiento de la insuficiencia cardíaca aguda / Clinical Practice Guidelines for Acute Heart Failure Treatment

RESUMEN Las guías de práctica clínica son el resultado de la compilación y evaluación de toda la evidencia relevante disponible, sobre un tema en particular, con el objetivo de ayudar a los médicos a seleccionar la mejor estrategia diagnóstica y terapéutica para aplicar a un paciente que sufre una enfermedad determinada. La presente guía aborda fundamentalmente los aspectos diagnósticos y terapéuticos de la insuficiencia cardiaca aguda, la cual se define como la rápida aparición o el empeoramiento de los síntomas o signos de insuficiencia cardiaca. Es una entidad potencialmente mortal, la cual puede estar causada por una disfunción cardíaca primaria o precipitada por factores extrínsecos, conllevando habitualmente a la hospitalización del paciente. Esta guía está dirigida tanto a especialistas, como a residentes de las especialidades de cardiología, medicina interna, medicina intensiva y emergencia, medicina general integral, anestesiología y reanimación, así como a estudiantes de la carrera de medicina.

ABSTRACT The clinical practice guidelines are the result of the compilation and evaluation of all the relevant evidence available, on a particular topic, with the aim of helping physicians select the best diagnostic and therapeutic strategy to apply to a patient suffering from a determined disease. This guide primarily addresses the diagnostic and therapeutic aspects of acute heart failure, which is defined as the rapid onset or worsening of symptoms or signs of heart failure. It is a life-threatening entity, which can be caused by a primary cardiac dysfunction or precipitated by extrinsic factors, usually leading to hospitalization of the patient. This guide is addressed to both specialists and residents of cardiology, internal medicine, intensive and emergency medicine, comprehensive general medicine, anesthesiology and resuscitation specialties, as well as medical students.

Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG.

BACKGROUND: Cognitive dysfunction (CD) is common among patients with the autoimmune disease systemic lupus erythematosus (SLE). Anti-ribosomal P autoantibodies associate with this dysfunction and have neuropathogenic effects that are mediated by cross-reacting with neuronal surface P antigen (NSPA) protein. Elucidating the function of NSPA can then reveal CD pathogenic mechanisms and treatment opportunities. In the brain, NSPA somehow contributes to glutamatergic NMDA receptor (NMDAR) activity in synaptic plasticity and memory. Here we analyze the consequences of NSPA absence in KO mice considering its structural features shared with E3 ubiquitin ligases and the crucial role of ubiquitination in synaptic plasticity. RESULTS: Electrophysiological studies revealed a decreased long-term potentiation in CA3-CA1 and medial perforant pathway-dentate gyrus (MPP-DG) hippocampal circuits, reflecting glutamatergic synaptic plasticity impairment in NSPA-KO mice. The hippocampal dentate gyrus of these mice showed a lower number of Arc-positive cells indicative of decreased synaptic activity and also showed proliferation defects of neural progenitors underlying less adult neurogenesis. All this translates into poor spatial and recognition memory when NSPA is absent. A cell-based assay demonstrated ubiquitination of NSPA as a property of RBR-type E3 ligases, while biochemical analysis of synaptic regions disclosed the tyrosine phosphatase PTPMEG as a potential substrate. Mice lacking NSPA have increased levels of PTPMEG due to its reduced ubiquitination and proteasomal degradation, which correlated with lower levels of GluN2A and GluN2B NMDAR subunits only at postsynaptic densities (PSDs), indicating selective trafficking of these proteins out of PSDs. As both GluN2A and GluN2B interact with PTPMEG, tyrosine (Tyr) dephosphorylation likely drives their endocytic removal from the PSD. Actually, immunoblot analysis showed reduced phosphorylation of the GluN2B endocytic signal Tyr1472 in NSPA-KO mice. CONCLUSIONS: NSPA contributes to hippocampal plasticity and memory processes ensuring appropriate levels of adult neurogenesis and PSD-located NMDAR. PTPMEG qualifies as NSPA ubiquitination substrate that regulates Tyr phosphorylation-dependent NMDAR stability at PSDs. The NSPA/PTPMEG pathway emerges as a new regulator of glutamatergic transmission and plasticity and may provide mechanistic clues and therapeutic opportunities for anti-P-mediated pathogenicity in SLE, a still unmet need.

Glutamatergic Receptor Trafficking and Delivery: Role of the Exocyst Complex.

Cells comprise several intracellular membrane compartments that allow them to function properly. One of these functions is cargo movement, typically proteins and membranes within cells. These cargoes ride microtubules through vesicles from Golgi and recycling endosomes to the plasma membrane in order to be delivered and exocytosed. In neurons, synaptic functions employ this cargo trafficking to maintain inter-neuronal communication optimally. One of the complexes that oversee vesicle trafficking and tethering is the exocyst. The exocyst is a protein complex containing eight subunits first identified in yeast and then characterized in multicellular organisms. This complex is related to several cellular processes, including cellular growth, division, migration, and morphogenesis, among others. It has been associated with glutamatergic receptor trafficking and tethering into the synapse, providing the molecular machinery to deliver receptor-containing vesicles into the plasma membrane in a constitutive manner. In this review, we discuss the evidence so far published regarding receptor trafficking and the exocyst complex in both basal and stimulated levels, comparing constitutive trafficking and long-term potentiation-related trafficking.

The Mitochondrial Unfolded Protein Response: A Hinge Between Healthy and Pathological Aging.

Aging is the time-dependent functional decline that increases the vulnerability to different forms of stress, constituting the major risk factor for the development of neurodegenerative diseases. Dysfunctional mitochondria significantly contribute to aging phenotypes, accumulating particularly in post-mitotic cells, including neurons. To cope with deleterious effects, mitochondria feature different mechanisms for quality control. One such mechanism is the mitochondrial unfolded protein response (UPRMT), which corresponds to the transcriptional activation of mitochondrial chaperones, proteases, and antioxidant enzymes to repair defective mitochondria. Transcription of target UPRMT genes is epigenetically regulated by Histone 3-specific methylation. Age-dependency of this regulation could explain a differential UPRMT activity in early developmental stages or aged organisms. At the same time, precise tuning of mitochondrial stress responses is crucial for maintaining neuronal homeostasis. However, compared to other mitochondrial and stress response programs, the role of UPRMT in neurodegenerative disease is barely understood and studies in this topic are just emerging. In this review, we document the reported evidence characterizing the evolutionarily conserved regulation of the UPRMT and summarize the recent advances in understanding the role of the pathway in neurodegenerative diseases and aging.

Adherencia a la guía de práctica clínica en pacientes con infarto agudo de miocardio con elevación del segmento ST y su relación con variables demográficas y clínicas / Following Clinical Practical Guidelines in Patients with Acute Myocardial Infarction with St Segment Elevation and its Relation with Clinical and Demographic Variables

RESUMEN Fundamento el infarto agudo de miocardio con elevación del segmento ST impone un gran desafío a los sistemas de salud. Por lo que es importante contar con protocolos de actuación para tratar este padecimiento. Objetivo medir el grado de adherencia a la Guía de Práctica Clínica en pacientes egresados con diagnóstico de infarto agudo de miocardio con elevación del segmento ST y relacionarlo con variables demográficas y clínicas. Métodos se realizó un estudio descriptivo, de serie de casos en la Unidad de Cuidados Integrales del Corazón y Unidad de Cuidados Intensivos Polivalentes del Hospital General Universitario Dr. Gustavo Aldereguía Lima de Cienfuegos desde el 1 de agosto de 2016 al 31 de julio de 2017 a todos los pacientes vivos y fallecidos (294) con diagnóstico al ingreso y al egreso de el infarto agudo de miocardio con elevación del segmento ST. El grado de adherencia se relacionó con variables demográficas (edad y sexo) y clínicas (comorbilidades seleccionadas y estado al egreso). Resultados en el 76,5 % de los pacientes el grado de adherencia fue adecuado. La gradación adecuada aumentó concordantemente con la edad (71,3 %, 77,2 % y 82,0 % en menores de 60, de 60 a 74 y de 75 y más años respectivamente) y fue superior en mujeres (84,1 %). Según las comorbilidades, el mayor porcentaje de adherencia adecuada, correspondió a la hipertensión arterial (77,2 %) y el menor (69,0 %) a la enfermedad renal crónica. Conclusiones se encontró un elevado porcentaje de gradación adecuado en la adherencia a la guía para pacientes con infarto agudo de miocardio con elevación del segmento ST en el período estudiado, tanto en el total de pacientes, como para cualquier grupo de edad, sexo, comorbilidades seleccionadas y en egresados vivos y fallecidos.

ABSTRACT Foundation acute myocardial infarction with elevation of the ST segment demands a great challenge from health systems. It is vital to rely on clinical practical guidelines. In attaining its degree of adherence may influence clinical and demographic variables. Objetive to measure the degree of adhesion to Clinical Practical Guidelines in discharged patients with a diagnosis of acute myocardial infarction and ST segment elevation and related to demographic and clinical variables. Method descriptive study which evaluated the adhesion to clinical practice guidelines in 294 patients by using an instrument of evaluation. The degree of adhesion was related with demographic variables (age and sex) and clinical (selected co-morbidities and state of the patient on discharge). Results in 76,5 % of the patients the degree of adhesion was adequate. Adequate grading increased accordingly to age (71,3 %, 77,2 % y 82,0 % in patients younger than 60, de 60 a 74 y de 75 and more respectively) and was higher in women (84,1 %). Regarding co-morbidities, the highest percentage of adequate adhesion corresponded to hypertension (77,2 %) and the lowest (69,0 %) to chronic renal disease. Conclusion a high percentage of ¨graded adequate¨ in adhesion to clinical and practical guidelines was found in patients with acute myocardial infarction and ST segment elevation in the period of study, either in the total of patients so as in any age, sex, co-morbidities selected, discharged alive and deceased groups.

Chitosan-DNA polyelectrolyte complex: Influence of chitosan characteristics and mechanism of complex formation.

Polyelectrolyte complexes formed between DNA and chitosan present different and interesting physicochemical properties combined with high biocompatibility; they are very useful for biomedical applications. DNA in its double helical structure is a semi-rigid polyelectrolyte chain. Chitosan, an abundant polysaccharide in nature, is considered as one of the most attractive vectors due to its biocompatibility and biodegradability. Here we study chitosan/DNA polyelectrolyte complex formation mechanism and the key factors of their stability. Compaction process of DNA with chitosan was monitored in terms of the ζ-potential and hydrodynamic radius variation as a function of charge ratios between chitosan and DNA. The influence of chitosan degree of acetylation (DA) and its molecular weight on the stoichiometry of chitosan/DNA complexes characteristics was also studied. It is shown that the isoelectric point of chitosan/DNA complexes, as well as their stability, is directly related to the degree of protonation of chitosan (depending on pH), to the DA and to the external salt concentration. It is demonstrated that DNA compaction process corresponds to an all or nothing like-process. Finally, since an important factor in cell travelling is the buffering effect of the vector used, we demonstrated the essential role of free chitosan on the proton-sponge effect.

Correction to: Adolescent Binge Alcohol Exposure Affects the Brain Function Through Mitochondrial Impairment.

The authors declare that the original version of this article contained a mistake in the data of the Figure 2, particularly in the LTP data.