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.

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.

Age-related NMDA signaling alterations in SOD2 deficient mice.

Oxidative stress affects the survival and function of neurons. Hence, they have a complex and highly regulated machinery to handle oxidative changes. The dysregulation of this antioxidant machinery is associated with a wide range of neurodegenerative conditions. Therefore, we evaluated signaling alterations, synaptic properties and behavioral performance in 2 and 6-month-old heterozygous manganese superoxide dismutase knockout mice (SOD2+/- mice). We found that their low antioxidant capacity generated direct oxidative damage in proteins, lipids, and DNA. However, only 6-month-old heterozygous knockout mice presented behavioral impairments. On the other hand, synaptic plasticity, synaptic strength and NMDA receptor (NMDAR) dependent postsynaptic potentials were decreased in an age-dependent manner. We also analyzed the phosphorylation state of the NMDAR subunit GluN2B. We found that while the levels of GluN2B phosphorylated on tyrosine 1472 (synaptic form) remain unchanged, we detected increased levels of GluN2B phosphorylated on tyrosine 1336 (extrasynaptic form), establishing alterations in the synaptic/extrasynaptic ratio of GluN2B. Additionally, we found increased levels of two phosphatases associated with dephosphorylation of p-1472: striatal-enriched protein tyrosine phosphatase (STEP) and phosphatase and tensin homolog deleted on chromosome Ten (PTEN). Moreover, we found decreased levels of p-CREB, a master transcription factor activated by synaptic stimulation. In summary, we describe mechanisms by which glutamatergic synapses are altered under oxidative stress conditions. Our results uncovered new putative therapeutic targets for conditions where NMDAR downstream signaling is altered. This work also contributes to our understanding of processes such as synapse formation, learning, and memory in neuropathological conditions.

Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies.

N-Methyl-D-aspartate receptors (NMDARs) have two opposing roles in the brain. On the one hand, NMDARs control critical events in the formation and development of synaptic organization and synaptic plasticity. On the other hand, the overactivation of NMDARs can promote neuronal death in neuropathological conditions. Ca(2+) influx acts as a primary modulator after NMDAR channel activation. An imbalance in Ca(2+) homeostasis is associated with several neurological diseases including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These chronic conditions have a lengthy progression depending on internal and external factors. External factors such as acute episodes of brain damage are associated with an earlier onset of several of these chronic mental conditions. Here, we will review some of the current evidence of how traumatic brain injury can hasten the onset of several neurological conditions, focusing on the role of NMDAR distribution and the functional consequences in calcium homeostasis associated with synaptic dysfunction and neuronal death present in this group of chronic diseases.

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 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.

[Olfactory ensheathing cell tumour: case report and literature review]. / Tumor de las células envolventes del olfatorio: caso clínico y revisión de la literatura.

Olfactory ensheathing cells are glial cells located in the olfactory bulb and nerve. Microscopically, both olfactory ensheathing cells and Schwann cells have similar morphological and immunohistochemical features. However, olfactory ensheathing cells are negative for Leu-7(CD-57), whereas Schwann cells are positive. We present the case of a 49 year-old male with a history of visual impairment and hyposmia. Radiological CT and MRI studies showed a subfrontal cystic extra-axial mass, which eroded the right cribriform plate, with heterogeneous contrast enhancement. Total excision of the tumour was performed by bifrontal craniotomy. Histological examination initially suggested a schwannoma, with immunohistochemical staining being positive for S-100 protein and negative for epithelial membrane antigen (EMA). However, the tumour was negative for Leu-7. Accordingly, the final diagnosis was olfactory ensheathing cell tumour. Herein, we describe the sixth case of intracranial olfactory ensheathing cell tumour and stress the important role of immunohistochemical techniques in obtaining a definitive diagnosis.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

In the young population, binge drinking is a pattern of problematic alcohol consumption, characterized by a short period of heavy drinking followed by abstinence which is frequently repeated over time. This drinking pattern is associated with mental problems, use of other drugs, and an increased risk of excessive alcohol intake during adulthood. However, little is known about the effects of binge drinking on brain function in adolescents and its neurobiological impact during the adulthood. In the present study, we evaluated the effects of alcohol on hippocampal memory, synaptic plasticity, and mitochondrial function in adolescent rats after a binge drinking episode in vivo. These effects were analyzed at 1, 3, or 7 weeks post alcohol exposure. Our results showed that binge-like ethanol pre-treated (BEP) rats exhibited early alterations in learning and memory tests accompanied by an impairment of synaptic plasticity that was total and partially compensated, respectively. These changes could be attributed to a rapid increase in oxidative damage and a late inflammatory response induced by post ethanol exposure. Additionally, BEP alters the regulation of mitochondrial dynamics and modifies the expression of mitochondrial permeability transition pore (mPTP) components, such as cyclophilin D (Cyp-D) and the voltage-dependent anion channel (VDAC). These mitochondrial structural changes result in the impairment of mitochondrial bioenergetics, decreasing ATP production progressively until adulthood. These results strongly suggest that teenage alcohol binge drinking impairs the function of the adult hippocampus including memory and synaptic plasticity as a consequence of the mitochondrial damage induced by alcohol and that the recovery of hippocampal function could implicate the activation of alternative pathways that fail to reestablish mitochondrial function.

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.