Agreement between an Early-Onset Neonatal Sepsis Risk Calculator and the Colombian Clinical Practice Guideline in Three Tertiary-Care Centers in Bogotá, Colombia.

OBJECTIVE: Clinical practice guidelines (CPG) worldwide help steer the management of early-onset neonatal sepsis (EONS). These documents typically discourage the use of risk assessment tools. However, prior work has shown that the Kaiser Permanente calculator (Early-Onset Sepsis Calculator [EOScalc]) could be a useful tool in EONS risk assessment. This study aimed to determine the agreement between the recommendations of the Colombian EONS CPG and those of the EOSCalc tool in a cohort of newborns in Bogotá, Colombia. STUDY DESIGN: Multicenter retrospective observational cohort study. We included newborns with a gestational age ≥ 34 weeks who were admitted to the neonatal care unit with a suspected diagnosis of EONS between 2017 and 2019. Agreement between the two tools was examined using Cohen's kappa under two scenarios (unequivocal and cautious). RESULTS: Of the 23.490 live births, 470 (1.71%) were admitted to the neonatal care unit with a presumptive diagnosis of EONS. This diagnosis was confirmed in seven patients by means of blood cultures, with group B streptococcus the most common organism (57%; 95% confidence interval [CI]: 18.4-90.1). A single death occurred among the patients with confirmed EONS (lethality: 14.3%). The overall incidence of EONS was 0.298 per 1,000 live births. After splitting the recommendations into two scenarios regarding antibiotic use, unequivocal and cautious, the agreement between EOSCalc and the CPG was below 15% (6 and 14%, respectively). CONCLUSION: Recommendations from the Colombian EONS CPG show poor agreement with the EOSCalc, with the latter detecting all newborns with EONS. Although the use of EOSCalc is clinically and administratively advantageous, further prospective studies are warranted to determine the safety of its implementation. KEY POINTS: · Colombian EONS CPGs recommend that an outsized number of newborns be given antibiotics.. · The KP EOSCalc risk assessment calculator shows poor agreement with CPG recommendations.. · The Colombian CPGs should be updated to include the use of risk assessment calculators..

Evaluation of the Antimicrobial Activity of Cationic Peptides Loaded in Surface-Modified Nanoliposomes against Foodborne Bacteria.

Bacteria are a common group of foodborne pathogens presenting public health issues with a large economic burden for the food industry. Our work focused on a solution to this problem by evaluating antibiotic activity against two bacteria (Listeria monocytogenes and Escherichia coli) of relevance in the field of foodstuffs. We used two approaches: (i) structural modification of the antimicrobial peptides and (ii) nano-vehiculisation of the modified peptides into polymer-coated liposomes. To achieve this, two antimicrobial peptides, herein named 'peptide +2' and 'peptide +5' were synthesised using the solid phase method. The physicochemical characterisation of the peptides was carried out using measurements of surface tension and dynamic light scattering. Additionally, nanoliposomes were elaborated by the ethanol injection method and coated with a cationic polymer (Eudragit E-100) through the layer-by-layer process. Liposome characterisation, in terms of size, polydispersity and zeta potential, was undertaken using dynamic light scattering. The results show that the degree of hydrophilic modification in the peptide leads to different characteristics of amphipathicity and subsequently to different physicochemical behaviour. On the other hand, antibacterial activity against both bacteria was slightly altered after modifying peptide sequence. Nonetheless, after the encapsulation of the peptides into polymer-coated nano-liposomes, the antibacterial activity increased approximately 2000-fold against that of L. monocytogenes.

Covered Stent Grafts for Acquired Arterial Venous Fistulas: A Case Series.

BACKGROUND: Stent grafts have become the preferred method for treating abdominal aortic aneurysms (AAAs) but also have utility in treating other vasculopathies. In 2005, peripheral stent grafts were approved for treating superficial femoral artery occlusive disease. This report describes our experience using covered stent grafts to treat acquired arterial venous fistulae (aAVF). METHODS: We reviewed the records of patients treated for aAVF with covered stent grafts. Eleven patients had 12 limbs treated with a stent graft. The data collected included presenting symptoms, mechanism of injury, vessel location, stent graft used for therapy, and patency. RESULTS: Eleven patients underwent successful treatment of 12 aAVF with a peripheral stent grafts. The average age was 55.6 (18-87), and there were 4 women and 7 men. The mechanisms of injuries were heart catheterization in 5 patients, penetrating trauma in 3 patients, and orthopedic injury in 3 patients. Five of the patients had concurrent pseudoaneurysms. Self-expanding expanded polytetrafluoroethelene (ePTFE) stent grafts were used in 8 patients, and balloon-expandable ePTFE stent grafts were used in 3 patients. Primary patency at 2 years is 100%, with all patients having significant relief of symptoms. CONCLUSIONS: Peripheral stent grafts are a useful tool for treating aAVF, with excellent patency. They provide a valuable minimally invasive approach to this disease.

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Progress in management of malperfusion syndrome from type B dissections.

OBJECTIVE: Malperfusion syndrome is a known predictor of poor outcomes in acute type B dissection. We describe our experience with revascularization in the acute setting. METHODS: Patients undergoing intervention for ischemia complicated acute type B dissection between November 1999 and March 2011 were reviewed. Details of presenting condition, surgical intervention, and postoperative course were collected. Descriptive and inferential statistical analyses included survival and freedom from reintervention using Cox proportional hazards models. RESULTS: A total of 61 patients were identified with malperfusion in at least one territory, including spinal cord 7/61 (12%), mesenteric 37/61 (61%), renal 45/61 (73%), and lower extremity 38/61 (62%). Thoracic stent grafts were placed in all patients, and 41% of patients required adjunctive branch vessel stenting. After intervention, resolution of the ischemia was reported in 57/61 (93%) of patients. The 30-day/in-hospital mortality was 21.3%. The 6-month, 1-year, and 5-year survival was 75% (95% CI, 65%-87%), 71% (95% CI, 61%-84%), and 56% (95% CI, 43%-74%), respectively. The 6-month, 1-year, and 5-year freedom from reintervention was 84% (95% CI, 75%-95%), 76% (95% CI, 65%-90%), and 42% (95% CI, 24%-76%), respectively. Territory of ischemia was not independently associated with mortality, but placement of a stent graft proximal to the subclavian artery was associated with poor outcome hazard ratio 2.91 (95% CI, 1.09-8.11; P = .034). CONCLUSIONS: Malperfusion in any territory at the time of presentation in patients with type B dissections can be treated with endovascular intervention with acceptable outcomes. Opposed to branch vessel intervention alone, increased aortic intervention with regard to proximal coverage may signify more serious disease is associated with worse outcome.

Lymphangitic carcinomatosis as the initial manifestation of primary signet-ring cell adenocarcinoma of the lung: A case report.

Signet-ring cell carcinomas are an aggressive, poorly differentiated, and highly invasive adenocarcinoma carrying a poor prognosis. Most of these tumors originate in gastrointestinal organs; however, primary lung signet-ring cell adenocarcinomas can rarely occur. Tumoral lymphatic infiltration is a complication of these tumors and can cause phenomena such as lymphangitic carcinomatosis, characterized by a nodular thickening of the pleura, pleural effusions, and mediastinal lymphadenopathies. We report a case of a 63-year-old ex-smoker with a 2-week clinical course of dyspnea and pleuritic chest pain in which a nodular thickening of the pleura and pleural effusion were documented and led to the diagnosis of a primary signet-ring cell adenocarcinoma of the lung with lymphangitic carcinomatosis. This complication has never been described in the context of a primary lung tumor of this subtype. Both entities carry a high mortality and have no therapeutical options. This report adds to the information available about them.

Unusual presentation of antisynthetase syndrome: a case series and review of the literature.

BACKGROUND: Antisynthetase syndrome is an inflammatory myopathy that is characterized by the presence of anti-aminoacyl-tRNA synthetase antibodies. Only 30% of those who suffer from the disease can be identified. We present three Hispanic cases of antisynthetase syndrome with unusual clinical pictures were extended myositis panel results enable disease diagnosis and treatment. CASE PRESENTATION: A 57-year-old Hispanic/Latino female with an erythematous scaly plaque, unresolved fever and non-immune haemolytic anaemia in whom inpatient work-up for fever of unknown origin was positive for anti-PL12 positive myositis extended panel. A 72-year-old Hispanic/Latino male with amyopathic weakness syndrome and mechanic hands in whom impatient work-up was relevant for proximal muscle uptake and anti-PM75 and AntiPL-12 myositis extended panel. And a 67-year-old Hispanic/Latino male with progressive interstitial lung disease and unresolved fever ended in myositis extended panel positive for antiPL-7. After systemic immunosuppressor treatment, patients had favourable clinical and paraclinical responses during outpatient follow-up. CONCLUSIONS: The high variability of the antisynthetase syndrome in these cases demonstrates the importance of identification through an expanded panel and highlights the probability that this is a variable disease and that we need to include emerging molecular tests to promote the timely treatment of patients.

Long-term follow-up of type II endoleak embolization reveals the need for close surveillance.

OBJECTIVE: Aneurysm growth after endovascular aneurysm repair (EVAR) in patients with type II endoleak is associated with adverse outcomes. This study evaluated the long-term success of embolization of type II endoleaks in preventing aneurysm sac growth. METHODS: We retrospectively reviewed outcomes of patients who underwent infrarenal EVAR who were treated for a type II endoleak between 2000 and 2008. Computed tomography scans were evaluated for aneurysm sac growth or shrinkage from the time of treatment of the endoleak. The embolization material used, graft type, target vessel embolized, and comorbidities were evaluated for their association with sac growth or shrinkage. RESULTS: Ninety-five patients underwent 140 embolization procedures. The mean time from EVAR to embolization was 26.1 ± 22.2 months, and the average increase in size of the aneurysm sac from EVAR to treatment was 0.7 × 0.5 cm. Patients underwent an average of 1.6 ± 0.8 embolization procedures after EVAR. Thirteen patients underwent initial simultaneous embolization of two targets. Embolization was with glue (61%), coils (29%), glue and coils (7%), and Gelfoam (3%; Pfizer Inc, New York, NY). No abdominal aortic aneurysms (AAA) ruptured. Eight patients (8.4%) underwent graft explant and open repair; 19 (20%) required two or more embolization procedures. There was no difference in the target vessel treated or the treatment used in halting sac expansion (>5 mm). Coil embolization alone resulted in more second procedures. The 5-year cumulative survival was 65% (95% confidence interval [CI], 52%-77%), freedom from explant was 89% (95% CI, 81%-97%), freedom from second embolization was 76% (95% CI, 66%-86%), and freedom from sac expansion >5 mm was 44% (95% CI 30%-50%). Univariable analysis identified continued tobacco use (hazard ratio [HR], 2.30; 95% CI, 1.02-5.13; P = .04) was associated with continued sac expansion, and hyperlipidemia (HR, 9.64; 95% CI, 2.22-41.86) was associated with patients requiring a second embolization procedure. CONCLUSIONS: Embolization of type II endoleaks is successful early in preventing aneurysm sac growth and rupture after EVAR. However, a significant number of patients require more than one procedure, and at 5 years, many patients who underwent embolization of a type II endoleak continued to experience sac growth. Patients with hyperlipidemia who undergo coil embolization are more likely to require a second embolization procedure, and patients who smoke have a higher likelihood of AAA sac expansion after embolization. Continued long-term surveillance is necessary in this cohort of patients.

Gender differences in the use of coping strategies to reduce food insecurity in Colombia.

This study explores the gender differences in the use of coping strategies to reduce food insecurity in Colombian urban and rural households. Data was collected from the Colombian National Survey of Nutritional Status (ENSIN 2015), and analyzed using ordinal logistic regression models, logistic models, and simultaneous equation models. Results show that rural households have a higher prevalence of food insecurity than their urban counterparts. After adjusting for household characteristics - e.g., head of household schooling level -, urban households were more likely to present severe and moderate food insecurity, whereas rural households were more likely to experience mild food insecurity. This result was explained by self-consumption and certain coping strategies, such as selling seeds from the next harvest or animals, implemented by rural households. Even though female-headed households present on average higher levels of food insecurity than male-headed ones, because they are more likely to use coping strategies, especially in rural areas, they can reduce and even cancel out this gap. Hence, female heads are more successful in mitigating food insecurity.

Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons.

Niemann-Pick type C (NPC) is a neurodegenerative disease characterized by the intralysosomal accumulation of cholesterol leading to neuronal apoptosis. We have previously reported the activation of the c-Abl/p73 proapoptotic pathway in the cerebellum of NPC mice; however, upstream signals underlying the engagement of this pathway remain unknown. Here, we investigate the possible role of oxidative stress in the activation of c-Abl/p73 using different in vitro and in vivo NPC models. Our results indicate a close temporal correlation between the appearance of nitrotyrosine (N-Tyr; a post-translational tyrosine modification caused by oxidative stress) and the activation of c-Abl/p73 in NPC models. To test the functional role of oxidative stress in NPC, we have treated NPC neurons with the antioxidant NAC and observed a dramatic decrease of c-Abl/p73 activation and a reduction in the levels of apoptosis in NPC models. In conclusion, our data suggest that oxidative stress is the main upstream stimulus activating the c-Abl/p73 pathway and neuronal apoptosis in NPC neurons.

COVID-19 presenting as acute generalized exanthematous pustulosis associated with multiorgan dysfunction in a 44-year-old female patient.

Acute generalised exanthematous pustulosis (AGEP) is an unusual cutaneous reaction, most often related with a hypersensitivity reaction to commonly used drugs. It is characterized by an abrupt onset of a pustular rash within hours or days after drug exposure and usually resolves spontaneously within 1-2 weeks after drug discontinuation. Some cases associated with systemic involvement and shock have been reported. We present the case of a severe AGEP, manifesting in association with systemic involvement and haemodynamic instability resulting in shock and multiorgan dysfunction in an adult female patient diagnosed with COVID-19 infection. There were no identifiable associated drugs, and the patient was not initiated on antimalarial drugs. Our patient improved rapidly, both hemodynamically and dermatologically with no directed therapy.

Predictive models for cardiovascular and kidney outcomes in patients with type 2 diabetes: systematic review and meta-analyses.

OBJECTIVE: To inform a clinical practice guideline (BMJ Rapid Recommendations) considering sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists for treatment of adults with type 2 diabetes, we summarised the available evidence regarding the performance of validated risk models on cardiovascular and kidney outcomes in these patients. METHODS: We systematically searched bibliographic databases in January 2020 to identify observational studies evaluating risk models for all-cause and cardiovascular mortality, heart failure (HF) hospitalisations, end-stage kidney disease (ESKD), myocardial infarction (MI) and ischaemic stroke in ambulatory adults with type 2 diabetes. Using a random effects model, we pooled discrimination measures for each model and outcome, separately, and descriptively summarised calibration plots, when available. We used the Prediction Model Risk of Bias Assessment Tool to assess risk of bias of each included study and the Grading of Recommendations, Assessment, Development, and Evaluation approach to evaluate our certainty in the evidence. RESULTS: Of 22 589 publications identified, 15 observational studies reporting on seven risk models proved eligible. Among the seven models with >1 validation cohort, the Risk Equations for Complications of Type 2 Diabetes (RECODe) had the best calibration in primary studies and the highest pooled discrimination measures for the following outcomes: all-cause mortality (C-statistics 0.75, 95% CI 0.70 to 0.80; high certainty), cardiovascular mortality (0.79, 95% CI 0.75 to 0.84; low certainty), ESKD (0.73, 95% CI 0.52 to 0.94; low certainty), MI (0.72, 95% CI 0.69 to 0.74; moderate certainty) and stroke (0.71, 95% CI 0.68 to 0.74; moderate certainty). This model does not, however, predict risk of HF hospitalisations. CONCLUSION: Of available risk models, RECODe proved to have satisfactory calibration in primary validation studies and acceptable discrimination superior to other models, though with high risk of bias in most primary studies. TRIAL REGISTRATION NUMBER: CRD42020168351.

Prognostic factors in hospitalized patients diagnosed with SARS-CoV-2 infection, Bogotá, Colombia / [Factores pronósticos en pacientes hospitalizados con diagnóstico de infección por SARS-CoV-2 en Bogotá, Colombia].

Introduction: Infection with the new SARS-Cov-2 coronavirus is a worldwide public health emergency; its diagnosis is based on molecular tests, while its prognosis depends on the patient's history and on some paraclinical tests. In Colombia, forecasts are not yet counted. Objective: To assess the factors associated with the development of severe disease in hospitalized patients diagnosed with SARS-CoV-2 infection, as well as the prognostic factors for the outcome of mortality. Materials and methods: We conducted an ambispective cohort study in hospitalized patients at the Fundación Cadioinfantil from March to June, 2020. Results: Of the 104 patients analyzed, 31.7% (n=33) had a severe presentation and 9.6% (n=10) had a mortality outcome. For mortality, the most important prognostic factor was the development of severe disease followed by age over 60 years and malnutrition. For the development of the severe disease, prognostic factors were a history of hemodialysis (HR=135), diabetes (HR=4.4), and an increased level of lactate dehydrogenase (LDH) (HR=1,004), while the lymphocyte count over 1,064 was a protective factor (HR=0.9). In the classification of patients, the National Early Warning Score (NEWS2) score in the high and low-risk categories corresponded to the best performance. There was no difference between the treatments administered. Conclusions: The most important prognostic factors for mortality were being over 60 years of age, hypertension, diabetes, and cirrhosis, while for the development of severe disease they were chronic kidney disease with hemodialysis, NEWS2 with high risk at admission, increased levels of LDH and C reactive protein (CRP), and leukocytosis.

Introducción. La infección por el nuevo coronavirus SARS-Cov-2 es una emergencia de salud pública en todo el mundo; su diagnóstico se basa en pruebas moleculares, en tanto que su pronóstico depende de los antecedentes del paciente y de algunos exámenes paraclínicos. En Colombia aún no se cuenta con datos de pronóstico en una población local. Objetivo. Evaluar los factores asociados con el desarrollo de la enfermedad grave en pacientes hospitalizados con diagnóstico de infección por SARS-CoV-2, así como los factores pronósticos de la mortalidad. Materiales y métodos. Se hizo un estudio de cohorte ambispectivo en pacientes hospitalizados en la Fundación Cardioinfantil entre marzo y junio de 2020. Resultados. De los 104 pacientes analizados, en el 31,7 % (n=33) la infección fue grave y en el 9,6 % (n=10) se produjo la muerte. El factor pronóstico más importante de la mortalidad fue el desarrollo de la enfermedad grave, seguido de una edad de más de 60 años y la desnutrición. Para el desarrollo de la enfermedad grave los factores pronósticos fueron los antecedentes de hemodiálisis (hazard ratio, HR=135), diabetes (HR=4,4) y el aumento en el nivel de la lactato deshidrogenasa (LDH) (HR=1,004), en tanto que un conteo de linfocitos superior a 1.064 fue un factor protector (HR=0,9). El puntaje del National Early Warning Score (NEWS2) correspondiente a las categorías de alto y bajo riesgo fue el que mejor rendimiento tuvo. No hubo diferencia entre los tratamientos administrados. Conclusiones. Los factores pronósticos más importantes para la mortalidad fueron tener más de 60 años, hipertensión, diabetes y cirrosis, en tanto que para el desarrollo de la enfermedad grave fueron la enfermedad renal crónica con hemodiálisis, un puntaje de NEWS2 de alto riesgo al ingreso, y aumento en los niveles de LDH y proteína C reactiva, y leucocitosis.

c-Abl modulates AICD dependent cellular responses: transcriptional induction and apoptosis.

APP intracellular domain (AICD) has been proposed as a transcriptional inductor that moves to the nucleus with the adaptor protein Fe65 and regulates transcription. The two proteins, APP and Fe65, can be phosphorylated by c-Abl kinase. Neprilysin has been proposed as a target gene for AICD. We found that AICD expression is decreased by treatment with STI-571, a c-Abl inhibitor, suggesting a modulation of AICD transcription by c-Abl kinase. We observed interaction between c-Abl kinase, the AICD fragment and the Fe65 adaptor protein. In addition, STI-571 reduces apoptosis in APPSw, and the apoptotic response induced by Fe65 over-expression was inhibited by with the expression of a kinase dead (KD) c-Abl and enhanced by over-expression of WT-c-Abl. However, in the APPSw cells, the ability of the KD-c-Abl to protect against Fe65 was reduced. Finally, in APPSw clone, we detected higher trans-activation of the pro-apoptotic p73 isoform, TAp73 promoter. Our results show that c-Abl modulates AICD dependent cellular responses, transcriptional induction as well as the apoptotic response, which could participate in the onset and progression of the neurodegenerative pathology, observed in Alzheimer's disease (AD).

Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a fatal autosomal recessive disorder characterized by the accumulation of free cholesterol and glycosphingolipids in the endosomal-lysosomal system. Patients with NPC disease have markedly progressive neuronal loss, mainly of cerebellar Purkinje neurons. There is strong evidence indicating that cholesterol accumulation and trafficking defects activate apoptosis in NPC brains. The purpose of this study was to analyze the relevance of apoptosis and particularly the proapoptotic c-Abl/p73 system in cerebellar neuron degeneration in NPC disease. We used the NPC1 mouse model to evaluate c-Abl/p73 expression and activation in the cerebellum and the effect of therapy with the c-Abl-specific inhibitor imatinib. The proapoptotic c-Abl/p73 system and the p73 target genes are expressed in the cerebellums of NPC mice. Furthermore, inhibition of c-Abl with imatinib preserved Purkinje neurons and reduced general cell apoptosis in the cerebellum, improved neurological symptoms, and increased the survival of NPC mice. Moreover, this prosurvival effect correlated with reduced mRNA levels of p73 proapoptotic target genes. Our results suggest that the c-Abl/p73 pathway is involved in NPC neurodegeneration and show that treatment with c-Abl inhibitors is useful in delaying progressive neurodegeneration, supporting the use of imatinib for clinical treatment of patients with NPC disease.

Increases in Hydrophilicity and Charge on the Polar Face of Alyteserin 1c Helix Change its Selectivity towards Gram-Positive Bacteria.

Recently, resistance of pathogens towards conventional antibiotics has increased, representing a threat to public health globally. As part of the fight against this, studies on alternative antibiotics such as antimicrobial peptides have been performed, and it has been shown that their sequence and structure are closely related to their antimicrobial activity. Against this background, we here evaluated the antibacterial activity of two peptides developed by solid-phase synthesis, Alyteserin 1c (WT) and its mutant derivative (ΔM), which shows increased net charge and reduced hydrophobicity. These structural characteristics were modified as a result of amino acid substitutions on the polar face of the WT helix. The minimum inhibitory concentration (MIC) of both peptides was obtained in Gram-positive and Gram-negative bacteria. The results showed that the rational substitutions of the amino acids increased the activity in Gram-positive bacteria, especially against Staphylococcus aureus, for which the MIC was one-third of that for the WT analog. In contrast to the case for Gram-positive bacteria, these substitutions decreased activity against Gram-negative bacteria, especially in Escherichia coli, for which the MIC was eight-fold higher than that exhibited by the WT peptide. To understand this, models of the peptide behavior upon interacting with membranes of E. coli and S. aureus created using molecular dynamics were studied and it was determined that the helical stability of the peptide is indispensable for antimicrobial activity. The hydrogen bonds between the His20 of the peptides and the phospholipids of the membranes should modulate the selectivity associated with structural stability at the carboxy-terminal region of the peptides.

c-Abl Deficiency Provides Synaptic Resiliency Against Aß-Oligomers.

Spine pathology has been implicated in the early onset of Alzheimer's disease (AD), where Aß-Oligomers (AßOs) cause synaptic dysfunction and loss. Previously, we described that pharmacological inhibition of c-Abl prevents AßOs-induced synaptic alterations. Hence, this kinase seems to be a key element in AD progression. Here, we studied the role of c-Abl on dendritic spine morphological changes induced by AßOs using c-Abl null neurons (c-Abl-KO). First, we characterized the effect of c-Abl deficiency on dendritic spine density and found that its absence increases dendritic spine density. While AßOs-treatment reduces the spine number in both wild-type (WT) and c-Abl-KO neurons, AßOs-driven spine density loss was not affected by c-Abl. We then characterized AßOs-induced morphological changes in dendritic spines of c-Abl-KO neurons. AßOs induced a decrease in the number of mushroom spines in c-Abl-KO neurons while preserving the populations of immature stubby, thin, and filopodia spines. Furthermore, synaptic contacts evaluated by PSD95/Piccolo clustering and cell viability were preserved in AßOs-exposed c-Abl-KO neurons. In conclusion, our results indicate that in the presence of AßOs c-Abl participates in synaptic contact removal, increasing susceptibility to AßOs damage. Its deficiency increases the immature spine population reducing AßOs-induced synapse elimination. Therefore, c-Abl signaling could be a relevant actor in the early stages of AD.

Glutamatergic stimulation induces GluN2B translation by the nitric oxide-Heme-Regulated eIF2α kinase in cortical neurons.

The activation of N-Methyl D-Aspartate Receptor (NMDAR) by glutamate is crucial in the nervous system function, particularly in memory and learning. NMDAR is composed by two GluN1 and two GluN2 subunits. GluN2B has been reported to participate in the prevalent NMDAR subtype at synapses, the GluN1/2A/2B. Here we studied the regulation of GluN2B expression in cortical neurons finding that glutamate up-regulates GluN2B translation through the action of nitric oxide (NO), which induces the phosphorylation of the eukaryotic translation initiation factor 2 α (eIF2α). It is a process mediated by the NO-heme-regulated eIF2α kinase (HRI), as the effect was avoided when a specific HRI inhibitor or a HRI small interfering RNA (siHRI) were used. We found that the expressed GluN2B co-localizes with PSD-95 at the postsynaptic ending, which strengthen the physiological relevance of the proposed mechanism. Moreover the receptors bearing GluN2B subunits upon NO stimulation are functional as high Ca2+ entry was measured and increases the co-localization between GluN2B and GluN1 subunits. In addition, the injection of the specific HRI inhibitor in mice produces a decrease in memory retrieval as tested by the Novel Object Recognition performance. Summarizing our data suggests that glutamatergic stimulation induces HRI activation by NO to trigger GluN2B expression and this process would be relevant to maintain postsynaptic activity in cortical neurons.

Factores pronósticos en pacientes hospitalizados con diagnóstico de infección por SARS-CoV-2 en Bogotá, Colombia / Prognostic factors in hospitalized patients diagnosed with SARS-CoV-2 infection, Bogotá, Colombia

Introducción. La infección por el nuevo coronavirus SARS-Cov-2 es una emergencia de salud pública en todo el mundo; su diagnóstico se basa en pruebas moleculares, en tanto que su pronóstico depende de los antecedentes del paciente y de algunos exámenes paraclínicos. En Colombia aún no se cuenta con datos de pronóstico en una población local. Objetivo. Evaluar los factores asociados con el desarrollo de la enfermedad grave en pacientes hospitalizados con diagnóstico de infección por SARS-CoV-2, así como los factores pronósticos de la mortalidad. Materiales y métodos. Se hizo un estudio de cohorte ambispectivo en pacientes hospitalizados en la Fundación Cardioinfantil entre marzo y junio de 2020. Resultados. De los 104 pacientes analizados, en el 31,7 % (n=33) la infección fue grave y en el 9,6 % (n=10) se produjo la muerte. El factor pronóstico más importante de la mortalidad fue el desarrollo de la enfermedad grave, seguido de una edad de más de 60 años y la desnutrición. Para el desarrollo de la enfermedad grave los factores pronósticos fueron los antecedentes de hemodiálisis (hazard ratio, HR=135), diabetes (HR=4,4) y el aumento en el nivel de la lactato deshidrogenasa (LDH) (HR=1,004), en tanto que un conteo de linfocitos superior a 1.064 fue un factor protector (HR=0,9). El puntaje del National Early Warning Score (NEWS2) correspondiente a las categorías de alto y bajo riesgo fue el que mejor rendimiento tuvo. No hubo diferencia entre los tratamientos administrados. Conclusiones. Los factores pronósticos más importantes para la mortalidad fueron tener más de 60 años, hipertensión, diabetes y cirrosis, en tanto que para el desarrollo de la enfermedad grave fueron la enfermedad renal crónica con hemodiálisis, un puntaje de NEWS2 de alto riesgo al ingreso, y aumento en los niveles de LDH y proteína C reactiva, y leucocitosis.

Introduction: Infection with the new SARS-Cov-2 coronavirus is a worldwide public health emergency; its diagnosis is based on molecular tests, while its prognosis depends on the patient's history and on some paraclinical tests. In Colombia, forecasts are not yet counted. Objective: To assess the factors associated with the development of severe disease in hospitalized patients diagnosed with SARS-CoV-2 infection, as well as the prognostic factors for the outcome of mortality. Materials and methods: We conducted an ambispective cohort study in hospitalized patients at the Fundación Cadioinfantil from March to June, 2020. Results: Of the 104 patients analyzed, 31.7% (n=33) had a severe presentation and 9.6% (n=10) had a mortality outcome. For mortality, the most important prognostic factor was the development of severe disease followed by age over 60 years and malnutrition. For the development of the severe disease, prognostic factors were a history of hemodialysis (HR=135), diabetes (HR=4.4), and an increased level of lactate dehydrogenase (LDH) (HR=1,004), while the lymphocyte count over 1,064 was a protective factor (HR=0.9). In the classification of patients, the National Early Warning Score (NEWS2) score in the high and low-risk categories corresponded to the best performance. There was no difference between the treatments administered. Conclusions: The most important prognostic factors for mortality were being over 60 years of age, hypertension, diabetes, and cirrhosis, while for the development of severe disease they were chronic kidney disease with hemodialysis, NEWS2 with high risk at admission, increased levels of LDH and C reactive protein (CRP), and leukocytosis.

Physiological Control of Nitric Oxide in Neuronal BACE1 Translation by Heme-Regulated eIF2α Kinase HRI Induces Synaptogenesis.

AIMS: Hippocampus is the brain center for memory formation, a process that requires synaptogenesis. However, hippocampus is dramatically compromised in Alzheimer's disease due to the accumulation of amyloid ß-peptide, whose production is initiated by ß-site APP Cleaving Enzyme 1 (BACE1). It is known that pathological stressors activate BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2α (eIF2α) by GCN2, PERK, or PKR kinases, leading to amyloidogenesis. However, BACE1 physiological regulation is still unclear. Since nitric oxide (NO) participates directly in hippocampal glutamatergic signaling, we investigated the neuronal role of the heme-regulated eukaryotic initiation factor eIF2α kinase (HRI), which can bind NO by a heme group, in BACE1 translation and its physiological consequences. RESULTS: We found that BACE1 is expressed on glutamate activation with NO being the downstream effector by triggering eIF2α phosphorylation, as it was obtained by Western blot and luciferase assay. It is due to the activation of HRI by NO as assayed by Western blot and immunofluorescence with an HRI inhibitor and HRI siRNA. BACE1 expression was early detected at synaptic spines, contributing to spine growth and consolidating the hippocampal memory as assayed with mice treated with HRI or neuronal NO synthase inhibitors. INNOVATION: We provide the first description that HRI and eIF2α are working in physiological conditions in the brain under the control of nitric oxide and glutamate signaling, and also that BACE1 has a physiological role in hippocampal function. CONCLUSION: We conclude that BACE1 translation is controlled by NO through HRI in glutamatergic hippocampal synapses, where it plays physiological functions, allowing the spine growth and memory consolidation.