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.

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.

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.

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..

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.

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.

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.

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.

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.

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.

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.

Reacciones adversas poco comunes a antibióticos: Agranulocitosis por vancomicina / Rare adverse reactions to antibiotics: Vancomycin induced agranulocytosis

Las discrasias hemáticas inducidas por fármacos, son causadas por la interacción de diferentes fármacos con las células hematopoyéticas por medio de receptores específicos. Otros mecanismos fisiopatológicos pueden ser por toxicidad directa sobre la médula ósea o las células periféricas, por hipersensibilidad, por defectos inmunológicos secundarios a infecciones virales, por mecanismos mixtos o desconocidos. Las primeras asociaciones se describieron en la década de los años treinta. Los fármacos con mayor riesgo relativo de agranulocitosis o anemia aplásica son los antitiroideos, carbamazepina, las sulfonilureas, la indometacina, el piroxicam, entre otros. Se presentaa continuación el reporte de un caso clínico en paciente adulto quien con la administración de vancomicina presento agranulocitosis resolviendo el cuadro posterior a su suspensión.

The drug-induced blood dyscrasias are caused by the interaction of different drugs with the hematopoietic cells through specific receptors. Other pathophysiologic mechanisms may be by direct toxicity to bone marrow or peripheral cells, hypersensitivity, immunological defects secondary to viral infections, mixed or unknown mechanisms. The first associations were described in the thirties. Drugs with higher relative risk of a granulocytosis or aplastic anemia are antithyroid, carbamazepine, sulfonylurea, indomethacin and piroxicam among others. The report of a clinical case in an adult patient who after the administration of vancomycin presented agranulocytosis with resolution of the clinical picture after its suspension, is presented.

EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-ß oligomers.

The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-ß oligomers (AßOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AßOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AßOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AßOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AßOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AßOs. According to this results, the EphA4 antagonistic peptide KYL and c-Abl inhibitor STI prevented i) dendritic spine reduction, ii) the blocking of LTP induction and iii) neuronal apoptosis caused by AßOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AßOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AßOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients.

Distribución de los patrones venosos de la fosa cubital en una muestra de personas nacidas en el departamento de santander, Colombia / Distribution pattern of the veins of the cubital fossa in a sample of people born in the department of santander, Colombia

Se determinó la frecuencia de los patrones venosos superficiales del miembro superior en una muestra de 885 personas (438 hombres y 447 mujeres) nacidas en el Departamento de Santander, Colombia de acuerdo a la clasificación propuesta por del Sol et al. El patrón que predominó fue el I con 524 casos (30%) seguido del patrón III con 451 casos (26%). El patrón I fue el más frecuente tanto en el miembro superior derecho con 286 casos (32%) como en el miembro superior izquierdo con 238 casos (27%). En hombres el patrón predominante fue el I con 307 casos (35%) seguido del patrón II con 228 casos (26%). En mujeres el patrón predominante fue el III con 367 casos (41%) seguido del patrón I con 217 casos (24%). El patrón en "M clásica" tuvo una frecuencia similar en hombres y mujeres con 8%.

We determined the frequency of superficial vein patterns of the upper limb in a sample of 885 people (438 men and 447 women) born in the department of Santander, Colombia according to the classification proposed by del Sol et al. The predominant pattern was I with 524 cases (30%) followed by pattern III with 451 cases (26%). Pattern I was the most prevalent in both the right arm with 286 cases (32%) and in the left upper limb with 238 cases (27%). In men, the pattern I was predominant with 307 cases (35%) followed pattern II with 228 cases (26%). In women the predominant pattern III was with 367 cases (41%) followed the pattern I with 217 cases (24%). The pattern in "M classic" frequency was similar in men and women with 8%.

Lower extremity amputations: factors associated with mortality or contralateral amputation.

BACKGROUND: Tissue loss or gangrene in the setting of lower extremity peripheral artery disease (PAD) may result in amputation. Previous studies have demonstrated elevated mortality rates after major transtibial and transfemoral amputation. Also, amputation of 1 leg may be associated with subsequent major amputation of the contralateral leg. The aim of our study was to identify patient variables associated with mortality and contralateral amputation. METHODS: We reviewed the medical records of patients who underwent transfemoral or transtibial amputation secondary to PAD from 2004 to 2009. A total of 454 consecutive major amputations were performed on 391 patients, with 63 of these having a subsequent contralateral amputation. Standard demographic information, comorbidities, prior vascular interventions, and relevant procedural information were extracted from patient records. Kaplan-Meier estimates of survival were calculated. Cox proportional hazard models were used to estimate the risk of death and contralateral amputation. Multivariate Cox proportional hazards models were fit for all variables shown to be marginally associated in the univariate model. RESULTS: In 391 amputees, the mean age was 67.3 years, 63% were male and 62% were caucasian. Patients had high rates of diabetes (63%), hypertension (83%), renal insufficiency (35%), hyperlipidemia (51%), and prior ipsilateral vascular intervention (75%). Seventy percent of patients had below-knee amputations. Perioperative mortality was 9.2% (n = 36). Survival at 12 and 24 months was 70% (95% confidence interval [CI], 65%-74%) and 60% (95% CI, 55%-65%), respectively. Multivariate analysis demonstrated that several independent factors were detrimental to survival including chronic obstructive pulmonary disease (hazard ratio [HR] 1.82, P = .002), dialysis dependence (HR 2.50, P < .001), high cardiac risk (HR 2.20, P < .001), and guillotine amputation (HR 2.49, P = .004). Dialysis (HR 2.42, P = .002) and revision of the index ipsilateral amputation to a higher level (HR 2.02, P = .014) were associated with a subsequent contralateral amputation. CONCLUSIONS: Patients with advanced PAD that require lower extremity amputation have diminished survival and significant contralateral amputation rates. Elderly patients on dialysis are particularly prone to dying or losing the other leg after a major amputation. These data support strategies to enhance limb preservation and optimize medical comorbidities in these patients.