The Insulin/IGF Signaling Regulators Cytohesin/GRP-1 and PIP5K/PPK-1 Modulate Susceptibility to Excitotoxicity in C. elegans

During ischemic stroke, malfunction of excitatory amino acid transporters and reduced synaptic clearance causes accumulation of Glutamate (Glu) and excessive stimulation of postsynaptic neurons, which can lead to their degeneration by excitotoxicity. The balance between cell death-promoting (neurotoxic) and survival-promoting (neuroprotective) signaling cascades determines the fate of neurons exposed to the excitotoxic insult. The evolutionary conserved Insulin/IGF Signaling (IIS) cascade can participate in this balance, as it controls cell stress resistance in nematodes and mammals. Blocking the IIS cascade allows the transcription factor FoxO3/DAF-16 to accumulate in the nucleus and activate a transcriptional program that protects cells from a range of insults. We study the effect of IIS cascade on neurodegeneration in a C. elegans model of excitotoxicity, where a mutation in a central Glu transporter (glt-3) in a sensitizing background causes Glu-Receptor –dependent neuronal necrosis. We expand our studies on the role of the IIS cascade in determining susceptibility to excitotoxic necrosis by either blocking IIS at the level of PI3K/AGE-1 or stimulating it by removing the inhibitory effect of ZFP-1 on the expression of PDK-1. We further show that the components of the Cytohesin/GRP-1, Arf, and PIP5K/PPK-1 complex, known to regulate PIP2 production and the IIS cascade, modulate nematode excitotoxicity: mutations that are expected to reduce the complex’s ability to produce PIP2 and inhibit the IIS cascade protect from excitotoxicity, while overstimulation of PIP2 production enhances neurodegeneration. Our observations therefore affirm the importance of the IIS cascade in determining the susceptibility to necrotic neurodegeneration in nematode excitotoxicity, and demonstrate the ability of Cytohesin/GRP-1, Arf, and PIP5K/PPK-1 complex to modulate neuroprotection

Desarrollo de un sistema de gestión para una biblioteca digital en la I.E Nuestra Señora del Perpetuo Socorro Piura - 2022

La finalidad de este proyecto de investigación es desarrollar e implementar un sistema de gestión para una biblioteca digital en la I.E Nuestra Señora del perpetuo socorro Piura – 2022, donde se puede almacenar y llevar de manera segura la información deseada además que permita gestionar de mejor manera la información del área bibliotecaria, así como también que permita a los usuarios buscar cualquier contenido bibliográfico que deseen ya sea por categorías tales como autor, materia, titulo, año de publicación, etc. Luego de evaluar y analizar las deficiencias que presentaba el área bibliotecaria, sobre todo en la búsqueda y préstamo del material bibliográfico, es por ello que tenemos como objetivo principal de nuestra investigación implementar un sistema de gestión para una biblioteca digital en la Institución Educativa Nuestra Señora del Perpetuo Socorro Piura – 2022. Para el desarrollo la metodología el tipo de investigación del estudio es de tipo aplicada, con respecto al diseño de investigación no experimental de corte Transversal, como metodología de desarrollo de software se utilizó la metodología Scrum, se precisó criterios de Inclusión y exclusión para el proceso de selección de la información a través de los instrumentos de recolección de datos. Como resultado tenemos que el tiempo de respuesta del servicio bibliotecario aumento un 42% al igual que la calidad del servicio aumento un 56.7% por último el tiempo de búsqueda del material bibliográfico aumento un 68.3% lo cual refleja un impacto positivo para el servicio bibliotecario brindando un mejor servicio para sus usuarios

ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma a

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Enhancing A Neurology Clerkship Curriculum Using Just-In-Time Teaching With Video-Based Learning

ENHANCING A NEUROLOGY CLERKSHIP CURRICULUM USING JUST-IN-TIME TEACHING WITH VIDEO-BASED LEARNING Moises Dominguez, Daniel DiCapua, Gary Leydon, Caitlin Loomis, Kevin Becker, Kamil Detyniecki, P. Christopher Gottschalk, Erin Longbrake, Arash Salardini, Sara M. Schaefer, John Encandela and Jeremy J. Moeller. Department of Neurology, Yale University School of Medicine, New Haven, CT. Introduction There are a number challenges medical education faces, such as the exponential increase in medical knowledge students must learn within their four years of medical school. Now more than ever is the time to implement evidence-based methods of teaching while utilizing advances in technology to deliver medical content to students. Just-In-Time Teaching is an active form of learning that uses web-based technology to create a feedback loop between the students and instructor. Students are assigned a task, which involves answering conceptual questions prior to the in-class session. The instructor receives the student results to adjust their lecture “just-in-time.” Based on the student responses, the instructor can address any common misconception amongst the students. Our goal is to enhance the student and lecturer experience, and to assess the effectiveness, feasibility, and acceptability of this pedagogy on student learning in third year medical students on their neurology rotation. Methods 8 short (~5-13 minute) video-based lectures (VBLs) were created to present the framework and “evergreen” knowledge of 8 subspecialty didactic sessions within the neurology clerkship. 4-8 multiple-choice questions (MCQs) were created and reflect the learning objectives faculty members identified for their subject, which students take after watching the VBL. We iteratively implemented the VBL/MCQ sets in order to incorporate the feedback from students and faculty member into the development of the next topic. This equated to incorporating 1-2 topics each month. Quantitative surveys from students and faculty were obtained. End-of-clerkship knowledge assessments were compared between the intervention and pre-intervention groups. Results 42.4% (56/132) of students, between October 2016 and April 2017, responded to the surveys. Most students agreed or strongly agreed that using this pedagogy enhanced their learning and felt more responsible for learning the material. Faculty agreed that they enjoyed using this pedagogy and that it helped prepare students for class. Most faculty felt that seeing how students did on the multiple-choice questions helped them better understand which areas of knowledge need further clarification. Most students watched the whole video-based lecture; however, there was decreased audience retention with longer videos. There was no statistically significant difference in the end-of-clerkship knowledge assessment scores when comparing the pre-intervention groups (traditional lecture) and intervention groups (JiTT with VBL.) Conclusion Just-In-Time Teaching combined with Video-Based Learning is an acceptable and feasible mode of teaching that enhances student learning and experience. Future research will focus on improving the quality of the end-of-clerkship knowledge assessment tools and implementing a randomized component to better evaluate the potential effectiveness of this approach

Novel ways of approaching the pharmacologic treatment of trigeminal neuralgia

Abstract not availabl