Hydroxytyrosol Prevents Increase of Osteoarthritis Markers in Human Chondrocytes Treated with Hydrogen Peroxide or Growth-Related Oncogene \u3b1

Hydroxytyrosol (HT), a phenolic compound mainly derived from olives, has been proposed as a nutraceutical useful in prevention or treatment of degenerative diseases. In the present study we have evaluated the ability of HT to counteract the appearance of osteoarthritis (OA) features in human chondrocytes. Pre-treatment of monolayer cultures of chondrocytes with HT was effective in preventing accumulation of reactive oxidant species (ROS), DNA damage and cell death induced by H2O2 exposure, as well as the increase in the mRNA level of pro-inflammatory, matrix-degrading and hypertrophy marker genes, such as iNOS, COX-2, MMP-13, RUNX-2 and VEGF. HT alone slightly enhanced ROS production, but did not enhance cell damage and death or the expression of OA-related genes. Moreover HT was tested in an in vitro model of OA, i.e. three-dimensional micromass cultures of chondrocytes stimulated with growth-related oncogene \u3b1 (GRO\u3b1), a chemokine involved in OA pathogenesis and known to promote hypertrophy and terminal differentiation of chondrocytes. In micromass constructs, HT pre-treatment inhibited the increases in caspase activity and the level of the messengers for iNOS, COX-2, MMP-13, RUNX-2 and VEGF elicited by GRO\u3b1. In addition, HT significantly increased the level of SIRT-1 mRNA in the presence of GRO\u3b1. In conclusion, the present study shows that HT reduces oxidative stress and damage, exerts pro-survival and anti-apoptotic actions and favourably influences the expression of critical OA-related genes in human chondrocytes treated with stressors promoting OA-like features

Short-Term and Two-Year Rate of Recurrent Cerebrovascular Events in Patients with Acute Cerebral Ischemia of Undetermined Aetiology, with and without a Patent Foramen Ovale

Purpose. We investigated stroke recurrence in patients with acute ischemic stroke of undetermined aetiology, with or without a patent foramen ovale (PFO). Methods. Consecutive stroke patients underwent to Transcranial Doppler and Transesophageal Echocardiography for PFO detection. Secondary stroke prevention was based on current guidelines. Results. PFO was detected in 57/129 (44%) patients. The rate of recurrent stroke did not significantly differ between patients with and without a PFO: 0.0% versus 1.4% (1 week), 1.7% versus 2.7% (1 month), and 3.5% versus 4.2% (3 months), respectively. The 2-year rates were 10.4% (5/48) in medically treated PFO and 8.3% (6/72) in PFO-negative patients (P = 0.65), with a relative risk of 1.25. No recurrent events occurred in 9 patients treated with percutaneous closure of PFO. Conclusion. PFO was not associated with increased rate of recurrent stroke. Age-related factors associated with stroke recurrence in cryptogenic stroke should be taken into account when patients older than 55 years are included in PFO studies

Pre-treatment prediction of response to peginterferon plus ribavirin in chronic hepatitis C genotype 3

AIM: To evaluate pre-treatment factors associated with sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 3 treated with peginterferon and ribavirin (RBV). METHODS: We retrospectively analyzed treatment naive, mono-infected HCV genotype 3 patients treated with peginterferon and RBV. Exclusion criteria included presence of other liver disease, alcohol consumption and African American or Asian ethnicity. The variables collected and compared between patients who achieved an SVR and patients who did not were as follows: gender, age, fibrosis stage, diabetes, body mass index, steatosis, INFL3 polymorphism, pre-treatment HCV-RNA, type of peginterferon, RBV dose and adherence. RESULTS: A total of 107 patients treated between June, 2004 and March, 2013 were included. Mean treatment duration was 25.1 (± 1.8) wk. Overall, 58% (62/107) of the patients achieved an SVR and 42% (45/107) did not. In the multivariate logistic regression analysis, pre-treatment HCV-RNA ≥ 600000 UI/mL (OR = 0.375, 95%CI: 0.153-0.919, P = 0.032) and advanced fibrosis (OR = 0.278, 95%CI: 0.113-0.684, P = 0.005) were significantly associated with low SVR rates. In patients with pre-treatment HCV-RNA ≥ 600000 UI/mL and advanced fibrosis, the probability of achieving an SVR was 29% (95%CI: 13.1-45.2). In patients with pre-treatment HCV-RNA < 600000 UI/mL and mild to moderate fibrosis, the probability of achieving an SVR was 81% (95%CI: 68.8-93.4). CONCLUSION: In patients with HCV genotype 3 infections the presence of advance fibrosis and high pre-treatment viral load might be associated with poor response to peginterferon plus RBV. These patients could benefit the most from new direct antiviral agents-based regimes.Fil: Marciano, Sebastián. Hospital Italiano; ArgentinaFil: Borzi, Silvia Mabel. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal General de Agudos "prof. Dr. Rodolfo Rossi".; ArgentinaFil: Dirchwolf, Melisa. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Ridruejo, Ezequiel. Universidad Austral. Hospital Universitario Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Bessone, Fernando. Sanatorio del Parque. Unidad de Hepatología; ArgentinaFil: Sirotinsky, María Ester. Hepatosur group; ArgentinaFil: Giunta, Diego Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano; ArgentinaFil: Trinks, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano; ArgentinaFil: Olivera Sendra, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Galdame, Omar Andres. Hospital Italiano; ArgentinaFil: Silva, Marcelo Oscar. Universidad Austral. Hospital Universitario Austral; Argentina. Hospital Italiano; ArgentinaFil: Fainboim, Hugo. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal General de Agudos "prof. Dr. Rodolfo Rossi".; ArgentinaFil: Gadano, Adrián Carlos. Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

mTOR, AMPK, and Sirt1: Key Players in Metabolic Stress Management

Cells adapt their metabolism and activities in response to signals from their surroundings, and this ability is essential for their survival in the face of environmental changes. In mammalian tissues a deficit of these mechanisms is commonly associated with cellular aging and degenerative diseases related to aging, such as cardiovascular disease, cancer, immune system decline, and neurological pathologies. Several proteins have been identified as able to respond directly to energy, nutrient, and growth factor levels and stress stimuli in order to mediate adaptations in the cell. Many of these proteins are enzymes that positively or negatively modulate the autophagic process. This review focuses on biochemical mechanisms involving enzymes-specifically, mTOR, AMPK, and Sirt1-that are currently considered important for these adaptive responses, providing an overview of the interactions of the main players in this process

An attack graph-based on-line multi-step attack detector

Modern distributed systems are characterized by complex deployment designed to ensure high availability through replication and diversity, to tolerate the presence of failures and to limit the possibility of successful compromising. However, software is not free from bugs that generate vulnerabilities that could be exploited by an attacker through multiple steps. This paper presents an attack-graph based multi-step attack detector aiming at detecting a possible on-going attack early enough to take proper countermeasures through; a Visualization interfaced with the described attack detector presents the security operator with the relevant pieces of information, allowing a better comprehension of the network status and providing assistance in managing attack situations (i.e., reactive analysis mode). We first propose an architecture and then we present the implementation of each building block. Finally, we provide an evaluation of the proposed approach aimed at highlighting the existing trade-off between accuracy of the detection and detection time

Síndrome de Dubin Johnson: presentación de un caso y revisión de la literatura

El síndrome de Dubin Johnson es un trastorno hereditario de la excreción intrahepatocitaria de la bilirrubina conjugada. Se caracteriza por hiperbilirrubinemia crónica a predominio de la fracción conjugada, alteración en el metabolismo de las coproporfirinas y el depósito intracelular de un pigmento oscuro, similar a la melanina, que le otorga al hígado un típico color negro. Presentamos un paciente varón de 28 años de edad que consultó por ictericia conjuntival e hiperbilirrubinemia conjugada sin ninguna otra alteración de las pruebas bioquímicas hepáticas. El diagnóstico de este síndrome fue realizado soslayando la clásica prueba de BSF debido a sus efectos colaterales graves utilizando métodos poco riesgosos como son la laparoscopía con biopsia hepática y la colecistografía oral. Enfatizamos el valor actual de estas pruebas para realizar el diagnóstico de este trastorno. No fue posible cuantificar los isómeros de las coproporfirinas urinarias ni una colescintigrafía (Tc 99-HIDA). En conclusión, postulamos que el diagnóstico de síndrome de Dubin Johnson es posible realizarlo con métodos con baja tasa de complicaciones como son la laparoscopía con biopsia hepática y la colecistografía oral