Neonatal hypoxic ischemic encephalopathy : inflammation and therapies

Neonatal hypoxic ischemia (HI) is a severe condition characterized by a complex pathophysiology. The lack of oxygen (hypoxia) and blood flow (ischemia) leads to neuronal cell death via necrosis and apoptosis, and a consequent post-ischemic inflammation. HI brain injury may lead to seizures, cognitive and motor impairments, and death. Worse neurodevelopmental outcomes have been observed in male than in female survivors, thus underlining sex-dependent differences. To date, hypothermia is the only available evidence-based treatment for neonatal HI that shows neuroprotection if applied within six hours after the insult. Although hypothermia reduces production of cytokines and metabolic stress, it was shown to not be effective in severe cases of neonatal HI. Additional therapies meant to alleviate the HI outcomes are therefore needed. In the present thesis we investigated the role of two key players involved in post-ischemic inflammation, namely resident microglia and infiltrating macrophages, and studied the effects of drug- and cell-based treatments aimed at reducing injury. HI was induced by occluding the common carotid artery in mouse pups that were then subjected to hypoxia. By investigating the dynamics of inflammatory cells in the hippocampus of injured mice, sex-specific differences were observed in microglia and infiltrating peripheral-macrophages. Sequencing data revealed that macrophages are the drivers of the post-ischemic inflammation through significant upregulation of cytokine, chemokine and sensome markers, as well as activation genes. In addition, microglial cells, which were shown to downregulate unique signature genes upon inflammation, restored their homeostatic role within three days after injury in males, suggesting a different mechanistic effect in response to the neuroinflammatory cascade. The role of resident microglia was further investigated in a Tamoxifen-based depletion model in which HI was then performed. While no difference in the speed of microglial repopulation was observed between males and females, the injury progression and cytokine production changed in a sex-dependent fashion. Specifically, depletion aggravated neuronal damage and apoptosis in male mice following HI. In order to reduce inflammation and to induce neuroprotection, therapies involving caffeine or bone marrow-derived macrophage administration were assessed in this thesis. Caffeine, which is an adenosine-receptor competitor, is currently used in the clinic as treatment for neonatal apnea. As long-term follow-up studies of apneic babies treated with caffeine showed a reduced incident of cerebral palsy, this drug was administered at different time points after HI. Our results revealed a reduced lesion and improved behavioral outcomes after a single dose of 5 mg/kg caffeine immediately post-HI, with a reduction of the lesion and glial scar extent, and modulation of microglia activation and pro-inflammatory genes. ii Bone marrow-derived macrophages were adoptively transferred 5 days after HI to investigate their immunomodulatory and wound healing properties. Our results showed a clear difference when anti-inflammatory macrophages (M2) or unpolarized control cells (M0) were administered. While M2 cell therapy led to functional recovery, we observed that M0 macrophages worsened behavioral outcomes and increased the injury size. In addition, in vitro studies in organotypic hippocampal slices co-cultured with these macrophages showed that, while M2 maintained memory of their phenotype, the M0 cells became polarized towards a pro-inflammatory state, thus suggesting how unpolarized cells could lead to exacerbation of the inflammation and the consequent worsening of injury extent and behavioral performance observed in vivo. In summary, in this thesis I highlight the importance of microglia and infiltrating macrophages in the post-ischemic inflammatory cascade, and how caffeine and bone-marrow derived macrophages may be of potential therapeutic interest in future studies

Comercio electrónico en Paraguay: alcanzando metas

La regulación normativa de la Sociedad de la Información en el Paraguay empieza en el año 2010, con la Ley de Firma Digital. El paso que se da en el 2013, con la promulgación de la Ley de Comercio Electrónico, constituye un hito en la historia normativa paraguaya, al introducir conceptos de responsabilidad de los proveedores, facturación electrónica y normas relativas a consumidores de servicios o productos adquiridos on line, hasta entonces, desconocidos. La Ley se reglamenta en el año 2014, así como también los llamados “monederos electrónicos” que, en el año 2013 ya habían movido en el país, USD 1300 millones.The legal regulation of the Information Society in Paraguay started in 2010 with the Digital Signature Act. The step taken in 2013, with the enactment of the Electronic Commerce Act, a milestone in the Paraguayan normative story, introducing concepts of liability of providers, electronic billing and rules on consumers of services or products purchased on line hitherto unknown. The Act was regulated in 2014, as well as the so-called "electronic purses" which in 2013 had moved into the country, USD 1.3 billion.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Comercio electrónico en Paraguay: alcanzando metas

La regulación normativa de la Sociedad de la Información en el Paraguay empieza en el año 2010, con la Ley de Firma Digital. El paso que se da en el 2013, con la promulgación de la Ley de Comercio Electrónico, constituye un hito en la historia normativa paraguaya, al introducir conceptos de responsabilidad de los proveedores, facturación electrónica y normas relativas a consumidores de servicios o productos adquiridos on line, hasta entonces, desconocidos. La Ley se reglamenta en el año 2014, así como también los llamados “monederos electrónicos” que, en el año 2013 ya habían movido en el país, USD 1300 millones.The legal regulation of the Information Society in Paraguay started in 2010 with the Digital Signature Act. The step taken in 2013, with the enactment of the Electronic Commerce Act, a milestone in the Paraguayan normative story, introducing concepts of liability of providers, electronic billing and rules on consumers of services or products purchased on line hitherto unknown. The Act was regulated in 2014, as well as the so-called "electronic purses" which in 2013 had moved into the country, USD 1.3 billion.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Gobierno electrónico y administración pública electrónica en la República del Paraguay: la perspectiva judicial

Los trabajos tendientes a la concreción del Gobierno Electrónico en el Paraguay, han aportado, hasta el momento, integración, armonización y coordinación de todo el trabajo gubernamental, además de un considerable ahorro por reducción de costos y mejora del servicio para todos los ciudadanos, permitiendo que trámites administrativos que no tengan carácter de personalísimos, puedan realizarse vía electrónica los trescientos sesenta y cinco días del año, veinticuatro horas al día.E-government works allowed Paraguay to have a Public Administration integrated and harmonized as well as to save costs and offer a better service. Almost every administrative proceedings could be done by using information techonology 365 days per year, 24 hours per day.Sociedad Argentina de Informática e Investigación Operativ

Comercio electrónico en Paraguay: alcanzando metas

La regulación normativa de la Sociedad de la Información en el Paraguay empieza en el año 2010, con la Ley de Firma Digital. El paso que se da en el 2013, con la promulgación de la Ley de Comercio Electrónico, constituye un hito en la historia normativa paraguaya, al introducir conceptos de responsabilidad de los proveedores, facturación electrónica y normas relativas a consumidores de servicios o productos adquiridos on line, hasta entonces, desconocidos. La Ley se reglamenta en el año 2014, así como también los llamados “monederos electrónicos” que, en el año 2013 ya habían movido en el país, USD 1300 millones.The legal regulation of the Information Society in Paraguay started in 2010 with the Digital Signature Act. The step taken in 2013, with the enactment of the Electronic Commerce Act, a milestone in the Paraguayan normative story, introducing concepts of liability of providers, electronic billing and rules on consumers of services or products purchased on line hitherto unknown. The Act was regulated in 2014, as well as the so-called "electronic purses" which in 2013 had moved into the country, USD 1.3 billion.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Renewable mixed hydrogels based on polysaccharide and protein for release of agrochemicals and soil conditioning

The study deals with the combination of biopolymers to develop hydrogels intended for agriculture application. The aim is to propose a renewable and eco-compatible solution to enhance agrochemicals and water efficiency and contribute to maintaining soil fertility. We developed a set of hydrogels based on casein and chitosan for water retention and release of agrochemicals, in particular nitrogen fertilizer urea. The weight ratio of biopolymers, from 0.5 to 2, was investigated to understand the influence of their content on the morphology, swelling, swelling-drying cycles, and water retention in soil. The average content of urea in the hydrogels was 30% of the total weight, and up to 80% was released in the soil in 50 days. The biodegradation of the hydrogels in soil has been investigated by the burial method and monitoring the release of CO2 . Results demonstrated that by increasing the content of chitosan, the biodegradation time is prolonged up to 20% in 90 days. The obtained results support the ultimate purpose of the work that the combination of two biopolymers at proper weight ratio could be a valid alternative of the marketed hydrogels with the final goal to promote soil fertility and water retention and prolong biodegradation. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Ministry of Science and Higher Education of the Russian Federation [WSWW-2020-0011]Ministry of Education and Science of the Russian Federation, Minobrnauka: WSWW-2020-001

Case Study: Intra-Patient Heterogeneity of Aneurysmal Tissue Properties

Introduction: Current recommendations for surgical treatment of abdominal aortic aneurysms (AAAs) rely on the assessment of aortic diameter as a marker for risk of rupture. The use of aortic size alone may overlook the role that vessel heterogeneity plays in aneurysmal progression and rupture risk. The aim of the current study was to investigate intra-patient heterogeneity of mechanical and fluid mechanical stresses on the aortic wall and wall tissue histopathology from tissue collected at the time of surgical repair.Methods: Finite element analysis (FEA) and computational fluid dynamics (CFD) simulations were used to predict the mechanical wall stress and the wall shear stress fields for a non-ruptured aneurysm 2 weeks prior to scheduled surgery. During open repair surgery one specimen partitioned into different regions was collected from the patient's diseased aorta according to a pre-operative map. Histological analysis and mechanical testing were performed on the aortic samples and the results were compared with the predicted stresses.Results: The preoperative simulations highlighted the presence of altered local hemodynamics particularly at the proximal segment of the left anterior area of the aneurysm. Results from the post-operative assessment on the surgical samples revealed a considerable heterogeneity throughout the aortic wall. There was a positive correlation between elastin fragmentation and collagen content in the media. The tensile tests demonstrated a good prediction of the locally varying constitutive model properties predicted using geometrical variables, i.e., wall thickness and thrombus thickness.Conclusions: The observed large regional differences highlight the local response of the tissue to both mechanical and biological factors. Aortic size alone appears to be insufficient to characterize the large degree of heterogeneity in the aneurysmal wall. Local assessment of wall vulnerability may provide better risk of rupture predictions