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

The fortifications on a Citizen scale. Analysis of visual storytelling in “Supplemento mensile illustrato del SECOLO” (1887-1902)

This paper deals with the analysis of the themes and codes characterizing the graphic/textual description of the cities and their fortifications, as well as narrated in The Hundred Town of Italy, the illustrated monthly supplement of the “Il Secolo” (Le Cento Città d’Italia, supplemento mensile illustrato del Secolo). Published in Milan by Sonzogno, between 1887 and 1902, the 192 four sides supplements still provide a vivid descriptive picture of the nation, at the turn of the nineteenth and twentieth century. Despite the poor quality of most of the illustrations in these sheets, they have acquired, over time, an appreciable documentary value. Therefore, a critical reading is capable of giving a new knowledge about the systems of fortifications in Italy. The performed analysis of places and cities is characterized by a descriptive storytelling of the fortifications, highlighting the specificity of communication and perception. What emerges is a strong landscaping connotation given to the city-fortification system in a socio-political reality, during a historical phase of transformation. The survey highlights how this architectural heritage can still be valuable cultural element, not only for the territory

A propósito de un caso: “Construyendo realidades: fallecer en casa”

El objetivo de una Unidad de Cuidados Paliativos Pediátricos es proporcionar los mejores cuidados para poder vivir con la enfermedad de la forma más humana y digna posible hasta que se produzca el fallecimiento. Para facilitar una muerte en paz es fundamental conocer de forma integral al paciente, su familia, su cultura, sus creencias y adecuar nuestra intervención a sus necesidades. Presentamos el caso de un niño que quería ser atendido en su casa pero que inicialmente parecía que no iba a hacerse realidad. El realizar una evaluación inicial de los problemas, las necesidades; establecer de forma conjunta nuestros objetivos y actuaciones; y el trabajo coordinado, permitió responder al deseo del paciente de estar en su casa, con su gente y activo el mayor tiempo posible así como la muerte sin dolor, acompañado por la familia en el domicilio.The purpose of a Pediatric Palliative Care Unit is to provide the best care to live with the disease in the most humane and dignifi ed as possible until death occurs. To facilitate a peaceful death is important to know the patient, their family, their culture, their beliefs. We report the case of a child who wanted to be cared at home. Performing an initial assessment of the problems, needs, establish our goals and actions toghether, and coordinated work, allowed respond to the patient’s desire to be at home accompanied by family

Petrologic features of mesoproterozoic lamprophyric dykes from Montevideo (Piedra Alta terrane, South Uruguay)

Mafic dykes of lamprophyric affinity cropping out along the coastal area of Montevideo city are described. These dykes trend N75º-85º and crosscut 2.1 Ga Paleoproterozoic metamorphic units of the Rio de la Plata craton. They show mainly porphyritic textures with phlogopite and clinopyroxene macrocrysts in a groundmass composed of carbonates, phlogopite, augite, and feldspathoids. Ocellar structures filled with leucite, carbonates, and fibrous alkaline amphibole are present. The mineralogical assembly allows their classification as lamprophyres (minettes), but according to their chemical nature, they can be classified as alkaline lamprophyres. A crystallization age of 1.42 Ga by Ar-Ar method (on biotite/phlogopite) was obtained