HBY

The Danish net of highways forms an ‘H’ connecting the country north-south and east-west. This is the starting point for a discussion of contemporary urbanism. The article points out that the increasing physical and virtual communication blurs well-known distinctions between centre/ periphery and urban/rural. The majority of planning tendencies aims at recreating and emphasising these distinctions by enhancing the public space of historical city centres and keeping the landscape clear of permanent human activities. The article argues against these tendencies. It refers to the Danish ‘golden age’ painters who successfully tried to construct a national identity in the first half of the 19th century. They did so by sampling parts of the existing cultural landscape and combine them to a slightly enhanced reality in their paintings. The article tries to do the same by combining already existing elements and tendencies to a polemical image of a partly existing reality based on hybrids between the urban and rural. &nbsp

Drought impact in the region of the watershed the Sauce Grande lagoon (Buenos Aires province, Argentina)

La distribución e intensidad de los extremos hídricos provoca un impacto directo sobre las actividades humanas. Las características particulares de los eventos secos y húmedos ocurridos en la región de la cuenca hidrográfica de la laguna Sauce Grande, durante el período 1971- 2010, se analizan mediante la aplicación del Índice de severidad de sequía de Palmer. El 49% de los casos analizados correspondieron a sequías débiles, e incipientes. Los valores más extremos de eventos secos (-4.31) ocasionaron daños irreparables en los rendimientos de granos, que disminuyeron un 19% respecto al promedio actual. Durante los meses estivales se observaron los casos secos severos y extremos (12%). Se identificaron los períodos secos que mayor injerencia tuvieron sobre la producción agrícola ganadera de la región, sucedidas durante los años 2008 y 2009, la relación existente entre los valores de los índices severos y extremos en la morfometría de la laguna y estuario del río Sauce Grande.The distribution and intensity of extreme water causes a direct impact on human activities. Dry and wet events in the region of the watershed of the Sauce Grande lagoon during the period 1971 - 2010 are analyzed through the application of Index of Palmer drought severity, 49% of the cases analyzed corresponded to weak, and emerging drought . The most extreme dry events values (-4.31) caused irreparable damage yields, which decreased by 19 % compared to the current average . During the summer months the severe and extreme (12 %) cases were observed. Dry periods had greater influence on livestock farming in the region, occurring during the years 2008 and 2009, the relationship between this values of the indices and severe extremes in the morphometry of the lagoon and the Sauce Grande estuary were identified.Este trabajo fue financiado parcialmente por subsidios del CONICET, proyecto redes PAMPA 2, Universidad Nacional del Sur y el Interamerican Institute for Global Change Research (IAI) CRN 3038 (under US NSF award GEO-1128040)

Discrecionalidad de los jueces de policia local ante las infracciones al tránsito cometidas por menores de edad

Tesis (Magíster en Intervención Socio-Jurídica en Familia)Este trabajo intenta revelar cómo la legislación chilena ha omitido pronunciarse sobre las infracciones de tránsito en las que se encuentra involucrado un menor de edad y cómo este silencio se ha suplido por la discrecionalidad de los Jueces, quienes a partir de sus conocimientos y entendimiento adaptan los procedimientos establecidos para los adultos a aquellos casos en que los menores de edad se tornan protagonistas de la infracción a la Ley de Tránsito. A lo largo de este estudio conoceremos los distintos aspectos del concepto de “Discrecionalidad”, analizaremos la Ley de Tránsito, la Ley de Responsabilidad Penal Adolescente y los diversos criterios aplicados por los Jueces de Policía Local ante las faltas al volante de los jóvenes infractores. Concluiremos este estudio de manera critica ante la inexistencia de legislación que regule las sanciones y eduque a los niños, niñas y adolescentes y a quienes los tengan a su cargo frente a su actuar negligente al conducir un vehículo motorizado sin la preparación psicológica y física para ello, asumiendo finalmente una postura protectora de los derechos de los menores de edad y la obligación de la sociedad toda de que logren su autonomía, mediante un ejercicio progresivo de sus derechos y facultades y también responsabilidades, acorde a su edad y madurez

Interleukin-1 blockade in recently decompensated systolic heart failure: study design of the recently decompensated heart failure anakinra response trial (RED-HART)

Heart Failure (HF) is a clinical syndrome characterized by dyspnea, fatigue, and poor exercise capacity due to impaired cardiac function. The incidence of HF is increasing and represents the leading cause of hospitalization in the United States among patients > 65 years of age. Neurohormonal blockade has proven to reduce morbidity and mortality; however the persistent toll of HF demonstrates the urgent need to continue to develop novel drugs that target other pathophysiological paradigms. The presence of inflammation in cardiovascular disease has been well-established and interleukin-1 (IL-1), the prototypical proinflammatory agent, has been shown in preclinical animal models to induce cardiac dysfunction. The current study will investigate the role of IL-1 as an inflammatory mediator of HF progression and investigate whether IL-1 blockade with anakinra, recombinant human IL-1 receptor antagonist, improves aerobic exercise performance in patients with recently decompensated systolic HF. This study will be composed of 3 treatment arms (20 patients each): 1) anakinra 100mg daily for 12 weeks; 2) anakinra 100mg daily for 2 weeks followed by placebo for 10 weeks; or 3) placebo for 12 weeks. All patients will be followed for at least 24 weeks. The co-primary endpoints will be placebo-corrected interval changes in peak oxygen consumption (VO2) and ventilatory efficiency (VE/VCO2 slope) measured by Cardiopulmonary Exercise Testing (CPX) after 2 weeks of anakinra treatment. Secondary endpoints will include interval changes in 1) CPX variables at 4, 12 and 24 weeks; 2) echocardiographic measures of cardiac dimension/function; 3) quality of life assessments; 4) inflammatory biomarkers; and 5) clinical outcome including days alive outside of the hospital and survival free of re-hospitalization for HF. The RED-HART study will be the first study to address the potential benefits of IL-1 blockade on aerobic exercise performance in patients with recently decompensated HF

Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection

Background: Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. Methods: Multiple regression was used to determine the relationship between abundance of specific blood lymphoid cell types, age, sex, requirement for hospitalization, duration of hospitalization, and elevation of blood markers of systemic inflammation, in adults hospitalized for severe COVID-19 (n=40), treated for COVID-19 as outpatients (n=51), and in uninfected controls (n=86), as well as in children with COVID-19 (n=19), recovering from COVID-19 (n=14), MIS-C (n=11), recovering from MIS-C (n=7), and pediatric controls (n=17). Results: This observational study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis. Among controls, the percentage of ILCs that produced amphiregulin was higher in females than in males, and people hospitalized with COVID-19 had a lower percentage of ILCs that produced amphiregulin than did controls. Conclusions: These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance contributes to increased COVID-19 severity with age and in males. Funding: This work was supported in part by the Massachusetts Consortium for Pathogen Readiness and NIH grants R37AI147868, R01AI148784, F30HD100110, 5K08HL143183

Secreted miR-210-3p as non-invasive biomarker in clear cell renal cell carcinoma

The most common subtype of renal cell carcinoma (RCC) is clear cell RCC (ccRCC). It accounts for 70-80% of all renal malignancies representing the third most common urological cancer after prostate and bladder cancer. The identification of non-invasive biomarkers for the diagnosis and responsiveness to therapy of ccRCC may represent a relevant step-forward in ccRCC management. The aim of this study is to evaluate whether specific miRNAs deregulated in ccRCC tissues present altered levels also in urine specimens. To this end we first assessed that miR-21-5p, miR-210-3p and miR-221-3p resulted upregulated in ccRCC fresh frozen tissues compared to matched normal counterparts. Next, we evidenced that miR-210-3p resulted significantly upregulated in 38 urine specimens collected from two independent cohorts of ccRCC patients at the time of surgery compared to healthy donors samples. Of note, miR- 210-3p levels resulted significantly reduced in follow-up samples. These results point to miR-210-3p as a potential non-invasive biomarker useful not only for diagnosis but also for the assessment of complete resection or response to treatment in ccRCC management

Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2)

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of con-firmed HF cases in the United States. However, there are no highly effective evidence-basedtreatments currently available for these patients. Inflammation correlates positively withadverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, hasbeen implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clini-cal trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 ran-domized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespi-ratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation inpatients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpointswill be placebo-corrected interval changes in peak oxygen consumption and ventilatory effi-ciency at week 12. In addition, secondary and exploratory analyses will investigate the effectsof IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function,quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinicaltrial will add to the growing body of evidence on the role of inflammation in cardiovascular dis-ease, specifically focusing on patients with HFpEF

Identification and Biological Characterization of the Pyrazolo[3,4-d]pyrimidine Derivative SI388 Active as Src Inhibitor

Src is a non-receptor tyrosine kinase (TK) whose involvement in cancer, including glioblastoma (GBM), has been extensively demonstrated. In this context, we started from our in-house library of pyrazolo[3,4-d]pyrimidines that are active as Src and/or Bcr-Abl TK inhibitors and performed a lead optimization study to discover a new generation derivative that is suitable for Src kinase targeting. We synthesized a library of 19 compounds, 2a-s. Among these, compound 2a (SI388) was identified as the most potent Src inhibitor. Based on the cell-free results, we investigated the effect of SI388 in 2D and 3D GBM cellular models. Interestingly, SI388 significantly inhibits Src kinase, and therefore affects cell viability, tumorigenicity and enhances cancer cell sensitivity to ionizing radiation