Systemic inflammation and experimental cancer in a murine model

La asociación entre cáncer e inflamación en un órgano o tejido se encuentra sólidamente establecida. En efecto, se sabe que en sitios de inflamación crónica, existe una mayor probabilidad de que se origine un tumor y que procesos inflamatorios locales pueden acelerar el crecimiento de tumores preexistentes en animales y seres humanos. Por otro lado, la relación entre cáncer e inflamación sistémica ha sido menos estudiada. En este trabajo, demostramos que el crecimiento de un fibrosarcoma de ratón (MC-C) fue acompa­ñado por inflamación sistémica, evidenciada por neutrofilia y por un aumento de la concentración sé rica de las citoquinas pro-inflamatorias interleuquina-1b (IL-1b), interleuquina-6 (IL-6) y factor de necrosis tumoral-a (TNF­- a) y de las proteínas de fase aguda C reactiva (CRP) y A amieloide (SAA). Hubo un pico de estas moléculas poco después de la inoculación del tumor, que cayó a valores normales después de la primera semana, para luego comenzar a incrementarse progresivamente en función del tamaño tumoral. Una variación similar fue vis­ta en el porcentaje de neutrófilos polimorfonucleares (PMN) circulantes. En ratones portadores de tumores grandes la mayoría de los PMN exhibían activación evidenciada por aumento en la generación de especies reactivas del oxígeno y alta expresión de [os marcadores Gr1+/Mac1+. La inoculación de tioglicolato, que produce una inflamación sistemática transitoria, aceleró el crecimiento de MC-C, mientras que el tratamiento anti-inflamatorio con indometacina revirtió ese efecto. Esto sugiere que MC-C podría utilizar el fenómeno de inflamación sistémica que genera por sí mismo, como parte de su estrategia de crecimiento.The link between cancer and inflammation in an organ or tissue has firmly been established on the basis that cancer tends to occur at sites of chronic inflammation and that local inflammatory processes can accelerate the growth of preexisting tumors in both animals and human beings. In contrast, the relationship between cancer and systemic inflammation has been less studied. In this work, we demonstrated that the growth of the murine fibrosarcoma MC-C, was accompanied by manifestations of systemic inflammation, as demonstrated by an increase in both the number of circulating polymorphonuclear neutrophils (PMN) and the serum concentration of the proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and the acute phase proteins C reactive (CRP) and serum A amyloid (SAA). Two temporally separate peaks of systemic inflammation were detected during tumor development. The first was displayed during the first week after tumor inoculation. The second peak began around day 14 and its intensity was proportional to tumor size. In mice bearing a large MC-C tumor, a high number of circulating PMN and myeloid precursors were evident. Most of these cells exhibited activation evidenced by an increased reactive oxygen species generation and high expression of the Gr1+/Mac1+ markers. Inoculation of thioglycolate -which generates a transient systemic inflammation- accelerated the growth of MC-C tumor and reciprocally, inhibition of such systemic inflammation by using indomethacin, prevented that enhancing effect. This suggests that the systemic inflammation that the tumor generates on its own, could be part of its growth strategy.Fil: Bruzzo Iraola, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Chiarella, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Fernández, Gabriela Cristina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bustuoabad, Oscar David. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Ruggiero, Raul Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentin

Self-perceptions of ageing and perceived health status: the mediating role of cognitive functioning and physical activity

There is evidence that perceived health status is relevant for older adults' wellbeing, and at the same time perceived health status can be influenced by self-perceptions of ageing. There is a lack of studies on the relationship between these variables. The aim of this study was to explore attitudes towards ageing and self-perceptions of ageing among Spanish middle-aged and older people, and to identify possible mediators in the relationship between self-perceptions of ageing on perceived health status. The sample comprised 1,124 individuals from 50 to 98 years old (mean = 64.84, standard deviation = 10.12) from the Ageing in Spain Longitudinal Study database, Pilot Survey (ELES-PS). Almost 70 per cent of the participants stated that old age begins at a specific chronological age and half of them considered that society treats older people with indifference. Self-perceptions of ageing, physical activity, cognitive functioning and age were significant predictors, and together these variables explained 15.9 per cent in the variance of perceived health status. The multiple mediation analysis revealed that self-perceptions of ageing predicted cognitive functioning (B = 0.848, p < 0.01) and physical activity (B = 2.9046, p < 0.001), and mediated the association between self-perceptions of ageing and perceived health status (B = 0.1144, standard error = 0.0147, p < 0.01). Results from this study highlight the importance of perceptions and attitudes towards ageing for older adults' health and wellbeing, thus this study contributes to a better understanding of how these variables are related. In this sense, results from this study can be useful for designing interventions for fostering wellbeing. Addressing negative self-perceptions of ageing and negative attitudes towards ageing can be particularly useful because they are associated with more pessimistic expectancies about the ageing process.Funding for open access charge: University of Granada.Programme of the Spanish Ministry of Science and Innovation (CSO2009-06637-E/SOCI; CSO2009-06638-E/SOCI; CSO2009-08645-E/SOCI)SAIOTEK 2009 Programme of the Basque GovernmentObra Social Caja Madrid Foundatio

Reflexiones sobre las destrezas con criterio de desempeño de la asignatura de Filosofía I desde la taxonomía de Bloom

Las destrezas con criterios de desempeño, así como las taxonomías son temas que no han tenido un trato de manera consciente, así mismo, la relación entre estos dos puntos para alcanzar un proceso educativo significativo característico del siglo XXI. El presente trabajo de titulación se centra en el análisis como punto clave para verificar la correspondencia en la adquisición de las destrezas con criterio de desempeño utilizando una organización jerárquica de los niveles cognitivos establecidos por Bloom que se establecen acorde a los años cursados desde la asignatura de Filosofía, la cual requiere mayor énfasis en la adquisición de las destrezas, puesto que, tiene el propósito de enseñar a pensar valiéndose de los propios argumentos e ideas. La presente aplicación establece una metodología documental-bibliográfica a partir de recursos como el Ministerio de educación, el currículo y otras investigaciones realizadas dentro del ámbito educativo lo que permitió alcanzar el objetivo de esta investigación de cómo la taxonomía de Bloom tiene validez al momento del cumplimiento de las destrezas con criterio de desempeño específicamente desde el nivel 4, en Filosofía 1. Del estudio, se concluye que no existe un rango de correlación tanto de las destrezas, el curso y las actividades que se proponen en los textos educativos, lo cual dificulta, en cierta medida, una organización para el desarrollo cognitivo, es decir, de los procesos mentalesThe skills with performance criteria, as well as the taxonomies are topics that have not been consciously addressed, as well as the relationship between these two points to achieve a meaningful educational process characteristic of the XXI century. This work focuses on the analysis as a key point to verify the correspondence in the acquisition of skills with performance criteria using a hierarchical organization of the cognitive levels established by Bloom, which are established according to the years taken from the subject of Philosophy, which requires more emphasis on the acquisition of skills because its purpose is to teach how to think using one's own arguments and ideas. The present application establishes a documentary-bibliographic methodology based on resources such as the Ministerio de Educación, the curriculum and other research carried out within the educational field, which made it possible to achieve the objective of this research on how Bloom's taxonomy is valid at the moment of the fulfillment of the skills with performance criteria specifically from level 4 in Philosophy 1. It is concluded that there is no correlation range between the skills, the course and the activities proposed in the educational texts and this makes it difficult to organize for cognitive development, that is, of mental processesLicenciado en Pedagogía de la FilosofíaCuenc

Proinflammatory response of human trophoblastic cells to Brucella abortus infection and upon interactions with infected phagocytes

Trophoblasts are targets of infection by Brucella spp. but their role in the pathophysiology of pregnancy complications of brucellosis is unknown. Here we show that Brucella abortus invades and replicates in the human trophoblastic cell line Swan-71 and that the intracellular survival of the bacterium depends on a functional virB operon. The infection elicited significant increments of interleukin 8 (IL8), monocyte chemotactic protein 1 (MCP-1), and IL6 secretion, but levels of IL1beta and tumor necrosis factor-alpha (TNF-alpha) did not vary significantly. Such proinflammatory response was not modified by the absence of the Brucella TIR domain-containing proteins BtpA and BtpB. The stimulation of Swan-71 cells with conditioned medium (CM) from B. abortus-infected human monocytes (THP-1 cells) or macrophages induced a significant increase of IL8, MCP-1 and IL6 as compared to stimulation with CM from non-infected cells. Similar results were obtained when stimulation was performed with CM from infected neutrophils. Neutralization studies showed that IL1beta and/or TNF-alpha mediated the stimulating effects of CM from infected phagocytes. Reciprocally, stimulation of monocytes and neutrophils with CM from Brucella-infected trophoblasts increased IL8 and/ or IL6 secretion. These results suggest that human trophoblasts may provide a local inflammatory environment during B. abortus infections either through a direct response to the pathogen or through interactions with monocytes/macrophages or neutrophils, potentially contributing to the pregnancy complications of brucellosis.Fil: Fernández, Gabriela Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Ferrero, Mariana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Hielpos, María Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Fossati, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Baldi, Pablo Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentin

Rituximab and hypogammaglobulinemia

El rituximab (RTX), un anticuerpo quimérico anti-CD20 que induce la depleción de linfocitos B, es utilizado para el tratamiento de enfermedades linfoproliferativas y autoinmunes. La inmunodeficiencia humoral relacionada al tratamiento con RTX comenzó a ser un motivo de derivación a nuestro Servicio, por lo que decidimos analizar a los pacientes con el antecedente de haber sido tratados con RTX que consultaron por hipogammaglobulinemia o infecciones recurrentes desde noviembre de 2010 hasta diciembre de 2014. Evaluamos a ocho pacientes, siete mujeres y un varón. El tiempo promedio de seguimiento fue de 19.3 ± 18.8 meses, rango 1 a 54, con una mediana de 13. Tres tenían proteinogramas normales previo a la administración de RTX, tres hipogammaglobulinemia, y de dos no hay datos. A ninguno se le realizó una determinación cuantitativa de inmunoglobulinas previa al tratamiento. Cuatro recibieron RTX por linfoma B no Hodgkin, dos por leucemia linfocítica crónica, uno por púrpura trombocitopénica autoinmune y otro por poliangeítis microscópica. A seis se les diagnosticó hipogammaglobulinemia y a uno deficiencia de IgM, IgA e IgG2. Cinco presentaron infecciones, cuatro con buena respuesta al tratamiento de reemplazo con gammaglobulina. La inmunodeficiencia humoral relacionada a RTX es una causa de consulta cada vez más frecuente. Resulta fundamental disponer de los niveles de inmunoglobulinas previo al inicio de su administración para poder establecer una relación etiológica y durante el seguimiento, para disminuir el retraso diagnóstico. El tratamiento con gammaglobulina en dosis sustitutivas parece ser de utilidad en pacientes con infecciones graves o recurrentes.Rituximab, a chimeric monoclonal antibody against CD20, induces the depletion of B lymphocytes. It is used for the treatment of lymphoproliferative and autoimmune diseases. Antibody immunodeficiency associated to RTX treatment is a new motif for consultation to our service. We decided to study those patients that having been treated with RTX, consulted for hypogammaglobulinemia or recurrent infections between November 2010 and December 2014. We evaluated eight patients, seven female and one male. The average follow up time was 19.3 ± 18.8 months, range 1 to 54, median 13. Three had a normal electrophoretic proteinogram before receiving RTX, three had hypogammaglobulinemia and in two data was not available. None of them had a quantitative determination of immunoglobulins before receiving RTX. Four received RTX as a treatment of non Hodking lymphoma, two as a treatment of chronic lymphocytic leukemia, one for immune thrombocytopenic purpura and other for microscopic polyangiitis. Six were diagnosed with hypogammaglobulinemia and one with combined IgM, IgA and IgG2 deficiency. Five presented infections, four of them with good response to intravenous immunoglobulin. RTX related antibody deficiency consultations are increasing. It is important to determine the immunoglobulin levels previously to RTX use in order to establish an etiologic relationship with RTX and a quick diagnosis of antibody deficiency. The substitutive treatment with gammaglobulin seems to be useful in patients with severe or recurrent infections.Fil: Fernández Romero, Diego S.. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Torre, María Gabriela. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Larrauri, Blas J.. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Malbran, Eloisa. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Juri, María Cristina. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; ArgentinaFil: Malbrán, Alejandro. Hospital Británico de Buenos Aires. Servicio de Alergia e Inmunología Clínica; Argentina. Unidad de Alergia, Asma e Inmunología Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Functional Capacity of Shiga-Toxin Promoter Sequences in Eukaryotic Cells

Shiga toxins (Stx) are the main virulence factors in enterohemorrhagic Escherichia coli (EHEC) infections, causing diarrhea and hemolytic uremic syndrome (HUS). The genes encoding for Shiga toxin-2 (Stx2) are located in a bacteriophage. The toxin is formed by a single A subunit and five B subunits, each of which has its own promoter sequence. We have previously reported the expression of the B subunit within the eukaryotic environment, probably driven by their own promoter. The aim of this work was to evaluate the ability of the eukaryotic machinery to recognize stx2 sequences as eukaryotic-like promoters. Vero cells were transfected with a plasmid encoding Stx2 under its own promoter. The cytotoxic effect on these cells was similar to that observed upon incubation with purified Stx2. In addition, we showed that Stx2 expression in Stx2-insensitive BHK eukaryotic cells induced drastic morphological and cytoskeletal changes. In order to directly evaluate the capacity of the wild promoter sequences of the A and B subunits to drive protein expression in mammalian cells, GFP was cloned under eukaryotic-like putative promoter sequences. GFP expression was observed in 293T cells transfected with these constructions. These results show a novel and alternative way to synthesize Stx2 that could contribute to the global understanding of EHEC infections with immediate impact on the development of treatments or vaccines against HUSFil: Bentancor, Leticia Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bilen, Marcos Fabian. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ingeniería Genética y Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mejias, María Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fernández Brando, Romina Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Panek, Cecilia Analía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ramos, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fernández, Gabriela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Isturiz, Martín Amadeo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ghiringhelli, Pablo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ingeniería Genética y Biología Molecular y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Palermo, Marina Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Tolerance to lipopolysaccharide promotes an enhanced neutrophil extracellular traps formation leading to a more efficient bacterial clearance in mice

Tolerance to lipopolysaccharide (LPS) constitutes a stress adaptation, in which a primary contact with LPS results in a minimal response when a second exposure with the same stimulus occurs. However, active important defence mechanisms are mounted during the tolerant state. Our aim was to assess the contribution of polymorphonuclear neutrophils (PMN) in the clearance of bacterial infection in a mouse model of tolerance to LPS. After tolerance was developed, we investigated in vivo different mechanisms of bacterial clearance. The elimination of a locally induced polymicrobial challenge was more efficient in tolerant mice both in the presence or absence of local macrophages. This was related to a higher number of PMN migrating to the infectious site as a result of an increased number of PMN from the marginal pool with higher chemotactic capacity, not because of differences in their phagocytic activity or reactive species production. In vivo, neutrophils extracellular trap (NET) destruction by nuclease treatment abolished the observed increased clearance in tolerant but not in control mice. In line with this finding, in vitro NETs formation was higher in PMN from tolerant animals. These results indicate that the higher chemotactic response from an increased PMN marginal pool and the NETs enhanced forming capacity are the main mechanisms mediating bacterial clearance in tolerant mice. To sum up, far from being a lack of response, tolerance to LPS causes PMN priming effects which favour distant and local anti-infectious responses.Fil: Landoni, Verónica Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Chiarella, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Martire Greco, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Schierloh, Luis Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: van Rooijen, N.. University Of Amsterdam. Department of Molecular Biology; Países BajosFil: Rearte, María Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Palermo, Marina Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Isturiz, Martín Amadeo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fernández, Gabriela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Utility of Transient Elastography for the Screening of Liver Disease in Patients with Alpha1-Antitrypsin Deficiency

Deficiència d'alfa1-antitripsina; Malaltia del fetge; Elastografia transitòriaAlpha1-antitrypsin deficiency; Liver disease; Transient elastographyDeficiencia de alfa1-antitripsina; Enfermedad del hígado; Elastografía transitoriaScreening of liver disease in alpha-1 antitrypsin deficiency (AATD) is usually carried out with liver enzymes, with low sensitivity. We conducted a multicenter cross-sectional study aiming to describe the utility of transient elastography for the identification of liver disease in patients with AATD. A total of 148 AATD patients were included. Among these, 54.7% were Pi*ZZ and 45.3% were heterozygous for the Z allele. Between 4.9% and 16.5% of patients had abnormal liver enzymes, without differences among genotypes. Liver stiffness measurement (LSM) was significantly higher in Pi*ZZ individuals than in heterozygous Z (5.6 vs. 4.6 kPa; p = 0.001). In total, in 8 (5%) individuals LSM was >7.5 kPa, considered significant liver fibrosis, and ≥10 kPa in 3 (1.9%) all being Pi*ZZ. Elevated liver enzymes were more frequently observed in patients with LSM > 7.5 kPa, but in 5 out of 8 of these patients all liver enzymes were within normal range. In patients with AATD, the presence of abnormal liver enzymes is frequent; however, most of these patients do not present significant liver fibrosis. Transient elastography can help to identify patients with liver fibrosis even with normal liver enzymes and should be performed in all Z-allele carriers to screen for liver disease.This research was funded by Grifols through an unrestricted grant from the Catalan Center for Research in Alpha-1 antitrypsin deficiency of the Vall d’Hebron Research Institute (VHIR) in the Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; from the Madrid Center for Research in Alpha-1 antitrypsin deficiency of the Hospital Clínico San Carlos, Madrid, Spain; from the Galicia Center for Research in Alpha-1 antitrypsin deficiency of the University Hospital Complex of Vigo, Spain; as well as a research grant from Fundació Catalana de Pneumologia (FUCAP)

Association of glomerular hyperfiltration with serum chemokine levels and metabolic features in prepubertal children with overweight/obesity

Background and aims Glomerular hyperfiltration (GH) is proposed as one of the earliest events in obesity (OB)-associated renal disease. Children with GH and type-1 diabetes showed increased chemokine levels. Chemokine associations with glomerular filtration rate (GFR) and metabolic features in prepubertal children with overweight (OW)/OB are unknown. Methods and results Cross-sectional study. 75 prepubertal children (aged: 9.0 ± 1.7 years) with OW/OB were studied. Clinical and metabolic characteristics (including non-esterified fatty acids, NEFA) and GFR (combined Zappitelli equation) were assessed. GH was defined as GFR >135 ml/min.1.73 m2. Serum levels of regulated on activation, normal T cell expressed and secreted (RANTES)/CCL5, interleukin-8 (IL-8)/CXCL8 and monokine-induced by interferon-γ (MIG)/CXCL9 were measured by ELISA. Age- and sex-adjusted correlations and differences were tested. 48% of the cohort was female and 13% were OW, 54% OB and 33% severe OB. Prepubertal children with GH showed lower z-BMI (−12%), NEFA (−26%) and uric acid (−22%) than those without GH (all p 0.05). Adjusted correlations were significant for RANTES and z-BMI (r = 0.26; p < 0.05) and for MIG with z-BMI (r = −0.26; p < 0.05) and with NEFA (r = 0.27; p < 0.05). Conclusion GH was not associated with higher chemokine levels in prepubertal children with OW/OB. Decreased rather than elevated GFR values were correlated with obesity and worse metabolic profiles. Chemokines levels in children with severe OB suggest a regulation of the immune response. Follow-up studies are needed to address the clinical implications of these findings. Keywords ObesityChildrenChemokinesHyperfiltrationRenal diseas

Novel use of all-trans-retinoic acid in a model of lipopolysaccharide-immunosuppression to decrease the generation of myeloid-derived suppressor cells by reducing the proliferation of cd34+ precursor cells

All-trans-Retinoic Acid (ATRA) is a derivative of vitamin A with anti-proliferative properties. Endotoxin shock and subsequent immunosuppression (IS) by lipopolysaccharide (LPS) stimulates myelopoiesis with expansion of myeloid-derived suppressor cells (MDSC). Since we have previously shown that ATRA reverses the IS state by decreasing functional MDSC, our aim was to investigate if ATRA was able to modulate MDSC generation by regulating myelopoiesis in murine hematopoietic organs. We found that ATRA administration in vivo and in vitro decreased the number of CD34+ precursor cells that were increased in IS mice. When we studied the cellular mechanisms involved, we did not find any differences in apoptosis of CD34+ precursors or in the differentiation of these cells to their mature counterparts. Surprisingly, ATRA decreased precursor proliferation, in vitro and in vivo, as assessed by a reduction in the size and number of colony forming units (CFU) generated from CD34+ cells and by a decreased incorporation of H-thymidine. Moreover, ATRA administration to IS mice decreased the number of MDSC in the spleen, with a restoration of T lymphocyte proliferation and a restitution of the histological architecture. Our results indicate, for the first time, a new use of ATRA to abolish LPS-induced myelopoiesis, affecting the proliferation of precursor cells, and in consequence, decreasing MDSC generation, having a direct impact on the improvement of immune competence. Administration of ATRA could overcome the immunosuppressive state generated by sepsis that often leads to opportunistic life-threatening infections. Therefore, ATRA could be considered a complementary treatment to enhance immune responsesFil: Martire Greco, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Rodriguez Rodrigues, Nahuel Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Castillo Montañez, Luis Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Vecchione, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: de Campos Nebel, Ildefonso Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Córdoba Moreno, Marlina Olyissa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Meiss, Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Vermeulen, Elba Monica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Landoni, Verónica Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fernández, Gabriela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin