Estudio cooperativo de detección de clones de Hemoglobinuria Paroxistica Nocturna (HPN) por Citometría de Flujo Multiparamétrica (CFM) de alta resolución en distintos centros del país

La HPN es una enfermedad clonal, no maligna, originada por mutación en el gen PIG-A en la célula progenitora hematopoyética, originando una ausencia total o parcial de múltiples proteínas unidas a la membrana a través del puente GPI. Nuevas estrategias de análisis permiten una mayor sensibilidad en la detección de clones pequeños. Objetivos: Estudiar la incidencia de clones HPN por CFM en distintos centros del país. Destacar la ventaja de protocolos estandarizados en la detección de clones HPN al diagnóstico.Fil: Halperin, Nora. Hospital de Clínicas José de San Martín; Argentina.Fil: Agriello, Evangelina. Laboratorio de Especialidades Bioquímicas; Argentina.Fil: Brodsky, Andrés. Hospital de Clínicas José de San Martín; Argentina.Fil: Drelichman, Guillermo. Hospital de Niños Ricardo Gutiérrez; Argentina.Fil: Galeazzi, Susana. Laboratorio de Diagnóstico; Argentina.Fil: Iommi, Paula. Laboratorio de Especialidades Bioquímicas; Argentina.Fil: Malusardi, Cecilia. Hospital de Clínicas José de San Martín; Argentina.Fil: Nuñez, Neri Alejandra. Hospital General de Agudos Dr. Carlos G. Durand. Laboratorio de Inmunología; Argentina.Fil: Novoa, Norma Viviana. Hospital General de Agudos Dr. Carlos G. Durand. Laboratorio de Inmunología; Argentina.Fil: Barrueco, Ximena. Universidad Nacional de Córdoba. Facultad de Ciencias Medicas.Laboratorio de Oncohematología; Argentina.Fil: Rodríguez, Cecilia. Universidad Nacional de Córdoba. Facultad de Ciencias Medicas.Laboratorio de Oncohematología; Argentina.Fil: Galeano, Adriana. Fundaleu; Argentina.Bioquímica y Biología Molecular (ídem 1.6.3

A dp53-Dependent Mechanism Involved in Coordinating Tissue Growth in Drosophila

A study in the Drosophila wing suggests a crucial role of p53 in the coordination of growth between adjacent cell populations to maintain organ proportions and shape

Characterization of lamin Mutation Phenotypes in Drosophila and Comparison to Human Laminopathies

Lamins are intermediate filament proteins that make up the nuclear lamina, a matrix underlying the nuclear membrane in all metazoan cells that is important for nuclear form and function. Vertebrate A-type lamins are expressed in differentiating cells, while B-type lamins are expressed ubiquitously. Drosophila has two lamin genes that are expressed in A- and B-type patterns, and it is assumed that similarly expressed lamins perform similar functions. However, Drosophila and vertebrate lamins are not orthologous, and their expression patterns evolved independently. It is therefore of interest to examine the effects of mutations in lamin genes. Mutations in the mammalian lamin A/C gene cause a range of diseases, collectively called laminopathies, that include muscular dystrophies and premature aging disorders. We compared the sequences of lamin genes from different species, and we have characterized larval and adult phenotypes in Drosophila bearing mutations in the lam gene that is expressed in the B-type pattern. Larvae move less and show subtle muscle defects, and surviving lam adults are flightless and walk like aged wild-type flies, suggesting that lam phenotypes might result from neuromuscular defects, premature aging, or both. The resemblance of Drosophila lam phenotypes to human laminopathies suggests that some lamin functions may be performed by differently expressed genes in flies and mammals. Such still-unknown functions thus would not be dependent on lamin gene expression pattern, suggesting the presence of other lamin functions that are expression dependent. Our results illustrate a complex interplay between lamin gene expression and function through evolution

Pheno-genotyping of inherited thrombocytopenias: our experience in 50 families

Dada la heterogeneidad de las entidades comprendi- das en las trombocitopenias hereditarias y la escasez de marcadores distintivos, su diagnóstico constituye un verdadero desafío. El abordaje clásico se basa en la caracterización fenotípica seguida del estudio mo- lecular de genes candidatos, orientado según la sos- pecha clínica. La introducción de la secuenciación de nueva generación (NGS), que permite evaluar múltiples genes simultáneamente, constituye una al- ternativa diagnóstica de alto costo, siendo de acceso limitado en nuestro medio. Nos propusimos evaluar la utilidad del abordaje clásico en una cohorte conse- cutiva de 50 familias y describir la aplicación de NGS en un subgrupo de pacientes sin diagnóstico etioló- gico luego del enfoque clásico. Mediante el abordaje clásico se efectuó el diagnóstico en 27 (54%) familias. Posteriormente, 8 familias que quedaron sin diag- nóstico luego del algoritmo clásico, se evaluaron me- diante NGS, identificando el gen causal en 4 de ellas. Considerando ambos abordajes, el rédito diagnóstico fue 31/50 (62%) familias, con la siguiente distribu- ción: 38% desorden relacionado a MYH9, 8% síndro- me de Bernard-Soulier (4% clásico, 4% monoalélico), 4% síndrome de plaquetas grises, 4% desorden pla- quetario con predisposición a leucemia, 6% trom- bocitopenia relacionada a ANKRD26, 2% síndrome Wiskott-Aldrich. Los pacientes en los que no se pudo efectuar un diagnóstico etiológico presentaban trom- bocitopenia aislada leve, con aumento moderado del tamaño plaquetario y sangrado escaso.En conclusión, la aplicación de NGS permitió au- mentar el rédito diagnóstico, si bien sería necesa- rio ampliar la población estudiada para establecer el valor real de este abordaje en nuestro medio. Por lo tanto, el uso inicial del abordaje clásico, reserván- dose la aplicación posterior de NGS a los casos que permanecen sin diagnóstico luego de este enfoque, constituiría una alternativa útil en países con pocos recursos, apuntando a un diagnóstico adecuado que posibilite la pesquisa de complicaciones sindrómicas, oriente al tratamiento y consejo genético acertado.Diagnosis of inherited thrombocytopenias represents a true challenge owing to heterogeneity of these disorders and the absence of distinctive features in a substantial proportion of patients. Classical diagnostic approach is based on phenotypic characterization followed by molecular analysis of candidate genes guided by clinical suspicion. The introduction of next generation sequencing (NGS), that allows multiple genes analysis, is a high-cost alternative with limited access in our country. The aim of this work was to evaluate the utility of the classical approach in a consecutive cohort of 50 families and to describe the application of NGS in a subgroup of patients without an etiological diagnosis after the initial approach. Through the conventional approach, an etiologic diagnosis was made in 27 (54%) families. NGS was performed in 8 that remained without diagnosis after initial characterization, attaining a diagnosis in 4. Combining both approaches, the diagnostic yield was 31/50 (62%) families: 38% MYH9-related disorder, 8% Bernard-Soulier syndrome, 4% gray platelet syndrome, 4% familial platelet disorder with predisposition to leukemia, 6% ANKRD26-related thrombocytopenia, 2% Wiskott-Aldrich syndrome. Most patients without diagnosis had isolated macrothrombocytopenia and mild bleeding. NGS increased the diagnostic rate in this cohort, although it would be necessary to expand the population to establish its actual value in our setting. Therefore, the use of the classical approach and subsequent application of NGS in undiagnosed patients would represent a useful alternative in low-income countries, pointing out that a correct etiological diagnosis enables the detection of syndromic complications, appropriate treatment and adequate genetic counseling.Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Goette, Nora Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Marin Oyarzún, Cecilia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Baroni Pietto, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Ayala, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Altuna, Diana R.. Instituto Universidad Escuela de Medicina del Hospital Italiano; ArgentinaFil: Arrieta, Maria Elizabeth. Hospital Público Descentralizado Dr. Guillermo Rawson.; ArgentinaFil: Arbesú, Guillermo. Hospital Dr. Humberto Notti; ArgentinaFil: Basqueira, Ana L.. Hospital Privado Universitario de Cordoba.; ArgentinaFil: Bazack, Nora. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Bonacorso, Silvina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Brodsky, Andrés. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Castro Rios, Miguel. No especifíca;Fil: Cosentini, María L.. Hospital Materno Infantil Doctor Hector Quintana ; Gobierno de la Provincia de Jujuy;Fil: Donato, Hugo Sebastian. Hospital Municipal del Niño de San Justo ; Municipalidad de la Matanza (buenos Aires);Fil: Korin, Jorge D.. No especifíca;Fil: Gomez, Silvina. No especifíca;Fil: Guglielmone, Hugo. Sanatorio Allende; ArgentinaFil: Lagrotta, Pablo. Hospital Nacional Profesor Alejandro Posadas.; ArgentinaFil: Marti, Alejandra. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; ArgentinaFil: Negro, Fernando Javier. Sanatorio Sagrado Corazon; ArgentinaFil: Rapetti, María C.. Hospital Municipal del Niño de San Justo ; Municipalidad de la Matanza (buenos Aires);Fil: Rosso, Diego. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ponzinibbio, Carlos. Hospital Italiano de La Plata; ArgentinaFil: Veber, Ernesto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Zerga, Marta Elisa. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Molinas, Felisa Concepción. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Savoia, Anna. Instituto para la Salud Materna e Infancia; Italia. Università degli Studi di Trieste; ItaliaFil: Pecci, Alessandro. Universita Degli Studi Di Pavia; ItaliaFil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Eculizumab in paroxysmal nocturnal hemoglobinuria with Budd-Chiari syndrome progressing despite anticoagulation

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive, life-threatening disorder characterized by chronic intravascular hemolysis caused by uncontrolled complement activation. Hepatic vein thrombosis (Budd-Chiari syndrome) is common in PNH patients. This case report describes the response to eculizumab (a humanized monoclonal antibody that inhibits terminal complement activation) in a 25-year-old male with progressive liver function deterioration despite standard anticoagulation therapy and transjugular intrahepatic porto-systemic shunt. The patient presented with anemia, severe thrombocytopenia, headache, abdominal pain, and distention. He was diagnosed with PNH, cerebral vein thrombosis, and Budd-Chiari syndrome. Despite adequate anticoagulation, diuretic administration, and placement of a transjugular shunt, additional thrombotic events and progressive liver damage were observed. Eculizumab therapy was initiated, resulting in rapid blockade of intravascular hemolysis, increased platelet counts, ascites resolution, and liver function recovery, all of which are presently sustained. Since starting eculizumab the patient has had no further thrombotic events and his quality of life has dramatically improved. This is the first report to confirm the role of complement-mediated injury in the progression of Budd-Chiari syndrome in a patient with PNH. This case shows that terminal complement blockade with eculizumab can reverse progressive thromboses and hepatic failure that is unresponsive to anticoagulation therapy and suggests that early initiation of eculizumab should be included in the therapeutic regimen of patients with PNH-related Budd-Chiari syndrome.</p

Manifestaciones clínicas, factores pronósticos y respuesta terapéutica del síndrome hemofagocítico: experiencia del HCJSM

Introduction Hemophagocytic syndrome (HS) is a rare but potentially fatal condition, which results from an excessive and ineffective immune response with continuous activation of mononuclear phagocyte system.  Objective To make a retrospective assessment of patients with HS reported in the last 8 years in the Hospital de Clínicas to asses prognostic and therapeutic factors. Material and methods Sixteen patients with primary (n=1) or secondary (n=15) HS were included. Patients were classified in four categories according to the etiology: lymphoma, infection, combined or unknown. Every patient received specific treatment of the underlying cause, as well as dexamethasone alone or combined with etoposide. Results Clinical signs and symptoms of our patients did not differ from the literature. Hemophagocytosis in bone marrow aspirate or biopsy was present in 15 cases (93.75%). The underlying diseases were lymphoma (46.7%; n=7), infection (33.3%; n=5) or combined (13.3%; n=2). The median survival of patients was of 79 days (CI95%: 29-not reached): 31 days for those with lymphoma, 160 days for those with combined etiology and not reached for those with infectious underlying cause (p=0.8). None of the variables assessed at the moment of diagnosis was predictive of survival, whereas hemoglobin decrease (p=0.019), LDH elevation (p=0.029) and ferritin incease (p=0.035) at 15th day correlated significantly with mortality. There was a non statistically significant survival benefit in those who received corticosteroids without etoposide. To achieve a complete response at week four (RC4) was significantly associated with improved survival (p=0.00016). There was a trend towards reduction of mortality in those who received prompt treatment, without reaching statistical signification (p=0.32). Conclusions The achievement of RC4 and the values of ferritin, LDH and hemoglobin at day 15th correlated significantly with the risk of death. New studies with more patients are needed to confirm the relevance of these findings.RESUMEN IntroducciónEl síndrome hemofagocítico (SHF) es una condición clínica poco frecuente pero de elevada mortalidad, resultado de una respuesta inmune hiperinflamatoria e inefectiva, con activación sostenida del sistema mononuclear fagocítico. ObjetivosAnalizar retrospectivamente los casos de SHF asistidos durante los últimos 8 años en el Hospital deClínicas, para evaluar factores pronósticos y terapéuticos. Material y métodos Se incluyeron 16 pacientes con SHF primario (n=1) o secundario (n=15). Según la causa se dividió a los pacientes con SHF secundario en 4 categorías: linfoma, infección, combinada o indeterminada. Todos recibieron tratamiento de la causa subyacente, así como dexametasona sola o combinada con etopósido. ResultadosLas manifestaciones clínicas de nuestros pacientes con SHF secundario y primario no difirieron de lo descripto en la literatura. El 93,75% (n=15) presentó hemofagocitosis en aspirado o biopsia de médula ósea. La enfermedad subyacente fue un linfoma (46,7%; n=7), una infección (33,3%; n=5) o etiología combinada (13,3%; n=2). La mediana de sobrevida (SV) de los pacientes fue de 79 días (IC95%: 29-no alcanzada): 31 días en el grupo con linfoma, 160días para aquellos de causa combinada y no alcanzada para aquellos de etiología infecciosa (p=0,8).Ninguna de las variables presentes al momento del diagnóstico fue predictora de SV, mientras que el descenso de la hemoglobina (p=0,019), el aumento de la LDH (p=0,029) y el descenso de la ferritina (p=0,035) al día 15 mostraron correlación significativa con la mortalidad. Hubo un beneficio no significativo en la SV en aquellos que recibieron corticoides sin etopósido. El tener respuesta completa a la semana cuatro (RC4) fue un predictor significativo  de SV (p=0,00016). Hubo una tendencia no significativa a una reducción de la mortalidad en el grupoque inició tratamiento tempranamente (p=0,32).  ConclusionesLa falta de RC4 y los valores de ferritina, LDH y hemoglobina al día 15 se correlacionaron de manera significativa con el riesgo de muerte. Nuevos estudios con un número mayor de pacientes podrán confirmar la relevancia clínica de estos hallazgos

Dogovoreni susret – Traženje

Kuća je imala tri sobe, dva dnevna boravka, kupaonicu, blagovaonicu, kuhinju, sobu za sluškinju, podrum, terasu i dvorište.Što je za Eduarda značilo dvorište?Značilo je zemlju kojom je jurio orući štapom, iskopanu krhotinu stakla iz kojeg je izišao crv prepolovljen napola, ali koji se još micao, uvijek moguće postojanje kakva blaga, lokve blatnjave vode u vrijeme kiša, papirnati brodić, jednog mrava u njemu, liniju mrava koju je pratio da vidi kamo idu. Išli su u mravinjak. Manga sapatinho, manga manga-coracao-de-boi. Šećerna jabuka, goiaba, gabiroba. Kokošinjac. Bijela kokoš bila je njegova, bilo je jasno iz imena: „Eduarda!”Stisnula bi se i dopustila mu da je uzme u ruke. Katkad bi snijela jaje. Kada bi odlazio u školu, Eduardo bi je ostavljao ispod lavora. Jednom zgodom otac mu je rekao da to nije u redu: zar bi volio da netko to radi tebi? I kokoši pate. Jedne nedjelje za vrijeme ručka zatekao je Eduardu na stolu, s nogama u zraku, pečenu. Pojeo ju je kroz suze. Da, pate, no svi ih jedu i misle da je to u redu

Strain and vector magnetic field tuning of the anomalous phase in Sr₃Ru₂O₇

A major area of interest in condensed matter physics is the way electrons in correlated electron materials can self-organize into ordered states, and a particularly intriguing possibility is that they spontaneously choose a preferred direction of conduction. The correlated electron metal Sr3Ru2O7 has an anomalous phase at low temperatures that features strong susceptibility toward anisotropic transport. This susceptibility has been thought to indicate a spontaneous anisotropy, that is, electronic order that spontaneously breaks the point-group symmetry of the lattice, allowing weak external stimuli to select the orientation of the anisotropy. We investigate further by studying the response of Sr3Ru2O7 in the region of phase formation to two fields that lift the native tetragonal symmetry of the lattice: in-plane magnetic field and orthorhombic lattice distortion through uniaxial pressure. The response to uniaxial pressure is surprisingly strong: Compressing the lattice by ~0.1% induces an approximately 100% transport anisotropy. However, neither the in-plane field nor the pressure phase diagrams are qualitatively consistent with spontaneous symmetry reduction. Instead, both are consistent with a multicomponent order parameter that is likely to preserve the point-group symmetry of the lattice, but is highly susceptible to perturbation.Instituto de Física de Líquidos y Sistemas BiológicosFacultad de Ciencias Exacta

Strain and vector magnetic field tuning of the anomalous phase in Sr₃Ru₂O₇

A major area of interest in condensed matter physics is the way electrons in correlated electron materials can self-organize into ordered states, and a particularly intriguing possibility is that they spontaneously choose a preferred direction of conduction. The correlated electron metal Sr3Ru2O7 has an anomalous phase at low temperatures that features strong susceptibility toward anisotropic transport. This susceptibility has been thought to indicate a spontaneous anisotropy, that is, electronic order that spontaneously breaks the point-group symmetry of the lattice, allowing weak external stimuli to select the orientation of the anisotropy. We investigate further by studying the response of Sr3Ru2O7 in the region of phase formation to two fields that lift the native tetragonal symmetry of the lattice: in-plane magnetic field and orthorhombic lattice distortion through uniaxial pressure. The response to uniaxial pressure is surprisingly strong: Compressing the lattice by ~0.1% induces an approximately 100% transport anisotropy. However, neither the in-plane field nor the pressure phase diagrams are qualitatively consistent with spontaneous symmetry reduction. Instead, both are consistent with a multicomponent order parameter that is likely to preserve the point-group symmetry of the lattice, but is highly susceptible to perturbation.Instituto de Física de Líquidos y Sistemas BiológicosFacultad de Ciencias Exacta