Thymic Dendritic Cells Express Inducible Nitric Oxide Synthase and Generate Nitric Oxide in Response to Self- and Alloantigens

Thymocytes maturing in the thymus undergo clonal deletion/apoptosis when they encounter self- or allo-Ags presented by dendritic cells (DCs). How this occurs is a matter of debate, but NO may play a role given its ability of inducing apoptosis of these cells. APC (a mixed population of macrophages (Mφ) and DCs) from rat thymus expressed high levels of inducible NO synthase (iNOS) and produced large amounts of NO in basal conditions whereas iNOS expression and NO production were very low in thymocytes. Analysis by FACS and by double labeling of cytocentrifuged preparations showed that DCs and MΦ both express iNOS within APC. Analysis of a purified preparation of DCs confirmed that these cells express high levels of iNOS and produce large amounts of NO in basal conditions. The capacity of DCs to generate NO was enhanced by exposure to rat albumin, a self-protein, and required a fully expressed process of Ag internalization, processing, and presentation. Peptides derived from portions of class II MHC molecules up-regulate iNOS expression and NO production by DCs as well, both in self and allogeneic combinations, suggesting a role of NO in both self and acquired tolerance. We also found that NO induced apoptosis of rat double-positive thymocytes, the effect being more evident in anti-CD3-stimulated cells. Altogether, the present findings might suggest that DC-derived NO is at least one of the soluble factors regulating events, in the thymus, that follow recognition of self- and allo-Ags

Two patients with history of STEC-HUS, posttransplant recurrence and complement gene mutations

Hemolytic uremic syndrome (HUS) is a disease of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. About 90% of cases are secondary to infections by Escherichia coli strains producing Shiga-like toxins (STEC-HUS), while 10% are associated with mutations in genes encoding proteins of complement system (aHUS). We describe two patients with a clinical history of STEC-HUS, who developed end-stage renal disease (ESRD) soon after disease onset. They received a kidney transplant but lost the graft for HUS recurrence, a complication more commonly observed in aHUS. Before planning a second renal transplantation, the two patients underwent genetic screening for aHUS-associated mutations that revealed the presence of a heterozygous CFI mutation in patient #1 and a heterozygous MCP mutation in patient #2, and also in her mother who donated the kidney. This finding argues that the two cases originally diagnosed as STEC-HUS had indeed aHUS triggered by STEC infection on a genetic background of impaired complement regulation. Complement gene sequencing should be performed before kidney transplantation in patients who developed ESRD following STEC-HUS since they may be undiagnosed cases of aHUS, at risk of posttransplant recurrence. Furthermore, genetic analysis of donors is mandatory before living-related transplantation to exclude carriers of HUS-predisposing mutations. Two patients with a clinical history of D+ hemolytic uremic syndrome associated with Shiga-toxin-producing 0157:H7 E. coli and recurrence in the kidney graft carry heterozygous mutations in the genes encoding complement factor I (patient 1) and membrane cofactor protein (patient 2). © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons

Factores determinantes del margen financiero neto en el sistema bancario Peruano 2001-2012

El presente trabajo de investigación tiene por finalidad establecer y analizar los factores determinantes del margen financiero neto en el sistema bancario peruano, en el periodo 2001 – 2012. Para el desarrollo de nuestro trabajo de investigación utilizamos el diseño descriptivo de grupo único, identificando como variable dependiente al Margen financiero neto (MF) y como variables independiente institucionales: los gastos de administración (GA), el riesgo crediticio (RC), la liquidez (L), las mismas que fueron obtenidas de los estados financieros consolidados desde el año 2001 hasta el año 2012, proporcionados por la Superintendencia de Banca y Seguros y AFP (SBS). A fin de complementar el análisis de correlación efectuado en la presente investigación, se procedió a realizar una regresión por mínimos cuadrados ordinarios (MCO) contemplando las variables más destacadas por su mayor incidencia en el comportamiento del margen financiero neto en el sistema bancario peruano. A partir de los resultados presentados, se confirma que el margen financiero neto en el Sistema bancario peruano se encuentra determinado por: los gastos de administración (GA), el riesgo crediticio (RC), la liquidez (L).This research aims to identify and analyze the determinants of the financial margin in the Peruvian banking system in the period 2001-2012. To develop our research used the descriptive design unique group , identifying as a dependent variable to Financial Margin (MF) and an independent institutional variables: administrative expenses (GA) , credit risk (RC) , liquidity ( L) , the same as were obtained from the consolidated from 2001 until 2012 , provided by Superintendencia de Banca y Seguros y AFP (SBS) financial statements. To complement the correlation analysis carried out in this investigation, we proceeded to perform a regression by ordinary least squares (MCO) contemplating the most important variables for their higher incidence in the behavior of the spread in the Peruvian banking system. From the results presented, it is confirmed that the Financial Margin in the Peruvian banking system is determined by administrative expenses (GA), credit risk (CR), liquidity (L)

Protein load impairs factor H binding promoting complement-dependent dysfunction of proximal tubular cells

Intrarenal complement activation plays an important role in the progression of chronic kidney disease. A key target of the activated complement cascade is the proximal tubule, a site where abnormally filtered plasma proteins and complement factors combine to promote injury. This study determined whether protein overloading of human proximal tubular cells (HK-2) in culture enhances complement activation by impairing complement regulation. Addition of albumin or transferrin to the cells incubated with diluted human serum as a source of complement caused increased apical C3 deposition. Soluble complement receptor-1 (an inhibitor of all 3 activation pathways) blocked complement deposition while the classical and lectin pathway inhibitor, magnesium chloride–EGTA, was, ineffective. Media containing albumin as well as complement had additive proinflammatory effects as shown by increased fractalkine and transforming growth factor-β mRNA expression. This paralleled active C3 and C5b-9 generations, effects not shared by transferrin. Factor H, one of the main natural inhibitors of the alternative pathway, binds to heparan sulfate proteoglycans. Both the density of heparan sulfate and factor H binding were reduced with protein loading, thereby enhancing the albumin- and serum-dependent complement activation potential. Thus, protein overload reduces the ability of the tubule cell to bind factor H and counteract complement activation, effects instrumental to renal disease progression

Gait Analysis of Autistic Children with Echo State Networks

Poster presented at the NIPS'06 Worshop on Echo State Networks and Liquid State Machine

WearCam: A head mounted wireless camera for monitoring gaze attention and for the diagnosis of developmental disorders in young children

Autism covers a large spectrum of disorders that affect the individual’s way of interacting socially and is often revealed by the individual’s lack of interest in gazing at human faces. Currently Autism is diagnosed in children no younger than 2 years old. This paper presents a new monitoring device, the WearCam, to help forming a diagnosis of this neurodevelopmental disorder at an earlier age than currently possible. The WearCam consists of a wireless camera located on the forefront of the child. The WearCam collects videos from the viewpoint of the child’s head. Color detection, face detection and gaze detection are run on the data in order to locate the approximate gaze direction of the child and determine where her attention is drawn to (persons, objects, etc.). We report on early tests of the camera within normally developing children. Firstly the technical characteristics of the current prototype of the WearCam will be described. Afterwards the type of data collected with this device with young children will be shown

International collaboration as a tool for diagnosis of patients with inherited thrombocytopenia in the setting of a developing country

Inherited thrombocytopenias (ITs) are heterogeneous genetic disorders that frequently represent a diagnostic challenge. The requirement of highly specialized tests for diagnosis represents a particular problem in resourcelimited settings. To overcome this difficulty, we applied a diagnostic algorithm and developed a collaboration program with a specialized international center in order to increase the diagnostic yield in a cohort of patients in Argentina. Methods: Based on the algorithm, initial evaluation included collection of clinical data, platelet size, blood smear examination and platelet aggregation tests. Confirmatory tests were performed according to diagnostic suspicion, which included platelet glycoprotein expression, immunofluorescence for myosin- 9 in granulocytes and platelet thrombospondin-1 and molecular screening of candidate genes. Results: Thirty-one patients from 14 pedigrees were included; their median age was 32 (4?72) years and platelet count 72 (4?147) · 109 L)1. Autosomal dominant inheritance was found in nine (64%) pedigrees; 10 (71%) had large platelets and nine (29%) patients presented with syndromic forms. A definitive diagnosis was made in 10 of 14 pedigrees and comprised MYH9-related disease in four, while classic and monoallelic Bernard?Soulier syndrome, gray platelet syndrome, X-linked thrombocytopenia, thrombocytopenia 2 (ANKRD26 mutation) and familial platelet disorder with predisposition to acute myelogenous leukemia were diagnosed in one pedigree each. Conclusions: Adoption of an established diagnostic algorithm and collaboration with an expert referral center proved useful for diagnosis of IT patients in the setting of a developing country. This initiative may serve as a model to develop international networks with the goal of improving diagnosis and care of patients with these rare diseases.Fil: 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; ArgentinaFil: 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: Pecci, Alessandro. Universita Degli Studi Di Pavia; ItaliaFil: de Rocco, Daniela. Institute for Maternal and Child Health – IRCCS "Burlo Garofolo"; ItaliaFil: Gnan, Chiara. Institute for Maternal and Child Health – IRCCS "Burlo Garofolo"; ItaliaFil: Espasandin, Yesica Romina. 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: Negro, F.. Instituto Médico Sagrado Corazón; ArgentinaFil: Noris, Patrizia. Universita Degli Studi Di Pavia; ItaliaFil: Savoia, Anna. Institute for Maternal and Child Health – IRCCS "Burlo Garofolo"; Italia. Università degli Studi di Trieste; ItaliaFil: Balduini, C. L.. Universita Degli Studi Di Pavia; ItaliaFil: 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: 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; Argentin

Mutations in FN1 cause glomerulopathy with fibronectin deposits

Glomerulopathy with fibronectin (FN) deposits (GFND) is an autosomal dominant disease with age-related penetrance, characterized by proteinuria, microscopic hematuria, hypertension, and massive glomerular deposits of FN that lead to end-stage renal failure. The genetic abnormality underlying GFND was still unknown. We hypothesized that mutations in FN1, which encodes FN, were the cause of GFND. In a large Italian pedigree with eight affected subjects, we found linkage with GFND at the FN1 locus at 2q32. We sequenced the FN1 in 15 unrelated pedigrees and found three heterozygous missense mutations, the W1925R, L1974R, and Y973C, that cosegregated with the disease in six pedigrees. The mutations affected two domains of FN (Hep-II domain for the W1925R and the L1974R, and Hep-III domain for the Y973C) that play key roles in FN-cell interaction and in FN fibrillogenesis. Mutant recombinant Hep-II fragments were expressed, and functional studies revealed a lower binding to heparin and to endothelial cells and podocytes compared with wild-type Hep-II and an impaired capability to induce endothelial cell spreading and cytoskeletal reorganization. Overall dominant mutations in FN1 accounted for 40% of cases of GFND in our study group. These findings may help understanding the pathogenesis of proteinuria and glomerular FN deposits in GFND and possibly in more common renal diseases such as diabetic nephropathy, IgA nephropathy, and lupus nephritis. To our knowledge no FN1 mutation causing a human disease was previously reported

Platelet size for distinguishing between inherited thrombocytopenias and immune thrombocytopenia: a multicentric, real life study.

The most frequent forms of inherited thrombocytopenia (IT) are characterized by platelet size abnormalities and it has been suggested that this parameter is useful for their differentiation from immune thrombocytopenia (ITP). Recently, a monocentric study identified cut-off values for mean platelet volume (MPV) and mean platelet diameter (MPD) with good diagnostic accuracy in this respect. To validate these cut-off values in a different and larger case series of patients, we enrolled 130 subjects with ITP and 113 with IT in six different centres. The platelet count and MPV was each measured by the instrument routinely used in each institution. In some centres, platelet count was also measured by optical microscopy. MPD was evaluated centrally by image analysis of peripheral blood films. The previously identified cut-off value for MPV had 91% specificity in distinguishing ITP from inherited macrothrombocytopenias (mono and biallelic Bernard-Soulier, MYH9-related disease), while its sensitivity was greatly variable depending on the instrument used. With an appropriate instrument, specificity was 83%. The diagnostic accuracy of MPD was lower than that obtained with MPV. We concluded that MPV is a useful parameter for differentiating ITP from IT provided that it is measured by appropriate cell counters