MODELO EXPERIMENTAL DE GLOMERULONEFRITIS MEMBRANOSA INDUCIDA CON ALBUMINA BOVINA

El objetivo del presente trabajo fue diseñar un modelo experimental de Glomerulonefritis Membranosa (GM) en ratas Wistar, inducida con Seroalbúmina Bovina (BSA), y validarlo mediante la determinación de parámetros bioquímicos, histológicos, ultraestructurales y detección de inmunocomplejos por inmunofluorescencia (IF). Los animales del grupo experimental fueron inmunizados por vía subcutánea, con dosis de 3 mg c/u de BSA/PBS con adyuvante de Freund. Se efectuaron diferentes esquemas de inmunización. Cuando el título de anticuerpos fue ≥1/2, comenzó la administración diaria de 2 mg, por vía endovenosa de BSA/PBS, durante 15 días. Se evaluó la funcionalidad renal por la proteinuria; después de la 5° semana, desde su aparición, se determinó: depuración (clearance) de creatinina, uremia, proteinemia y perfil lipídico. Los dos riñones se usaron para estudios histológicos, ultraestructurales y detección de inmunocomplejos por IF. Los resultados mostraron que la inmunización fue efectiva con 5 R E S U M E N inoculaciones c/15 días. En los animales nefróticos la proteinuria, depuración (clearance) de creatinina, proteinemia , uremia y el perfil lipídico presentaron alteraciones significativas (p<0.0001). Al microscopio óptico se observó hipercelularidad, engrosamiento difuso de las membranas basales de los capilares glomerulares y diferentes grados de atrofia, esclerosis e hialinización de los glomérulos. Por IF se detectó inmunocomplejos IgG en el 100 % de los glomérulos. Ultraestructuralmente, se observaron depósitos subepiteliales electrodensos en la membrana basal engrosada, compatibles con inmunocomplejos . Se encontraron alteraciones en la estructura de los podocitos. En conclusión, los estudios bioquímicos, estructurales y ultraestructurales permitieron inferir la inducción de un síndrome nefrótico experimental. Concluimos que el protocolo utilizado tiene validez para la inducción de una glomerulonefritis membranosa en ratas Wistar

Allogeneic hsct with reduced intensity conditioning regimens in high risk patients with myelofibrosis

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Association of G6PD 202A,376G with lower haemoglobin concentration but not increased haemolysis in patients with sickle cell anaemia

The genetic bases of the highly variable degrees of anaemia and haemolysis in persons with Hb SS are not fully known, but several studies have indicated that G6PD deficiency is not a factor. The G6PD 202A and G6PD 376G alleles and α-thalassaemia were determined by molecular genetic testing in 261 children and adolescents with Hb SS in a multicentre study. G6PD 202A,376G (G6PD A−) was defined as hemizygosity for both alleles in males and homozygosity in females. Among the participants 41% were receiving hydroxycarbamide. The prevalence of G6PD 202A,376G was 13·6% in males and 3·3% in females with an overall prevalence of 8·7%. G6PD 202A,376G was associated with a 10 g/l decrease in haemoglobin concentration ( P  = 0·008) but not with increased haemolysis as measured by lactate dehydrogenase, bilirubin, aspartate-aminotransferase, reticulocyte count or a haemolytic component derived from these markers ( P  > 0·09). Similar results were found within a sub-group of children who were not receiving hydroxycarbamide. By comparison, single and double α-globin deletions were associated with progressively higher haemoglobin concentrations ( P  = 0·005 for trend), progressively lower values for haemolytic component ( P  = 0·007), and increased severe pain episodes ( P  < 0·001). In conclusion, G6PD 202A,376G may be associated with lower haemoglobin concentration in sickle cell anaemia by a mechanism other than increased haemolysis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79250/1/j.1365-2141.2010.08215.x.pd

Multiple functional regression with both discrete and continuous covariates

International audienceIn this paper we present a nonparametric method for extending functional regression methodology to the situation where more than one functional covariate is used to predict a functional response. Borrowing the idea from Kadri et al. (2010a), the method, which support mixed discrete and continuous explanatory variables, is based on estimating a function-valued function in reproducing kernel Hilbert spaces by virtue of positive operator-valued kernels

Angiogenic and Inflammatory Markers of Cardiopulmonary Changes in Children and Adolescents with Sickle Cell Disease

Background: Pulmonary hypertension and left ventricular diastolic dysfunction are complications of sickle cell disease. Pulmonary hypertension is associated with hemolysis and hypoxia, but other unidentified factors are likely involved in pathogenesis as well. Design and Methods: Plasma concentrations of three angiogenic markers (fibroblast growth factor, platelet derived growth factor-BB [PDGF-BB], vascular endothelial growth factor [VEGF]) and seven inflammatory markers implicated in pulmonary hypertension in other settings were determined by Bio-Plex suspension array in 237 children and adolescents with sickle cell disease at steady state and 43 controls. Tricuspid regurgitation velocity (which reflects systolic pulmonary artery pressure), mitral valve E/Edti ratio (which reflects left ventricular diastolic dysfunction), and a hemolytic component derived from four markers of hemolysis and hemoglobin oxygen saturation were also determined. Results: Plasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P≤0.003). By logistic regression, greater values for PDGF-BB (P = 0.009), interleukin-6 (P = 0.019) and the hemolytic component (P = 0.026) were independently associated with increased odds of elevated tricuspid regurgitation velocity while higher VEGF concentrations were associated with decreased odds (P = 0.005) among the patients with sickle cell disease. These findings, which are consistent with reports that PDGF-BB stimulates and VEGF inhibits vascular smooth muscle cell proliferation, did not apply to E/Etdi. Conclusions: Circulating concentrations of angiogenic and pro-Inflammatory markers are altered in sickle cell disease children and adolescents with elevated tricuspid regurgitation velocity, a subgroup that may be at risk for developing worsening pulmonary hypertension. Further studies to understand the molecular changes in these children are indicated

Results of Phase II Clinical Trial MPD-RC 101: Allogeneic Hematopoietic Stem Cell Transplantation Conditioned with Fludarabine/Melphalan in Patients with Myelofibrosis

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Estimates of recent and historical effective population size in turbot, seabream, seabass and carp selective breeding programmes

BACKGROUND: The high fecundity of fish species allows intense selection to be practised and therefore leads to fast genetic gains. Based on this, numerous selective breeding programmes have been started in Europe in the last decades, but in general, little is known about how the base populations of breeders have been built. Such knowledge is important because base populations can be created from very few individuals, which can lead to small effective population sizes and associated reductions in genetic variability. In this study, we used genomic information that was recently made available for turbot (Scophthalmus maximus), gilthead seabream (Sparus aurata), European seabass (Dicentrarchus labrax) and common carp (Cyprinus carpio) to obtain accurate estimates of the effective size for commercial populations. METHODS: Restriction-site associated DNA sequencing data were used to estimate current and historical effective population sizes. We used a novel method that considers the linkage disequilibrium spectrum for the whole range of genetic distances between all pairs of single nucleotide polymorphisms (SNPs), and thus accounts for potential fluctuations in population size over time. RESULTS: Our results show that the current effective population size for these populations is small (equal to or less than 50 fish), potentially putting the sustainability of the breeding programmes at risk. We have also detected important drops in effective population size about five to nine generations ago, most likely as a result of domestication and the start of selective breeding programmes for these species in Europe. CONCLUSIONS: Our findings highlight the need to broaden the genetic composition of the base populations from which selection programmes start, and suggest that measures designed to increase effective population size within all farmed populations analysed here should be implemented in order to manage genetic variability and ensure the sustainability of the breeding programmes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12711-021-00680-9

Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea

Prior studies have reported high response rates with recombinant interferon-a (rIFN-a) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-a,we investigated the outcomes of pegylated-rIFN-a2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PVwho were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 monthswere 69.2%(43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P 5 .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was 26% (range, 284%to 47%) in patients achieving a CR vs 14%(range, 218% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU