Microelectrode Arrays Measure Blocking of Voltage-Gated Calcium Ion Channels on Supported Lipid Bilayers Derived from Primary Neurons.

Drug studies targeting neuronal ion channels are crucial to understand neuronal function and develop therapies for neurological diseases. The traditional method to study neuronal ion-channel activities heavily relies on the whole-cell patch clamp as the industry standard. However, this technique is both technically challenging and labour-intensive, while involving the complexity of keeping cells alive with low throughput. Therefore, the shortcomings are limiting the efficiency of ion-channel-related neuroscience research and drug testing. Here, this work reports a new system of integrating neuron membranes with organic microelectrode arrays (OMEAs) for ion-channel-related drug studies. This work demonstrates that the supported lipid bilayers (SLBs) derived from both neuron-like (neuroblastoma) cells and primary neurons are integrated with OMEAs for the first time. The increased expression of voltage-gated calcium (CaV) ion channels on differentiated SH-SY5Y SLBs  compared to non-differentiated ones is sensed electrically. Also, dose-response of the CaV ion-channel blocking effect on primary cortical neuronal SLBs from rats is monitored. The dose range causing ion channel blocking is comparable to literature. This system overcomes the major challenges from traditional methods (e.g., patch clamp) and showcases an easy-to-test, rapid, ultra-sensitive, cell-free, and high-throughput platform to monitor dose-dependent ion-channel blocking effects on native neuronal membranes.

Controversias en neuroinmunología: esclerosis múltiple, vacunación, SARS-CoV-2 y otros dilemas / Controversies in neuroimmunology: multiple sclerosis, vaccination, SARS-CoV-2 and other dilemas

La neuroinmunología es una disciplina que cada vez amplía más sus horizontes en la comprensión de las enfermedades neurológicas. Contemporáneamente, y a la luz de los nexos fisiopatológicos de las enfermedades neurológicas y la inmunología, se han planteado enfoques diagnósticos y terapéuticos específicos. A pesar de los importantes avances de esta disciplina, existen múltiples dilemas que le conciernen y se filtran en la práctica clínica. En esta revisión, se presentan y discuten 15 controversias, las cuales se construyen con la información clínica disponible más actualizada. Los temas incluidos son: disminución de esteroides en recaídas de esclerosis múltiple; recomendaciones terapéuticas en esclerosis múltiple a la luz de la pandemia por el SARS-CoV-2; evidencia de vacunación en esclerosis múltiple y en otras enfermedades desmielinizantes; panorama actual del síndrome clínico y radiológico aislado; y fallas terapéuticas en esclerosis múltiple; además, criterios para suspender las terapias modificadoras de la enfermedad; evidencia del manejo en recaídas leves; recomendaciones para la profilaxis contra Strongyloides stercolaris; utilidad de un segundo ciclo de inmunoglobulina en el síndrome de Guillain-Barré; criterios para diferenciar una polineuropatía crónica desmielinizante inflamatoria de inicio agudo de un síndrome de Guillain-Barré y, utilidad de la enzima convertidora de angiotensina en neurosarcoidosis. En cada una de las controversias, se presenta la problemática general y se ofrecen recomendaciones específicas que pueden adoptarse en la práctica clínica diaria.

Neuroimmunology is a discipline that increasingly broadens its horizons in the understanding of neurological diseases. At the same time, and in front of the pathophysiological links of neurological diseases and immunology, specific diagnostic and therapeutic approaches have been proposed. Despite the important advances in this discipline, there are multiple dilemmas that concern and filter into clinical practice. This article presents 15 controversies and a discussion about them, which are built with the most up-to-date evidence available. The topics included in this review are: steroid decline in relapses of multiple sclerosis; therapeutic recommendations in MS in light of the SARS-CoV-2 pandemic; evidence of vaccination in multiple sclerosis and other demyelinating diseases; overview current situation of isolated clinical and radiological syndrome; therapeutic failure in multiple sclerosis, as well as criteria for suspension of disease-modifying therapies; evidence of the management of mild relapses in multiple sclerosis; recommendations for prophylaxis against Strongyloides stercolaris; usefulness of a second course of immunoglobulin in the Guillain-Barré syndrome; criteria to differentiate an acute-onset inflammatory demyelinating chronic polyneuropathy versus Guillain-Barré syndrome; and, the utility of angiotensin-converting enzyme in neurosarcoidosis. In each of the controversies, the general problem is presented, and specific recommendations are offered that can be adopted in daily clinical practice.

Aneurisma trombosado de arteria comunicante anterior asociado a síntomas visuales / Thrombosed anterior communicating artery aneurysm associated with visual symptoms

Introducción: Los aneurismas de la arteria comunicante anterior (AComA) se presentan frecuentemente como causa de hemorragia subaracnoidea espontánea (HSAE), en casos raros se asocian a síntomas visuales por compresión mecánica o ruptura y su tratamiento quirúrgico a menudo representa un desafío. Descripción del caso: Se presenta el caso clínico de una paciente adulta con disminución de la agudeza visual del ojo derecho a predominio temporal, y hallazgos en RMN cerebral y angiografía compatibles con un aneurisma grande de AcomA, asociado a trombosis parcial; se realizó clipaje y trombectomía del aneurisma, la panangiografia de control evidenció exclusión completa de la lesión con posterior resolución del déficit visual. Discusión: El déficit visual por un aneurisma de la AcoA se puede generar por varios mecanismos, uno de ellos es la ruptura del aneurisma hacia el nervio óptico, con la subsecuente formación de un hematoma, adherencias y fibrosis; el otro mecanismo es la compresión mecánica de un aneurisma gigante no roto. El manejo quirúrgico a menudo implica técnicas complejas microquirúrgicas para intentar resolver el efecto de masa y excluir el aneurisma. La terapia endovascular es otra alternativa de tratamiento, pero tiene desventajas respecto a la cirugía. Conclusión: Los aneurismas de la AComA en raros casos se pueden asociar a síntomas visuales, debido a que por lo general se romepen cuando son pequeños, y no alcanzan a tener el tamaño suficiente para generar compresión de la vía óptica. Las técnicas microquirúrgicas ofrecen un método efectivo para disminuir el efecto de masa y mejorar los síntomas visuales

Introduction: Aneurysms of the anterior communicating artery (AComA) frequently present as a cause of spontaneous subarachnoid hemorrhage (HSAE), in rare cases they are associated with visual symptoms due to mechanical compression or rupture and their surgical treatment often represents a challenge. Description of the case: We present the clinical case of an adult patient with a decrease in visual acuity due to the right eye with a temporal predominance and findings on brain MRI and angiography compatible with a large AcomA aneurysm associated with partial thrombosis; clipping and thrombectomy of the aneurysm were performed, the control panangiography showed complete exclusion of the lesion. With subsequent resolution of the visual deficit. Discussion: The visual deficit due to an AcoA aneurysm can be generated by several mechanisms, one of them is the rupture of the aneurysm towards the optic nerve, with the subsequent formation of a hematoma, adhesions and fibrosis; The other mechanism is mechanical compression of a giant, unruptured aneurysm. Surgical management often involves complex microsurgical techniques to try to resolve the mass effect and exclude the aneurysm. Endovascular therapy is another treatment alternative, but it has disadvantages compared to surgery. Conclusion: AComA aneurysms in rare cases can be associated with visual symptoms, because they generally rupture when they are small, and are not large enough to generate compression of the optic pathway. Microsurgical techniques offer an effective method to alleviate the mass effect and improve visual symptoms

Characteristics, clinical outcomes, and risk factors of SARS-COV-2 infection in adult acute myeloid leukemia patients: experience of the PETHEMA group.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces higher morbidity and mortality in hematological malignancies, but evidence in acute myeloid leukemia (AML) is scarce. A multicenter observational study was conducted to determine the clinical outcomes and assess the impact of therapeutic approaches in adult AML patients with SARS-CoV-2 infection in the first wave (March-May 2020). Overall, 108 patients were included: 51.9% with active leukemia and 70.4% under therapeutic schedules for AML. Signs and symptoms of SARS-CoV-2 were present in 96.3% of patients and 82.4% received specific treatment for SARS-CoV-2. The mortality rate was 43.5% and was correlated with age, gender, active leukemia, dyspnea, severe SARS-CoV-2, intensive care measures, neutrophil count, and D-dimer levels. A protective effect was found with azithromycin, lopinavir/ritonavir, and normal liver enzyme levels. During the SARS-CoV-2 first wave, our findings suggested an increased mortality in AML in a short period. SARS-CoV-2 management could be guided by risk factors in AML patients.

[Consensus document for the diagnosis and treatment of pyruvate kinase deficiency]. / Documento de consenso para el diagnóstico y tratamiento del déficit de piruvato quinasa.

Pyruvate kinase (PK) deficiency is the second most frequent enzymopathy and the most common cause of chronic hereditary non-spherocytic haemolytic anaemia. Its global prevalence is underestimated due to low clinical suspicion of mild cases, associated with difficulties in the performance and interpretation of PK enzymatic activity assays. With the advent of next generation sequencing techniques, a better diagnostic approach is achieved. Treatment remains based on red blood cell transfusions and splenectomy, with special attention to iron overload, not only in transfusion-dependent patients. Nowadays, allogeneic hematopoietic stem cell transplantation is the only curative treatment, recommended only in selected cases of severely affected patients with an HLA-identical donor. Novel pharmacological and gene therapies are in clinical trials, with promising results. In this article, the Spanish Erythropathology Group reviews the current situation of PK deficiency, paying special attention to the usefulness of different diagnostic techniques and to actual and emerging treatments.

Why is the novel Hb Miguel Servet visualised by CE-HPLC newborn and not by the CE-HPLC ß-thalassaemia programme?

Screening of haemoglobinopathies is indicated for the detection of sickle cell anaemia; thus, neonates can benefit from early and adequate treatment that prevents neurological damage, reduces morbidity and mortality associated with the disease. These types of programmes sometimes lead to unexpected findings. We present a new haemoglobin (Hb) variant (Hb Miguel Servet) detected by newborn screening. During neonatal screening of haemoglobinopathies by cation-exchange high-performance liquid chromatography (CE-HPLC) newborn, an Hb variant was detected. An analysis at 8 months of age using capillary zone electrophoresis (CZE) confirmed the presence of this new Hb. The molecular characterisation was performed by automatic sequencing of the α and ß globin genes in an ABI PRISM 3100 Genetic Analyzer. Hb analysis by CE-HPLC ß-thalassaemia short programmedid not indicate the presence of abnormal Hbs. By CZE showed a peak in the zone 12 zone comprising 3.3% of the total Hb. A new analysis by CE-HPLC on a Tosoh G8-2 (Horiba) shown a peak, in the region of HbA1b, did not interfere with the quantification of HbA1c. Sequencing of the ß gene revealed the substitution of a guanine for a thymine (GGT >TGT) in codon 69 of the second exon, resulting in substitution of cysteine for the amino acid glutamine (HBB:c.208G>T). Hb Miguel Servet is a ß-chain globin variant detected by CE-HPLC newborn (BioRad), by CZE and by CE-HPLC-CE Tosoh G8-2 (Horiba), but no by CE-HPLC-CE ß-thalassaemia short programme (BioRad). In fact, for all the techniques that are visualised, what would be detected would be the glutathione variant of Hb (Miguel Servet).

Depresión y funcionamiento familiar en adolescentes de un municipio de Quindío, Colombia / Depression and family functioning in adolescents from a municipality of Quindío, Colombia

RESUMEN Introducción: la depresión en los adolescentes se ha asociado con diferentes factores, aquellos de tipo familiar cobran cada vez mayor relevancia. En la región quindiana se conocen pocos estudios al respecto. Objetivo: analizar la asociación entre depresión y funcionamiento familiar en adolescentes escolarizados del municipio de Circasia, Quindío. Material y métodos: se contó con la participación de 240 adolescentes, hombres y mujeres, entre 15 y 19 años escolarizados en las instituciones educativas del municipio de Circasia, seleccionados a través de un muestreo aleatorio simple. Se aplicó el Inventario de Depresión de Beck, el APGAR familiar de Smilkstein y una encuesta para indagar datos sociodemográficos, familiares y de salud. Resultados: Se identificó algún nivel de depresión en el 45,8 por ciento de los participantes y disfuncionalidad familiar en el 46,3 por ciento. Se encontró asociación estadísticamente significativa entre depresión moderada/grave y disfunción familiar leve y grave (p< 0,001). La depresión también se asoció con antecedentes personales y familiares de conducta suicida, relaciones familiares regulares o malas y conflictos familiares. Conclusiones: la disfunción familiar se asocia con síntomas depresivos moderados y graves en los adolescentes. Se requieren estudios posteriores que profundicen el análisis de diferentes variables familiares(AU)

ABSTRACT Introduction: Depression in teenagers has been associated with different factors and those of familiar type are gaining greater relevance. Few research works on this topic are known in the department of Quindío. Objective: To analyze the association between depression and family functioning in schooled teenagers in the municipality of Circasia, Quindío. Material and Methods: A total of 240 male and female adolescents between 15 and 19 years of age who received schooling in Educational Institutions of that region were evaluated. They were selected through a simple random sampling. The Beck Depression Inventory, the Smilkstein, G family APGAR and a survey about sociodemographic, family and health data were applied. Results: Different depression levels were identified in 45,8 percent of the participants; family dysfunction was found in 46,3 percent of them. A statistically significant association between moderate and severe depression and mild and severe family dysfunction (p <0.001) was found. Depression was also associated with personal and family history of suicidal behavior, regular or poor family relationships, and family conflicts. Conclusions: Family dysfunction is associated with moderate and severe depressive symptoms in adolescents. Future research is needed to analyze different family variables(AU)

Intramitochondrial proteostasis is directly coupled to α-synuclein and amyloid ß1-42 pathologies.

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-ß 1-42 (Aß42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin-proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

Nondeletional α-Thalassemia: Two New Mutations on the α2 Gene.

About 10.0% of α-thalassemia (α-thal) cases are due to point mutations, small deletions, or insertions of one or more bases on the α genes that can alter mRNA processing at the transcription, translation, or post-translation level; these cases are called nondeletional α-thalassemias (α-thal). Most occur within the domain of the α2 gene without changes in the expression of the α1 gene. We present two new frameshift mutations on the HBA2 gene, associated with a nondeletional α-thal phenotype. The probands were referred to our clinic because of persistent microcytosis and hypochromia. The molecular characterization was performed by automatic sequencing of the α-globin genes. Two new mutations were detected on the HBA2 gene; HBA2: c.85delG, p.(Ala29fs*21), and HBA2: c.268_280delCACAAGCTTCGGG, p.(His90Trpfs*9). These new mutations cause a change of the reading frame, the first on codon 28 and the second from codons 89 to 93. In the first mutation, the result is an altered amino acid sequence and a premature termination codon at position 87, while the elimination of 13 bp generates a protein of 95 residues and in this case, the premature termination codon is at position 96. These types of mutation are among the most damaging changes to the coding of a protein. Not only do they lead to changes in the length of the polypeptide, but they also vary the chemical composition, which would result in a nonfunctional protein. The importance of identifying these new mutations lies in their possible association with α0-thal, which could lead to a severe thalassemia.

Improving safety in blood transfusion using failure mode and effect analysis.

BACKGROUND: One of the medical areas where errors can have more serious consequences is the process of blood transfusion. We used failure mode and effect analysis (FMEA) for evaluating potential failures and improving transfusion safety in a medium-size urban hospital with a highly complex transfusion service. STUDY DESIGN AND METHODS: Each failure mode was evaluated using the likelihood of occurrence, severity of the effect, and probability of detection. The obtained results allowed each failure to be prioritized and decisions to be made in an organized manner to determine solutions. We define measures and indicators that allow the comparison of their results in a longer time period than most of the previous studies. RESULTS: The most important failures were those regarding 1) transmitting information about the transfusion request, 2) patient identification, 3) sample identification, 4) cross-matching ordered tests, 5) transfusing blood components, 6) completing and sending the transfusion control document, and 7) reporting of transfusion reactions. The application of the FMEA methodology allowed implementation of safety measures and monitoring of the measures using indicators, including the mandatory records of the hemovigilance system. There was a 56% improvement in the risk prioritization numbers in the second stage of the FMEA. CONCLUSION: FMEA allows for identification of factors that reduce safety in this hospital, analysis of the causes and consequences of these errors, design of corrective measures, and establishment of indicators to monitor their application. The FMEA methodology can help other institutions to identify their own specific vulnerabilities.

Extravascular hemolysis and complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing eculizumab treatment.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n=12) for signs of hemolysis and assessed complement biomarkers. Patients were also genotyped for complement receptor 1 (CR1, CD35) and C5 polymorphisms and evaluated for free eculizumab in plasma. We report that 10 patients (83%) present parameters suggesting persistent hemolysis, although they did not require additional transfusions. Seven of them (58%) become direct Coombs-test positive as a consequence of treatment, including all patients carrying the low-expression CR1-L allele. CH50 and sC5b-9 assays demonstrate that the persistent low-level hemolysis identified in our treated patients is not a consequence of incomplete C5 blockade, supporting that this hemolysis, as has been suggested previously, results from the extravascular removal of C3 opsonized PNH erythrocytes. We also show that continuous alternative pathway activation in eculizumab-treated individuals carrying the CR1-L allele results in abnormally decreased levels of C3 in plasma that could, potentially, increase their susceptibility to bacterial infections. Finally, we encourage a routine evaluation of free eculizumab levels and terminal pathway activity to personalize eculizumab administration.

A 12-mer repetitive antigenic epitope from Trypanosoma cruzi is a potential marker of therapeutic efficacy in chronic Chagas' disease.

OBJECTIVES: The objective was to characterize a Trypanosoma cruzi repetitive amino acid sequence that can be used as a marker of therapeutic drug efficacy in patients with chronic Chagas' disease. METHODS: Reactivities to the 3973 peptide were measured in 85 patients with Chagas' disease (41 in the asymptomatic stage and 44 in the cardiomyopathy stage) before and 9 and 24 months after benznidazole administration. Additionally, the levels of IL-6 and C-reactive protein were measured in serum samples from patients with cardiomyopathy. RESULTS: In 85% of the asymptomatic patients and 73% of the symptomatic chronic patients, modifications of the reactivity to the 3973 peptide were observed at 9 and 24 months post-benznidazole treatment. Significant variations in reactivities to the total antigens of T. cruzi were not observed at these times. Significant decreases in the reactivity to the 3973 peptide were observed after treatment in 20 of 41 (49%) asymptomatic patients and 15 of 44 (34%) cardiac chagasic patients (P < 0.001). In these patients, the decreases in reactivity at 24 months post-treatment were at least 40% lower than those detected before treatment. No correlations were found of the detected modifications in reactivity to the 3973 peptide after treatment with the levels of C-reactive protein or IL-6. CONCLUSIONS: Decreases in reactivity to the 3973 peptide may be relevant in the post-treatment follow-up of chronic chagasic patients.

[Spanish consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria]. / Consenso español para el diagnóstico y tratamiento de la hemoglobinuria paroxística nocturna.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of the haematopoietic progenitor cells due to a somatic mutation in theX-linked phosphatidylinositol glycan class A gene. The disease is characterized by intravascular haemolytic anaemia, propensity to thromboembolic events and bone marrow failure. Other direct complications of haemolysis include dysphagia, erectile dysfunction, abdominal pain, asthenia and chronic renal failure (65% of patients). The disease appears more often in the third decade of life and there is no sex or age preference. Detection of markers associated with glucosyl phosphatidyl inositol deficit by flow cytometry is currently used in the diagnosis of PNH. For years, transfusions have been the mainstay of therapy for PNH. A breakthrough in treatment has been the approval of the humanized monoclonal antibody eculizumab, which works by blocking the C5 complement protein, preventing its activation and therefore haemolysis. Several studies have confirmed that treatment with eculizumab avoids or decreases the need for transfusions, decreases the probability of thrombosis, improves the associated symptomatology and the quality of life in patients with PNH, showing an increase in survival. Because of rapid advances in the knowledge of the disease and its treatment, it may become necessary to adapt and standardize clinical guidelines for the management of patients with PNH.

Differentiation and Distribution of Marrow Stem Cells in Flex-Flow Environments Demonstrate Support of the Valvular Phenotype.

For treatment of critical heart valve diseases, prosthetic valves perform fairly well in most adults; however, for pediatric patients, there is the added requirement that the replacement valve grows with the child, thus extremely limiting current treatment options. Tissue engineered heart valves (TEHV), such as those derived from autologous bone marrow stem cells (BMSCs), have the potential to recapitulate native valve architecture and accommodate somatic growth. However, a fundamental pre-cursor in promoting directed integration with native tissues rather than random, uncontrolled growth requires an understanding of BMSC mechanobiological responses to valve-relevant mechanical environments. Here, we report on the responses of human BMSC-seeded polymer constructs to the valve-relevant stress states of: (i) steady flow alone, (ii) cyclic flexure alone, and (iii) the combination of cyclic flexure and steady flow (flex-flow). BMSCs were seeded onto a PGA: PLLA polymer scaffold and cultured in static culture for 8 days. Subsequently, the aforementioned mechanical conditions, (groups consisting of steady flow alone-850ml/min, cyclic flexure alone-1 Hz, and flex-flow-850ml/min and 1 Hz) were applied for an additional two weeks. We found samples from the flex-flow group exhibited a valve-like distribution of cells that expressed endothelial (preference to the surfaces) and myofibroblast (preference to the intermediate region) phenotypes. We interpret that this was likely due to the presence of both appreciable fluid-induced shear stress magnitudes and oscillatory shear stresses, which were concomitantly imparted onto the samples. These results indicate that flex-flow mechanical environments support directed in vitro differentiation of BMSCs uniquely towards a heart valve phenotype, as evident by cellular distribution and expression of specific gene markers. A priori guidance of BMSC-derived, engineered tissue growth under flex-flow conditions may serve to subsequently promote controlled, engineered to native tissue integration processes in vivo necessary for successful long-term valve remodeling.

Evolution of iron overload in patients with low-risk myelodysplastic syndrome: iron chelation therapy and organ complications.

This study aimed to evaluate the evolution of iron overload, assessed by serum ferritin (SF), in transfusion-dependent lower risk patients with myelodysplastic syndrome (MDS), as well as to describe the occurrence of organ complications, and to analyze its relationship with iron chelation therapy. This observational retrospective study was conducted from March 2010 to March 2011 in 47 Spanish hospitals. A total of 263 patients with lower risk MDS (International Prognostic Scoring System [IPSS] low/intermediate-1 risk or Spanish Prognostic Index [SPI] 0-1 risk), transfusion-dependent, and who had received ≥10 packed red blood cells (PRBC) were included. At MDS diagnosis, patients received a mean of 2.8 ± 3.9 PRBC/month, and 8.7% of patients showed SF ≥1000 µg/L. Over the course of the disease, patients received a mean of 83.4 ± 83.3 PRBC, and 36.1% of patients presented SF ≥2500 µg/L. Cardiac, hepatic, endocrine, or arthropathy complications appeared/worsened in 20.2, 11.4, 9.9, and 3.8% of patients, respectively. According to investigator, iron overload was a main cause of hepatic (70.0%) and endocrine (26.9%) complications. A total of 96 (36.5%) patients received iron chelation therapy for ≥6 months, being deferasirox the most frequent first chelation treatment (71.9%). Chelation-treated patients showed longer overall survival (p < 0.001), leukemia-free survival (p = 0.007), and cardiac event-free survival (p = 0.017) than non-chelated patients. In multivariable analyses, age (p = 0.011), IPSS (p < 0.001), and chelation treatment (p = 0.015) were predictors for overall survival; IPSS (p = 0.014) and transfusion frequency (p = 0.001) for leukemia-free survival; and chelation treatment (p = 0.040) and Sorror comorbidity index (p = 0.039) for cardiac event-free survival. In conclusion, these results confirm the potential survival benefit of iron chelation therapy and provide additional evidence on the deleterious effect of iron overload in lower risk MDS patients.

Interobserver variance in myelodysplastic syndromes with less than 5 % bone marrow blasts: unilineage vs. multilineage dysplasia and reproducibility of the threshold of 2 % blasts.

Previous studies have shown the reproducibility of the 2008 World Health Organization (WHO) classification in myelodysplastic syndromes (MDS), especially when multilineage dysplasia or excess of blasts are present. However, there are few data regarding the reproducibility of MDS with unilineage dysplasia. The revised International Prognostic Scoring System R-IPSS described two new morphological categories, distinguishing bone marrow (BM) blast cell count between 0-2 % and >2- < 5 %. This distinction is critical for establishing prognosis, but the reproducibility of this threshold is still not demonstrated. The objectives of our study were to explore the reliability of the 2008 WHO classification, regarding unilineage vs. multilineage dysplasia, by reviewing 110 cases previously diagnosed with MDS, and to study whether the threshold of ≤2 % BM blasts is reproducible among different observers. We used the same methodology as in our previous paper [Font et al. (2013) Ann Hematol 92:19-24], by encouraging investigators to include patients with <5 % BM blasts. Samples were collected from 11 hospitals and were evaluated by 11 morphologists. Each observer evaluated 20 samples, and each sample was analyzed independently by two morphologists. Discordance was observed in 36/108 suitable cases (33 %, kappa test 0.503). Diagnosis of MDS with unilineage dysplasia (refractory cytopenia with unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts (RARS) or unclassifiable MDS) was assessed in 33 patients, by either of the two observers. We combined this series with the cases with RCUD or RARS included in our 2013 paper, thus obtaining 50 cases with unilineage dysplasia by at least one of the observers. The whole series showed very low agreement regarding RCUD (5/23, 21 %) and RARS (5/28, 18 %). Regarding BM blast count, the threshold of ≤2 % was not reproducible (discordance rate 32/108 cases, kappa test 0.277). Our study shows that among MDS WHO 2008 categories, interobserver discordance seems to be high in cases with unilineage dysplasia. We also illustrate that the threshold of ≤2 % BM blasts as settled by the R-IPSS may be not easy to reproduce by morphologists in real practice.

Paroxysmal nocturnal hemoglobinuria: a single Spanish center's experience over the last 40 yr.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease. To date, many reviews and series have been described. We report the experience of our center by presenting a review of 56 PNH patient cases with an average age at diagnosis of 38 yr and follow-ups beginning at approximately 40 yr; the median survival rate was 11 yr. The average clonal size upon diagnosis was 48%, presenting a variable evolution. Thrombotic episodes and cancer were five each, and the main causes of death among our patients were equal at 8.9%. Radiological study by magnetic resonance imaging is presented as a fundamental technique for estimating the deposit of iron levels in the liver and kidney, as well as in some decisive cases at the start of eculizumab therapy. Sixteen patients have been treated with eculizumab so far in our series, and being a safe drug, it provides improvement in the patients' quality of life, and the disappearance of clinical symptoms, and avoids the emergence of new thrombosis.

Nuevas configuraciones de lo escolar: pensar la autoridad pedagógica emancipatoria en la educación de jóvenes y adultos / New school configurations: thinking pedagogical authority in youth and adult education

En el marco del proyecto de investigación "configuraciones de la autoridad en educación"¹, este artículo se propone caracterizar y analizar experiencias educativas que colaboran en la configuración de nuevas formas de autoridad pedagógica en escenarios escolares destinados a jóvenes y adultos en situaciones de vulnerabilidad educativa. El análisis se organiza en torno a dos ejes que consisten en la problematización de la relación pedagógica tradicional y en el desdibujamiento de la frontera entre saber escolar y no escolar. En función de ello, nos preguntamos cuáles son aquellos rasgos, gestos y iguras que surgen en las escenas educativas y que habilitan nuevos procesos de subjetivación acercándonos a imaginar una educación emancipadora.

Whitin de framework of the research "configurations of the educational authority"², this article proposes characterize and analyze educational experiences which contribute to new forms of pedagogical authority into schools for youths and adults in a vulnerability situation. This project is organized around two central themes based on the critical analysis of the tradicional pedagogical relationship and the undefined line between school knowledge and non school knowledge. Based on this, we look for those characteristics, gestures and igures that emerge in educational scenes and enable new processes of subjectivation in order to imagine an emancipatory education.