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Los sínodos y concilios americanos anteriores a la formulación del decreto tridentino de 1563, relativo a la invocación y veneración de las reliquias de los santos y de las sagradas imágenes, establecieron criterios y orientaciones respecto de la pintura y la escultura religiosa. Los obispos y sacerdotes que participaron en estas discusiones tuvieron presente la práctica pastoral, el discurso teológico anterior, así como lo resuelto por sínodos y concilios españoles. El presente texto se propone caracterizar estos documentos eclesiásticos americanos e identificar las fuentes que están alimentando su formulación. Se presentan como factores decisivos de esta genealogía del pensamiento americano sobre las imágenes sagradas, la doctrina elaborada desde los primeros padres hasta los documentos eclesiásticos europeos de comienzos del siglo XVI; la tensión que el asunto de las imágenes sagradas provocaba entre la población española de judíos y musulmanes conversos, así como las prácticas que se implementaron desde 1492 para cristianizar a la población musulmana de Granada.

Androgens have represented the historical therapeutic backbone of bone marrow failure (BMF) syndromes. However, their role has been rarely analyzed in prospective setting and systematic and long-term data are currently unavailable regarding their usage, effectiveness and toxicity in both acquired and inherited BMF. Here, taking advantage of a unique disease-specific international dataset, we retrospectively analyzed the so far largest cohort of BMF patients who received androgens before or in absence of an allogeneic hematopoietic cell transplantation (HCT), reappraising their current use in these disorders. We identified 274 patients across 82 EBMT affiliated centers, 193 with acquired (median age of 32) and 81 with inherited BMF (median age of 8 years). With a median duration of androgen treatment of 5.6 and 20 months respectively, complete/partial remission rates at 3 months were of 6%/29% in acquired and 8%/29% in inherited disorders. Five-year overall survival and failure free survival (FFS) were respectively 63% and 23% in acquired and 78% and 14% in inherited contexts. Androgen initiation after second line treatments for acquired, and after > 12 months post-diagnosis for inherited group were identified as factors associated with improved FFS in multivariable analysis. Androgen use was associated with a manageable incidence of organ-specific toxicity and low rates of solid and hematological malignancies. Sub-analysis of transplant-related outcomes after exposure to these compounds showed probabilities of survival and complications similar to other transplanted BMF cohorts. This study delivers a unique opportunity to track androgen use in BMF syndromes and represents the basis for general recommendations on their use on behalf of the SAAWP of the EBMT.

METID – Learning Innovation, Task Force del Politecnico di Milano, in collaborazione con la Rete Open Education Italia,con il supporto del Creative Commons Chapter Italiano e il patrocinio di Wikimedia Italia, ha proposto una serie di 4 webinar gratuiti sul tema “Open Education per innovare la didattica”. In questa pagina sono disponibili le slide presentate durante ilquarto incontrodal titoloMettere in atto Open Educational Practices. La registrazione dell'evento è disponibile sul canale YouTube di Polimi Open Knowledge nella playlist dedicata alla serie:https://tinyurl.com/OpenEdPOK

Iron overload (IOL) is a frequently reported complication following hematopoietic stem cell transplantation (HSCT) that has been investigated extensively in the field of hemoglobinopathies but has not been thoroughly characterized after HSCT in pediatric malignancies. Our aim was to assess prevalence, severity, risk factors, and management of IOL, as defined using biochemical (serum ferritin) and radiologic tools (T2*-weighted magnetic resonance imaging [MRI]), in a cohort of pediatric patients who underwent HSCT for either malignant or benign diseases. This monocentric, retrospective, observational study included all the 163 patients alive and in continuous remission at 24 months post-HSCT out of the 219 consecutive children and adolescents who underwent HSCT at our institution between 2012 and 2018, were included in the study. IOL was classified into 4 categories: absent, mild, moderate, and severe. Among the 163 patients, 73% had some degree of IOL (mild in 37%, moderate in 29%, and severe in 7%). Moderate/severe IOL was more frequent among patients diagnosed with a malignant disease versus those with a benign disease (43% versus 19%; P =.0065). Trend lines for serum ferritin showed a “bell-shaped” distribution, with the highest levels recorded during the first 6 months post-HSCT, followed by a spontaneous reduction. Both pre-HSCT (1659 ng/mL versus 617 ng/mL; P

The paper reports the case of a three-month-old girl presenting with maculopapular lesions all over her scalp, trunk, axilla region and groin. One month earlier she had been diagnosed with LCH through skin biopsy for persisting maculopapular rash. No other organs appeared to be involved: blood and urine tests, chest X-rays and abdominal ultrasound were normal. On physical examination, the child’s general conditions were poor and she was pale and dyspneic. Massive cervical lymphadenopathy and hepatosplenomegaly were diagnosed. Laboratory tests showed anaemia and thrombocytopenia, coagulopathy and hypoalbuminemia while chest X-rays revealed a mediastinal mass. Multisystem LCH with risk organs involvement (liver, spleen, bone marrow) was diagnosed. Despite the initial good response, the disease relapsed following first and second-line chemotherapy. Due to the evidence of B-RAFV600E mutation, targeted therapy with vemurafenib was introduced with excellent response. This case highlights the importance of surveillance in skin-limited neonatal LCH due to the risk of rapid evolution into an aggressive and refractory multisystem disease.

Cytoglobin is a highly conserved redox sensor heme protein with unknown physiological function. Unexpectedly, genetic deletion of zebrafish cytoglobin (cygb2) causes cardiac and gastro-intestinal tract laterality defects, modeling Kartagener’s syndrome, which in humans is associated with low airway epithelial nitric oxide (NO) production. Cygb2 co-localized with cilia and the NO synthase Nos2b in the Kupffer’s vesicle (KV) laterality organ and the structure and function of cilia were disrupted in cygb2 mutants, abolishing fluid flow within the KV. Abnormal ciliary function and organ laterality was phenocopied by depletion of nos2band gucy1a, the canonical NO receptor soluble guanylate cyclase (sGC) homolog in fish, and rescued by exposing cygb2 mutant embryos to an NO donor or an sGC stimulator and with over-expression of nos2b. Consistent with a conserved role in the modulation of ciliary function, cytoglobin knock out in the mouse also impaired airway epithelial ciliary structure and beat frequency. This is the first evidence that cytoglobin is essential for normal development stage-specific NO signaling, ciliogenesis and cilia motility, required for the establishment of left-right patterning.

BackgroundWhile cardiomyocytes undergo terminal differentiation postnatally and rarely re-enter the cell cycle, the endogenous mechanisms that propagate differentiation and prevent de-differentiation remain unclear. The monomeric heme protein myoglobin, which stores oxygen and regulates reactive oxygen/nitrogen species balance in the heart, increases in expression by over 50% during cardiomyocyte differentiation. Though myoglobin deletion without significant compensation is embryonic lethal in mice, a role for the protein in regulating cardiomyocyte differentiation has not been tested. We hypothesized that myoglobin expression is required for cardiomyocyte differentiation and the loss of myoglobin enables de-differentiation.MethodsMyoglobin was genetically silenced in HL-1, H9C2 cells, and neonatal rat ventricular cardiomyocytes (NRVM) to examine myoglobin-dependent effects on differentiation, proliferation, and Hippo pathway signaling. A zebrafish model of Mb depletion was made using CRISPR-Cas9 to test the effect of myoglobin depletion on cardiac regeneration after apical resection injury in vivo.ResultsMyoglobin deletion in cultured cell lines and NRVM decreased the gene expression of cardiomyocyte differentiation markers (troponin, myosin light chain, and myosin heavy chain), upregulated markers of dedifferentiation (runx1 and dab2) and stimulated cell proliferation. Mechanistically, we show that the heme prosthetic group of myoglobin catalyzes the oxidation of the Hippo pathway kinase LATS1, which activates the enzyme to phosphorylate the downstream Yes-associated protein (YAP) transcription factor, which prevents its transcriptional activity. Thus, the loss of myoglobin results in the de-phosphorylation and nuclear translocation of YAP, which propagates proliferation and fetal gene expression. In vivo, myoglobin-deficient zebrafish hearts recapitulated the increase in YAP signaling and showed accelerated regeneration at 20 days post apical injury.ConclusionWe a novel role for myoglobin as an endogenous driver of cardiomyocyte differentiation, and a regulator of the Hippo pathway. These findings suggest myoglobin as a potential target for strategies to enhance cardiac development and improve cardiac repair and regeneration.

Western blots are employed to detect and characterize amounts of proteins in biological samples. Quantifications are traditionally carried out through data normalization by housekeeping protein method. This approach does not account for variations not intrinsically dependent on the sample such as different experimental conditions and type of samples. Zebrafish researchers often face the challenge of comparing embryos at different developmental stages or from different strains. Housekeeping protein amount can change in these conditions therefore adding an unwanted quantification error. Here we describe the method to analyze mutant zebrafish embryos at different stages by western blot using the Stain-Free technology for normalization. We present Globin X quantification at 2 and 5 days postfertilization in wild type and in the bloodless Vlad Tepes (vlt) zebrafish mutant that lack red blood cells.

Complete blood count (CBC) is one of the mostly performed diagnostic exam. It can give a variety of informations about a child’s health status. The article has the aim of guiding the pediatrician into reading the the different values of the CBC, in order to properly recognize and interpret the alterations and underlying the red flags which must be identified in order to proceed into further investigations or to request a specialist consultation (pediatric hematologist).

Aims: Nitrite is reduced to nitric oxide (NO) under physiological and pathological hypoxic conditions to modulate angiogenesis and improve ischemia–reperfusion injury. Although adult mammals lack the ability to regenerate the heart after injury, this is preserved in neonates and efforts to reactivate this process are of great interest. Unlike mammals, the adult zebrafish maintain the innate ability to regenerate their hearts after injury, providing an important model to study cardiac regeneration. We thus explored the effects of physiological levels of nitrite on cardiac and fin regeneration and downstream cellular and molecular signaling pathways in response to amputation and cryoinjury. Results: Nitrite treatment of zebrafish after ventricular amputation or cryoinjury to the heart in hypoxic water (∼3 parts per million of oxygen) increases cardiomyocyte proliferation, improves angiogenesis, and enhances early recruitment of thrombocytes, macrophages, and neutrophils to the injury. When tested in a fin regeneration model, neutrophil recruitment to the injury site was found to be dependent on NO. Innovation: This is the first study to evaluate effects of physiological levels of nitrite on cardiac regeneration in response to cardiac injury, with the observation that nitrite in water accelerates zebrafish heart regeneration. Conclusion: Physiological and therapeutic levels of nitrite increase thrombocyte, neutrophil, and macrophage recruitment to the heart after amputation and cryoinjury in zebrafish, resulting in accelerated cardiomyocyte proliferation and angiogenesis. Translation of this finding to mammalian models of injury during early development may provide an opportunity to improve outcomes during intrauterine fetal or neonatal cardiac surgery.

Oral ferrous salts are standard treatment for children with iron deficiency anemia (IDA). The objective of our study was to monitor oral iron therapy in children, aged 3 months-12 years, with IDA. We prospectively collected clinical and hematological data of children with IDA, from 15 AIEOP (Associazione Italiana di Ematologia ed. Oncologia Pediatrica) centers. Response was measured by the increase of Hb from baseline. Of the 107 analyzed patients, 18 received ferrous gluconate/sulfate 2 mg/kg (ferrous 2), 7 ferrous gluconate/sulfate 4 mg/kg (ferrous 4), 7 ferric iron salts 2 mg/kg (ferric), 62 bis-glycinate iron 0.45 mg/kg (glycinate), and 13 liposomal iron 0.7-1.4 mg/kg (liposomal). Increase in reticulocytes was evident at 3 days, while Hb increase appeared at 2 weeks. Gain of Hb at 2 and 8 weeks revealed a higher median increase in both ferrous 2 and ferrous 4 groups. Gastro-intestinal side effects were reported in 16% (ferrous 2), 14% (ferrous 4), 6% (glycinate), and 0 (ferric and liposomal) patients. The reticulocyte counts significantly increased after 3 days from the start of oral iron supplementation. Bis-glycinate iron formulation had a good efficacy/safety profile and offers an acceptable alternative to ferrous iron preparations.

The case of an 11-year-old girl affected by hereditary spherocytosis admitted to hospital for abdominal pain is described. The diagnosis of cholelithiasis was eventually made.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, intellectual disability and immunodeficiency. Here we report on one RSTS patient who experienced hemophagocytic lymphohystiocytosis (HLH) and disseminated herpes virus 1 ( HSV-1) disease. The clinical picture of RSTS is expanding to include autoinflammatory, autoimmune, and infectious complications. Prompt treatment of HLH and disseminated HSV-1 can lower the mortality rate of these life-threatening conditions.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53–71%) for MMUD, versus 80% (66–95%) for HDs with only in vivo T cell depletion and 60% (47–73%) for HDs with in vivo and ex vivo T cell depletion (p =.22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73–99%) than for those transplanted from a MMUD 58% (48–68%) or those with graft manipulation 56% (42–69%) (p =.046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p =.005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts. © 2021 Wiley Periodicals LLC., The authors are particularly thankful to all centers from the Severe Aplastic Anemia Working Party and the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation, who kindly agreed to participate in this study (see Appendix S1). We would also like to thank Anne E. Lippinkhof, Study Coordinator, Severe Aplastic Anemia Working Party for her invaluable help.

Pseudoxanthoma elasticum is a rare cause for ischaemic stroke. Little is known about acute and secondary prevention strategies in these subjects given the increased risk of gastrointestinal and urinary bleedings. Here we present the case of a 62 years old man affected by pseudoxanthoma elasticum who presented with acute ischaemic stroke and was successfully treated with intravenous thrombolysis. Neurological signs improved after intravenous thrombolysis without bleeding complication. To our knowledge, this is the first case of pseudoxanthoma elasticum-related stroke undergoing intravenous thrombolysis.

Objective To describe the hematologic outcome and long-term survival of patients enrolled in the Shwachman-Diamond syndrome Italian Registry. Study design A retrospective and prospective study of patients recorded in the Shwachman-Diamond syndrome Italian Registry. Results The study population included 121 patients, 69 males and 52 females, diagnosed between 1999 and 2018. All patients had the clinical diagnosis confirmed by mutational analysis on the SBDS gene. During the study period, the incidence of SDS was 1 in 153 000 births. The median age of patients with SDS at diagnosis was 1.3 years (range, 0-35.6 years). At the first hematologic assessment, severe neutropenia was present in 25.8%, thrombocytopenia in 25.5%, and anemia in 4.6% of patients. A normal karyotype was found in 40 of 79 patients, assessed whereas the most frequent cytogenetic abnormalities were isochromosome 7 and interstitial deletion of the long arm of chromosome 20. The cumulative incidence of severe neutropenia, thrombocytopenia, and anemia at 30 years of age were 59.9%, 66.8%, and 20.2%, respectively. The 20-year cumulative incidence of myelodysplastic syndrome/leukemia and of bone marrow failure/severe cytopenia was 9.8% and 9.9%, respectively. Fifteen of 121 patients (12.4%) underwent allogeneic stem cell transplantation. Fifteen patients (12.4%) died; the probability of overall survival at 10 and 20 years was 95.7% and 87.4%, respectively. Conclusions Despite an improvement in survival, hematologic complications still cause death in patients with SDS. Further studies are needed to optimize type and modality of hematopoietic stem cell transplantation and to assess the long-term outcome in nontransplanted patients.

In the freezing waters of the Southern Ocean, Antarctic teleost fish, the Notothenioidei, have developed unique adaptations to cope with cold, including, at the extreme, the loss of hemoglobin in icefish. As a consequence, icefish are thought to be the most vulnerable of the Antarctic fish species to ongoing ocean warming. Some icefish also fail to express myoglobin but all appear to retain neuroglobin, cytoglobin-1, cytoglobin-2, and globin-X. Despite the lack of the inducible heat shock response, Antarctic notothenioid fish are endowed with physiological plasticity to partially compensate for environmental changes, as shown by numerous physiological and genomic/transcriptomic studies over the last decade. However, the regulatory mechanisms that determine temperature/oxygen-induced changes in gene expression remain largely unexplored in these species. Proteins such as globins are susceptible to environmental changes in oxygen levels and temperature, thus playing important roles in mediating Antarctic fish adaptations. In this study, we sequenced the full-length transcripts of myoglobin, neuroglobin, cytoglobin-1, cytoglobin-2, and globin-X from the Antarctic red-blooded notothenioid Trematomus bernacchii and the white-blooded icefish Chionodraco hamatus and evaluated transcripts levels after exposure to high temperature and low oxygen levels. Basal levels of globins are similar in the two species and both stressors affect the expression of Antarctic fish globins in brain, retina and gills. Temperature up-regulates globin expression more effectively in white-blooded than in red-blooded fish while hypoxia strongly up-regulates globins in red-blooded fish, particularly in the gills. These results suggest globins function as regulators of temperature and hypoxia tolerance. This study provides the first insights into globin transcriptional changes in Antarctic fish.

Background: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. Objective: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. Methods: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. Results: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P

The presence of large granular lymphocytes has been reported in patients with ADA2 deficiency and T-LGL leukemia. Here we describe two siblings with novel ADA2 variants, expanding the mutational spectrum of ADA2 deficiency. We show that lymphoproliferation, persistence of large granular lymphocytes, T-cell perturbations, and activation of PI3K pathway, measured by means of phosphorylation levels of S6, are detectable in DADA2 patients without T-LGL leukemia.

Manual erythroexchange (MEEX) was proven to be effective and safe in the management of sickle cell disease (SCD). The goal is to quickly reduce the percentage of hemoglobin S (HbS%). A national survey of the Italian Society for Thalassemia and Hemoglobinopathies (SITE) observed a great variability among MEEX protocols none of which were found to be predictive of the values of HbS% and hemoglobin (Hb) after the exchange. Two equations to estimate the HbS% and Hb values to be obtained after MEEX were developed based on the results of the MEEX procedures in place in the centers participating in the present study. A standard protocol was subsequently defined to evaluate the volumes to exchange to obtain the target values of HbS% and Hb. The protocol was tested in 261 MEEX performed in SCD patients followed in the 5 participating centers that belong to the Italian Hemoglobinopathy Comprehensive Care Network, with the support of the SITE. The results showed a correlation between the estimated and measured values of HbS% and Hb (Rp 0.95 and 0.65 respectively, p < 0.001). A negligible bias was found for the prediction of HbS% and a bias of 1g/dl for Hb. From consecutive MEEX, a rate of increase of HbS% between two exchanges of around 0.4% per day (p < 0.001) was measured. This protocol was shown to be effective and safe, as all patients reached the target value of HbS%. All the MEEX procedures were carried out with single venous access. No adverse events or reactions such as hypotension or electrolyte imbalance were reported nor were any complaints concerning the procedures received from patients.

Shwachman-Diamond syndrome (SDS) is a rare multi-organ recessive disease mainly characterised by pancreatic insufficiency, skeletal defects, short stature and bone marrow failure (BMF). As in many other BMF syndromes, SDS patients are predisposed to develop a number of haematopoietic malignancies, particularly myelodysplastic syndrome and acute myeloid leukaemia. However, the mechanism of cancer predisposition in SDS patients is only partially understood. In light of the emerging role of mesenchymal stromal cells (MSCs) in the regulation of bone marrow homeostasis, we assessed the ability of MSCs derived from SDS patients (SDS-MSCs) to recreate a functional bone marrow niche, taking advantage of a murine heterotopic MSC transplant model. We show that the ability of semi-cartilaginous pellets (SCPs) derived from SDS-MSCs to generate complete heterotopic ossicles in vivo is severely impaired in comparison with HD-MSC-derived SCPs. Specifically, after in vitro angiogenic stimuli, SDS-MSCs showed a defective ability to form correct networks, capillary tubes and vessels and displayed a marked decrease in VEGFA expression. Altogether, these findings unveil a novel mechanism of SDS-mediated haematopoietic dysfunction based on hampered ability of SDS-MSCs to support angiogenesis. Overall, MSCs could represent a new appealing therapeutic target to treat dysfunctional haematopoiesis in paediatric SDS patients.