Anemia sideroblástica una enfermedad infrecuente de causas múltiples / Sideroblastic anemia, a rare disease of multiple causes

Introducción: La anemia sideroblástica es un trastorno hematológico que altera el proceso de la hematopoyesis, en la cual se ve afectada en mayor proporción la línea eritroide. Además, se presentan alteraciones en la síntesis del grupo hemo por disfunción mitocondrial en las células de la médula ósea. Objetivo: Indagar sobre la anemia sideroblástica, sus variables y los diferentes tipos de presentación que puede tener esta enfermedad. Métodos: Se llevó a cabo una revisión de la literatura en las bases de datos MEDLINE, EMBASE, Lilacs y ScienceDirect, con los descriptores: anemia sideroblástica, hematopoyesis, anomalías congénitas y 5-aminolevulinato sintetasa, en español e inglés. Se seleccionaron 26 artículos relacionados. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: Es una enfermedad de origen congénito o secundario a otros procesos como el consumo de alcohol o inducido por algunos medicamentos. Se presenta con poca frecuencia y, en su mayoría, el diagnóstico se hace mediante estudios de laboratorio, como extendido de sangre periférica, estudio de médula ósea, a los que se les pueden aplicar diversas tinciones, realizar secuenciación o incluso realizar reacción en cadena de polimerasa. Conclusión: La anemia sideroblástica es una enfermedad puede relacionarse con otras alteraciones hematológicas que modifican el metabolismo del hierro. El tratamiento curativo es la trasfusión de hemocomponentes y debe hacerse un enfoque individualizado de cada paciente según el tipo de anemia sideroblástica(AU)

Introduction: Sideroblastic anemia is a hematological disorder that alters the hematopoiesis process. This condition affects, to a great extent, the erythroid line. In addition, alterations occur in the synthesis of the heme group due to mitochondrial dysfunction in the bone marrow cells. Objective: To investigate sideroblastic anemia, its variables and the different types of presentation of this disease. Methods: A literature review was carried out in the MEDLINE, EMBASE, Lilacs and ScienceDirect databases, using the descriptors anemia sideroblástica [sideroblastic anemia], hematopoyesis [hematopoiesis], anomalías congénitas [congenital anomalies] and 5-aminolevulinato sintetasa [5-aminolevulinate synthetase], in Spanish and English. Twety-six articles related to the topic were selected. An analysis and summary of the revised bibliography was carried out. Information analysis and synthesis: It is a disease of congenital origin or secondary to other processes such as alcohol consumption or induced by some medications. It occurs infrequently and its diagnosis is mostly made through laboratory studies, such as peripheral blood smear and bone marrow study, to which various stains can be applied, as well as sequencing or even polymerase chain reaction. Conclusion: Sideroblastic anemia is a disease that can be related to other hematological alterations that modify iron metabolism. The curative treatment is the transfusion of blood components. An individualized approach should be used according to the type of sideroblastic anemia(AU)

Insulin Substrate Receptor (IRS) proteins in normal and malignant hematopoiesis

The insulin receptor substrate (IRS) proteins are a family of cytoplasmic proteins that integrate and coordinate the transmission of signals from the extracellular to the intracellular environment via transmembrane receptors, thus regulating cell growth, metabolism, survival and proliferation. The PI3K/AKT/mTOR and MAPK signaling pathways are the best-characterized downstream signaling pathways activated by IRS signaling (canonical pathways). However, novel signaling axes involving IRS proteins (noncanonical pathways) have recently been identified in solid tumor and hematologic neoplasm models. Insulin receptor substrate-1 (IRS1) and insulin receptor substrate-2 (IRS2) are the best-characterized IRS proteins in hematologic-related processes. IRS2 binds to important cellular receptors involved in normal hematopoiesis (EPOR, MPL and IGF1R). Moreover, the identification of IRS1/ABL1 and IRS2/JAK2V617F interactions and their functional consequences has opened a new frontier for investigating the roles of the IRS protein family in malignant hematopoiesis. Insulin receptor substrate-4 (IRS4) is absent in normal hematopoietic tissues but may be expressed under abnormal conditions. Moreover, insulin receptor substrate-5 (DOK4) and insulin receptor substrate-6 (DOK5) are linked to lymphocyte regulation. An improved understanding of the signaling pathways mediated by IRS proteins in hematopoiesis-related processes, along with the increased development of agonists and antagonists of these signaling axes, may generate new therapeutic approaches for hematological diseases. The scope of this review is to recapitulate and review the evidence for the functions of IRS proteins in normal and malignant hematopoiesis.

Alterações bucais em pacientes submetidos ao transplante de células tronco hematopoiéticas: estudo longitudinal / Oral complications in patients undergoing hematopoietic stem cell transplantation: a longitudinal study

A boca é local de frequentes complicações relacionadas ao transplante de células tronco hematopoiéticas (TCTH) tais como xerostomia, disgeusia, disfagia, mucosite, infecções oportunistas e doença do enxerto contra hospedeiro (DECH). Sabe-se que estas complicações podem comprometer a qualidade de vida do paciente e interferir na morbidade pós-TCTH. O dentista é o profissional da saúde que deverá intervir no momento correto para tratar e minimizar esses efeitos secundários do TCTH. Para tanto é importante conhecermos o momento em que cada complicação ocorre para que a intervenção seja pronta e eficiente. O objetivo principal deste estudo foi identificar e quantificar as alterações bucais em indivíduos submetidos ao TCTH em cinco momentos consecutivos desde antes do início do condicionamento pré-TCTH até o dia 100 pós-TCTH. Como objetivos secundários buscamos investigar possíveis relações entre a severidade da mucosite oral e a manifestação da DECH com dados demograficos (sexo, idade), com o status de saude bucal (por meio dos índices IHO-S, CPOD, número de dentes cariados) e com a realização de adequação bucal pré-TCTH, e ainda, somente para a DECH, também foi investigada a possível relação entre esta doença com infecção sistêmica por citomegalovírus e com a manifestação de mucosite oral severa. Foram incluídos no estudo 27 indivíduos com doenças hematológicas do Serviço de Transplante de Medula Óssea do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), com idade 12 anos que receberam TCTH alogênico.

Os indivíduos foram examinados em cinco momentos consecutivos. No primeiro momento, pré-TCTH, foi realizada a coleta de índices de saúde bucal e aplicação de questionário sobre o histórico de tratamentos odontológico prévios. Nos momentos de 10, 20, 60 e 100 dias pós-TCTH foram avaliadas as manifestações bucais presentes. A incidência de mucosite oral foi de 82,6% considerando todos os momentos avaliados. Mucosite oral severa, ou seja, graus 3 e 4 (OMS) foi observada em 57,9% dos pacientes avaliados nos momentos 2 e 3. Dez (37%) pacientes apresentaram GVHD em algum órgão, e destes, 8 (80%) apresentaram GVHD de boca. Infecção sistêmica por CMV foi diagnosticada em 6 (22,2%) pacientes. Concluímos que entre as queixas levantadas, dor bucal e disfagia foram as mais referidas. O período de maior incidência das complicações bucais foi nos segundo e terceiro momentos, ou seja, D+10 e D+20, representando deste forma, o período de maior morbidade do tratamento. Não houve associação entre a severidade de mucosite oral e idade, sexo, fonte de células, regime de condicionamento, número de dentes cariados, IHO-S, CPOD e preparo bucal pré-TCTH. Para a DECH a única relação encontrada foi para fonte de células, tendo sido observada menor chance de ocorrer DECH quando a fonte de células foi o sangue periférico.

The mouth is a well-known site of complications of the hematopoietic stem cell transplantation (HSCT) such as dry mouth, dysgeusia, dysphagia, mucositis, opportunistic infections and graft versus host disease (GVDH). It is known that these complications can compromise the patients quality of life and morbidity post-HSCT. The dentist is the health professional who should interfere at the right time to treat and minimize these side effects of HSCT. Thus, it is important to know the time at which each complication occurs to be dynamic and efficient. The main objective of this study was to identify and quantify the oral complications in patients treated with HSCT in five consecutive moments starting before conditioning chemotherapy until day 100 post-HSTC. As secondary objectives we seek to investigate possible relationships between the severity of oral mucositis and the manifestation of GVHD with demographic data (gender, age), with the oral health status (IHO-S, CPOD, number of decayed teeth) and dental treatment previously HSCT, and, only for GVHD, was also investigated the possible relationship between this disease with systemic cytomegalovirus infection and the manifestation of severe oral mucositis. It was included in the study 27 patients with hematologic diseases who were admitted in the Unit of Bone Marrow Transplantation, Hospital of Clinics, Faculty of Medicine, University of Sao Paulo (HC-FMUSP), 12 years old whom received allogeneic HSCT

The subjects were examined in five consecutive moments. At the first moment, before HSCT, the oral health índex evaluation and a questionnaire about history of previous dental treatments were performed. Besides that, 10, 20, 60 and 100 days after HSCT they were evaluated for oral manifestations. Oral mucositis incidence was 82,6% and 57,9% of these patients presented severe mucositis. Ten (37%) patients had GVHD in any organ, and of these, 8 (80%) had oral GVHD. Infection by CMV was diagnosed in 6 (22.2%) patients. We conclude that among the complaints raised, mouth pain and dysphagia were the most mentioned. The period of increased incidence of oral complications was the second and third times (D +10 and +20), representing the increased morbidity period. There was no association between the severity of oral mucositis and age, sex, cell source, conditioning regimen, number of decayed teeth, IHO-S, CPOD and dental treatment pre-HSCT. For GVHD the only relation found was with source of cells, in which, GVHD was less likely to occur when the source of cells was peripheral blood.

El ciclo celular y su papel en la biología de las células progenitoras hematopoyéticas / The cell cycle and its role in the biology of haematopoietic progenitor cells

El ciclo celular constituye el conjunto de eventos que determinan la actividad metabólica de toda célula así como su división y la generación de células hijas. Este proceso está involucrado en todos los procesos celulares tales como proliferación y diferenciación. Se ha demostrado que diversos elementos moleculares participan en su regulación y que alteraciones en este proceso pueden conducir a trastornos fisiológicos e incluso a la muerte del organismo. En los mamíferos, uno de los tejidos con mayor recambio celular es el hematopoyético, por lo que se requiere un control muy estricto del ciclo celular, principalmente a nivel de células troncales y progenitoras para la óptima producción de células sanguíneas. En este artículo presentamos un panorama general de los principales mecanismos y factores involucrados en la regulación del ciclo celular, poniendo particular énfasis en su papel en la biología de las células hematopoyéticas primitivas.

The cell cycle comprises a group of biological events that determine the metabolic activity of any cell, as well as its division and the generation of new daughter cells. It is involved in every cellular process, such asproliferation and differentiation. It has been shown that several molecular elements regulate the cell cycle, and that alterations in any of its phases and/or regulators could give rise to physiologic deficiencies, and even death. In mammals, the haematopoietic tissue is one of the most active in terms of cell replacement; thus, a tight cell cycle control, particularly at the level of stem and progenitors cells is crucial for optimal blood cell production. In the present article, we give a comprehensive overview of the major mechanisms and regulatory, molecules that participate in the cell cycle of mammalian cells, with particular emphasis on its role in the biology of primitive cells of the hematopoietic system.

Regulation of stem cell fate in hematopoietic development.

Stem cells are broadly classified into two categories; embryonic stem cell and somatic stem cell. Both types of stem cells can be differentiated into many cell types of the body with a different capability. Blood cells are examples of the cells that can be derived from both embryonic and somatic stem cells, both in vivo and in vitro. In adults, blood cells are mainly derived from hematopoietic stem cells (HSC) in the bone marrow. HSC growth and differentiation is tightly regulated which require both intrinsic and extrinsic signals. In this regard, transcription factors are critical for the development of HSC and specific cell lineages, in part, by regulating the expression of hematopoietic growth factor (HGF) receptors, other transcription factors and lineage specific genes transcription. This review will focus on the role of Id transcription factors in stem cell fate regulation.

Niveles de citoquinas megacariocitopoyéticas en pacientes con trombocitemia esencial y su relación con características clínicas y bioquímicas / Megakaryopoietic cytokine levels in patients with essential thrombocythemia and their relationship with clinical and biochemical features

La megacariocitopoyesis y la producción de plaquetas están regidas por factores de transcripción y citoquinas presentes en el microambiente medular. La trombocitemia esencial (TE) es una enfermedad mieloproliferativa crónica caracterizada por aumento del recuento de plaquetas e hiperplasia megacariocítica. En el presente trabajo se evaluaron los niveles de las citoquinas que participan en el desarrollo megacariocítico en plasma de pacientes con TE que se encontraban sin tratamiento y los de trombopoyetina (TPO) antes y durante el tratamiento con anagrelide. Las determinaciones se realizaron por técnica de ELISA. Dentro de las citoquinas involucradas en la etapa de proliferación, los niveles de interleuquina 3 (IL-3) se encontraron aumentados en los pacientes (p=0.0383) respecto al grupo control. Los niveles de factor estimulante de colonias granulocito-macrofágico y stem cell factor fueron normales. Dentro de las citoquinas con acción sobre la maduración megacariocítica, tanto la interleuquina 6 como la interleuquina 11 y la eritropoyetina estuvieron normales. Los niveles de TPO antes del tratamiento no difirieron del grupo control y durante el tratamiento aumentaron de manera no significativa. Los pacientes que presentaron agregación espontánea tuvieron niveles más altos de TPO que los que no lo hicieron (p=0.049). Los niveles de las citoquinas no tuvieron relación con ninguno de los parámetros clínicos ni de laboratorio evaluados. El aumento de los niveles de IL-3 podría contribuir al incremento en la proliferación megacariocítica en este grupo. La presencia simultánea de niveles más altos de TPO y trombocitosis sería un factor predisponente para la ocurrencia de agregación espontánea en los pacientes con TE

Megakaryopoiesis and platelet production are driven by transcription factors and cytokines present in bone marrow environment. Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by high platelet count and megakaryocytic hyperplasia. In the present work we evaluated plasmatic levels of cytokines involved in megakaryocytic development in a group of patients with ET that were not on treatment, as well as thrombopoietin (TPO) levels before and during anagrelide treatment. The assays were carried out using ELISA techniques. Among the cytokines mainly involved in proliferation of megakaryocytic progenitors, interleukin 3 (IL-3) levels were found increased in patients compared to normal controls (p=0.0383). Granulocyte-macrophage colony stimulating factor and stem cell factor levels were normal. Interleukin 6, as well as interleukin 11 and erythropoietin (EPO), cytokines mainly related to megakaryocytic maturation, were normal. Plasma TPO levels before treatment were within the normal range and increased during treatment but the difference was not statistically significant. Patients who displayed spontaneous platelet aggregation had higher plasma TPO levels compared to those who did not (p=0.049). We did not find any relationship between cytokine levels and clinical or laboratory parameters. The high IL-3 levels seen in some patients with ET could contribute to megakaryocytic proliferation. The simultaneous occurrence of higher TPO levels and elevated platelet count could be a predisposing factor for the development of spontaneous platelet aggregation in ET patients

Autologous peripheral blood stem cell transplantation: predictors for haematopoietic reconstitution.

Autologous peripheral blood stem cell transplantation is currently used in the treatment of various haematological and non-haematological cancers. Until recently, colony forming unit-granulocyte-macrophage (CFU-GM) assay and mononuclear cell (MNC) count were the indices commonly used to determine the quality of stem cell grafts and the haematopoietic reconstitutive capacity of transplanted stem cells. However, the discovery of CD34 as a stem cell marker has revolutionized the assessment of progenitor cells present in the peripheral blood stem cell graft. Many studies have included enumeration of CD34+ cells, MNCs and CFU-GM assay in stem cell grafts, and their correlation with engraftment has also been studied. However, there is no consensus regarding the optimum dose of each parameter that ensures haematopoietic recovery in all patients. We discuss the stem cell biology and review the literature on stem cell characteristics influencing successful haemopoietic reconstitution.

Haemopoietic organs and effect of their ablation on total haemocyte count in lemon-butterfly, Papilio demoleus L.

The haemopoietic organs in Vth instar larvae of P. demoleus are in the form of thin transparent cellular sheets, closely wrapped around the base of each wing-pad. Three cell types viz; prohaemocytes, plasmatocytes and oenocytoids appear to be derived from these organs and their ablation caused a reduction in cell number which, in turn, revealed that the haemocytes in general are derived both from the haemopoietic organs as well as from the circulating blood cells.

Biomedical significance of endothelial cell specific growth factor, angiopoietin

Until recently, vascular endothelial growth factor (VEGF) was the only growth factor proven to be specific and critical for blood vessel formation. Other long-known factors, such as the fibroblast growth factors (FGFs), platelet-derived growth factor, or transforming growth factor-beta, had profound effects in endothelial cells. But such factors were nonspecific, in that they could act on many other cells, and it seemed unlikely that these growth factors would be effective targets for treatment of endothelial cell diseases. A recently discovered endothelial cell specific growth factor, angiopoietin, has greatly contributed to our understanding of the development, physiology, and pathology of endothelial cells (Davis et al., 1996; Yancopoulos et al., 2000). The recent studies that identified and characterized the physiological and pathological roles of angiopoietin have allowed us to widen and deepen our knowledge about blood vessel formation and vascular endothelial function. Therefore, in this review, we describe the biomedical significance of these endothelial cell growth factors, the angiopoietins, in the vascular system under normal and pathological states.

Biología de las células totipotenciales hematopoyéticas / Biology of hemopoietic stem cells

Todas las células que comprenden el sistema hematopoyético son derivadas de un precursor común, la célula totipotencial hematopoyética (CTH), la cual por procesos de proliferación y diferenciación da lugar a las células maduras que se localiza en la sangre y órganos linfohematopoyéticos. Para que se lleven a cabo los procesos de proliferación, supervivencia, apoptosis,inhibición y diferenciación desde las CTH hasta las células maduras funcionales, se requiere de la participación de proteínas denominadas colectivamente citocinas, las cuales promueven y regulan una o varias funciones celulares, e intervienen en una o varías etapas de diferenciación de las CTH. Por el empleo de diferentes técnicas de cultivo, se concluyó que el estroma de la médula ósea: fibroblastos, células endoteliales y adipocitos, tiene un papel importante. La participación de esta células radica en la producción de citocinas, así como en proveer de un soporte sobre el cual se asientan las CTH. Aunque podría parecer que las citocinas son los factores fundamentales para regular los procesos mencionados de las células hematopoyéticas, se han propuesto dos hipótesis principales para explicar cómo se lleva a cabo la hematopoyesis: el modelo determinístico y el modelo estocástico. Ambos modelos aportan pruebas para apoyar sus postulados; sin embargo, a la fecha decidir cuál modelo es el acertado es todavía materia de controversia. Aunque el estudio de las CTH plantea muchas preguntas de orden básico, en muchos laboratorios en el mundo se han comenzado a indagar sobre la aplicación de las CTH en terapia humana: su uso en transplantes, sustituyendo el trasplante de médula ósea completa y, aún en etapas experimentales, el empleado de las CTH para insertar genes que pudieran ser de importancia terapéutica en enfermedades deficitarias o incluso en el tratamiento contra el cáncer

Role of bone marrow and thymus secretory protein in maintaining immune homeostasis and haemopoiesis in control and malnourished mice.

Injection of Salmonella typhi 'H' antigen was observed to produce a differential effect on bone marrow and thymus secretory profile depending upon the nutritional status of the host. The paracrine effect of Thy F1 (thymus fraction 1) was more significant (P < 0.01) than the autocrine effect of BIM (Bone marrow immunomodulator) in malnourished mice. BIM moreover, also had a paracrine effect on thymus irrespective of the nutritional status of the host. An improvement in neutrophil population (P < 0.01) and phagocytic myeloperoxidase activity (P < 0.01) was observed in BIM treated malnourished immuno-suppressed mice, whereas no appreciable change was observed by Thy F1. However, Thy F1 irrespective of the nutritional status of the host improved large lymphocyte population in circulation (P < 0.01). These findings indicate that both bone marrow and thymus play a major role in haemopoietic microenvironment of BDF (basal diet fed) control and malnourished mice.

Detecçäo precoce de recaída em transplante de medula óssea: revisäo da metodologia atual e uso da técnica de hibridizaçäo in situ (FISH) / Early detection of relapse in bone marrow transplantation. A review of the current diagnostic methodology and the use of in situ hybridization

O método tradicionalmente utilizado para detecçäo de quimerismo e de recaída precoce após transplante de medula óssea é a citogenética com bandeamento. Esta técnica tem como desvantagens o tempo de análise, que pode ser inaceitavelmente prolongado, e a dificuldade de quantificaçäo. A técnica de FISH (hibridizaçäo in situ fluorescente) pode se tornar uma excelente alternativa à citogenética convencional, já que pode ser executada em células em interfase, abreviando o tempo de análise e por fornecer resultados quantificados, permitindo a determinaçäo mais clara de quimerismo. Cento e vinte indivíduos do sexo feminino e 120 do masculino foram analisados inicialmente para a determinaçäo de sensibilidade e especficidade da técnica de FISH para cromossomos X e Y. Quando utilizadas combinadamente, ambas as sondas fornecem níveis de sensibilidade e especificidade maiores que 99 por cento. Quatro pacientes, submentidos a transplante de medula óssea com doadores de sexo diferentes, foram analisados para a observaçäo de recaída precoce. Em dois casos praticamente toda a hematopoese voltou a ser do receptor, indicando recaída da doença antes que análise citogenética pudesse ser utilizada. Em um dos casos encontrou-se um estado de quimera mista sugerindo fortemente a possibilidade de recaída, o que se cofirmou algumas semanas após. O último caso apresentava hematopoese oriunda do doador, indicando que a doença de base näo havia retornado. Concluímos que a técnica de FISH é superior à de citogenética para a detecçäo precoce de recaída pós-transplante em casos onde doador e receptor säo se sexos diferentes

Temporary appearance of a circulating granulocyte-macrophage colony-stimulating factor in lethal murine malaria.

Infection of mice with Plasmodium berghei engendered a temporary appearance of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum. The peak of GM-CSF levels was detected at day 2 post-infection, and then gradually decreased. On the other hand, the number of committed stem cells for granulocytes and macrophages (CFU-GM) in bone marrow transiently decreased at day 2 post-infection, and then increased and peaked at day 6 post-infection. When the serum of P. berghei-infected mice was fractionated by gel chromatography on Sephacryl S-300, GM-CSF activity was detected as a single peak with an apparent molecular weight of 64 KDa. GM-CSF was entirely adsorbed to concanavalin A-Sepharose 4B affinity chromatography, and was sensitive to pronase digestion, indicating its glycoprotein nature. These results suggest that the circulating GM-CSF would contribute the increase of granulocyte-macrophage hemopoiesis in the early phase of malaria.

The role of collagen in hematopoiesis

Several types of collagen, including types I, III, IV, V and VI, are produced by bone marrow stromal cells. Current information indicates that changes in collagen production result in profound alterations in the capacity of hematopoietic precursors to proliferate and differentiate. Although not definitively established, collagen molecules may be involved in the establishment and conformation of the stroma-associated extracellular matrix and/or in adhesive interactions with progenitor cells. The dynamic role of collagen in hematopoiesis is indicated by the observation that collagen production and processing are regulated by several factors such as glucocorticoids, cytokines, collagenases and collagenase-inhibitory proteins.

Hematopoese, fatores de crescimento e aplicacao clinica da eritropoetina na anemia da prematuridade

Os autores apresentam inicialmente uma revisao sobre a hematopose enfocando a fisiologia, a circulacao das stem cells e sua relacao com os diversos fatores de crescimento celular nos diversos periodos de formacao das celulas do sangue durante a gestacao. A producao de hemoglobina na sequencia do desenvolvimento da hematopoese, a regulacao e as caracteristicas da eritropoetina sao a seguir descritas. Finalizamos a revisao com a fisiologia das anemias no periodo neonatal do recem-nascido de termo e em prematuros alem de uma breve abordagem terapeutica.