Analysis of Iron Metabolism in Chronic Chagasic Cardiomyopathy / Análise do Metabolismo do Ferro na Cardiomiopatia Chagásica Crônica

Abstract Changes in iron metabolism in heart failure (HF) have been described as an important prognostic marker. To check if the markers of iron kinetics are related to the morbidity and etiology of chagasic cardiomyopathy. Patients with Chronic Chagasic Cardiomyopathy (CCC, n = 40), with indeterminate form (IND, n = 40), besides non-chagasic cardiomyopathy (NCh, n = 40). The mean age was 50.98 ± 5.88 in CCC, 50% were male, 49.68 ± 5.28 in IND, 52.2% were male, and 49.20 ± 10.09 in NCh, 12.5% were male. Lower levels of iron (FeSe) were observed in the CCC groups (93.15 ± 36.53), when compared to IND (125.30 ± 22.79) and NCh (114.77 ± 18.90) (p = 0.0004), lower IST transferrin saturation index in CCC (29.48 ± 6.59), when compared to IND (30.95 ± 7.06) and in the NCh group (39.70 ± 7.54) p = 0.0001), total binding capacity of the lower CTLF iron in the CCC group (297.30 ± 36.46), when compared to the IND group (196.52 ± 56.95) and the NCh group (275.18 ± 33, 48) (p = 0.0001), lower ferritin in the CCC group (134.55, 1.56-42.36), when compared to the IND group (156,25, 1,72-42,20) and the NCh group (112.95, 2.88-42.66) (p = 0.0004). It was also observed that FeSe (95% CI 1.00-1.04, p = 0.0014), IST (95% CI 1.02-1.22) (p = 0.0012) and gender (95% CI 1.07-14.43 p = 0.0038) were independently associated with the degree of ventricular dysfunction in chagasic cardiomyopathy. CCC patients showed greater change in iron metabolism regarding the indeterminate form and other forms of cariomyopathies.

Resumo A alteração do metabolismo do ferro na insuficiência cardíaca (IC) tem sido descrita como um importante marcador prognóstico. Verificar se os marcadores da cinética do ferro guardam relação com a morbidade e a etiologia da cardiomiopatia chagásica. Pacientes com cardiomiopatia chagásica crônica (CCC, n = 40), com a forma indeterminada (IND, n = 40), além de cardiomiopatia não chagásica (NCh, n = 40). A idade média foi de 50,98 ± 5,88 no CCC, 50% eram do sexo masculino, 49,68 ± 5,28 no IND, 52,2% eram do sexo masculino e 49,20 ±10,09 no NCh, 12,5% eram do sexo masculino. Observaram-se níveis de ferro (FeSe) menores no grupos CCC (93,15 ± 36,53), quando comparados ao IND (125,30 ± 22,79) e NCh (114,77 ± 18,90) (p = 0,0004), índice de saturação de transferrina (IST) menor no CCC (29,48 ± 6,59), quando comparado ao IND (30,95 ± 7,06) e no grupo NCh (39,70 ± 7,54) (p= 0,0001), capacidade total de ligação do ferro CTLF menor no grupo CCC (297,30 ± 36,46), quando comparado ao grupo IND (196,52 ± 56,95) e ao grupo NCh (275,18 ± 33,48) (p = 0,0001), ferritina menor no grupo CCC (134,55, 1,56-42,36), quando comparada ao grupo IND (156,25, 1,72 - 42,20) e ao grupo NCh (112,95, 2,88-42,66) (p = 0.0004). Verificou-se também que o FeSe (IC% 95% 1,00-1,04; p = 0,0014), o IST (IC 95% 1,02-1,22) (p = 0,0012) e o sexo (IC 95% 1,07-14,43 p = 0,0038) associaram-se independentemente ao grau de disfunção ventricular na cardiomiopatia chagásica. Os pacientes com CCC demonstraram maior alteração no metabolismo do ferro em relação a forma indeterminada e outras formas de miocardiopatias.

Sox2 function as a negative regulator to control HAMP expression

BACKGROUND: Hepcidin, encoding by HAMP gene, is the pivotal regulator of iron metabolism, controlling the systemic absorption and transportation of irons from intracellular stores. Abnormal levels of HAMP expression alter plasma iron parameters and lead to iron metabolism disorders. Therefore,itis animportant goal to understand the mechanisms controlling HAMP gene expression. RESULTS: Overexpression of Sox2 decrease basal expression of HAMP or induced by IL-6 or BMP-2, whereas, knockdown of Sox2 can increase HAMP expression, furthermore, two potential Sox2-binding sites were identified within the human HAMP promoter. Indeed, luciferase experiments demonstrated that deletion of any Sox2-binding site impaired the negative regulation of Sox2 on HAMP promoter transcriptional activity in basal conditions. ChIP experiments showed that Sox2 could directly bind to these sites. Finally, we verified the role of Sox2 to negatively regulate HAMP expression in human primary hepatocytes. CONCLUSION: We found that Sox2 as a novel factor to bind with HAMP promoter to negatively regulate HAMP expression, which may be further implicated as a therapeutic option for the amelioration of HAMP-overexpression-related diseases, including iron deficiency anemia.

Anemia en el paciente crítico y el rol de la hepcidina: entendiendo los nuevos conceptos sobre la interacción entre lesión, inflamación y anemia / Anemia in critically ill patient: role of hepcidin

La anemia es un trastorno multifactorial común en el paciente crítico, en que influyen hemodilución, aumento de pérdidas sanguíneas, inflamación y déficit de hierro, a través de una homeostasis patológica de hierro, con producción alterada de eritropoyetina y alteración de la eritropoyesis. Durante la inflamación los elevados niveles de hepcidina se correlacionan con la disminución del hierro disponible para la eritropoyesis quedando almacenado en depósitos principalmente en los macrófagos tisulares. Por el contrario cuando los niveles de hepcidina son bajos, el hierro se vuelve disponible para la eritropoyesis. La hepcidina sería un factor clave tanto en la homeostasis del hierro como en la eritropoyesis, sin embargo, nuestro conocimiento de su comportamiento en el trauma, la sepsis y otras condiciones críticas, es todavía limitado. Recientes estudios han venido a ampliar nuestra comprensión del rol de la hepcidina durante la sepsis o el síndrome de respuesta inflamatoria sistémica (SIRS). Los ensayos de hepcidina en plasma u orina aún no están ampliamente disponibles y es deseable que haya muy pronto un desarrollo permanente y una validación clínica de estos ensayos. Adicionalmente, la introducción de agonistas y antagonistas farmacológicos de la hepcidina pudieran mejorar las terapias corrientes de los desórdenes del hierro. Resumimos en este artículo información actual sobre la anemia en el paciente crítico y discutimos los avances recientes.

Anemia is a common multifactorial disorder in critically ill patients, which hemodilution influence, increased blood loss, swelling and deficit iron through a pathological iron homeostasis, with production erythropoietin altered and impaired erythropoiesis. During the inflammation high hepcidin levels correlate with decrease the iron available for erythropoiesis being stored in deposits primarily in tissue macrophages. On the contrary when hepcidin levels are low iron becomes available for erythropoiesis. Hepcidin would be a key factor in both the homeostasis as iron in erythropoiesis, however, our knowledge of behavior intrauma, sepsis and other critical conditions, is still limited. Recent studies have expanded our understanding the role of hepcidin during sepsis or response syndrome systemic inflammation (SIRS). Trials of hepcidin in plasma or urine even are not widely available and it is desirable to development and clinical validation of these tests has been published assoon is possible. Additionally, the introduction of pharmacological agonists and antagonists hepcidin could improve current therapies for disorders iron. This article summarized current information on anemia in critically ill patient and discuss recent developments.

Effects of the partial gastrectomy associated to anterior truncal vagotomy in the metabolism of the iron in rats / Efeitos da gastrectomia parcial e vagotomia troncular anterior no metabolismo de ferro de ratos

PURPOSE: To evaluate the effects of the partial gastrectomy associated to anterior truncal vagotomy in the absorption and metabolism of iron. METHODS: Eighteen adults male Wistar rats were submitted to the partial gastrectomy associated to anterior truncal vagotomy (eight animals) and the sham operation (10 animals, control group). The diet consumption and the weight gains of the animals were monitored three times during the week. The animals received supplements of vitamin B12, for the prevention of the megaloblastic anemia, and a formulated experimental diet orally and denominated AIN-93M by 8 weeks. The fecal iron, apparent absorption of the iron, haematocrit, haemoglobin and serum iron were measured after 60 days. RESULTS: The animals undergoing sham operation presented larger statistical averages (p<0.05) for the diet consumption, weight gains, apparent absorption of iron, haematocrit, haemoglobin and serum iron compared to the gastrectomized group. However, the excretion of iron in feces was larger in the gastrectomized group (+14.3 percent) (p<0.05) when compared to the control group. CONCLUSION: Partial gastrectomy associated to anterior truncal vagotomy showed to be a good experimental model the study of iron metabolism, decreasing the haematocrit, the haemoglobin and the iron absorption, consequently causing anemia.

OBJETIVO: Avaliar os efeitos da gastrectomia parcial associada a vagotomia troncular anterior na absorção e metabolismo do ferro. MÉTODOS: Dezoito ratos Wistar machos e adultos foram submetidos a gastrectomia parcial e vagotomia troncular anterior (oito animais) e à laparotomia simples como grupo controle (10 animais). O consumo de dieta e o peso dos animais foram monitorados três vezes por semana. Os animais receberam suplementos de vitamina B12 para prevenção de anemia megaloblástica, além de dieta oral formulada experimentalmente e denominada AIN-93M, durante 8 semanas. O ferro fecal, a absorção aparente de ferro, o hematócrito a hemoglobina e o ferro sérico foram mensurados, após 60 dias de observação. RESULTADOS: Os animais controles apresentaram médias estatísticas maiores (p <0.05) para o consumo de dieta, ganho de peso, absorção aparente de ferro, hematócrito, hemoglobina e ferro sérico comparados aos animais gastrectomizados. Entretanto, a excreção de ferro nas fezes foi superior no grupo de animais gastrectomizados (+14.3 por cento) (p<0.05) quando comparado com o grupo controle. CONCLUSÃO: A gastrectomia parcial associada a vagotomia troncular anterior mostrou ser um bom modelo experimental para o estudo do metabolismo do ferro, ocasionando diminuição do hematócrito, da hemoglobina e absorção de ferro, e conseqüentemente causando anemia.

Doses intermitentes de estatina em pacientes em hemodiálise com LDL-colesterol espontaneamente baixo / Intermittent doses of statin in hemodialysis patients with spontaneous low LDL cholesterol levels

FUNDAMENTO: A mortalidade na diálise continua elevada e ocorre principalmente por causas cardiovasculares. A inflamação participa da gênese da aterosclerose acelerada, calcificação vascular, desnutrição e anemia, e tem enorme impacto na sobrevida destes pacientes. As estatinas, através dos seus efeitos pleiotrópicos, podem representar uma opção terapêutica para atenuação do processo inflamatório crônico dos pacientes em hemodiálise. OBJETIVO: Avaliar os efeitos de uma baixa dose de sinvastatina sobre marcadores inflamatórios, parâmetros hematimétricos e nutricionais de pacientes em hemodiálise. MÉTODOS: Pacientes em hemodiálise clinicamente estáveis foram divididos, segundo os níveis basais de LDL-colesterol, em um grupo com níveis abaixo (Grupo 1) e outro com níveis iguais ou superiores a 100 mg/dl (Grupo 2) e tratados com sinvastatina por oito semanas. O Grupo 1 recebeu apenas 20 mg após cada sessão de diálise (dose intermitente), enquanto o Grupo 2 recebeu 20 mg/dia. Dados laboratoriais, índice de resistência a eritropoetina e parâmetros nutricionais foram obtidos antes e após o tratamento. RESULTADOS: Houve redução significativa e equivalente dos níveis de proteína C-reativa em ambos os grupos (35,97±49,23 por cento vs 38,32±32,69 por cento, p=0,86). No Grupo 1 também houve tendência a queda da resistência a eritropoetina (228,6±16,2 vs 208,9±16,2, p=0,058) e melhora dos parâmetros hematimétricos (hematócrito: 33,1±5,9 por cento vs 36,1±4,5 por cento, p=0,021). CONCLUSÃO: A dose intermitente mostrou-se tão eficaz quanto a dose usual em reduzir os níveis de proteína C-reativa e resistência a eritropoetina, além de melhorar os parâmetros hematimétricos, apontando para uma importante redução do risco cardiovascular avaliado por esses parâmetros.

BACKGROUND: Mortality in dialysis patients remains high and is due mainly to cardiovascular causes. Inflammation has a role in the genesis of accelerated atherosclerosis, vascular calcification, malnutrition and anemia, and a huge impact on the survival of these patients. The pleiotropic effects of statins can be a therapeutic option for reducing chronic inflammatory processes of patients undergoing hemodialysis. OBJECTIVE: To evaluate the effects of low doses of simvastatin on inflammatory markers, hematimetric and nutritional parameters of patients undergoing hemodialysis. METHODS: Clinically-stable patients undergoing hemodialysis were classified according to their baseline LDL-cholesterol levels in two groups: those with levels below 100mg/dl (Group 1) and those with levels equal to or greater than 100mg/dl (Group-2), and were treated with simvastatin during eight weeks. Group 1 received 20mg only after each session of hemodialysis (intermittent dose), whereas Group 2 received 20mg/daily. Laboratory data, erythropoietin resistance index and nutritional parameters were obtained before and after treatment. RESULTS: A significant and equivalent reduction in C-reactive protein levels in both groups was observed (35.97±49.23 percent vs 38.32±32.69 percent, p=0.86). In group 1, there was also a tendency towards reduced resistance to erythropoietin (228.6±16.2 vs 208.9±16.2, p=0.058) and improvement of hematimetric parameters (hematocrit: 33.1±5.9 percent vs 36.1±4.5 percent, p=0.021). CONCLUSION: Intermittent doses proved to be as effective as the usual dose in reducing C-reactive protein levels and resistance to erythropoietin, besides improving the hematimetric parameters, indicating an important reduction of the cardiovascular risk evaluated by these parameters.

Erythropoietin does not affect nitric oxide system in rats with chronic renal failure

We investigated to see whether an altered role of nitric oxide (NO) system is involved in erythropoietin (EPO)-induced hypertension in chronic renal failure (CRF). Male Sprague-Dawley rats were five-sixths nephrectomized to induce CRF. Six weeks after the operation, EPO or vehicle was injected for another 6 weeks. Plasma and urine nitrite/nitrate (NOx) levels were determined. Expression of NO synthase (NOS) proteins in the aortae and kidneys were also determined. In addition, the isometric tension of isolated aorta in response to acetylcholine and nitroprusside was examined. Blood pressure progressively rose in CRF groups, the degree of which was augmented by EPO treatment. Plasma NOx levels did not differ among the groups, while urine NOx levels were lower in CRF groups. Endothelial NOS expression was lower in the kidney and aorta in CRF rats, which was not further affected by EPO-treatment. The inducible NOS expression in the kidney and aorta was not different among the groups. Acetylcholine and sodium nitroprusside caused dose-dependent relaxations of aortic rings, the degree of which was not altered by EPO-treatment. Taken together, EPO-treatment aggravates hypertension in CRF, but altered role of NO system may not be involved.

Actualización de los criterios del tratamiento de la deficiencia de hierro / Update on iron deficiency treatment criteria

La deficiencia de hierro constituye un problema de salud pública. Recientemente se han desarrollado nuevos protocolos para la profilaxis y tratamiento de esta carencia nutricional. Biología molecular del hierro orgánico. Se revisa la relación del hierro con importantes macromoléculas que captan, transportan y utilizan el hierro. Factores que determinan el estado nutricional relativo al hierro. El balance del hierro se ve influido por la pérdida crónica de sangre, los altos requerimentos de hierro en la lactancia, la adolescencia y el embarazo. Estrategias para la profilaxis y el tratamiento de la deficiencia de hierro. Se comenta la importancia de la determinación del receptor soluble de la transferrina; así como los programas para suplementar a los lactantes con leche fortificada con hierro o azúcar fortificada con la sal ferrosa de EDTA sódico, o bien tabletas de sulfato ferroso en protocolo de dosis bisemanal

Indicadores del metabolismo del hierro: efecto de la hemoterapia en su medición / Iron metabolisms indicators: effect of the hemotherapy in its measurement

En este estudio se incluyeron veintisiete pacientes con diagnóstico de anemia de múltiples causas, quienes recibieron transfusiones de concentrado globular para evaluar la influencia que ejerce la transfusión sanguínea sobre los niveles séricos de ferritina, capacidad total de fijación del hierro, hierro sérico; los cuales fueron determinados entes y 2-14 días posterior a la transfusión sanguínea. No se lograron determinar cambios significativos en estos niveles en las muestras después de la transfusión a los 2 y 14 días. Sin embargo la transfusión sanguínea ejerció efectos sobre los niveles de hierro sérico cuando éste se encontró por debajo de 35 mcg/dl en el valor pretransfusional

Oxygen transfer in fish: morphological and molecular adjustments

A wide range of organismic, physiological and biochemical adjustments to improve oxygen transfer is observed in fish exposed to environmental hypoxia and during anemia. Many fish species of the Amazon obtain oxygen directly from air when water oxygen is low. The accessory air-breathing organs include modifications of the gills, mouth, stomach and intestine, and swimbladder vascularization. Other species extend the lower lip and skim to improve oxygen uptake from the oxygen-rich surface layer of the water. The amount of oxygen uptake from air wp estimated for Hoplosternum littorale and Lipossarcus pardalis. In addition, the oxygen uptake from the water surface was estimated for Colossoma macropomum. Blood oxygen content was reduced by 30 per cent in Hoplostemum littorale and Colossoma macropomum and 70 per cent in Lipossarcus pardalis if they were denied access to air. Adjustments of intraerythrocytic levels of ATP and GTP significantly improve oxygen transfer in fish during environmental hypoxia and anemia. In contrast to environmental hypoxia, intraerythrocytic levels of ATP and GTP increase during anemia in fish facilitating oxygen unloading to the tissues. It is suggested that the increase in ATP and GTP levels during anemia occurs because the conditions required to increase the activity of adenylate and guanylate phosphate synthetic pathways are similar.

Enfoque hemodinámico y metabólismo en el sangrado genital grave / Hemodynamic and metabolic views in the serious genital bleeding

La hemorragia genital grave en la mujer, casi siempre se presenta durante el estado grávido puerperal, por lo que es importante recordar los cambios hemodinámicos y metabólicos que fisiológicamente se presentan durante la gestación: hipovolemia, hemodilución, taquicardia, modificaciones en los factores de la coagulación sanguínea y en el electrocardiograma. Se expone una clasificación del sangrado genital en 4 clases, de acuerdo a la magnitud de la pérdidad sanguínea, donde las clases III y IV corresponden al estado de choque hipovolémico y ameritan cuidados intensivos. Se enfatiza en la necesidad de contar con todos los recursos materiales necesarios para el manejo de estos casos y con la participación de un equipo humano multidisciplinario. Se recuerda la necesidad de preservar también la vida y la integridad del producto de la concepción en los casos en que sea viable y todavía se encuentre in utero

Effect of anaemia on respiratory and metabolic parameters during third trimester of pregnancy.

Pregnancy involves a considerable increase of metabolically active tissue. Anaemia a common occurrence during pregnancy hampers the normal metabolism of body due to Anaemic hypoxia. In present study oxygen uptake, Co2 output, Respiratory Exchange Ratio (RE) Resting Metabolic Rate (RMR) and Peak Expiratory Flow Rate (PEFR) were compared in normal women in IIIrd trimester of pregnancy (Hb 12 gm% or above) with anaemic women. Oxygen uptake and Co2 output were measured by Noyon's Dioferometer and PEFR by Wright's Peak Expiratory Flow Meter. RE and RMR were calculated. O2 uptake, Co2 output, RE and RMR were significantly increased whereas PEFR was significantly decreased in anaemic than in normal subjects during third trimester of pregnancy.