Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vast majority of the 1-2 million malaria associated deaths that occur each year are due to anemia and cerebral malaria (the attachment of erythrocytes containing mature forms of Plasmodium falciparum to the endothelial cells that line the vascular beds of the brain). A "model system" for the study of cerebral malaria employs amelanotic melanoma cells as the "target" cells in an in vitro cytoadherence assay. Using this model system we determined that the optimum pH for adherence is 6.6 to 6.8, that high concentrations of Ca2+ (50mM) result in increased levels of binding, and that the type of buffer used influences adherence (Bis Tris > MOPS > HEPES > PIPES). We also observed that the ability of infected erythrocytes to cytoadhere varied from (erythrocyte) donor to donor. We have produced murine monoclonal antibodies against P. falciparum-infected red cells which recognize modified forms of human band 3; these inhibit the adherence of infected erythrocytes to melanoma cells in a dose-responsive fashion. Antimalarials (chloroquine, quinacrine, mefloquine, artemisinin), on the other hand, affected adherence in an indirect fashion i.e. since cytoadherence is due, in part, to the presence of knobs on the surface of the infected erythrocyte, and knob formation is dependent on intracellular parasite growth, when plasmodial development is inhibited so is knob production, and consequently adherence is ablated.
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PMID:Optimization and inhibition of the adherent ability of Plasmodium falciparum-infected erythrocytes. 134 7

Tissues are usually considered as being supply-dependent (e.g., heart and brain) and supply-independent (e.g., splanchnic area, kidneys, skin, and resting muscle) for oxygen delivery. When cardiovascular function is compromised, circulatory compensations are aimed at maintaining supply-dependent tissues. In the long term, this leads to the possibility of an inadequate blood flow to supply independent tissues. The perfusion maintenance of all organs requires adequate cardiac output, blood volume, and arterial BP. When BP and cardiac output fail, regional perfusion diminishes. Although the human system tolerates anemia well, optimum Hct levels are probably between 30% to 40%. Inadequate perfusion can be supplemented partially by increasing the FIO2 on a temporary basis. Hyperoxic arterial oxygen tensions may cause maldistribution of blood flow within organs.
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PMID:Blood flow to organs: parameters for function and survival in critical illness. 327 75

A randomized, double-blind, placebo-controlled, multicenter trial was performed to assess the safety and efficacy of subcutaneous recombinant erythropoietin (EPO) in peritoneal dialysis patients. Seventy-eight patients were randomized to receive EPO and 74 received placebo during the first 12 wk. After this, placebo patients with hematocrit less than 32% entered the EPO maintenance phase along with the initial EPO patients. Hematocrit rose significantly in the EPO group from 23.8 to 32% after 6 wk, and this was sustained at 33.7% at 12 wk. In the placebo group, the prestudy hematocrit was 23.8% as well, and no significant change in hematocrit occurred over 12 wk. Concomitant with the rise in hematocrit, transfusion requirements fell only in the EPO group. Eighty-eight percent of patients receiving EPO had their anemia ameliorated by Week 12 of the study. There was a wide range of dosage requirements during the maintenance phase, ranging from 8,000 U thrice weekly to 4,000 U every other week. Adverse events after EPO were similar to those seen in hemodialysis patients given this agent, with hypertension developing or worsening in 55% of EPO patients during the initial 12 wk of therapy. Blood pressure was more likely to rise in patients with hypertension before receiving EPO. EPO is safe and effective in peritoneal dialysis patients, as it is in hemodialysis patients. Other than a rise in blood pressure, which is manageable with antihypertensives and ultrafiltration with dialysis, no serious side effects are seen. The optimal target hematocrit, effects of anemia improvement on quality of life, and end-organ (heart, brain) effects of anemia improvement in this patient population require further study.
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PMID:Multicenter trial of erythropoietin in patients on peritoneal dialysis. 770 90

Copper deficiency was induced in Sprague Dawley rats by dietary restriction to confirm and extend studies on copper, zinc-superoxide dismutase (Cu,Zn-SOD). Male rats restricted from copper in two models, a traditional postweanling model examining 50-day-old rats fed a low copper diet for 32 days (postnatal) and a gestational-lactational model examining 23-day-old male offspring of dams started on copper deficiency at day 7 of gestation (perinatal), showed signs of severe copper deficiency including anemia, and cardiac hypertrophy. Compared to control rats, copper-deficient rats exhibited lower copper concentrations in the liver, heart, brain, and kidney and lower Cu,Zn-SOD activity in the same organs with the exception of the brain in the postnatal model. In addition, there was a significant reduction in Cu,Zn-SOD protein detected by Western immunoblot proportional (r = 0.96) to the reduction in Cu,Zn-SOD activity. In the liver the reduction in Cu,Zn-SOD protein was approximately 50%. The reduction in Cu,Zn-SOD protein is likely due to a post-transcriptional mechanism as steady-state Cu,Zn-SOD mRNA levels measured by Northern hybridization were not altered by copper deficiency in any organ studied (liver, heart, and brain). Perhaps apo-Cu,Zn-SOD is degraded faster than fully metal-loaded enzyme. The loss of Cu,Zn-SOD activity and protein reduces the antioxidant defense capacity of copper-deficient organs.
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PMID:Lower copper, zinc-superoxide dismutase protein but not mRNA in organs of copper-deficient rats. 1151 74

The present study analyses the cardiovascular response to acute hypocapnic hypoxia (simulating the effect of respiration at high altitude) both in healthy, unacclimatised subjects and in subjects with moderate anaemia, by means of a mathematical model of short-term cardiovascular regulation. During severe hypoxia, cardiac output and heart rate (HR) exhibit a significant increase compared with the basal level (cardiac output: +90%; HR: +64%). Systemic arterial pressure remains quite constant or shows a mild increase. Coronary blood flow increases dramatically (+200%), thus maintaining a constant oxygen delivery to the heart. However, blood oxygen utilisation in the heart augments, to fulfil the increased power of the cardiac pump during hypoxia. Cerebral blood flow rises only at very severe hypoxia but, owing to the vasoconstrictory effect of hypocapnia, its increase (+80%) is insufficient to maintain oxygen delivery to the brain. The model suggests that a critical level for the aerobic metabolism in these organs (heart and brain) is reached at an oxygen partial pressure in arterial blood (PaO2) of approximately 25 mmHg. Moderate anaemia during normoxia is compensated by an increase in cardiac output (+22%), a decrease in total peripheral resistance (-30%) and an increase in O2 extraction from blood (+40%). As cardiovascular regulation mechanisms are already recruited in anaemic subjects at rest, their action soon becomes exhausted during hypocapnic hypoxia. Critical levels for vital functions are already reached at a PaO2 of approximately 45 mmHg.
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PMID:Modelling study of the acute cardiovascular response to hypocapnic hypoxia in healthy and anaemic subjects. 1512 44

Recombinant human erythropoietin (rhEPO) is receiving increasing attention as a potential therapy for prevention of injury and restoration of function in nonhematopoietic tissues. However, the minimum effective dose required to mimic and augment these normal paracrine functions of erythropoietin (EPO) in some organs (e.g., the brain) is higher than for treatment of anemia. Notably, a dose-dependent risk of adverse effects has been associated with rhEPO administration, especially in high-risk groups, including polycythemia-hyperviscosity syndrome, hypertension, and vascular thrombosis. Of note, several clinical trials employing relatively high dosages of rhEPO in oncology patients were recently halted after an increase in mortality and morbidity, primarily because of thrombotic events. We recently identified a heteromeric EPO receptor complex that mediates tissue protection and is distinct from the homodimeric receptor responsible for the support of erythropoiesis. Moreover, we developed receptor-selective ligands that provide tools to assess which receptor isoform mediates which biological consequence of rhEPO therapy. Here, we demonstrate that rhEPO administration in the rat increases systemic blood pressure, reduces regional renal blood flow, and increases platelet counts and procoagulant activities. In contrast, carbamylated rhEPO, a heteromeric receptor-specific ligand that is fully tissue protective, increases renal blood flow, promotes sodium excretion, reduces injury-induced elevation in procoagulant activity, and does not effect platelet production. These preclinical findings suggest that nonerythropoietic tissue-protective ligands, which appear to elicit fewer adverse effects, may be especially useful in clinical settings for tissue protection.
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PMID:Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. 1658 2

Observational clinical studies in perioperative medicine have defined a progressive increase in mortality that is proportional to both chronic preoperative anaemia and acute interpretative reductions in haemoglobin concentration (Hb). However, this knowledge has not yet helped to define the critical Hb threshold for organ injury and mortality in specific patient populations or in individual patients. Nor has this knowledge enabled us to develop effective treatment strategies for anaemia, as evident from the lack of a demonstrable improvement in survival in patients randomised to higher Hb levels by various treatment strategies including allogeneic red blood cell transfusion, erythropoiesis-stimulating agents (ESAs) and haemoglobin-based oxygen carriers (HBOCs). These findings emphasise the need for a clearer understanding of the mechanism of anaemia-induced mortality. Towards achieving this goal, experimental studies have defined adaptive mechanism by which oxygen homeostasis is maintained during acute anaemia. The mechanisms include: (1) effective sensing of anaemia-induced tissue hypoxia; (2) adaptive cardiovascular responses to maintain adequate tissue oxygen delivery; (3) heterogeneity of organ-specific oxygen delivery to preferentially sustain vital organs which are essential for acute survival (heart and brain); (4) evidence of increased vital organ injury with interruption of cardiovascular responses to anaemia and (5) evidence of activation of adaptive cellular responses to maintain oxygen homeostasis and support survival during acute anaemia. Understanding these mechanisms may allow us to define treatment thresholds and novel treatment strategies for acute anaemia based on biological markers of tissue hypoxia. The overall goal of these approaches is to improve patient outcomes, including event-free perioperative survival.
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PMID:Anaemia: can we define haemoglobin thresholds for impaired oxygen homeostasis and suggest new strategies for treatment? 2359 Sep 18

The prevalence of iron deficiency is high -even in the absence of anaemia- in patients with chronic heart failure (HF). Although iron deficiency is easily diagnosed with two biomarkers (serum ferritin and transferrin saturation), it is underdiagnosed in patients with HF. Iron is not only necessary for red blood cells, but also for cells in tissues with high-energy demands (heart, muscle, brain). Even before the onset of anaemia, HF patients with iron deficiency have decreased physical and cognitive performances and a poorer quality of life. Moreover, iron deficiency is a risk factor, independent of anaemia, of unfavourable outcome (death or heart transplantation) in patients with chronic HF. Several randomized controlled studies have shown improvement in exercise capacity, New York Heart Association functional class and quality of life after correction of iron deficiency. The results of these clinical trials, which are supported by European guidelines, suggest considering iron deficiency in HF as a possible therapeutic target.
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PMID:Diagnosis and treatment of iron deficiency in patients with heart failure: expert position paper from French cardiologists. 2523 45

Iron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver also produces hepcidin, which may regulate fetal iron endowment by controlling placental iron export. To determine the relative contribution of maternal vs embryo hepcidin to the control of embryo iron endowment in iron-sufficient or iron-overloaded mice, we generated combinations of mothers and embryos that had or lacked hepcidin. We found that maternal, but not embryonic, hepcidin determined embryo and placental iron endowment in a healthy pregnancy. We further determined that inflammation can counteract pregnancy-dependent suppression of maternal hepcidin. To establish how essential maternal hepcidin suppression is for embryo iron homeostasis, we mimicked the range of maternal hepcidin activity by administering a hepcidin peptide mimetic to pregnant mice. This also allowed us to determine the effect of isolated maternal hepcidin excess on pregnancy, in the absence of other confounding effects of inflammation. Higher doses of hepcidin agonist caused maternal iron restriction and anemia, lower placenta and embryo weight, embryo anemia, and increased embryo mortality. Low agonist doses did not cause maternal anemia but still adversely affected the embryo, causing anemia, tissue iron deficiency (including in the brain), and decreased weight. Our studies demonstrate that suppression of maternal hepcidin during pregnancy is essential for maternal and embryo iron homeostasis and health.
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PMID:Maternal hepcidin determines embryo iron homeostasis in mice. 3258 57