losartan-potassium and Acute-Disease

Berger, Marc Moritz, Peter H. Hackett, and Peter Bärtsch. No relevant analogy between COVID-19 and acute mountain sickness.

Topics: Acute Disease; Altitude Sickness; Angiotensin-Converting Enzyme 2; COVID-19; COVID-19 Drug Treatment; Erythropoietin; Humans; Hypoxia; Inflammation; SARS-CoV-2; Symptom Assessment

Clinical case reports and prospective trials have demonstrated a reproducible benefit of hypothalamic-pituitary-adrenal (HPA) axis modulation on the rate of recovery from acute inflammatory central nervous system (CNS) demyelination. As a result, corticosteroid preparations and adrenocorticotrophic hormones are the current mainstays of therapy for the treatment of acute optic neuritis (AON) and acute demyelination in multiple sclerosis.Despite facilitating the pace of recovery, HPA axis modulation and corticosteroids have failed to demonstrate long-term benefit on functional recovery. After AON, patients frequently report visual problems, motion perception difficulties and abnormal depth perception despite 'normal' (20/20) vision. In light of this disparity, the efficacy of these and other therapies for acute demyelination require re-evaluation using modern, high-precision paraclinical tools capable of monitoring tissue injury.In no arena is this more amenable than AON, where a new array of tools in retinal imaging and electrophysiology has advanced our ability to measure the anatomic and functional consequences of optic nerve injury. As a result, AON provides a unique clinical model for evaluating the treatment response of the derivative elements of acute inflammatory CNS injury: demyelination, axonal injury and neuronal degeneration.In this article, we examine current thinking on the mechanisms of immune injury in AON, discuss novel technologies for the assessment of optic nerve structure and function, and assess current and future treatment modalities. The primary aim is to develop a framework for rigorously evaluating interventions in AON and to assess their ability to preserve tissue architecture, re-establish normal physiology and restore optimal neurological function.

Topics: Acute Disease; Adrenal Cortex Hormones; Erythropoietin; Humans; Immunoglobulins, Intravenous; Magnetic Resonance Imaging; Optic Neuritis; Plasma Exchange; Scanning Laser Polarimetry

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic diseases, with an increasing rate in morbidity and mortality. In recent years, there has been a greater awareness about the clinical importance of systemic effects and other chronic conditions associated with COPD, as these significantly impact on the course of disease. The most studied extrapulmonary manifestations in COPD include the presence of concomitant cardiovascular disease, skeletal muscle wasting, osteoporosis and lung cancer. Anaemia is a recognised independent marker of mortality in several chronic diseases. Recent studies have shown that anaemia in patients with COPD may be more frequent than expected, with a prevalence ranging from 5% to 33%. Some evidence suggests that systemic inflammation may play an important pathogenic role, but anaemia in COPD is probably multifactorial and may be caused by others factors, such as concealed chronic renal failure, decreased androgenic levels, iron depletion, angiotensin-converting enzyme inhibitor treatment and exacerbations. Low levels of haemoglobin and haematocrit in COPD patients have been associated with poor clinical and functional outcomes as well as with mortality and increased healthcare costs. Despite the potential clinical benefit of successfully treating anaemia in these patients, evidence supporting the importance of its correction on the prognosis of COPD is uncertain.

Topics: Acute Disease; Androgens; Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Exercise Tolerance; Glomerular Filtration Rate; Health Resources; Hemoglobins; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Renal Insufficiency, Chronic; Renin-Angiotensin System

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Diazepam; Erythropoietin; Fatal Outcome; Humans; Jaundice, Obstructive; Liver Function Tests; Male; Melphalan; Multiple Myeloma; Omeprazole; Pneumonia; Polypharmacy; Prednisolone; Thalidomide

Erythropoietin (EPO) is a hematopoietic hormone with extensive nonhematopoietic properties. The discovery of an EPO receptor outside the hematopoietic system has fuelled research into the beneficial effects of EPO for various conditions, predominantly in cardiovascular disease. Experimental evidence has revealed the cytoprotective properties of EPO, and it seems that the EPO-EPO receptor system provides a powerful backbone against acute myocardial ischemia, gaining from the different properties of EPO. There is an ongoing discussion about possible discrepancy between preclinical and clinical effects of EPO on the cardiovascular system. Large, randomized, placebo-controlled clinical trials are underway to give a final verdict on EPO treatment for acute coronary syndromes.

Topics: Acute Coronary Syndrome; Acute Disease; Anemia; Erythropoiesis; Erythropoietin; Humans; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Receptors, Erythropoietin; Syndrome

Topics: Acute Disease; Aged; Azacitidine; Chelation Therapy; Chromosome Deletion; Chromosomes, Human, Pair 5; Clinical Trials as Topic; Decitabine; Disease Progression; DNA Methylation; Erythropoietin; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Iron Chelating Agents; Lenalidomide; Leukemia, Myeloid; Myelodysplastic Syndromes; Severity of Illness Index; Thalidomide; Transplantation, Homologous

Because of the firm refusal of transfusion of blood and blood components by Jehovah's Witnesses, the management of Jehovah's Witness patients with severe bleeding is often complicated by medical, ethical, and legal concerns. Because of a rapidly growing and worldwide membership, physicians working in hospitals should be prepared to manage these patients. Appropriate management of a Jehovah's Witness patient with severe bleeding entails understanding of the legal and ethical issues involved, and meticulous medical management, including treatment of hypovolemic shock, local hemostatic interventions, and administration of prohemostatic agents, when appropriate. In addition, high-dose recombinant erythropoietin in combination with supplemental iron may enhance the speed of hemoglobin synthesis.

Topics: Acute Disease; Adult; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Transfusion; Contraindications; Emergencies; Erythropoietin; Hemorrhage; Hemostatic Techniques; Humans; Informed Consent; Jehovah's Witnesses; Phlebotomy; Recombinant Proteins; Shock; Treatment Refusal; Unconsciousness; Vitamin K

Recombinant human erythropoietin was produced soon after the discovery of the erythropoietin gene in 1985 and since then, it is used in various clinical conditions such as chronic renal failure. Moreover, experimental studies have shown that erythropoietin exerts neuroprotective action as well. Recently, a clinical trial yielded promising results concerning the use of erythropoietin in stroke management. In this review, we summarize the main data which suggest that recombinant human erythropoietin and its analogues may indeed have a role in stroke treatment.

Topics: Acute Disease; Animals; Brain; Brain Ischemia; Clinical Trials as Topic; Erythropoietin; Humans; Neuroprotective Agents; Recombinant Proteins; Stroke; Treatment Outcome

Despite the well-recognized effects of erythropoietin (EPO) on augmenting red blood cell production, EPO exerts multiple additional effects in diverse tissues. Evidence indicating the potential for tissue protection is reviewed as is a description of a study now initiated, in which its potential benefit on the evolution of acute myocardial infarction in patients is being explored.. The literature demonstrating tissue-protective effects of EPO in experimental animals and patients is cited as is the protocol of the recently undertaken Vermont/Dubai study assessing the potential benefits conferred by EPO on the evolution of infarction in patients.. Compelling arguments can be made indicating that EPO and its congeners, some of which are devoid of erythropoietic effects, can protect tissue against injurious stimuli. Accordingly, the promise of EPO for favorably altering the evolution of acute myocardial infarction merits exploration. Congeners of erythropoietin or EPO itself may be beneficial in protecting the heart against injury induced by ischemia thereby favorably modifying infarct size. Rigorous testing of this hypothesis is now in progress in a study involving patients with acute myocardial infarction admitted to hospital within 6 h after the onset of chest pain in whom infarct size is being evaluated based on serial analyses of concentrations of creatine kinase in plasma and thrombolysis is induced pharmacologically as promptly as possible.. EPO is promising for myocardial protection. Its potential is being delineated in a clinical study of myocardial infarction treated with tenecteplase with or without concomitant EPO.

Topics: Acute Disease; Animals; Cardiotonic Agents; Clinical Trials as Topic; Dogs; Erythropoietin; Heart; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Recombinant Proteins; Tenecteplase; Time Factors; Tissue Plasminogen Activator

The vascular events that happen during ischemic stroke worsen outcomes in patients by causing edema, hemorrhagic transformation, and general neurologic tissue compromise. In the past 2 decades, clinical trials in patients after ischemic stroke focused on neuroprotection, but these strategies have failed in providing actual benefit. Vascular protection represents a new field to be explored in acute ischemic stroke in order to develop new approaches to therapeutic intervention.. We identified tactics likely to provide vascular protection in patients with ischemic stroke. These tactics are based on knowledge of the molecular processes involved.. The pathologic processes due to vascular injury after an occlusion of a cerebral artery can be separated into acute (those occurring within hrs), subacute (hrs to days), and chronic (days to mo). Targets for intervention can be identified for all three stages. In the acute phase, superoxide is the predominant mediator, followed by inflammatory mediators and proteases in the subacute phase. In the chronic phase, proapoptotic gene products have been implicated. Many already-marketed therapeutic agents (statins, angiotensin modulators, erythropoietin, minocycline, and thiazolidinediones), with proven safety in patients, have been shown to have activity against some of the key targets of vascular protection.. Currently available pharmacologic agents are poised for clinical trials of vascular protection after acute ischemic stroke.

Topics: Acute Disease; Angiotensin-Converting Enzyme Inhibitors; Brain; Brain Edema; Brain Ischemia; Cerebral Hemorrhage; Chronic Disease; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Minocycline; Stroke; Thiazolidinediones; Thrombolytic Therapy

Sickle cell disease is numerically as common as thalassaemia. However, it affects relatively under privileged population i.e. tribal population belonging to economically poor class and having inadequate access to education and modern health facilities. A recent explosion acknowledged in understanding the pathogenesis of this disease has lead to newer dimensions in treatment. Some of these viz. prevention of overwhelming bacterial infection, present indications and controversies regarding blood transfusion, prevention of stroke, acute chest syndrome, hydroxyurea therapy--probably the best disease modifying agent at the moment, stem cell transplantation--a cure and certain promising experimental therapies including gene therapy have been discussed in this review.

Topics: Acute Disease; Adolescent; Anemia, Sickle Cell; Antisickling Agents; Bacterial Infections; Blood Transfusion; Child; Child, Preschool; Erythropoietin; Humans; Hydroxyurea; Infant; Infant, Newborn; Recombinant Proteins; Respiratory Tract Diseases; Stem Cell Transplantation; Stroke; Syndrome

Erythropoietin and its receptor function as primary mediators of the normal physiological response to hypoxia. Erythropoietin is recognized for its central role in erythropoiesis, but studies in which recombinant human erythropoietin (epoetin alfa) is injected directly into ischaemic rodent brain show that erythropoietin also mediates neuroprotection. Abundant expression of the erythropoietin receptor has been observed at brain capillaries, which could provide a route for circulating erythropoietin to enter the brain. In confirmation of this hypothesis, systemic administration of epoetin alfa before or up to 6 h after focal brain ischaemia reduced injury by 50-75%. Epoetin alfa also limited the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis and excitotoxicity induced by kainate. Thus, systemically administered epoetin alfa in animal models has neuroprotective effects, demonstrating its potential use after brain injury, trauma and multiple sclerosis. It is evident that erythropoietin has biological activities in addition to increasing red cell mass. Given the excellent safety profile of epoetin alfa, clinical trials evaluating systemically administered epoetin alfa as a general neuroprotective treatment are warranted.

Topics: Acute Disease; Animals; Autoimmune Diseases; Brain; Brain Ischemia; Cerebral Cortex; Encephalitis; Epoetin Alfa; Erythropoietin; Humans; Kainic Acid; Neuroprotective Agents; Recombinant Proteins; Stroke; Wounds, Nonpenetrating

Topics: Acute Disease; Anemia; Blood Loss, Surgical; Cell Division; Erythrocytes; Erythroid Precursor Cells; Erythropoietin; Humans; Iron

With the identification of recombinant production of the hematopoietic growth factors, these cytokines have been evaluated in the treatment of primary bone marrow failure states and after myelosuppressive chemo- or radiotherapy. Granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and erythropoietin have been approved for clinical use, and others including c-mpl-ligand (also called megakaryocyte growth and development factor or thrombopoietin) are in phase I and II trials. Most studies have been done with granulocyte and granulocyte-macrophage colony-stimulating factors; their beneficial effects are proven regarding acceleration of granulocyte recovery after chemo- and radiotherapy. In the majority of trials, this acceleration results in a reduction of infectious risks, a shortening of drug- and radiation-induced myelosuppression, and a higher chemotherapy dose intensity; however, an improved remission rate and improved long-term survival rates have not yet been definitively documented. Guidelines have been published to provide a rational basis for the use of these factors in clinical practice. It should be emphasized, however, that for many of the recommendations data from randomized clinical trials are lacking.

Topics: Acute Disease; Antineoplastic Agents; Clinical Trials as Topic; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Neoplasms; Recombinant Proteins; Thrombopoietin

Three patients with paroxysmal nocturnal hemoglobinuria (PNH) and severe anemia were treated with high-dose recombinant human erythropoietin (rHEpo) and low-dose corticosteroids. During therapy their hemoglobin levels gradually improved and no blood transfusions were required. Neither rHEpo nor corticosteroids caused any side effects. This study shows that high rHEpo and low corticosteroid doses may improve the anemia of PNH patients.

Topics: Acute Disease; Adolescent; Adult; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Hemoglobinuria, Paroxysmal; Humans; Male; Prednisolone; Recombinant Proteins; Remission Induction

The hemopoietic growth factors are peptide hormones that are known to be responsible for the in vitro and in vivo proliferation of bone marrow progenitor cells into mature differentiated cells. These cytokines have had a major impact on the management of patients with cytopenias and have been extensively used as an adjunct to the management of patients with hematologic malignancies, with or without prior intensive chemotherapy. Other potential uses, being rigorously studied, include the potential mobilization of stem cells as well as recruitment phase-specific cells into the cell cycle, thus providing a more sensitive environment for targeting specific chemotherapeutic agents.

Topics: Acute Disease; Anemia; Anemia, Aplastic; Bone Marrow Transplantation; Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Leukemia; Myelodysplastic Syndromes; Neutropenia

Topics: Acute Disease; Animals; Arteries; Chronic Disease; Erythropoietin; Hematopoietic System; Hemoglobins; Humans; Hypoxia; Methods; Mice; Oxygen; Partial Pressure; Time Factors

To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE.. Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system.. Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities.. Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.. ClinicalTrials.gov: NCT02811263.

Topics: Acute Disease; Chronic Disease; Cohort Studies; Double-Blind Method; Erythropoietin; Female; Gestational Age; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Placenta Diseases; Pregnancy; Risk Factors

Im Rahmen der vorliegenden Studie sollte der Einfluss des Weichteilschadens auf das klinische Ergebnis nach offener Ellenbogenluxation untersucht werden.. Von Oktober 2008 bis August 2015 wurden insgesamt 230 Patienten mit Ellenbogenluxation behandelt. Diese retrospektive Studie umfasst 21 Fälle von offenen Ellenbogenluxationen. Das Durchschnittsalter der Patienten betrug 49 Jahre alt (20–83 Jahre), 6 Patienten waren weiblich (29%), 15 männlich (71%). Das Bewegungsausmaß des verletzten und unverletzten Ellenbogens wurde erhoben und das funktionelle Ergebnis u. a. mittels Mayo Elbow Performance Score (MEPS), Mayo Wrist Score (MWS) und dem Disability of Arm, Shoulder and Hand (DASH) Score erfasst. Zusätzlich wurden Komplikationen und Revisionsoperationen aufgezeichnet. Der Einfluss des Weichteilschadens (I°/II° offen vs. III° offen) und des Luxationstyps (einfach vs. komplex) auf das klinische Ergebnis wurde analysiert.. Offene Ellenbogenluxationen können mit einem zufriedenstellenden klinischen Ergebnis einhergehen. Insbesondere komplexe offene Ellenbogenluxationen sind jedoch sehr komplikationsbehaftet, wobei neurovaskuläre Komplikationen am häufigsten auftreten.. The current high rate of multidrug-resistant gram-negative bacteria infections among hospitalised patients with cUTIs in the studied area is alarming. Our predictive model could be useful to avoid inappropriate antibiotic treatment and implement antibiotic stewardship policies that enhance the use of carbapenem-sparing regimens in patients at low risk of multidrug-resistance.. The results indicated differential patterns of Inhibition of Return between the High and Low shape/weight based self-worth groups. The High group displayed increased inhibition of return for the shape/weight stimuli relative to control stimuli, while the Low group displayed reduced inhibition of return for the shape/weight stimuli compared to control stimuli. The ED group displayed a similar pattern of results to the High group, but this did not reach significance.. The current findings indicate that young women without an eating disorder who base their self-worth on shape/weight display a pattern of avoidance of shape/weight stimuli that is in direct contrast to those at low risk of developing eating disorders. The possible implications of these specific patterns of inhibition of return across those at varying levels of risk for an eating disorder are discussed along with their implications for intervention approaches.. These results indicated that Sr. An unusually high HbA

Topics: Activities of Daily Living; Acute Disease; Adalimumab; Adaptation, Physiological; Adenosine Triphosphate; Adipose Tissue; Administration, Intravaginal; Adolescent; Adsorption; Adult; Adverse Childhood Experiences; Age Distribution; Age Factors; Aged; Aged, 80 and over; Air Pollution, Indoor; Aldehyde Oxidase; Alginates; Alloys; alpha-Globins; Aluminum Hydroxide; Alveolar Bone Loss; Anaerobiosis; Anesthesia, General; Anesthetics; Animals; Anovulation; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Bacillus cereus; Bacterial Typing Techniques; Bacteroidetes; Base Composition; Biocompatible Materials; Biofilms; Biological Availability; Biological Transport; Biosensing Techniques; Bipolar Disorder; Blood Glucose; Body Mass Index; Bone Regeneration; Boranes; Brachial Artery; Butyric Acid; Candida albicans; Carbon; Carcinoembryonic Antigen; Cell Differentiation; Cell Line, Tumor; Cell Respiration; Cell Survival; Cells, Cultured; Cerebrovascular Circulation; Charcoal; Child; Child Health; China; Chloride Channels; Chlorides; CHO Cells; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromium; Chronic Disease; Chronic Periodontitis; Circular Dichroism; Cities; Cohort Studies; Comamonadaceae; Comorbidity; Coronary Artery Disease; Corrosion; Cricetinae; Cricetulus; Cross Infection; Cross-Sectional Studies; Crowding; Culture Media; Cytokines; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes, Gestational; Diarylheptanoids; Diclofenac; Disability Evaluation; Diterpene Alkaloids; DNA; DNA Mutational Analysis; DNA, Bacterial; Drug Liberation; Drug Resistance, Multiple, Bacterial; Electrochemical Techniques; Electrodes; Electrolytes; Endothelium, Vascular; Enterococcus faecalis; Epithelial Cell Adhesion Molecule; Epithelial Cells; Erbium; Erythropoietin; Ethanol; Ethylenediamines; Fast Foods; Fatty Acids; Female; Fermentation; Ferric Compounds; Fibroblasts; Flavobacteriaceae; Fluorides; Fluorodeoxyglucose F18; Food Microbiology; Formaldehyde; Furaldehyde; Gamma Cameras; Gene Expression; Geologic Sediments; Glucose Tolerance Test; Glycated Hemoglobin; Glycolipids; Glycosylation; Gracilaria; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Guanine; Health Surveys; HeLa Cells; Hemoglobins, Abnormal; Hexosamines; High Fructose Corn Syrup; High-Intensity Interval Training; Hip Fractures; Hippocampus; HLA-B27 Antigen; Hospitalization; Housing; Humans; Hydrogen-Ion Concentration; Hydrolysis; Hydroxides; Hypercapnia; Hypertension; Hypocreales; Hypromellose Derivatives; Image Processing, Computer-Assisted; Incidence; Indole Alkaloids; Indonesia; Inflammation Mediators; Infrared Rays; Insulin Resistance; Intercalating Agents; Ion Transport; Ionophores; Japan; Kinetics; Kluyveromyces; Letrozole; Linear Models; Lipopolysaccharides; Liposomes; Liver; Lung Diseases; Magnesium Hydroxide; Magnetic Resonance Spectroscopy; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mice, Inbred BALB C; Microbial Sensitivity Tests; Microbial Viability; Microscopy, Electron, Transmission; Middle Aged; Mitochondria; Mitochondria, Muscle; Molecular Docking Simulation; Molecular Structure; Muscle, Skeletal; Mutant Proteins; Mutation; Mutation, Missense; Nanocomposites; Nanoparticles; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Nucleic Acid Hybridization; Obesity; Occupational Exposure; Oceans and Seas; Odds Ratio; Organometallic Compounds; Osteogenesis; Ovulation Induction; Oxidation-Reduction; Particle Size; Periodontal Ligament; Permeability; Phaseolus; Phenotype; Philippines; Phosphatidylethanolamines; Phospholipids; Photochemical Processes; Phylogeny; Pichia; Pigmentation; Plant Extracts; Polycystic Ovary Syndrome; Polysaccharides; Postprandial Period; Pregnancy; Pregnancy Rate; Prevalence; Product Surveillance, Postmarketing; Progesterone; Progestins; Protein Engineering; Pseudomonas aeruginosa; Psoriasis; Public Facilities; Rats; Rats, Wistar; Receptors, Thyrotropin; Recombinant Proteins; Reproducibility of Results; Republic of Korea; Retrospective Studies; Rhodobacteraceae; Risk; Risk Assessment; Risk Factors; RNA, Ribosomal, 16S; ROC Curve; Saccharomyces cerevisiae; Salinity; Saliva; Seawater; Seaweed; Sensitivity and Specificity; Sequence Analysis, DNA; Sex Factors; Silver Compounds; Smokers; Social Class; Socioeconomic Factors; Soil Microbiology; Solubility; Soy Foods; Spectrometry, Mass, Electrospray Ionization; Spondylitis, Ankylosing; Staphylococcus aureus; Static Electricity; Steroids; Strontium; Sucrose; Surface Properties; Survival Rate; Sweden; Swine; Synapses; Synchrotrons; Tandem Mass Spectrometry; Tannins; Tea; Temperature; Terpenes; Thalidomide; Thermodynamics; Thiadiazoles; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyroidectomy; Time Factors; Tissue Distribution; Titanium; Toilet Facilities; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Ubiquinone; Urinary Tract Infections; Vaginal Creams, Foams, and Jellies; Venezuela; Vitamin K 2; Waist Circumference; Waste Disposal, Fluid; Wastewater; Water Microbiology; Water Pollutants, Chemical; Whole Body Imaging; X-Ray Diffraction; Young Adult; Ytterbium; Yttrium; Yttrium Radioisotopes; Zinc Compounds

To compare the effect of adding recombinant human erythropoietin (rhEPO) to intravenous methylprednisolone for the treatment of unilateral acute optic neuritis of unknown or demyelinative origin on the logarithm of the minimum angle of resolution (logMAR), perimetric variables [mean deviation (MD) and pattern standard deviation (PSD)], and retinal nerve fiber layer (RNFL) thickness in optical coherence tomography (OCT).. Thirty patients (15 patients in each group) diagnosed with unilateral acute optic neuritis of unknown or demyelinative origin were included. All patients received 1, 000 mg intravenous methylprednisolone per day for 3 days. One intravenous bullous dose of rhEPO with the dose of 33,000 IU was administered at days 1-3 for the patients in group 2. One intravenous bullous dose of 0.9 % normal saline was administered at days 1-3 for group 1 patients. At 6 months post-intervention, in the involved eye, logMAR, MD, PSD, and mean RNFL thickness in each of four quadrants and post-intervention changes in each of the variables were compared between group 1 and group 2.. The amount of MD improvement after the intervention (difference of pre- and post-intervention MDs) was significantly higher in the group 2 patients (p = 0.04). The other post-intervention variables, including post-intervention PSD, amount of PSD improvement, and total and four-quadrant post-intervention RNFL thickness and RNFL loss (difference of pre- and post-intervention RNFL thicknesses), demonstrated no significant differences between group 1 and group 2.. Until more controlled studies are available, the rhEPO is not recommended as an add-on treatment for optic neuritis.

Topics: Acute Disease; Adolescent; Adult; Demyelinating Diseases; Double-Blind Method; Drug Therapy, Combination; Erythropoietin; Female; Glucocorticoids; Humans; Infusions, Intravenous; Male; Methylprednisolone; Nerve Fibers; Optic Neuritis; Recombinant Proteins; Retinal Ganglion Cells; Tomography, Optical Coherence; Visual Acuity; Young Adult

This study was performed to evaluate whether increasing hemoglobin before ascent by prophylactic erythropoietin injections prevents acute mountain sickness (AMS). This open-label, randomized, controlled trial involved 39 healthy volunteers with hemoglobin ≤ 15.5 g/dL who were divided randomly into erythropoietin (n=20) and control (n=19) groups. Epoetin alpha 10,000 IU injections were given weekly for four consecutive weeks. On day 1, and 7 days after the last injection (day 29), oxygen saturation (SaO2), and hemoglobin were measured. The subjects departed Seoul on day 30 and arrived at Annapurna base camp (ABC, 4,130 m) on day 34. AMS was diagnosed when headache and Lake Louise score (LLS) of ≥ 3 were present. Immediate descent criteria followed US Army recommendations. Two groups differ in hemoglobin levels on day 29 (15.4 ± 1.1 vs 14.2 ± 1.0 g/dL, P=0.001). At ABC, erythropoietin group had a significantly lower mean LLS, AMS incidence, and number of subjects who met immediate descent criteria. Multiple logistic regression analysis showed that SaO2<87% and control group, but not hemoglobin<15.0 g/dL, independently predicted satisfaction of immediate descent criteria. Erythropoietin-related adverse effects were not observed. In conclusion, erythropoietin may be an effective prophylaxis for AMS.(Clinical Trial Registry Number; NCT 01665781).

Topics: Acute Disease; Adult; Altitude Sickness; Blood Pressure; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Headache; Hemoglobins; Humans; Incidence; Logistic Models; Male; Middle Aged; Odds Ratio; Oxygen; Recombinant Proteins; Surveys and Questionnaires

Recent studies in animal models indicate that recombinant human erythropoietin (rhEPO) is very effective in enhancing neurological recovery after spinal cord injury (SCI). We aimed to evaluate the effect of rhEPO plus methylprednisolone sodium succinate (MPSS) compared to MPSS alone to improve neurological function of patients after SCI in a randomized clinical trial. During a 15-month period 30 patients presenting to emergency departments of two university affiliated hospitals within less than 6 hours after acute SCI were randomized to two groups. Both groups received MPSS 30 mg/kg initially and 5.4 mg/kg every hour till 23 hours if admitted within 3 hours and till 47 hours if recruited within 3-6 hours after injury. Group EPO also received 500 unit/kg rhEPO on admission and another 500 unit/kg 24 hours later instead of placebo in group MPSS. Neurologic evaluation was performed on admission, 24, 48, 72 hours and one and 6 months later. Range of patients' age was 18-65 years. There was no significant difference between patients receiving two types of treatment in neurological exam on admission (P=0.125), 24 hours after admission (P=0.108) and 48 hours after admission (P=0.085). However, one week (P=0.046), one month (P=0.021) and six months (P=0.018) after admission these differences were significant. MPSS plus rhEPO started within 6 hours after acute spinal injury may be more effective than MPSS plus placebo in improvement of neurologic dysfunction. More studies with larger sample sizes are warranted.

Topics: Acute Disease; Adolescent; Adult; Aged; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Methylprednisolone; Middle Aged; Neuroprotective Agents; Recombinant Proteins; Spinal Cord Injuries; Treatment Outcome

In the German Multicenter Erythropoietin (EPO) Stroke Trial, patients not receiving thrombolysis most likely benefited from EPO on clinical recovery, whereas a combination of rtPA and EPO was associated with increased mortality. We investigated whether the combination of rtPA and EPO increased release of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA), and thereby potentially deteriorated ischemic stroke outcome, as suggested from experimental data.. ADMA was determined in serum samples from 90 patients of the German Multicenter EPO Stroke Trial taken at days 1 (within 6 hours after symptom onset), 2, 3, 4, and 7 after stroke using high-performance liquid chromatography-tandem mass spectrometry. ADMA was analyzed for the different treatment groups (EPO, n=25; placebo, n=30; rtPA+placebo, n=18; EPO+rtPA, n=17). Clinical outcome was expressed as difference between National Institutes of Health Stroke Scale at baseline and 90 days.. ADMA levels significantly increased during the observation time in EPO, EPO+rtPA, and placebo groups (P<0.05). A treatment effect on ADMA levels was revealed by repeated measures ANOVA only in the rtPA+placebo group (P=0.027). Here, ADMA levels were decreased compared with the placebo group (P<0.05). Both the EPO and the rtPA+placebo groups in the Hannover subgroup of the EPO trial had better outcome than the placebo group (P<0.05).. Our data underscore the potential benefit of EPO in ischemic stroke. The hypothesis from experimental data, that EPO treatment increases ADMA in stroke patients, was disproved. Further studies are needed to clarify whether decreased ADMA might contribute to therapeutic rtPA effects.

Topics: Acute Disease; Aged; Aged, 80 and over; Arginine; Double-Blind Method; Drug Therapy, Combination; Erythropoietin; Female; Humans; Male; Middle Aged; Severity of Illness Index; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome

Recent findings suggest that besides renal tissue hypoxia, relative decrements in tissue oxygenation, using a transition of the breathing mixture from hyperoxic to normoxic, can also stimulate erythropoietin (EPO) production. To further clarify the importance of the relative change in tissue oxygenation on plasma EPO concentration [EPO], we investigated the effect of a consecutive hyperoxic and hypoxic breathing intervention. Eighteen healthy male subjects were assigned to either IHH (N = 10) or CON (N = 8) group. The IHH group breathed pure oxygen (F(i)O(2) ~ 1.0) for 1 h, followed by a 1-h period of breathing a hypoxic gas mixture (F(i)O(2) ~ 0.15). The CON group breathed a normoxic gas mixture (F(i)O(2) ~ 0.21) for the same duration (2 h). Blood samples were taken just before, after 60 min, and immediately after the 2-h exposure period. Thereafter, samples were taken at 3, 5, 8, 24, 32, and 48 h after the exposure. During the breathing interventions, subjects remained in supine position. There were significant increases in absolute [EPO] within groups at 8 and 32 h in the CON and at 32 h only in the IHH group. No significant differences in absolute [EPO] were observed between groups following the intervention. Relative (∆[EPO]) levels were significantly lower in the IHH than in the CON group, 5 and 8 h following exposure. The tested protocol of consecutive hyperoxic-hypoxic gas mixture breathing did not induce [EPO] synthesis stimulation. Moreover, the transient attenuation in ∆[EPO] in the IHH group was most likely due to a hyperoxic suppression. Hence, our findings provide further evidence against the "normobaric O(2) paradox" theory.

Topics: Acute Disease; Adult; Erythropoietin; Humans; Hyperoxia; Hypoxia; Male; Models, Theoretical; Nitrogen; Oxygen; Oxygen Consumption; Respiration; Time Factors; Young Adult

To determine whether newer combination cytokine treatment with granulocyte colony-stimulating factor (G-CSF) and darbepoetin can improve efficacy of stem cell therapy, we evaluated safety and peripheral blood stem/progenitor cell (PBSC) mobilizing effects of combination cytokine in comparison with G-CSF alone in patients with acute myocardial infarction (AMI). We randomized 60 patients with AMI into two groups under 2:1 ratio; combination treatment with darbepoetin and G-CSF (n = 41: Combicytokine group) and the G-CSF alone (n = 19: G-CSF group). After coronary angioplasty, G-CSF was treated for 3 days with dose of 10 μg/kg/day in both groups. Only in the combicytokine group, additional single intravenous injection of 4.5 μg/kg of darbepoetin was administrated immediate after coronary angioplasty. Combination cytokine treatment was well tolerated as was G-CSF alone. PBSCs were obtained by apheresis for intracoronary infusion after completion of cytokine treatment and were analyzed by flow cytometry. The purity of proangiogenic cells was higher in combination cytokine group than the G-CSF group. Specifically, proportion of CD34(+)/KDR(+) endothelial progenitor cells, CD3(+)/CD31(+) angiogenic T cells and Tie2(+)/CXCR4(+) cells in apheresis products were higher in the combicytokine group. These meant that the combicytokine treatment recruited PBSCs in higher purity and fewer unwanted inflammatory cells than G-CSF alone in apheresis products. Combination treatment with darbepoetin and G-CSF is safe and more efficient to mobilize and recruit proangiogenic cells than G-CSF alone in patients with AMI. (. www.ClinicalTrials. gov identifier: NCT00501917).

Topics: Acute Disease; Adult; Aged; Antigens, CD34; Blood Component Removal; Coronary Angiography; Darbepoetin alfa; Drug Therapy, Combination; Endothelium, Vascular; Erythropoietin; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Male; Middle Aged; Myocardial Infarction; Receptor, TIE-2; Stem Cells; T-Lymphocytes

To investigate the safety, tolerability, and short-term efficacy of treatment with erythropoietin in patients with optic neuritis as a first demyelination event.. We conducted this randomized double-blind pilot study in the Shiraz University of Medical Sciences, Shiraz, Iran, from March 2007 to January 2009. The participants were patients aged 18-45 years with optic neuritis and at least 3 hyperintense lesions on T2-weighted and FLAIR MRI, but no clinically definite multiple sclerosis (MS). They were randomized into 2 groups. The case group (5 patients) received intravenous methyl prednisolone (1000 mg/24 hours) and intravenous erythropoietin (20,000 unit/24 hours) for 5 consecutive days, and the control group (5 patients) received intravenous methyl prednisolone at the same dose as the case group, and a placebo. The groups were followed for one year and compared for adherence to protocol, adverse drug effects, mean duration of conversion to clinically definite MS, and MRI changes.. All patients tolerated the protocol. One patient who received erythropoietin developed cerebral venous sinus thrombosis and anti-cardiolipin antibody positivity. One patient in the control group, but no patients in the case group, fulfilled the McDonald criteria for MS during the follow-up period, but none of the participants in either group developed clinically definite MS according to the Poser criteria.. Erythropoietin may be effective, but should be used with caution.

Topics: Acute Disease; Adolescent; Adult; Demyelinating Diseases; Drug Therapy, Combination; Erythropoietin; Female; Follow-Up Studies; Glucocorticoids; Humans; Magnetic Resonance Imaging; Middle Aged; Multiple Sclerosis; Optic Neuritis; Pilot Projects; Prednisolone; Severity of Illness Index; Treatment Outcome; Young Adult

If controllable, stem cell activation following injury has the therapeutic potential for supporting regeneration in acute or chronic wounds. Human dermally-derived stem cells (FmSCs) were exposed to the cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) in the presence of erythropoietin (EPO). Cells were cultured under ischemic conditions and phenotypically characterized using flow cytometry. Topical EPO application was performed in three independent clinical wound healing attempts. The FmSCs expressed the receptor for EPO. EPO had a strong inhibitory effect on FmSC growth in the absence of IL-6 and TNF-α. With IL-6, the EPO effects were reversed to that of growth stimulation. TNF-α had the strongest stimulatory effect. In contrast, IL-1β had an inhibitory effect. Topically applied EPO considerably enhanced wound healing and improved wound conditions of acute and chronic wounds. Site specificity of stem cell activation is mediated by IL-6 and TNF-α. In trauma, EPO ceases its inhibitory role and reverts to a clinically relevant boosting function. EPO may be an important therapeutic tool for the topical treatment of acute and chronic wounds.

Topics: Acute Disease; Adult; Aged; Biomarkers; Cell Proliferation; Cells, Cultured; Child, Preschool; Chronic Disease; Cytokines; Dermis; Drug Synergism; Erythropoietin; Female; Flow Cytometry; Humans; Male; Middle Aged; Phenotype; Receptors, Erythropoietin; Sequence Analysis, Protein; Stem Cells; Wounds and Injuries

We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.

Topics: Acute Disease; Aged; Alkaline Phosphatase; Biomarkers; Creatinine; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; gamma-Glutamyltransferase; Hematinics; Humans; Intensive Care Units; Kidney Diseases; Male; Middle Aged; New Zealand; Patient Selection; Placebo Effect; Predictive Value of Tests; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Triage

Delayed ischemic deficits (DIDs), a major source of disability following aneurysmal subarachnoid hemorrhage (aSAH), are usually associated with severe cerebral vasospasm and impaired autoregulation. Systemic erythropoietin (EPO) therapy has been demonstrated to have neuroprotective properties acting via EPO receptors on cerebrovascular endothelia and ischemic neurons. In this trial, the authors explored the potential neuroprotective effects of acute EPO therapy following aSAH.. Within 72 hours of aSAH, 80 patients (age range 24-82 years) were randomized to receive intravenous EPO (30,000 U) or placebo every 48 hours for a total of 90,000 U. Primary end points were the incidence, duration, and severity of vasospasm and impaired autoregulation on transcranial Doppler ultrasonography. Secondary end points were incidence of DIDs and outcome at discharge and at 6 months.. Randomization characteristics were balanced except for age, with the EPO group being older (mean age 59.6 vs 53.3 years, p=0.034). No differences were demonstrated in the incidence of vasospasm and adverse events; however, patients receiving EPO had a decreased incidence of severe vasospasm from 27.5 to 7.5% (p=0.037), reduced DIDs with new cerebral infarcts from 40.0 to 7.5% (p=0.001), a shortened duration of impaired autoregulation (ipsilateral side, p<0.001), and more favorable outcome at discharge (favorable Glasgow Outcome Scale score, p=0.039). Among the 71 survivors, the EPO group had fewer deficits measured with National Institutes of Health Stroke Scale (median Score 2 vs 6, p=0.008).. This preliminary study showed that EPO seemed to reduce delayed cerebral ischemia following aSAH via decreasing severity of vasospasm and shortening impaired autoregulation.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blood Pressure; Blood Transfusion; Brain Ischemia; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Homeostasis; Humans; Male; Middle Aged; Neuroprotective Agents; Placebos; Subarachnoid Hemorrhage; Treatment Outcome; Ultrasonography, Doppler, Transcranial; Vasospasm, Intracranial; Young Adult

Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke.. This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40,000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for.. Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke.. Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Double-Blind Method; Drug Administration Schedule; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Humans; Infarction, Middle Cerebral Artery; Injections, Intravenous; Male; Middle Aged; Mortality; Neuroprotective Agents; Patient Selection; Placebo Effect; Recombinant Proteins; Stroke; Tissue Plasminogen Activator; Treatment Outcome; Young Adult

Anaemia caused by acute upper gastrointestinal bleeding is treated with blood transfusion or iron, but patients usually face a two-month recovery period from post-haemorrhage anaemia. This prospective, randomised, open, pilot study was designed to investigate whether recombinant human erythropoietin (Epoetin) therapy accelerate haematocrit increase in the post-bleeding recovery period.. We studied hospitalised patients admitted because of acute ulcer bleeding or haemorrhagic gastritis, who had a haematocrit of 27-33% and did not receive blood transfusions. One day after the endoscopic confirmation of cessation of bleeding, they were randomised either to erythropoietin (20 000 IU Epoetin alfa subcutaneously, on days 0, 4 and 6) plus iron (100 mg im, on days 1- 6, (G(1)) or iron only (G(2)). Haematocrit was measured on days 0, 6, 14, 30, 45, and 60, respectively.. One patient from G(1) and two from G(2) were lost to follow-up. Therefore, 14 and 13 patients from G(1) and G(2) respectively were analysed. Demographic characteristics, serum iron, ferritin, total iron binding capacity, reticulocytes, and haematocrit were not significantly different at entry to the study. Median reticulocyte counts were significantly different between groups on day six (G(1): 4.0, 3.0-6.4 vs G(2): 3.5, 2.1-4.4%, P=0.03) and median haematocrit on day fourteen [G(1): 35.9, 30.7-41.0 vs G(2): 32.5, 29.5-37.0% (median, range), P=0.04].. Erythropoietin administration significantly accelerates correction of anemia after acute ulcer bleeding. The haematocrit gain is equivalent to one unit of transfused blood two weeks after the bleeding episode.

Topics: Acute Disease; Adult; Aged; Anemia; Erythropoietin; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Peptic Ulcer; Pilot Projects; Prospective Studies; Recombinant Proteins; Treatment Outcome

To study the effect of infection on iron status in children suffering from acute, mild or severe respiratory infections and to determine the nature of anemia in infection using serum transferrin receptor (sTfR) levels.. Forty-three children aged between 3 and 5 y with no evidence of infection and receiving iron supplements in the preceding 100 days served as controls. Twenty-one children with mild upper respiratory infection and 94 children hospitalized for acute pneumonia constituted the experimental group. Hemoglobin (Hb), sTfR and serum ferritin were estimated in all the children at the time of diagnosis and again on the 15th and 30th days after the infection in those who were available for follow-up.. Mean (95% CI) sTfR was 6.08 (5.1-7.1) mg/l in healthy non-anemic children. Upper respiratory infection had no impact on Hb or sTfR but it significantly elevated serum ferritin levels. Eighty-three percent of the children with pneumonia had Hb less than 110 g/l at the time of diagnosis and had elevated mean sTfR, 18.0 (15.7-20.3) mg/l. There was a decline in mean sTfR by the 15th day of infection to 14.3 (11.3-17.4) mg/l with further rise to 22.9 (13.0-31.9) mg/l by 30 days. Serum ferritin was significantly elevated at the time of diagnosis (85.9; 71.1-100.8 micro g/l) as well as at 15 days (89.1; 68-110.1 micro g/l) with a decline by 30 days.. Severe lower respiratory infection exaggerates iron-deficient erythropoiesis by blocking release of iron from the storage pools. sTfR may not be a sensitive and specific tool of assessing true iron status of children exposed to severe infections.

Topics: Acute Disease; Anemia, Iron-Deficiency; Child, Preschool; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Iron Deficiencies; Male; Pneumonia; Receptors, Transferrin; Respiratory Tract Infections; Time Factors

In cell culture, hypoxia stabilizes a transcriptional complex called hypoxia-inducible factor-1 (HIF-1) that increases erythropoietin (Epo) formation. One hallmark of HIF-1 responses is that they can be induced by iron chelation. The first aim of this study was to examine whether an infusion of desferrioxamine (DFO) increased serum Epo in humans. If so, this might provide a paradigm for identifying other HIF-1 responses in humans. Consequently a second aim was to determine whether an infusion of DFO would mimic prolonged hypoxia and increase the acute hypoxic ventilatory response (AHVR). Sixteen volunteers undertook two protocols: 1) continuous infusion of DFO over 8 h and 2) control. Epo and AHVR were measured at fixed times during and after the protocols. The results show that 1) compared with control, Epo increased in most subjects at 8 h [52.8 +/- 57.7 vs. 6.9 +/- 2.5 (SD) mIU/ml, for DFO = 4 g/70 kg body wt, P < 0.05] and 12 h (63.7 +/- 76.3 vs. 7.3 +/- 2.5 mIU/ml, P < 0.001) after the start of DFO administration and 2) DFO had no significant effect on AHVR. We conclude that, whereas infusions of DFO mimic hypoxia by increasing Epo, they do not mimic prolonged hypoxia by augmenting AHVR.

Topics: Acute Disease; Adolescent; Adult; Carbon Dioxide; Carotid Body; Deferoxamine; Erythropoietin; Female; Humans; Hypoxia; Infusions, Intravenous; Male; Middle Aged; Respiratory Mechanics

The use of hydroxyurea for the prevention of sickle cell crises in patients with homozygous HbS disease is now well established. The beneficial effects of this compound stem from (a) selective enrichment of red cells containing an increased amount of fetal hemoglobin, which inhibits HbS polymerization, and (b) a decrease of leukocytes, platelets, and reticulocytes, which significantly limits their adherence to the vascular wall. We report the results of a clinical trial of hydroxyurea on 55 Greek-origin patients with sickle cell/beta-thalassemia and 14 patients with homozygous HbS disease who have been treated with hydroxyurea for several years. Such patients have a higher probability to benefit from hydroxyurea therapy, since in addition to its antisickling effect, the increase of gamma-chain synthesis is expected to diminish the deleterious effects of the unbound alpha-globin chains. Selection of patients and monitoring throughout the whole trial were done by the same clinicians. Quantitative expression of the clinical condition was done using a system scoring several outcome parameters. For a period of 52 months prior to starting treatment, the total score of severity for 59 evaluable patients was 1182 points (3068 patient-weeks), while for the 12,018 patient-weeks of the trial this parameter fell to only 82 points. Other observations of interest include the significant improvement of a group of patients with hepatic cholestasis, the development of leg ulcers possibly related to the treatment, and the dramatic increase of hemoglobin F, often in association with an increase of the total hemoglobin levels as a result of decreased hemolysis.

Topics: Acute Disease; Adolescent; Adult; Anemia, Sickle Cell; Antisickling Agents; beta-Thalassemia; Erythrocyte Count; Erythrocyte Indices; Erythrocytes; Erythropoietin; Female; Fetal Hemoglobin; Greece; Hemoglobins; Humans; Hydroxyurea; Leg Ulcer; Male; Middle Aged; Pancreatitis; Patient Compliance; Patient Selection; Receptors, Transferrin; Severity of Illness Index

BUT: The present clinical study was undertaken to evaluate the efficacy, safety and tolerability of r-HuEPO in the treatment of severe anaemia post partum.. Five women received Eprex (Cilag), for five days, and iron and folic acid twice daily. Haematological indices were investigated on the 2d, 5th, 14th and 30th day.. On the 30th day the mean haemoglobin concentration was 110 g/l. A rapid haematopoietic effect was shown by an increase in the number of reticulocytes. The peak reticulocytes counts was achieved on the fifth day. The blood pressure at the course of the puerperium was normal. There was no changes in serum electrolytes during treatment with Eprex. The women noted no side effect from rHuEPO.. The use of rHuEPO may decrease the need for red cell transfusions in severe anaemia postpartum.

Topics: Acute Disease; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Folic Acid; Hematinics; Humans; Iron; Obstetric Labor Complications; Pregnancy; Puerperal Disorders; Recombinant Proteins; Time Factors

Pluripotent stem cells of hematopoiesis and lymphopoiesis are among the CD34+ cells in blood or bone marrow. After granulocyte-colony stimulating factor (G-CSF) treatment, 1% to 2% of the mononuclear cells in blood are CD34+ cells, which can be procured by leukapheresis. We investigated the potential of CD34+ blood cells for reconstituting hematopoiesis and lymphopoiesis after allogeneic transplantation. HLA-identical sibling donors of 10 patients with hematologic malignancies were treated with G-CSF (filgrastim), 5 microgram/kg subcutaneously twice daily for 5 to 7 days. CD34+ cells were selected from the apheresis concentrates by immunoadsorption, concomitantly the number of T cells was reduced 100- to 1,000-fold. After transplantation, five patients received cyclosporine A for graft-versus-host disease (GvHD) prophylaxis (group I); five patients additionally received methotrexate (group II). G-CSF and erythropoietin were given to all patients. Mean numbers of 7.45 x 10(6) CD34+ and 1.2 x 10(6) CD3+ cells per kilogram were transplanted. In group I, the median times of neutrophil recovery to 100, 500, and 1,000 per mm3 were 10, 10, and 11 days, respectively. Group II patients reached these neutrophil levels after 10, 14, and 15 days, respectively. Platelet transfusions were administered for a median of 18 days in group I and 30 days in group II, and red blood cells for 9 and 12 days, respectively. Between day 30 and 60, lymphocytes reached levels of 353 +/- 269 cells per mm3. The median grades of acute GvHD were III in group I and I in group II. Two patients in group I died from acute GvHD. Two leukemic relapses occurred in group II. Complete and stable donor hematopoiesis was shown in all patients with a median follow up of 370 (45 to 481) days. Allogeneic blood CD34+ cells can successfully reconstitute hematopoiesis and lymphopoiesis. Reduction of T cells by CD34+ blood cell enrichment and cyclosporine A alone might not be sufficient for prophylaxis of severe acute GvHD.

Topics: Acute Disease; Adult; Antigens, CD34; Bone Marrow; Cell Division; Cyclosporine; Erythropoietin; Female; Filgrastim; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immunosuppressive Agents; Leukapheresis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Methotrexate; Middle Aged; Platelet Transfusion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins; T-Lymphocytes; Transplantation, Homologous

Erythropoietin (EPO) is widely used among patients with end-stage renal disease awaiting transplantation. Data suggest that EPO therapy may be immunomodulatory. The purpose of this study was to assess the effects of pretransplant EPO therapy on renal allograft outcome. We evaluated 120 consecutive renal transplant recipients to assess the effect of EPO on graft outcome following renal transplantation. Among the study population, 58 patients were receiving EPO before transplantation (EPO group) and 62 patients were not treated with EPO (non-EPO group). Twenty-four of 58 EPO-treated patients (41%) experienced delayed graft function after transplantation, compared with 11 of 62 (18%) non-EPO-treated patients (P<0.05). The incidence of acute rejection, time to first rejection, and 1-year graft survival rate did not differ between the two groups. In conclusion, pretransplant EPO therapy does not appear to adversely impact on the incidence of acute rejection or 1 year graft survival rate. However, EPO-treated patients may be predisposed to the development of delayed graft function.

Topics: Acute Disease; Adjuvants, Immunologic; Adult; Erythropoietin; Female; Graft Rejection; Graft Survival; Humans; Kidney Transplantation; Male; Middle Aged; Treatment Outcome

Cord blood pH, lactate, hypoxanthine, and erythropoietin levels have all been used as markers of either acute or chronic asphyxia. We sought to determine whether these index values were significantly different in infants with or without meconium-stained amniotic fluid.. Fifty-six pregnant women in spontaneous labor at term were divided into two groups on the basis of the presence or absence of meconium-stained amniotic fluid. All meconium-stained fluid was centrifuged, and the volume percentage of particulate matter (i.e., meconium) was recorded. Umbilical artery blood and mixed arterial and venous cord blood were obtained at each delivery. Lactate, hypoxanthine, and erythropoietin levels were measured. Statistical analysis included Student t test and rank sum statistics where appropriate. Normal and Spearman correlation coefficients were also used.. There were no significant differences in mean umbilical artery pH (7.26 +/- 0.06 vs 7.25 +/- 0.10), lactate levels (32.8 +/- 10 mg/dl vs 30.4 +/- 14.2 mg/dl), and hypoxanthine levels (13.4 +/- 6.7 mumol/L vs 14.0 +/- 6.0 mumol/L) in newborns with meconium (n = 28) compared with controls (n = 28). Erythropoietin levels were significantly greater in newborns with meconium (median 39.5 mIU/ml vs 26.8 mIU/ml, p = 0.039). There was no correlation between the amount of particulate matter and any marker of asphyxia.. There was no correlation between markers of acute asphyxia (i.e., umbilical artery blood pH, lactate, or hypoxanthine) and meconium. However, erythropoietin levels were significantly elevated in newborns with meconium-stained amniotic fluid. This latter marker may better correlate with chronic asphyxia.

Topics: Acute Disease; Adolescent; Adult; Amniotic Fluid; Asphyxia Neonatorum; Biomarkers; Chronic Disease; Erythropoietin; Female; Fetal Blood; Humans; Hydrogen-Ion Concentration; Hypoxanthines; Infant, Newborn; Lactates; Meconium

Chemotherapy-induced anemia in children with cancer is usually of acute onset. To investigate an alternate treatment to transfusion (Tx), we undertook a phase I-II clinical trial of daily administrations of recombinant erythropoietin (rHuEPO). Patients with a hemoglobin (Hgb) value < 75 g/l were treated for 14 days in cohorts of 3 at escalating daily doses of 25, 50, 70, 80, 90, and 100 U/kg respectively. The maximum-tolerated dose was not encountered. Of 18 courses given to 15 children aged 0.5-18 years, 7 (39%) were associated with increased or stable Hgb levels (courses without Tx), while 11 (61%) were terminated by a Tx, without evidence of a dose-response relationship. Changes in mean Hgb levels and absolute reticulocyte counts were paralleled by those of mean white blood cell, platelet, and absolute neutrophil counts during the first 7 days and when the end-points of the study were reached. Numbers of circulating burst-forming units-erythroid remained low throughout courses without Tx. No cumulative increase of serially determined serum EPO levels was observed and serum ferritin levels were elevated in both groups of courses. We conclude that daily administration of rHuEPO were safe but ineffective in our trial. Recovery of chemotherapy-induced myelosuppression appeared to be the rate-limiting factor for the outcome, without evidence of an enhanced stimulation of erythropoiesis. The lack of a proliferative response of specific progenitor cells suggested a mechanism of transient primary resistance to rHuEPO.

Topics: Acute Disease; Adolescent; Anemia; Antineoplastic Agents; Child; Child, Preschool; Erythropoietin; Female; Humans; Infant; Infant, Newborn; Iron; Male; Neoplasms; Recombinant Proteins

We carried out a pilot study on the use of recombinant human erythropoietin (rHuEPO) in children undergoing allogeneic or mafosfamide-purged autologous BMT for ALL or AML. rHuEPO was administered intravenously at a dose of 75 U/kg/day for 30 days after transplant. Ten rHuEPO-treated patients receiving allogeneic BMT and 10 given autologous BMT were compared with 15 allogeneic and 10 autologous historical controls. Endogenous EPO production was appropriate for the degree of anemia after autologous BMT. In these patients, rHuEPO did not accelerate erythroid repopulation and did not modify transfusion requirements. With allogeneic BMT, erythroid marrow activity increased faster in patients given rHuEPO than in controls and resulted in higher red cell production, the mean reticulocyte count on day +30 being 187 +/- 51 x 10(9)/l in treated patients versus 107 +/- 63 x 10(9)/l in controls (p < 0.01). The total number of RBC units administered was 1.7 +/- 1.3 in the rHuEPO group versus 5.1 +/- 3.0 in the control group (p < 0.001). The total number of platelet transfusions was 4.0 +/- 2.3 for patients given allogeneic BMT and receiving rHuEPO versus 8.4 +/- 6.8 for historical controls (p < 0.05) whereas it was similar in rHuEPO-treated and control autologous BMT patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Anemia; Blood Transfusion; Bone Marrow Transplantation; Child; Cost-Benefit Analysis; Erythropoiesis; Erythropoietin; Graft Survival; Humans; Immunologic Factors; Leukemia; Recombinant Proteins; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome

Chronic hypoxemia is associated with development of secondary polycythemia. To evaluate effects of transient hypoxemia on serum EPO activity in patients with chronic lung disease, we studied six oxygen-dependent patients who underwent either a 4-h oxygen withdrawal or their routine therapy, in a randomized, blinded fashion, on two separate days. Serum EPO did not differ at baseline between study days. Erythropoietin levels did not change significantly over time during normoxic conditions. Under hypoxic conditions, serum EPO levels rose over 4 h with the change from baseline first becoming significant at 2 h. The log of serum EPO response showed an inverse correlation with the level of arterial oxygen saturation. We conclude that patients with chronic lung disease are able to produce EPO in response to acute hypoxemic stress. Transient episodes of hypoxemia, such as occur during sleep or exercise, may result in increased red blood cell production stimulated by this EPO response.

Topics: Acute Disease; Animals; Biological Assay; Erythropoietin; Female; Humans; Hypoxia; Lung Diseases, Obstructive; Male; Mice; Oxygen; Oxygen Inhalation Therapy; Time Factors

Peripheral nerve injury (PNI) often leads to significant functional loss in patients and poses a challenge to physicians since treatment options for improving functional outcomes are limited. Recent studies suggest that erythropoietin and glucocoticoids have beneficial effects as mediators of neuro-regenerative processes. We hypothesized that combination treatment with erythropoietin and glucocoticoids would have a synergistic effect on functional outcome after PNI.. Sciatic nerve crush injury was simulated in ten-week-old male C57BL/6 mice. The mice were divided into four groups according to the type of drugs administered (control, erythropoietin, dexamethasone, and erythropoietin with dexamethasone). Motor functional recovery was monitored by walking track analysis at serial time points up to 28 days after injury. Morphological analysis of the nerve was performed by immunofluorescent staining for neurofilament (NF) heavy chain and myelin protein zero (P0) in cross-sectional and whole-mount nerve preparations. Additionally, morphological analysis of the muscle was performed by Hematoxylin and eosin staining.. Combination treatment with erythropoietin and dexamethasone significantly improved the sciatic functional index at 3, 7, 14, and 28 days after injury. Fluorescence microscopy of cross sectional nerve revealed that the combination treatment increased the ratio of P0/NF-expressing axons. Furthermore, confocal microscopy of the whole-mount nerve revealed that the combination treatment increased the fluorescence intensity of P0 expression. The cross-sectional area and minimum Feret's diameter of the muscle fibers were significantly larger in the mice which received combination treatment than those in the controls.. Our results demonstrated that combination treatment with erythropoietin and dexamethasone accelerates functional recovery and reduces neurogenic muscle atrophy caused by PNI in mice, which may be attributed to the preservation of myelin and Schwann cell re-myelination. These findings may provide practical therapeutic options for patients with acute PNI.

Topics: Acute Disease; Animals; Axons; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Male; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Muscles; Muscular Atrophy; Myelin P0 Protein; Peripheral Nerve Injuries; Recovery of Function; Remyelination; Schwann Cells; Sciatic Nerve

Obesity has been linked with altered acute inflammation resolution which contributes to obesity-related clinical complications; however, the mechanisms that contribute to obesity-related unresolved inflammation are not fully known. Here we demonstrated that the deficiency of macrophage erythropoietin (EPO) signaling contributed to delayed acute inflammation resolution in diet-induced obese mice. In zymosan-induced acute peritonitis, in line with the delayed resolution of inflammation, the induction of macrophage EPO signaling was significantly reduced in obese mice relative to normal mice. Exogenous EPO induced macrophage EPO signaling and promoted acute inflammation resolution in obese mice. Efferocytosis of apoptotic cells by macrophages which is central in inflammation resolution was impaired in obese mice and restored by exogenous EPO. Mechanistically, macrophage peroxisome proliferator-activated receptor-γ (PPARγ) was greatly reduced in obese mice and EPO increased macrophage PPARγ to promote efferocytosis in obese mice. Together, our results identify an important mechanism underlying aberrant acute inflammation resolution in obesity, with important implications for regulating unresolved acute inflammation and normalizing macrophage defects in obese and diabetic individuals.

Topics: Acute Disease; Animals; Diet; Erythropoietin; Humans; Inflammation; Macrophages; Mice, Inbred C57BL; Mice, Obese; Phagocytosis; PPAR gamma; Recombinant Proteins; Signal Transduction

This study aimed to characterize the pathophysiology, including possible correlations, of clock gene expression and erythropoietin (EPO) production in the acute stage of blood hemorrhage. Specimens of human cortical tissues (right and left kidneys) and cardiac blood were collected at autopsy from 52 cases following mortality due to acute-stage blood hemorrhage following sharp instrument injury. BMAL1 and PER2 mRNA levels were determined by reverse transcription-polymerase chain reaction; BMAL1 and PER2 protein levels were assessed using immunohistochemistry; BMAL1 protein levels were quantitatively measured by western blotting; and serum EPO levels were measured by chemiluminescent enzyme immunoassay. Separately, a rat model of hemorrhagic conditions was generated and used to confirm the results obtained with autopsy-derived specimens. A positive correlation was observed between BMAL1 protein and serum EPO levels, but not between BMAL1 mRNA levels and serum EPO levels. We also noted that Per2 mRNA expression became elevated in humans who survived for > 3 h after acute hemorrhagic events, with subsequent decreases in serum EPO levels. The rat model showed that even short (30-min) intervals of blood loss yielded increases in both Bmal1 mRNA and serum EPO levels; longer (60-min) intervals resulted in increases in Per2 mRNA expression along with decreases in serum EPO. Thus, the acute-stage human hemorrhage cases and the rat hemorrhage model yielded similar tendencies for clock gene expression and EPO secretion. In conclusion, our results indicated that clock genes are involved in the regulation of EPO production during the early stages of hypoxia/ischemia resulting from the acute hemorrhagic events.

Topics: Acute Disease; Animals; ARNTL Transcription Factors; Disease Models, Animal; Erythropoietin; Gene Expression; Hemorrhage; Humans; Male; Period Circadian Proteins; Postmortem Changes; Rats, Sprague-Dawley; RNA, Messenger; Shock, Hemorrhagic; Time Factors

In patients with acute symptomatic moyamoya (<2 weeks), the feasibility of a combination therapy of multiple burr hole procedure under local anesthesia and intravenous erythropoietin pretreatment was assessed. We also identified the factors associated with transdural revascularization.. In this prospective single-arm study, perfusion-impaired patients presenting with transient ischemic attack or acute cerebral infarction were assessed. Combination therapy was performed to patients lacking transdural collaterals. Primary outcomes were evaluated clinically with modified Rankin Scale scores and radiologically with revascularization success (transhemispheric, trans-burr hole, and sufficient revascularizations [filling ≥33% of ipsilateral supratentorium]) at 6 months. Treatment-related adverse events were analyzed in 3 phases: pre burr hole, post burr hole, and after-discharge as secondary outcome. Factors associated with sufficient revascularization were investigated.. Fifty hemispheres from 37 patients were included. Compared with discharge, modified Rankin Scale score at 6 months significantly improved (2.0 [0.0-5.0] versus 1.0 [0.0-4.0];. Combination therapy allows safe and effective revascularization in moyamoya patients with acute ischemic presentation.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT03162588.

Topics: Acute Disease; Adult; Cerebral Infarction; Cerebral Revascularization; Combined Modality Therapy; Erythropoietin; Feasibility Studies; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Moyamoya Disease; Odds Ratio; Prospective Studies; Trephining

Acute and severe anemia of inflammation (AI) is a common complication of various clinical syndromes, including fulminant infections, critical illness with multiorgan failure, and exacerbations of autoimmune diseases. Building on recent data showing beneficial results with isocitrate treatment for chronic low-grade AI in a rat model, we used a mouse model of acute and severe AI induced by intraperitoneal heat-killed Brucella abortus to determine if isocitrate would be effective in this more stringent application. Inflamed mice treated with isocitrate developed an early but transient improvement in hemoglobin compared to solvent-treated controls, with a robust improvement on day 7, and only a trend towards improvement by day 14. Reticulocyte counts were increased in treated mice transiently, with no significant difference by day 21. Serum erythropoietin (EPO) levels were similar in treated versus control mice, indicating that isocitrate increased sensitivity to EPO. Serum and tissue iron levels showed no significant differences between the treated and control mice, ruling out improved iron availability as the cause of the increased response to endogenous EPO. Compared to the milder rat model, much higher doses of isocitrate were required for a relatively modest benefit.

Topics: Acute Disease; Anemia; Animals; Brucella abortus; Brucellosis; Disease Models, Animal; Erythropoiesis; Erythropoietin; Hepcidins; Inflammation; Iron; Isocitrates; Male; Mice

Although previous reports suggest that an elevated endogenous erythropoietin (EPO) level is associated with worse clinical outcomes in chronic heart failure (HF) patients, the prognostic implication of EPO in patients with acute decompensated HF (ADHF) and underlying mechanisms of the high EPO level in severe HF patients who have a poor prognosis remain unclear.. We examined 539 consecutive ADHF patients with EPO measurement on admission from our registry. During a median follow-up period of 329 days, a higher EPO level on admission was independently associated with worse clinical outcomes [hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.06-1.48, P = 0.008], and haemoglobin level was the strongest determinant of EPO level (P < 0.001), whereas estimated glomerular filtration rate (eGFR) was not significant in multivariate regression analysis. In the anaemic subgroup of 318 patients, a higher EPO level than expected on the basis of their haemoglobin level was related to increased adverse events (HR 1.63, 95% CI 1.05-2.49, P = 0.028). Moreover, estimated plasma volume excess rate was positively associated with EPO level (P = 0.003), and anaemic patients with a higher than expected EPO level tended to have a higher estimated plasma volume excess rate and plasma lactate level, and lower systemic oxygen saturation level with the preservation of the reticulocyte production index than those with a lower than expected EPO level.. A high EPO level predicts long-term worse clinical outcomes in ADHF patients, independent of anaemia and impaired renal function. Anaemia and hypoxia due to severe congestion may synergistically contribute to a high EPO level in high-risk HF patients.

Topics: Acute Disease; Aged; Aged, 80 and over; Anemia; Cause of Death; Cohort Studies; Disease Progression; Erythropoietin; Female; Glomerular Filtration Rate; Heart Failure; Hemoglobins; Humans; Lactic Acid; Male; Middle Aged; Mortality; Multivariate Analysis; Oximetry; Plasma Volume; Prognosis; Proportional Hazards Models; Prospective Studies; Registries; Renal Insufficiency

Hyperhemolysis is a serious transfusion reaction, most often described in patients with hemoglobinopathies. Hyperhemolysis is characterized by the destruction of host red blood cells (RBCs), in addition to donor RBCs, via an unknown mechanism.. We present the case of a 58-year-old woman with treated human immunodeficiency virus and a normal hemoglobin (Hb) electrophoresis who developed hyperhemolysis in the setting of a delayed hemolytic transfusion reaction (DHTR).. The patient was ABO group B and had a previously identified anti-Fy(b) alloantibody. After transfusion of Fy(b)--RBCs, she developed a DHTR and was found to have anti-E, anti-C(w), anti-s, and an additional antibody to an unrecognized high-frequency RBC alloantigen. Subsequent transfusion of ABO-compatible RBCs that were negative for Fy(b), E, C(w), and s antigens resulted in immediate intravascular hemolysis. In the absence of bleeding, her hematocrit (Hct) decreased to 10.2%. An extensive serologic evaluation failed to identify the specificity of the high-frequency antibody. Severe hemolytic reactions also occurred despite pretransfusion conditioning with eculizumab. The Hct and clinical symptoms slowly improved after the cessation of transfusions and treatment with erythropoietin and steroids. This case demonstrates several noteworthy features including hyperhemolysis in a patient without a Hb disorder, the development of an antibody to an unknown RBC antigen, and the failure of eculizumab to prevent intravascular hemolysis after transfusion.. Hyperhemolysis is not restricted to patients with hemoglobinopathies. Whether eculizumab offers any benefit in the hyperhemolysis syndrome or in the prevention of intravascular hemolysis due to RBC alloantibodies remains uncertain.

Topics: Acute Disease; Adrenal Cortex Hormones; Anemia, Hemolytic; Antibodies, Monoclonal, Humanized; Blood Group Incompatibility; Cholecystitis; Coombs Test; Drug Resistance; Duffy Blood-Group System; Dyspnea; Erythrocyte Transfusion; Erythropoietin; Female; Hematocrit; Hepatitis C, Chronic; HIV Infections; Humans; Isoantibodies; Middle Aged; Oxygen Inhalation Therapy; Premedication; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface; Syndrome; Transfusion Reaction

We performed high-dose erythropoietin therapy (hEPO) for acute encephalopathy or encephalitis (AE), and evaluated its safety and efficacy.. We performed hEPO in AE patients with widespread lesions demonstrated by diffusion-weighted imaging, and prospectively investigated changes in hemoglobin levels, adverse events, changes in images, and developmental quotients.. All four patients showed neither an increase in the hemoglobin level nor adverse event possibly related to hEPO. One patient with acute encephalitis showed resolution of the lesion and normal developmental quotient. Two patients who had acute encephalopathy with febrile convulsive status epilepticus showed mild cerebral atrophy in the recovery phase;one had a normal developmental quotient. The patient with acute necrotizing encephalopathy including a brainstem lesion avoided acute-phase death.. Two patients showed no sequelae despite images indicating widespread abnormality. hEPO could be performed safely in patients with AE, however further trials are necessary concerning its efficacy.

Topics: Acute Disease; Child, Preschool; Diffusion Magnetic Resonance Imaging; Electroencephalography; Encephalitis; Erythropoietin; Female; Humans; Infant; Male; Treatment Outcome

Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-α co-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-α is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-α agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.

Topics: Acute Disease; Anemia; Anemia, Hemolytic; Animals; Butyrates; Cell Culture Techniques; Cells, Cultured; Chromatin; Chronic Disease; Disease Models, Animal; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Fenofibrate; Glucocorticoids; Humans; Liver; Mice; Phenylhydrazines; Phenylurea Compounds; PPAR alpha; Receptors, Glucocorticoid; Signal Transduction

A biomarker of hypoxic exposure would be useful in clinical diagnosis and prognosis. Acute hypoxia stimulates large increases in serum erythropoietin (EPO), and EPO induces formation of characteristic enlarged red blood cells (RBCs). The presence of large RBCs perturbs red cell distribution width (RDW).. Using a >2M patient medical claims database, the human pathome was scanned for diseases where RDW rose 0-50days following a new diagnosis. The course of RDW after selected diagnoses was visualized by registering RDW measurements by diagnosis date.. Acute hemorrhage, which provokes EPO-driven erythropoiesis, is followed by increases in RDW but not mean cell volume (MCV). Similar RDW increases follow many acute diseases with risk of hypoxia, including heart failure, pneumonia, atelectasis, pulmonary embolism, pneumothorax, and sepsis. Elevations reach maximum within 1month after onset and subside to pre-disease levels about 6months later. Unlike the case with iron-deficiency anemia (IDA), RDW elevations after hypoxia-associated diseases are unaccompanied by discernible change in average RBC size.. As predicted by a model risk pathway linking hypoxia to formation of enlarged RBCs via EPO, acute hypoxemia-related disease episodes induce change in RBC size distribution. Further study is needed to explore whether a more sensitive and specific signal can be extracted from the fine structure of the RBC size distribution routinely measured in automated hemocytometers.

Topics: Acute Disease; Biomarkers; Cell Size; Erythrocyte Indices; Erythrocytes; Erythropoietin; Humans; Hypoxia

The rapid death of many spinal motor neurons after nerve root avulsion injury results in limited functional recovery following replantation surgery of avulsed nerves into the spinal cord. Therefore, we investigated the neuroprotective effect of erythropoietin (EPO) on motor neurons after nerve root avulsion injury using a rat model.. After C6 nerve root avulsion injury, EPO (2680 U/kg) was injected subcutaneously once a day for 3 consecutive days with various starting time points. At 28 and 56 days after injury, histological and immunohistological investigations were performed.. EPO-treated rats showed a significant increase in the number of surviving motor neurons at day 28 when the initial dose was started within 96 h after injury. In EPO-treated rats, superoxide formation in the motor neurons and proliferation of microglia were markedly suppressed in the acute phase. GAP-43-positive surviving motor neurons were significantly increased in EPO-treated rats at day 28. However, at 56 days after surgery, EPO-treated rats showed a much greater decrease of surviving motor neurons compared with those at day 28.. The neuroprotective effect of EPO is not long lasting, but may prolong the time before replantation surgery.

Topics: Acute Disease; Animals; Cell Survival; Cervical Vertebrae; Chronic Disease; Disease Models, Animal; Erythropoietin; Injections, Subcutaneous; Male; Microglia; Motor Neurons; Nerve Regeneration; Neuroprotective Agents; Radiculopathy; Random Allocation; Rats, Sprague-Dawley; Receptors, Erythropoietin; Spinal Cord; Superoxides; Treatment Outcome

Low levels of hemoglobin (Hb) are not rare in patients who refuse blood components but this case is unique due to the severity of anemia and the possibility that her previous episode of acute normovolemic hemodilution has influenced her outcome.. We report an incident involving acute blood loss after surgery with an extremely low hematocrit. Despite her Hb levels (2.8 g/dL) she remained lucid, expressing her wish not to receive transfusion. When the patient lost consciousness (Hb, 1.4 g/dL) she was promptly sedated, curarized, and put onto mechanical controlled ventilation. Aggressive erythropoietin therapy increased the patient's Hb level by 240% in 10 days, despite a high platelet count. This case demonstrates that critical levels of oxygen delivery may be lower than previously thought possible.. This case is an example of the resilience of the human body in an extreme circumstance. It might be the most severe case of anemia that a person has survived without any sequelae.

Topics: Acute Disease; Adult; Anemia; Blood Transfusion; Erythropoietin; Female; Humans; Jehovah's Witnesses; Postoperative Hemorrhage; Respiration, Artificial; Severity of Illness Index; Treatment Refusal

Tissue hypoxia likely contributes to anemia-induced organ injury and mortality. Severe anemia activates hypoxia-inducible factor (HIF) signaling by hypoxic- and neuronal nitric oxide (NO) synthase- (nNOS) dependent mechanisms. However, organ-specific hemoglobin (Hb) thresholds for increased HIF expression have not been defined. To assess organ-specific Hb thresholds for tissue hypoxia, HIF-α (oxygen-dependent degradation domain, ODD) luciferase mice were hemodiluted to mild, moderate, or severe anemia corresponding to Hb levels of 90, 70, and 50 g/l, respectively. HIF luciferase reporter activity, HIF protein, and HIF-dependent RNA levels were assessed. In the brain, HIF-1α was paradoxically decreased at mild anemia, returned to baseline at moderate anemia, and then increased at severe anemia. Brain HIF-2α remained unchanged at all Hb levels. Both kidney HIF-1α and HIF-2α increased earlier (Hb ∼70-90 g/l) in response to anemia. Liver also exhibited an early HIF-α response. Carotid blood flow was increased early (Hb ∼70, g/l), but renal blood flow remained relatively constant, only increased at Hb of 50 g/l. Anemia increased nNOS (brain and kidney) and endothelia NOS (eNOS) (kidney) levels. Whereas anemia-induced increases in brain HIFα were nNOS-dependent, our current data demonstrate that increased renal HIFα was nNOS independent. HIF-dependent RNA levels increased linearly (∼10-fold) in the brain. However, renal HIF-RNA responses (MCT4, EPO) increased exponentially (∼100-fold). Plasma EPO levels increased near Hb threshold of 90 g/l, suggesting that the EPO response is sensitive. Collectively, these observations suggest that each organ expresses a different threshold for cellular HIF/NOS hypoxia responses. This knowledge may help define the mechanism(s) by which the brain and kidney maintain oxygen homeostasis during anemia.

Topics: Acute Disease; Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Biomarkers; Brain; Cerebrovascular Circulation; Disease Models, Animal; Erythropoietin; Hemodilution; Hemodynamics; Hemoglobins; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Liver; Luciferases, Firefly; Mice; Mice, Transgenic; Monocarboxylic Acid Transporters; Muscle Proteins; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Recombinant Fusion Proteins; Renal Circulation; Severity of Illness Index

Approximately one-half of patients with inflammatory bowel disease (IBD) suffer from anemia, with the most prevalent cause being iron deficiency. Accompanying the anemia are increases in erythropoietin, a plasma protein that can initiate the feedback production of new red blood cells. Anemia also occurs in animal models that are used to investigate the mechanisms of IBD; however, the extent to which iron deficiency produces the anemia in these animal models is unknown. Also unknown in the different animal models of IBD is whether the anemia upregulates the production of erythropoietin or, alternatively, whether a decrease in erythropoietin contributes to the induction of anemia.. Two mouse models of colitis were used in this study: (1) acute 6-day ingestion of dextran sodium sulfate and (2) T-cell transfer into lymphopenic recipient mice. Measurements included indices of colitis severity, hematocrit, blood hemoglobin, plasma erythropoietin, serum iron concentration, plasma iron-binding capacities, transferrin saturation, and tissue iron concentrations.. Both models of colitis induced significant decreases in hematocrit, blood hemoglobin, and transferrin saturation, with the spleen and liver showing a decrease in iron content in the T-cell transfer model. Additionally, both models of colitis demonstrated significant increases in plasma erythropoietin and plasma iron-binding capacities.. The measurements of iron, whether in acute (dextran sodium sulfate) or chronic (T-cell transfer) models of colitis, were generally consistent with iron-deficient anemia, with large increases in erythropoietin indicative of tissue hypoxia. These changes in animal models of colitis are similar to those found in human IBD.

Topics: Acute Disease; Anemia; Animals; Chronic Disease; Colitis; Dextran Sulfate; Disease Models, Animal; Erythropoietin; Homeodomain Proteins; Humans; Interleukin-10; Iron; Mice; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes

To investigate the relation between the need for red blood cell transfusion and serum levels of soluble-Fas, erythropoietin and inflammatory cytokines in critically ill patients with and without acute kidney injury.. We studied critically ill patients with acute kidney injury (n=30) and without acute kidney injury (n=13), end-stage renal disease patients on hemodialysis (n=25) and healthy subjects (n=21). Serum levels of soluble-Fas, erythropoietin, interleukin 6, interleukin 10, iron status, hemoglobin and hematocrit concentration were analyzed in all groups. The association between these variables in critically ill patients was investigated.. Critically ill patients (acute kidney injury and non-acute kidney injury patients) had higher serum levels of erythropoietin than the other groups. Hemoglobin concentration was lower in the acute kidney injury patients than in other groups. Serum soluble-Fas levels were higher in acute kidney injury and end-stage renal disease patients. Critically ill patients requiring red blood cell transfusions had higher serum levels of soluble-Fas (5,906±2,047 and 1,920±1,060; p<0.001), interleukin 6 (518±537 and 255+502; p=0.02) and interleukin 10 (35.8±30.7 and 18.5±10.9; p=0.02), better iron status and higher mortality rates in the first 28 days in intensive care unit. Serum soluble-Fas levels were independently associated with the number of red blood cell units transfused (p=0.02). Serum soluble-Fas behaved as an independent predictor of the need for red blood cell transfusion in critically ill patients (p=0.01).. Serum soluble-Fas level is an independent predictor of the need for red blood cell transfusion in critically ill patients with or without acute kidney injury. Further studies are warranted to reconfirm this finding.

Topics: Acute Disease; Adult; Biomarkers; Case-Control Studies; Critical Illness; Enzyme-Linked Immunosorbent Assay; Erythrocyte Transfusion; Erythropoietin; fas Receptor; Female; Humans; Interleukins; Male; Middle Aged

Erythropoietin (EPO) preserves arterial oxygen content by controlling red blood cell and plasma volumes. Synthesis of EPO was long thought to relate inversely to renal oxygenation, but in knockout mice, brain and skin have been identified as essential for the acute hypoxic EPO response. Whether these findings apply to humans remains unknown. We exposed healthy young subjects to hypoxia (equivalent to 3800 m) and measured EPO in arterial and jugular venous plasma and in cerebrospinal fluid. To examine the role of the skin for EPO production during hypoxia, subjects were exposed to 8 h of hypobaric hypoxia with or without breathing oxygen-enriched air to ensure systemic normoxemia. With 9 h of hypoxia, arterial EPO increased (from 6.0±2.2 to 22.0±6.0 mU/ml, n=11, P<0.0001) and jugular venous EPO displayed a similar response (to 22.2±6.0 mU/ml, n=11). Thus, the arterio-jugular venous EPO difference was unaffected by hypoxia and also in cerebrospinal fluid EPO remained stable following hypoxic exposure (0.33±0.15 mU/ml, n=9 in normoxia vs. 0.41±0.20 mU/ml, n=9 in hypoxia, P=0.40). No change in plasma EPO was observed when only skin was exposed to hypobaric hypoxia (n=8). Thus, neither dermal oxygen exposure nor cerebral EPO production appears to be important for the systemic EPO response to acute hypoxia in healthy humans.

Topics: Acute Disease; Adult; Brain; Erythropoietin; Female; Humans; Hypoxia; Male; Skin

To evaluate the effect of pretreatment with erythropoietin (EPO) on disordered pro- and anti- inflammatory balance in rats with severe acute pancreatitis (SAP) and explore the underlying mechanisms.. Ninety healthy male SD rats were randomized equally into sham-operated group, SAP group and EPO pretreatment group. SAP model was induced in the latter two groups by retrograde injection of 1 ml/kg 3.5% sodium traurocholate into the biliopancreatic duct. In EPO group, 3000 U/kg EPO (1000 U/ml) was administered intravenously 1 h before SAP, and normal saline was administered in the other two groups. Serum amylase activity, interleukin-10 (IL-10)and IL-18 levels were measured at different time points after the operation. The translocation and activation of nuclear factor-κB (NF-κB) in the pancreatic tissue was detected using immunofluorescence staining, and pancreatic pathologies were evaluated.. Compared with SAP group, EPO group showed a markedly decreased activation rate of NF-κB after SAP except for 12 h (P<0.05), significantly decreased serum amylase activity at 3, 6, and 12 h (P<0.05) and decreased serum IL-18 levels at 3, 6, 24 h (P<0.05), whereas serum IL-10 underwent no significant changes. The rats in EPO group showed an obviously milder pancreatic pathology than those in SAP group at 6, 12, and 24 h (P<0.05).. EPO can effectively inhibit NF-κB activation by regulating the inflammatory mediators and restoring the pro-and anti-inflammatory balance to alleviate SAP in rats.

Topics: Acute Disease; Animals; Cytokines; Erythropoietin; Interleukin-10; Interleukin-18; Male; NF-kappa B; Pancreatitis; Rats; Rats, Sprague-Dawley

To investigate intestinal motility changes due to uremia, and the effect of pretreatment with erythropoietin.. This randomized control study was conducted in the Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt from September 2010 to July 2011. Forty adult female Wistar albino rats were allocated into 3 groups: control group, gentamicin-treated group, receiving intraperitoneal gentamicin sulphate (100 mg/kg for 5 days), and erythropoietin-gentamicin-treated group, receiving subcutaneous erythropoietin (1000 IU/kg for 3 days) prior to gentamicin injection. Isolated segments of duodenum and descending colon was subjected to in vitro motility study. Plasma creatinine and urea were assayed.. Induction of acute renal failure by gentamicin treatment resulted in a significant decrease in frequency of contraction of the duodenum and descending colon, an increase in the average duration of contraction of the duodenum, and a significant decrease in the average force of contraction in the descending colon. Moreover, the average force of contraction in response to acetylcholine was significantly decreased in the duodenum. The erythropoietin-gentamicin-treated group revealed a significant decrease in plasma creatinine and urea, and a significant increase in the duodenal average force of contraction and motility index, and colonic frequency. The duodenal absolute and average forces of contraction after acetylcholine increased significantly.. Acute uremia impairs small and large intestinal motility, probably due to uremic toxins and autonomic dysfunction. Erythropoietin pretreatment protected against intestinal dysmotility through the improvement of renal function and its neurotropic action.

Topics: Acute Disease; Animals; Colon; Creatinine; Disease Models, Animal; Duodenum; Erythropoietin; Female; Gastrointestinal Motility; Gentamicins; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Uremia

This study was conducted to investigate the effects of erythropoietin (Epo) on both acute and chronic limb ischemia (ALI and CLI) and to evaluate the differences in mechanisms according to the method of Epo administration. Hindlimb ischemia was made in BALB/c mice with femoral artery ligation. The mice were divided into four groups: Group 1 (control, no treatment), Group 2 (ALI, early multiple doses), Group 3 (ALI, early single high dose), Group 4 (CLI, late multiple doses). Blood flow ratio significantly increased in Group 2 in 4 weeks. Expression of pAkt and Erythropoietin receptor were significantly higher in Group 2 on postoperative day (POD) 7. The number of CD31- and vascular endothelial growth factor-positive cells were significantly higher in Group 2 on POD 7 and 56. Group 3 and 4 showed a tendency of higher cell counts than the control. The early sustained Epo was effective in improving blood flow through angiogenesis. In chronic phase, weekly multiple dosing of Epo induced angiogenesis, however, the blood flow ratio did not increase significantly. The results of this study suggest that Epo administration during the acute phase followed by maintenance for several days may be important for increasing blood flow and angiogenesis.

Topics: Acute Disease; Animals; Chronic Disease; Erythropoietin; Hindlimb; Ischemia; Laser-Doppler Flowmetry; Male; Mice; Mice, Inbred BALB C; Neovascularization, Physiologic; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Vascular Endothelial Growth Factor A

Erythropoietin provides cellular protection by inhibiting apoptosis. Myocardial damage related to the cardiac ischemia is more prominent especially in the first 6 h. In the present study, circulatory erythropoietin levels in response to cardiac ischemia were evaluated.. Patients with stable angina who underwent balloon angioplasty (study group, n = 55) and hospitalized for coronary angiography (as control group, n = 23) were enrolled into the study. Serum erythropoietin levels were measured in both groups in baseline, 6 and 18 h after the procedure.. Coronary balloon inflation time was accepted as duration of myocardial ischemia. Study group showed significant erythropoietin reduction at sixth hour compared to control group. Erythropoietin reduction at sixth hour was significantly correlated with duration of myocardial ischemia.. Decreased circulatory erythropoietin levels in the early phase of acute cardiac ischemia may accelerate the apoptotic activity. Recombinant erythropoietin replacement to prevent erythropoietin decrease following cardiac ischemia may have negative effect on myocyte loss.

Topics: Acute Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Myocardial Ischemia

To study levels of hepsidine (Hp), hypoxia-inducible factor-1alpha (HIF-1alpha), erythropoietin (EP) and ferritin in patients with acute leukemia (AL), effects of protein fractions of homogenate of blastic cells (BC) on regulatory proteins studied.. Depending on leukocyte count in the onset of AL, 70 patients with first ever diagnosed AL were divided into two groups: group 1 - 17 patients with leukocyte count > 30 x 10(9)/l, group 2 - 53 patients with leukocyte count < 30 x 10(9)/l. Serum and leukocyte parameters were studied before treatment, during the treatment with cytostatic drugs, in the course of myelotoxic agranulocytosis (MTA), after normalization of hemograms. EP was detected with enzyme immunoassay, serum and leukocyte ferritin - with radioimmunoassay; HIF-1alpha, Hp - sandwich enzyme immunoassay using monospecific antisera and monoclonal antibodies against relevant antigens. Leukocytes were isolated in ficol and verografin solutions density gradient. Chromatographic division of the protein fractions in 3 patients with leukocytosis in AL onset and leukocytes of 3 donors was made by the method of preparative isoelectrofocusing of BC and leukocytes on LKB colon (Sweden). Effects of these fractions were studied on 11 plasma samples from hematological patients and 4 plasma samples from patients with normal hemopoiesis.. Leukocytosis patients with initial AL have serum ferritin, Hp and HIF-1alpha levels about 2-5 times lower than patients without leukocytosis. Cytostatic treatment raises an HIF-1alpha level in BC about 15-fold (85.8 +/- 24.5 pg/ml), in the study group - 3-fold (15.2 +/- 3.3 pg/ml). The highest EP levels were seen in MTA. It is detected that protein fractions isolated from leukocytes of patients with leukocytosis in the disease onset raise HIF-1alpha content irrespective of HIF-1alpha presence in the fraction. Patients free of hematological diseases have no changes of the above proteins.. Great difficulties exist in ferritin and Hp levels between AL patients with leukocytosis in the onset of the disease and without of leukocytosis. The study of leukocytes suggests that tumor cells of such patients contain compounds which can regulate production of HIF-1alpha, Hp and ferritin.

Topics: Acute Disease; Erythropoietin; Ferritins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Leukemia; Leukocytosis; Radioimmunoassay

During the early post transplant period, the tubular epithelium is the main target of injuries including ischemia reperfusion and toxicity effects from calcineurin inhibitors. Taking into account the tissue protective effects of erythropoietin mediated through its antiapoptotic properties, we tested whether administration of recombinant human erythropoietin protects against acute cyclosporine nephrotoxicity. Four groups of five rats were intraperitoneally treated over 28 days with 100UI/Kg/48h Epoetin beta (15mg/kg/day CsA diluted in olive oil, 100UI/Kg/48h Epoetin beta+15mg/kg/day CsA, or olive oil. Histological changes due to tubular necrosis were evaluated with Masson'Trichrome staining. Apoptotic nuclei in kidneys were detected using the Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) method. Phospho-Akt, Akt, cleaved caspase 3 and non cleaved caspase 3 expression were evaluated using immunblotting. We demonstrate that recombinant human erythropoietin (epoetin beta) improves renal function and protects against acute tubular injury. Our data suggest that this nephroprotective effect is mediated by Akt activation and inhibition of tubular apoptosis. Indeed, western blotting analysis of caspase 3 cleavage and Akt phosphorylation demonstrates that rhEPO activate Akt signaling and inhibits caspase 3 cleavage induced by CsA. TUNEL staining confirms that rhEPO inhibits CsA-induced tubular apoptosis. In conclusion, we describe here a new potential target of recombinant human erythropoietin and our results provide an interesting framework for further nephroprotective therapies based on recombinant human erythropoietin.

Topics: Acute Disease; Animals; Apoptosis; Biomarkers; Blotting, Western; Caspase 3; Creatinine; Cyclosporine; Cytoprotection; Disease Models, Animal; Erythropoietin; Humans; In Situ Nick-End Labeling; Kidney Cortex Necrosis; Kidney Tubules; Male; Necrosis; Phosphorylation; Protective Agents; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction

Whether and when to intervene and with which therapeutic agent are key questions physicians face daily in managing patients. Biomarkers are emerging to define the course of acute kidney injury and offer an opportunity to provide targeted interventions. The EARLYARF study by Endre et al. provides a glimpse of the challenges and opportunities that lie ahead.

Topics: Acute Disease; Alkaline Phosphatase; Biomarkers; Creatinine; Drug Administration Schedule; Erythropoietin; gamma-Glutamyltransferase; Hematinics; Humans; Intensive Care Units; Kidney Diseases; Patient Selection; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Triage

The impact of epoetin beta (recombinant human erythropoietin) on brain infarction area (BIA) and neurological status in a rat model of acute ischemic stroke (IS) induced by distal left internal carotid artery occlusion was investigated.. Adult male Sprague-Dawley rats (n = 30) were categorized into group 2 (IS only) and group 3 (IS plus intraperitoneal erythropoietin 5000 IU/kg at 0, 12, and 24 hours after IS). Healthy Sprague-Dawley rats (n = 10) served as group 1.. Analysis of brain tissues showed larger BIA in group 2 than in group 3 (P < 0.001). Corner test identified highest frequency of left turn in group 2 (P < 0.05). The mRNA expressions of Bax, caspase 3, interleukin 18, toll-like receptor 4, and plasminogen activator inhibitor 1 were highest, whereas Bcl-2 was lowest in group 2 (P < 0.05). Lower CXCR4 and stromal cell-derived factor 1 expressions were noted in group 2 than in group 3 (P < 0.01). Immunohistofluorescence staining showed lower expressions of CXCR4, stromal cell-derived factor 1, von Willebrand factor, and doublecortin with higher number of apoptotic nuclei in group 2 than in group 3 (P < 0.001). Immunohistochemical staining demonstrated lower cellular proliferation and number of small vessels with higher glial fibrillary acid protein expression in group 2 than in group 3 (P < 0.01).. Erythropoietin significantly limited BIA and improved sensorimotor dysfunction after acute IS.

Topics: Acute Disease; Animals; Apoptosis; Brain Infarction; Brain Ischemia; Disease Models, Animal; Doublecortin Protein; Encephalitis; Erythropoietin; Hematinics; Humans; Male; Neovascularization, Physiologic; Neurogenesis; Oxidative Stress; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Recovery of Function

To determine the aqueous concentration of erythropoietin (EPO) in patients with and without glaucoma.. Prospective, comparative control study. Concentrations of EPO in the aqueous humor were measured using ELISA kits from 75 patients, of whom 55 had glaucoma (14 primary acute angle-closure glaucoma, PAACG; 26 primary chronic angle-closure glaucoma, PCACG; 11 primary open-angle glaucoma, POAG; 4 neovascular glaucoma, NVG), and 20 had cataract only as control.. EPO concentrations in eyes with glaucoma (71.0 +/- 12.0 mU/mL) were significantly higher than those in eyes with cataract (6.4 +/- 0.8 mU/mL, P < 0.001). There were no significant differences (P = 0.421) between PCACG (28.84 +/- 3.9 mU/mL) and POAG (20.2 +/- 2.0 mU/mL); however, EPO concentrations in eyes with PAACG (118.5 +/- 14 mU/mL) were significantly higher than these two chronic subtypes of glaucoma (P < 0.001, respectively). Unusually high EPO concentrations were detected in four eyes with NVG (319.5 +/- 47.7 mU/mL). No effect of age, gender, different eyes, body mass index of the aqueous humor EPO concentration could be detected (P > 0.05). No significant correlation was found between aqueous humor and plasma EPO concentrations in PAACG and control group (P = 0.285, 0.500, respectively).. Our prospective study suggests that the aqueous humor EPO concentrations are increased in eyes with glaucoma.

Topics: Acute Disease; Aged; Aqueous Humor; Case-Control Studies; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Glaucoma, Angle-Closure; Glaucoma, Neovascular; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Prospective Studies

Core-binding factor leukemia (CBFL) is a subgroup of acute myeloid leukemia (AML) characterized by genetic mutations involving the subunits of the core-binding factor (CBF). The leukemogenesis model for CBFL posits that one, or more, gene mutations inducing increased cell proliferation and/or inhibition of apoptosis cooperate with CBF mutations for leukemia development. One of the most common mutations associated with CBF mutations involves the KIT receptor. A high expression of KIT is a hallmark of a high proportion of CBFL. Previous studies indicate that microRNA (MIR) 222/221 targets the 3' untranslated region of the KIT messenger RNA and our observation that AML1 can bind the MIR-222/221 promoter, we hypothesized that MIR-222/221 represents the link between CBF and KIT. Here, we show that MIR-222/221 expression is upregulated after myeloid differentiation of normal bone marrow AC133(+) stem progenitor cells. CBFL blasts with either t(8;21) or inv(16) CBF rearrangements with high expression levels of KIT (CD117) display a significantly lower level of MIR-222/221 expression than non-CBFL blasts. Consistently, we found that the t(8;21) AML1-MTG8 fusion protein binds the MIR-222/221 promoter and induces transcriptional repression of a MIR-222/221-LUC reporter. Because of the highly conserved sequence homology, we demonstrated concomitant MIR-222/221 down-regulation and KIT up-regulation in the 32D/WT1 mouse cell model carrying the AML1-MTG16 fusion protein. This study provides the first hint that CBFL-associated fusion proteins may lead to up-regulation of the KIT receptor by down-regulating MIR-222/221, thus explaining the concomitant occurrence of CBF genetic rearrangements and overexpression of wild type or mutant KIT in AML.

Topics: AC133 Antigen; Acute Disease; Adolescent; Adult; Aged; Animals; Antigens, CD; Cell Differentiation; Cell Line, Tumor; Cells, Cultured; Core Binding Factor Alpha 2 Subunit; Core Binding Factor alpha Subunits; Down-Regulation; Erythropoietin; Female; Flow Cytometry; Glycoproteins; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; Male; MicroRNAs; Middle Aged; Mutation; Oncogene Proteins, Fusion; Peptides; Proto-Oncogene Proteins c-kit; Reverse Transcriptase Polymerase Chain Reaction; RUNX1 Translocation Partner 1 Protein; U937 Cells

Topics: Acute Disease; Anemia; Blood Transfusion; Chronic Disease; Erythropoietin; Hemodynamics; Humans; Perioperative Care; Recombinant Proteins

Individually, the cytokines erythropoietin (EPO) and insulin-like growth factor-I (IGF-I) have both been shown to reduce neuronal damage significantly in rodent models of cerebral ischemia. The authors have previously shown that EPO and IGF-I, when administered together, provide acute and prolonged neuroprotection in cerebrocortical cultures against N-methyl-D-aspartate-induced apoptosis. The aim of this study was to determine whether intranasally applied EPO plus IGF-I can provide acute neuroprotection in an animal stroke model and to show that intranasal administration is more efficient at delivering EPO plus IGF-I to the brain when compared with intravenous, subcutaneous, or intraperitoneal administration.. The EPO and IGF-I were administered intranasally to mice that underwent transient middle cerebral artery occlusion (MCAO). Stroke volumes were measured after 1 hour of MCAO and 24 hours of reperfusion. To evaluate the long-term effects of this treatment, behavioral outcomes were assessed at 3, 30, 60, and 90 days following MCAO. Radiography and liquid scintillation were used to visualize and quantify the uptake of radiolabeled 125I-EPO and 125I-IGF-I into the mouse brain after intranasal, intravenous, subcutaneous, or intraperitoneal administration.. Intranasal administration of EPO plus IGF-I reduced stroke volumes within 24 hours and improved neurological function in mice up to 90 days after MCAO. The 125I-EPO and 125I-IGF-I were found in the brain within 20 minutes after intranasal administration and accumulated within the injured areas of the brain. In addition, intranasal administration delivered significantly higher levels of the applied 125I-EPO and 125I-IGF-I to the brain compared with intravenous, subcutaneous, or intraperitoneal administration.. The data demonstrate that intranasal EPO plus IGF-I penetrates into the brain more efficiently than other drug delivery methods and could potentially provide a fast and efficient treatment to prevent chronic effects of stroke.

Topics: Acute Disease; Administration, Intranasal; Animals; Disease Models, Animal; Drug Delivery Systems; Drug Therapy, Combination; Erythropoietin; Infarction, Middle Cerebral Artery; Insulin-Like Growth Factor I; Iodine Radioisotopes; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents

Hepcidin, a key iron-regulator secreted from the liver, consists of 25 amino acids (hepcidin-25), blocks iron release from macrophages via internalization and degradation of cellular iron exporter ferroportin, and restrains the use of iron in organs. Hepcidin mRNA and protein are also expressed in the human heart. A short form of hepcidin that lacks 5 amino-acid residues in the N-terminus (hepcidin-20) has been found in human serum, although its physiological role is unknown. Here, we successfully measured the serum levels of hepcidin-25 and hepcidin-20 in 12 patients with acute myocardial infarction (AMI) using surface-enhanced laser desorption ionization time of flight mass spectrometry. Among the selected 10 patients, whose blood samples were taken within 4 hours after a heart attack, all the patients showed elevated serum levels of hepcidin-20 [between 31.7 and 285.1 arbitrary unit (AU); normal level < 9.3 AU], while 8 patients showed high levels of hepcidin-25 (9.3-271.4; normal < 25.5 AU). The hepcidin-20 level was decreased to nearly the normal level on day 7 (range of 2.9 to 12.5 AU) in the 12 patients, whereas the hepcidin-25 level remained high on day 7 in 8 patients. Furthermore, the elevated levels of hepcidin-25 and hepcidin-20 were not correlated with the serum levels of markers for inflammation, interleukin-6 and C-reactive protein, in the patients with AMI. In conclusion, the serum hepcidin-20 is transiently elevated in response to acute cardiac ischemia. Measurement of serum hepcidin-20, rather than hepcidin-25, is helpful for diagnosis of acute myocardial infarction.

Topics: Acute Disease; Adult; Aged; Amino Acid Sequence; Antimicrobial Cationic Peptides; Biomarkers; C-Reactive Protein; Creatine Kinase; Erythropoietin; Female; Hepcidins; Humans; Inflammation; Insulin; Interleukin-6; Male; Middle Aged; Molecular Sequence Data; Myocardial Infarction; Peptide Fragments; Sequence Homology, Amino Acid; Time Factors

We previously demonstrated that utilization of erythropoietin (r-EPO) did not significantly reduce blood utilization in trauma patients. We undertook this study to analyze blood utilization 1 year after r-EPO removal from our trauma service anaemia practice management guideline.. Electronic records of patients admitted to the trauma service were retrospectively reviewed for units of packed red blood cells (pRBCs) transfused and for units of r-EPO administered 12 months before the initiation of an anaemia practice guideline (PRE), 12 months during the use of an anaemia guideline (GUIDE), and 12 months following removal of r-EPO from the guideline (POST). Hospital acquisition cost was also reviewed for the respective time periods. Nominal data were analyzed using chi-squared or Fisher's exact tests, and interval data were compared using ANOVA followed by Tukey's test where appropriate. Results were considered significant for P<0.05.. Over the 3-year study period, 4881 patients were admitted to the trauma service and included in this study. The hospital length of stay, intensive care unit length of stay, and units of pRBC transfused were similar among all three groups. Group I (PRE) received a total of 228 doses of r-EPO at a cost of $102,600. Group II (GUIDE) received a total of 410 doses at a cost of $184,500. Group III (POST) received 28 doses of r-EPO at a cost of $12,600.. Removal of erythropoietin from our trauma service anaemia practice management guideline did not result in increased blood utilization. However, it yielded a hospital acquisition cost savings of $171,900.

Topics: Acute Disease; Adult; Analysis of Variance; Anemia; Cost Savings; Critical Care; Electronic Health Records; Erythrocyte Transfusion; Erythropoietin; Health Care Costs; Humans; Length of Stay; Middle Aged; Recombinant Proteins; Retrospective Studies; Trauma Centers; Wounds and Injuries

Renal ischemia and reperfusion injury leads to acute renal failure when proinflammatory and apoptotic processes in the kidney are activated. The increase in hypoxia-inducible transcription factor-alpha (HIF-alpha), an important transcription factor for several genes, can attenuate ischemic renal injury. We recently identified a novel WD-repeat protein designated Morg1 (MAPK organizer 1) that interacts with prolyl hydroxylase 3 (PHD3), an important enzyme involved in the regulation of HIF-1alpha and HIF-2alpha expression. While homozygous Morg1 -/- mice are embryonic lethal, heterozygous Morg1 +/- mice have a normal phenotype. We show here that Morg1 +/- were partially protected from renal ischemia-reperfusion injury compared with wild-type Morg1 +/+ animals. Morg1 +/- mice compared with wild-type animals revealed a stronger increase in HIF-1alpha and HIF-2alpha expression in the ischemic-reperfused kidney associated with enhanced serum erythropoietin levels. However, no significant expression of HIF-1alpha and HIF-2alpha was found in nonischemic kidneys without any difference between Morg1 +/- and Morg1 +/+ mice. Ischemic kidneys of Morg1 +/- mice expressed more erythropoietin mRNA than ischemic kidneys from wild-type animals. Renal ischemia in Morg1 +/- mice resulted in a decrease in renal inflammation and reduction of proinflammatory cytokines (MCP-1, IP-10, MIP-2) compared with wild-type mice. Furthermore, there was significantly less apoptosis and tubular damage in Morg1 +/- kidneys after ischemia-reperfusion, and this was also reflected in significantly improved renal function compared with wild-type. Thus Morg1 may be a novel therapeutic target to limit renal injury after ischemia-reperfusion.

Topics: Acute Disease; Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Blotting, Western; DNA, Complementary; Electrophoretic Mobility Shift Assay; Erythropoietin; Female; Heterozygote; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Kidney; Kidney Diseases; Kidney Function Tests; Mice; Mice, Inbred C57BL; Mice, Knockout; Pregnancy; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA

Topics: Acute Disease; Acute Kidney Injury; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cholesterol; Erythropoietin; Hepcidins; Humans; Peritoneal Dialysis; Time Factors

To detect serum erythropoietin (EPO) levels in patients with acute leukemia (AL) and iron deficient anemia (IDA) with moderate or severe anemia and explore the mechanism of anemia in these patients.. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of EPO in 59 patients with AL, among whom 15 had complete remission without anemia and 44 had moderate or severe anemia (including 12 receiving the initial treatment, 13 with complete remission and concurrent anemia, and 19 with bone marrow suppression). Serum EPO was also detected in 15 IDA patients and 12 healthy individuals.. The IDA patients and healthy individuals had similar serum EPO levels (P>0.05), and by comparison, the EPO levels were significantly increased in AL patients upon the initial treatment, those with bone marrow suppression and those with complete remission and anemia, but comparable between the latter 3 groups (P>0.05). Among the patients with complete remission, the EPO levels were significantly higher in anemic patients than in those without anemia (P<0.05), and the latter patients had similar EPO levels with the healthy individuals (P>0.05). In both AL and IDA patients with moderate or severe anemia, the serum EPO level was inversely correlated to the level of hemoglobin (r=-0.697 and -0.970, respectively, P<0.05).. AL patients with anemia have significantly higher serum EPO levels than healthy individuals. In AL and IDA patients with moderate or severe anemia, EPO levels are inversely correlated to the level of hemoglobin, suggesting the integrity of the EPO synthesis mechanism in AL patients. Serum EPO level is also associated with bone marrow function in addition to hypoxia and hemoglobin levels, and hematopoiesis deficit in the early stage may be the main cause of anemia.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Humans; Leukemia; Male; Middle Aged; Young Adult

The aim of this study was to clarify whether erythropoietin (EPO) with a retrobulbar administration could protect retinal ganglion cells (RGCs) from acute elevated intraocular pressure (IOP).. The anterior chamber of the right eye was cannulated, and the IOP was raised to 70 mm Hg for a duration of up to 60 min. One thousand (1000) units of recombinant erythropoietin (rhEPO) or vehicle solution was administered a retrobulbar injection immediately after the onset of the acute elevated IOP. After 1 week, RGCs were labeled with a commercially available retrograde tracer applied to the superior colliculi. Densities of surviving RGCs were estimated by counting retrograde-tracer-labeled cells in whole-mounted retinas. The ultrastructural changes of RGCs were observed by transmission electron microscope. Immunocytochemistry was used to detect EPO and erythropoietin receptor (EPOR) expression in the RGCs layer.. The acute elevated IOP could result in the loss of RGCs. The number of surviving RGCs per square millimeter in the eyes of the acute elevated IOP + rhEPO retrobulbar injection group was significantly higher than that in the eyes of the acute elevated IOP and acute elevated IOP + vehicle solution retrobulbar injection groups (P < 0.05). The number of the organelles in the RGCs plasm decreased, but some intact mitochondrian still existed in the RGCs plasm in the eyes of the acute elevated IOP + rhEPO retrobulbar injection group. The densities of EPO and EPOR expression of the RGCs layer in the eyes of the acute elevated IOP + rhEPO retrobulbar injection group were significantly higher than that in the eyes of the acute elevated IOP and acute elevated IOP + vehicle solution retrobulbar injection groups (P < 0.01).. EPO with a retrobulbar administration could protect RGCs from acute elevated IOP.

Topics: Acute Disease; Animals; Cell Survival; Erythropoietin; Immunohistochemistry; Intraocular Pressure; Male; Microscopy, Electron, Transmission; Neuroprotective Agents; Ocular Hypertension; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; Retinal Ganglion Cells

Head trauma is a dynamic process characterized by a cascade of metabolic and molecular events. Erythropoietin (EPO) has been shown to have neuroprotective effects in animal models of traumatic brain injury (TBI). Acute in vivo mechanisms and pathological changes associated with EPO following TBI are unknown. In this study the authors compare acute metabolic and pathological changes following TBI with and without systemically administered EPO.. Right frontal lobe microdialysis cannulae and right parietal lobe percussion hubs were inserted into 16 Sprague-Dawley rats. After a 4- to 5-day recovery, TBI was induced via a DragonFly fluid-percussion device at 2.5-2.8 atm. Rats were randomized into 2 groups, which received 5000 U/kg EPO or normal saline intraperitoneally 30 minutes after TBI. Microdialysis samples for glucose, lactate, pyruvate, and glutamate were obtained every 25 minutes for 10 hours. Rats were killed, their brains processed for light microscopy, and sections stained with H & E.. Erythropoietin administered 30 minutes after TBI directly affects acute brain metabolism. Brains treated with EPO maintain higher levels of glucose 4-10 hours after TBI (p<0.01), lower levels of lactate 6-10 hours after TBI (p<0.01), and lower levels of pyruvate 7.5-10 hours after TBI (p<0.01) compared with saline-treated controls. Erythropoietin maintains aerobic metabolism after TBI. Systemic EPO administration reduces acute TBI-induced lesion volume (p<0.05).. Following TBI, neuron use initially increases, with subsequent depletion of extracellular glucose, resulting in increased levels of extracellular lactate and pyruvate. This energy requirement can result in cell death due to increased metabolic demands. These data suggest that the neuroprotective effect of EPO may be partially due to improved energy metabolism in the acute phase in this rat model of TBI.

Topics: Acute Disease; Animals; Brain Injuries; Disease Models, Animal; Energy Metabolism; Erythropoietin; Glucose; Glutamic Acid; Lactic Acid; Microdialysis; Neuroprotective Agents; Pyruvic Acid; Rats; Rats, Sprague-Dawley

Reduced oxygen supply during the pre- and perinatal period often leads to acquired neonatal brain damage. So far, there are no reliable markers available to assess the hypoxic cerebral damage and the resulting prognosis during the immediate postnatal period. Thus we aimed to determine whether the hypoxia-inducible transcription factors (HIF-1 and HIF-2) and/or their target genes in the placenta represent reliable indicators of hypoxic distress of the developing brain during systemic hypoxia at the end of gestation. To this end, pregnant mice were exposed to systemic hypoxia (inspired O2 fraction: 6%, 6 h) at gestational day 20. This hypoxic exposure significantly increased HIF-1alpha and HIF-2alpha protein levels in brain and placental tissue. Compared with normoxic controls, an increase of HIF-1alpha-immunoreactive neurons and HIF-2alpha-positive glial cells and vascular endothelial cells was observed in hypoxic cerebral cortex and hippocampus. In placenta, HIF-1alpha and HIF-2alpha were expressed in labyrinthine layer with increased staining intensity during hypoxia compared with normoxia. Significant upregulation of VEGF mRNA and protein in brain and placenta, as well as erythropoietin protein in placenta, indicated activity of the HIF system upon fetal hypoxia. Notably, hypoxia did not affect expression of the HIF target genes inducible nitric oxide synthase and GLUT-1. Taken together, at gestational day 20, systemic hypoxia led to upregulation of HIF-alpha in mouse brain that was temporally paralleled in placenta, implying that alpha-subunits of both HIF-1 and HIF-2 are indeed early markers of hypoxic distress in vivo. If our data reflect the situation in humans, analysis of the placenta will allow early identification of the hypoxic brain distress occurring near birth.

Topics: Acute Disease; Animals; Basic Helix-Loop-Helix Transcription Factors; Biomarkers; Brain; Erythropoietin; Female; Fetal Hypoxia; Gene Expression Regulation; Gestational Age; Glucose Transporter Type 1; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia, Brain; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Placenta; Pregnancy; Protein Stability; RNA, Messenger; Severity of Illness Index; Up-Regulation; Vascular Endothelial Growth Factor A

To elucidate the relationship between falciparum malaria-associated anemia and serum erythropoietin (Epo) levels and reticulocyte response during acute malaria infection, 87 adults aged 18-65 years presenting with acute, uncomplicated malaria were examined on enrollment and for 28 days of follow-up. The 87 patients were divided into 2 groups: those with anemia (n = 45) and those without (n = 42). Serum samples were taken on admission (Day 0), then on Days 7, 21, and 28, to measure the reticulocyte count, absolute reticulocyte count, reticulocyte hemoglobin content, and erythropoietin level (Epo). The absolute reticulocyte counts for the anemic patients were significantly higher than for those without anemia on Days 0, 7, 21, and 28. The serum Epo levels for the anemic patients were significantly higher than the non-anemic group only on Day 0 (44.39 +/- 4.06 vs 25.91 +/- 4.86 mlU/ml, p < 0.001). Inadequate Epo production was found in 31.03% (27/87) of patients on Day 0, 37.93% (33/87) on Day 7, 43.67% (38/87) on Day 21, and 39.08% (34/87) on Day 28. These results indicate defective Epo production and reticulocyte response in adult patients suffering from acute P. falciparum malaria, which differs from pediatric patients. Our findings may provide the basis for further study into the choice of therapeutic strategies to treat acute P. falciparum malaria-associated anemia with recombinant human Epo to correct refractory anemia due to malaria.

Topics: Acute Disease; Adolescent; Adult; Aged; Anemia; Erythropoietin; Female; Hematocrit; Humans; Longitudinal Studies; Malaria, Falciparum; Male; Middle Aged; Reticulocyte Count; Reticulocytes; Young Adult

We first describe the onset of acute myositis in a patient suffering from systemic sclerosis after the administration of darbepoetin alpha for renal failure-related anemia. Therapeutic implications and risks are discussed.

Topics: Acute Disease; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Humans; Injections, Subcutaneous; Methylprednisolone; Middle Aged; Myositis; Prednisone; Scleroderma, Systemic; Severity of Illness Index; Treatment Outcome

We studied plasma erythropoietin (EPO) levels and their relation with CD34(+)VEGFR-2(+) (mature and progenitor endothelial cells) and CD34(+) CD133(+)VEGFR-2(+), or CD34(+) CD117(+)VEGFR-2(+) (early/immature endothelial progenitors) cells in patients with acute myocardial infarction (AMI).. Fifty AMI patients undergoing percutaneous coronary intervention (PCI) within 6 h of symptom onset were enrolled. EPO, measured by ELISA, and cell subsets, by cytofluorimetric analysis, were evaluated before PCI, 24 h and 7 days afterwards. Forty-five healthy subjects (CTRLs) were studied. Plasma EPO levels were higher in AMI patients at admission, 24 h, and 7 days (P = 0.04, P = 0.0001, P = 0.001, respectively) than in CTRLs. No correlation was evidenced between EPO and haemoglobin (Hb) or haematocrit at admission or 24 h after AMI. Differently, both Hb and haematocrit inversely correlated with EPO at day 7 (P = 0.0016, P = 0.029, respectively). Plasma EPO levels correlated with CD34(+)CD133(+)VEGFR-2(+) cells at day 7 (P = 0.03).. AMI patients have increased plasma EPO levels until day 7. In the early phase, plasma EPO levels are Hb-independent; at day 7, an Hb-modulated increase of EPO correlates with the percentage of CD34(+)CD133(+)VEGFR-2(+) cells.

Topics: Acute Disease; Antigens, CD34; Coronary Angiography; Erythroid Precursor Cells; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Prospective Studies; Risk Factors; Time Factors; Vascular Endothelial Growth Factor A

Topics: Acute Disease; Endothelium; Erythroid Precursor Cells; Erythropoietin; Humans; Myocardial Infarction; Prognosis; Time Factors

To evaluate the potential protective affects of Epo on left ventricular (LV) function and remodeling after acute myocardial infarction (MI).. Epo was injected into the peritoneum of male Wistar rats (250 g) during 6 weeks post induction of MI. Rats were divided into five groups: MI treated with single high dose (MT1, 5,000 U/kg, n=10), single high dose (5,000 U/kg) and repeated high doses (MTHi, 1,000 U/kg twice a week; n=8), or single high dose (5,000 U/kg) and repeated low doses (MTLo, 750 U/kg once a week, n=10), MI non-treated (MNT, n=10), sham (S, n=5). Echocardiography was performed 3.6+/-1.5 days and 43.7+/-2.3 days post MI. Collagen deposition and infarct size were measured on histological sections using computerized image analysis. Apoptosis was assessed by ApopTag staining.. Baseline fractional shortening (FS) was similar between groups. Six weeks after MI the FS of MTLo (26.9%) was significantly higher compared to MNT (17.8%), MT1 (19.5%) and MTH (22.3%) (p=0.01). However, remodeling indices (end diastolic and end systolic areas, LV circumference) did not improve in the Epo groups, and even worsened in the MTHi group. There was significantly less collagen staining in non-infarct areas in MT1 and MTHi groups compared to MNT and MTLo (0.38+/-0.3%, 0.49+/-0.34%, vs 0.89+/-0.41%, 0.95+/-0.33%, respectively, p<0.001). The number of ApopTag positive nucleus was significantly higher in the MNT group compared to the MT1, MTHi, MTLo groups (14.4+/-8, 7.6+/-4, 5.8+/-7, 4.8+/-5, respectively, p=0.01 for trend).. Repeated low doses of Epo after MI improved LV function, but the role of Epo on remodeling is not clear. It did not reduce left ventricular indices, but reduces fibrosis and apoptosis. High Epo doses reduced LV function and aggravated remodeling.

Topics: Acute Disease; Animals; Apoptosis; C-Reactive Protein; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Erythropoietin; Hemoglobins; Male; Myocardial Infarction; Rats; Rats, Wistar; Survival Rate; Ventricular Function, Left; Ventricular Remodeling

In humans, neurotrauma is suspected to cause brain atrophy and accelerate slowly progressive neurodegenerative disorders, such as Alzheimer's disease or schizophrenia. However, a direct link between brain injury and subsequent delayed global neurodegeneration has remained elusive. Here we show that juvenile (4-week-old) mice that are given a discrete unilateral lesion of the parietal cortex, develop to adulthood without obvious clinical symptoms. However, when monitored 3 and 9 months after lesioning, using high-resolution three-dimensional MRI and behavioural testing, the same mice display global neurodegenerative changes. Surprisingly, erythropoietin, a haematopoietic growth factor with potent neuroprotective activity, prevents behavioural abnormalities, cognitive dysfunction and brain atrophy when given for 2 weeks after acute brain injury. This demonstrates that a localized brain lesion is a primary cause of delayed global neurodegeneration that can be efficiently counteracted by neuroprotection.

Topics: Acute Disease; Animals; Atrophy; Brain; Brain Injuries; Erythropoietin; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred BALB C; Models, Animal; Neurodegenerative Diseases; Neuropsychological Tests; Time Factors

Hypoxia-induced angiogenesis may play an important role in the pathophysiology of sickle cell disease (SCD). Serum levels of angiopoietin (Ang)-1, Ang-2, vascular endothelial growth factor, placenta growth factor (PlGF), soluble tunica intima endothelial kinase 2 (sTIE2), erythropoietin (EPO) and endothelial activation markers (soluble vascular adhesion molecule-1, soluble intercellular adhesion molecule-1) were determined in controls, HbSS (n = 35) and HbSC (n = 23) patients. In the asymptomatic phase, serum Ang-2 (P < 0.001), EPO (P < 0.001) and sTIE2 (P = 0.03) were elevated in patients. During painful crises, increased Ang-2 (P < 0.001) and PlGF (P = 0.04) occurred in HbSS and Ang-2 (P = 0.05) in HbSC patients. These results indicate a pro-angiogenic state in SCD, mainly because of elevated Ang-2 levels.

Topics: Acute Disease; Anemia, Sickle Cell; Angiogenesis Inducing Agents; Angiopoietin-1; Angiopoietin-2; Case-Control Studies; Erythropoietin; Fetal Hemoglobin; Humans; Intercellular Adhesion Molecule-1; Leukocyte Count; Neovascularization, Pathologic; Placenta Growth Factor; Pregnancy Proteins; Receptor, TIE-2; Statistics, Nonparametric; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Topics: Acute Disease; Anemia, Refractory; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Erythropoietin; Etoposide; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Male; Methotrexate; Middle Aged; Mitoxantrone; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Primary Myelofibrosis; Recombinant Proteins; Transplantation Conditioning; Transplantation, Autologous; Whole-Body Irradiation

Activation of the phosphoinositide 3 kinase (PI3K)/Akt signalling pathway has been linked with resistance to chemotherapeutic drugs, and its downregulation, by means of PI3K inhibitors, lowers resistance to various types of therapy in tumour cell lines. Recently, it has been reported that deguelin, a naturally occurring rotenoid, is a powerful inhibitor of PI3K. We investigated whether or not deguelin could enhance the sensitivity to chemotherapeutic drugs of human U937 leukaemia cells and acute myeloid leukaemia (AML) blasts with an activated PI3K/Akt network. Deguelin (10 nmol/l) induced S phase arrest with interference of progression to G2/M, and at 100 nmol/l significantly increased apoptotic cell death of U937. At 10-100 nmol/l concentrations, deguelin downregulated Akt phosphorylation of leukaemia cells and markedly increased sensitivity of U937 cells to etoposide or cytarabine. A 10 nmol/l concentration of deguelin did not negatively affect the survival rate of human cord blood CD34+ cells, whereas it increased sensitivity of AML blasts to cytarabine. Deguelin was less toxic than wortmannin on erythropoietin- and stem cell factor-induced erythropoiesis from CD34+ progenitor cells. Overall, our results indicate that deguelin might be used in the future for increasing sensitivity to therapeutic treatments of leukaemia cells with an active PI3K/Akt signalling network.

Topics: Acute Disease; Antigens, CD34; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cells, Cultured; Cytarabine; Drug Resistance, Neoplasm; Erythropoietin; Etoposide; HL-60 Cells; Humans; Leukemia; Leukemia, Myeloid; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Rotenone; Signal Transduction; Stem Cell Factor; Stem Cells

In order to determine the initial values and dynamic changes of EPO (erythropoietin) after therapy, 57 consecutively presenting, typical COPD (chronic obstructive pulmonary disease) patients with chronic hypoxia and acute exacerbated serum EPO levels were serially measured. Initial mean EPO levels were slightly above the normal range (41.4 +/- 83.5 units/l), but in the majority of patients the initial EPO levels were significantly reduced. Following the correction of hypoxaemia, mean EPO levels decreased to 14.1 +/- 16.9 units/l (P=0.0093). However, not all COPD patients showed this pattern; in an important subset of patients (36.8%), who had initially lower EPO levels and lower erythrocyte count, EPO levels were significantly increased (by more than 60%; P=0.0028) on the second day of treatment, despite correction of the hypoxaemia. This finding was unexpected and paradoxical when compared with physiological studies addressing the same issue. The data presented support previous reports of variable EPO levels in severely hypoxic COPD patients and suggest that the haematological response is already hampered at an early stage, at the level of EPO production, and much less likely at later steps in the haemopoietic response by failure to respond to elevated EPO levels. Our data are consistent with recent discoveries that the O2 sensing and regulation of EPO production is a complex process in which multiple factors, including cytokines and therapeutic agents, play a role by enhancing or inhibiting the response. We believe that further studies on this clinical condition are complementary to basic physiological research and may help to elucidate the role of cytokines and other individual factors in complex clinical hypoxic situations.

Topics: Acute Disease; Aged; Carbon Dioxide; Erythropoietin; Female; Hemoglobins; Humans; Hypoxia; Male; Middle Aged; Oxygen; Partial Pressure; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Insufficiency

Lipid peroxidation has been reported to play an important role in spinal cord injury (SCI). Erythropoietin (EPO) is a hematopoietic growth factor that stimulates proliferation and differentiation of erythroid precursor cells and is also known to exert neurotrophic activity in the central nervous system. The purpose of this study was to investigate the effectiveness of recombinant human EPO in attenuating the severity of experimental SCI. Rats were divided into seven groups. Controls (1) received only laminectomy. The trauma-only group (2) underwent 50-g/cm contusion injury and had no medication. In group 3, 30 mg/kg of methylprednisolone was introduced. The vehicle group (4) received vehicle solution containing human serum albumin, which is a solvent of EPO. Groups 5, 6, and 7 received 100 IU/kg, 1,000 IU/kg, and 5,000 IU/kg of EPO, respectively. All treatments were given as single doses, intraperitoneally, immediately after injury. Thiobarbituric acid-reactive substances were estimated to demonstrate lipid peroxidation, and ultrastructure was evaluated by electron microscopy. The results showed that lipid peroxidation by-products increased after injury. Administration of EPO and methylprednisolone sodium succinate (MPSS) reduced thiobarbituric acid-reactive substances after trauma. The best biochemical results were obtained with 5,000 IU/kg of EPO. Electron microscopic findings showed that EPO protected the spinal cord from injury. Although 1,000 IU/kg and 5,000 IU/kg of EPO inhibited lipid peroxidation better than MPSS, ultrastructural neuroprotection was similar.

Topics: Acute Disease; Animals; Disease Models, Animal; Erythropoietin; Lipid Peroxidation; Male; Methylprednisolone; Neuroprotective Agents; Rats; Rats, Wistar; Spinal Cord; Spinal Cord Injuries; Thiobarbituric Acid Reactive Substances; Time Factors; Trauma Severity Indices

Overexpression of erythropoietin (Epo) in mice (Epo-tg6) leads to an increase in hematocrit and blood volume, and strongly reduces endurance upon exercise. It was the aim of this study to characterize the mechanisms underlying the reduced cardiac performance.. Left (LV) and right (RV) ventricular function was measured with and without norepinephrine (NE) stimulation in 12 anaesthetized Epo-tg6 and in 13 wild-type (WT) control mice.. There were no differences in heart function under baseline resting conditions. Stimulation with NE (10 microl bolus injections of 1-100 ng per mouse) in WT mice led to a dose-dependent increase in heart rate (HR), LV developed pressure (LVDP) and rate of rise in LV pressure (LV dP/dt(max)), while LV end-diastolic pressure (LVEDP) was unchanged. Except for HR, these parameters increased to a lesser extent in EPO-tg6 mice. Strikingly, LVEDP strongly increased in Epo-tg6 mice after NE (up to >20 mmHg). Eleven out of 13 Epo-tg6, but none of the WT mice died or required resuscitation after high-doses of NE. In these cases severe diastolic dysfunction became overt since the relative myocardial relaxation time was significantly prolonged and the duration of diastole was shortened. Moreover, the ECG showed a marked ST segment depression as well as deep negative T-waves. The NE-induced reduction in myocardial adenosin-triphosphate (ATP) content was more pronounced in Epo-tg6 mice after 10 min of continuous NE infusion (50 ng/min per mouse).. NE-induced stress in Epo-tg6 mice led to acute heart failure associated with diastolic dysfunction and myocardial ischemia.

Topics: Acute Disease; Adenosine Triphosphate; Animals; Diastole; Dose-Response Relationship, Drug; Electrocardiography; Erythropoietin; Heart Rate; Mice; Mice, Transgenic; Myocardial Ischemia; Myocardium; Norepinephrine; Stimulation, Chemical; Ventricular Pressure

Topics: Acute Disease; Coronary Artery Disease; Erythropoietin; Humans; Insulin-Like Growth Factor I; Kidney Diseases; Myocardial Infarction; Myocardial Ischemia; Syndrome

The regulatory mechanism responsible for a paradoxal, rapid drop in the erythropoietin (EPO) plasma level seen 2 to 4 days after acute, phlebotomy-induced anemia was investigated in seven adult sheep. To introduce acute anemia, each sheep underwent two phlebotomies where the hemoglobin (Hb) was reduced to 3 or 4 g/dl over 4 to 5 h. The phlebotomies were spaced 4 to 6 weeks apart in three animals, and 8 days apart in four other animals. EPO plasma levels, reticulocyte count, Hb, and p50 for oxygen-Hb dissociation were determined from frequent blood samplings throughout the study period. EPO's disposition pharmacokinetic (PK) and plasma clearance were determined from i.v. bolus injections of tracer amounts of a recombinant human EPO tracer. The controlled drop in Hb resulted in a rapid increase in plasma EPO to 836 +/- 52 mU/ml (mean +/- coefficient of variation percentage) that was followed by a paradoxical rapid drop 2 to 4 days after the phlebotomy while the animals were still very anemic (Hb = 4.3 +/- 15 g/dl). The rapid drop in plasma EPO level could not be explained by the up-regulated clearance (clearance increased by a factor of less than 2.5) or by physiological adaptation (no change in p50, p > 0.05, second phlebotomy to Hb = 3g/dl inadequately stimulated the EPO production). The PK/pharmacodynamic (PD) analysis supports the hypothesis of a limited sustained high EPO production rate in acute anemia, which indicates an apparent deficiency in the regulation of EPO production in acute anemia. The hypothesis was supported by a PK/PD feedback inhibition model that showed good agreement with the data (r = 0.973 +/- 1.57).

Topics: Acute Disease; Anemia; Animals; Erythropoietin; Hemoglobins; Kinetics; Phlebotomy; Reticulocytes; Sheep; Social Control, Formal

Reticulocyte hemoglobin content (CHr) has recently become available as a direct marker of the iron status in hemodialysis patients undergoing recombinant human erythropoietin (rHuEPO) therapy. This study evaluated the stability of CHr in hemodialysis patients with acute infectious disease.. We retrospectively selected 22 hemodialysis patients who had acute respiratory tract infection and who showed transient elevation of C-reactive protein (CRP), and we investigated changes in parameters for erythropoiesis, iron status, and inflammation, i.e., hematocrit (Ht), transferrin saturation (TSAT), CHr, serum ferritin, and CRP, in the preinfection, infection, and postinfection phases. Throughout the observation period, doses of rHuEPO and iron supplements had not been changed. We divided the patients into two groups, those who showed a decrease in Ht in the infection phase (group 1; n = 12) and those who did not show a change in Ht in this phase (group 2; n = 10). We defined the differences between the parameters in the preinfection phase and the infection phase as Delta, and performed correlation analysis between them.. CRP in group 1 was significantly higher than that in group 2 in the infection phase. In group 1, TSAT significantly decreased, from 32.9 +/- 8.8% (preinfection phase) to 16.9 +/- 5.0% (infection phase), and CHr also significantly decreased, from 33.1 +/- 1.5 pg to 30.4 +/- 2.0 pg. In group 2, however, although TSAT significantly decreased, from 34.8 +/- 4.6% to 27.0 +/- 9.3%, CHr showed no significant change (from 33.4 +/- 0.9 pg to 33.0 +/- 1.4 pg). There was a significantly high correlation between DeltaHt and DeltaCHr, but there was a low correlation between DeltaHt and DeltaTSAT ( r = 0.505; P = 0.0153 versus r = 0.175; P = 0.4420). Furthermore, the correlation between DeltaCRP and DeltaCHr was quite high ( r = -0.722; P = 0.0001).. TSAT overreacts to inflammation, failing to reveal the correct status of available iron for erythropoiesis in acute inflammatory disease, but the use of CHr is expected to avoid these disadvantages, providing a reliable direct marker of iron status in the acute infection phase.

Topics: Acute Disease; Aged; C-Reactive Protein; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Respiratory Tract Infections; Reticulocytes; Retrospective Studies; Transferrin

To estimate the rate of erythropoietin (EPO) production under physiological, conditions and to examine the regulatory mechanism of EPO production in response to acute phlebotomy-induced anemia.. Six sheep each underwent two phlebotomies in which the hemoglobin (Hb) was reduced to 3-4 g/dl over 4-5 h. The EPO plasma level, reticulocytes, Hb and EPO clearance were followed by frequent blood sampling. The EPO production rate was determined by a semi-parametric method based on a disposition decomposition analysis that accounts for the nonlinear disposition kinetics of EPO and corrects for time-dependent changes in the clearance.. The controlled drop in hemoglobin resulted in an abrupt increase in the plasma EPO concentration (peak level 812+/-40 mU/ml, mean+/-CV%) that was followed by a rapid drop 2-4 days after the phlebotomy at a time when the sheep were still anemic (Hb=4.3+/-16 g/dl). The EPO production rate at baseline was 43+/-52 U/day/kg and the amounts of EPO produced over an 8 day period resulting from the first and second phlebotomy were 2927+/-40 U/kg and 3012+/-31 U/kg, respectively.. The rapid reduction in the EPO plasma level observed 2-4 days following the phlebotomy cannot be explained solely by the increase in EPO clearance but also by a reduction in EPO production.

Topics: Acute Disease; Anemia; Animals; Erythropoietin; Hemoglobins; Linear Models; Models, Biological; Nonlinear Dynamics; Phlebotomy; Sheep; Time Factors

PURE RED CELL APLASIA: Designated by the acronym PRCA or the term erythroblastopenia, pure red cell aplasia is characterised by severe anaemia with reticulocytopenia. It may occur in acute form induced by infectious agents, following drug toxicity or transplantation of allogeneic haematopoietic cells, associated with autoimmune haemolytic anaemia. The chronic form is rarely constitutional but can be acquired and is usually associated with blood or idiopathic diseases. IMMUNOLOGICAL INHIBITION OF ERYTHROPOIESIS: Among the mechanisms responsible for PRCA is immunological erythropoiesis inhibition. This may be of lymphocyte T cell origin or due to the presence of antibodies in the patient's serum. Although observations of PRCA with presence of neutralising antierythropoietin antibodies in patient's serum have multiplied over the past 5 years, they still remain extremely rare. From a therapeutic point of view, they require withdrawal of epoetin and often the administration of immunosuppressors and transfusion for symptomatic treatment. GROWTH FACTORS: The role of growth factors in restoring aplastic anaemia appears to be only partial, at random and temporary.

Topics: Acute Disease; Anemia, Aplastic; Autoantibodies; Chronic Disease; Erythropoietin; Humans; Immunosuppressive Agents; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Factors

Alternative therapeutic approaches with low dose chemotherapy and differentiative-maturative treatment by growth factors are under consideration for elderly patients with acute leukemia. Two patients with AML-M6 with maturation, one refractory to standard chemotherapy and the other ineligible for cytoxic treatment, obtained complete remission from leukemia using high dose recombinant erythropoietin and granulocyte colony-stimulating factor.

Topics: Acute Disease; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Erythroblastic, Acute; Male; Remission Induction

In our previous study, approximately 60% of aplastic anemia (AA) and refractory anemia (RA) patients treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human erythropoietin (rhEpo) showed a multilineage response. In this study, we analyzed the long-term follow-up of the multilineage responders (multi-R). In the follow-up analysis of 11 multi-R (6 AA and 5 RA), 10 patients (5 AA and 5 RA) were evaluable. The range of time from the start of treatment to the final contact was 50 to 125 months. Analysis of survival times revealed a significant difference between multi-R and non-multi-R among AA patients given this treatment (P = .016). One AA and 1 RA patient among the multi-R developed acute leukemia. Of 7 living multi-R, 3 AA and 2 RA patients did not need transfusion at final contact. Four of them maintained the target hemoglobin concentration of more than 11 g/dL for quality-of-life benefit. The findings suggested that this result is an important advantage of this treatment.

Topics: Acute Disease; Adolescent; Adult; Aged; Anemia, Aplastic; Anemia, Refractory; Blood Transfusion; Erythropoietin; Female; Follow-Up Studies; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Male; Middle Aged; Survival Analysis

To determine by pharmacodynamic (PD) analysis physiologically relevant parameters of the cellular kinetics of erythropoiesis in acute anemia.. The PD relationships among erythropoietin (EPO), reticulocyte, and RBC (Hb) responses were investigated in young adult sheep in acute anemia induced twice by two controlled phlebotomies separated by a 4-week recovery period.. The phlebotomies resulted in rapid increases in plasma EPO, with maximal levels occurring at 3 to 8 days, followed by a reticulocyte response with a delay of 0.5 to 1.5 days. The Hb returned to prephlebotomy base line at the end of the 4-week recovery period. The EPO, reticulocyte count, and Hb responses were well described by a PK/PD model (r = 0.975) with the following cellular kinetics parameters: the lag time between EPO activation of erythroid progenitor cells and reticulocyte formation; the reticulocyte-to-RBC maturation time; the reticulocyte and Hb formation efficacy coefficients, quantifying EPO's efficacy in stimulating the formation of reticulocytes and Hb, respectively; the C50 PK/PD transduction parameter defined as the EPO level resulting in half the maximum rate of erythropoiesis.. Physiologically relevant cellular kinetics parameters can be obtained by an endogenous PK/PD analysis of phlebotomy data and are useful for elucidating the pathophysiologic etiology of various anemias.

Topics: Acute Disease; Anemia; Animals; Erythropoietin; Hemoglobins; Phlebotomy; Reticulocytes; Sheep

Increased fetal plasma erythropoietin concentration is an indicator of chronic fetal hypoxia. Amniotic fluid erythropoietin levels correlate highly significantly with fetal erythropoietin levels before labor. We studied AF erythropoietin levels after fetal death in order to determine whether this could differentiate between stillbirths from acute or chronic causes.. Amniotic fluid was obtained after fetal death for erythropoietin measurement following fetal death in 21 pregnancies. Two of the pregnancies had twins, of which one infant was born alive. All 22 stillborn fetuses had an autopsy. None had malformations. Without prior knowledge of the results of the erythropoietin analyzes, the causes of fetal death were divided into acute, chronic or unknown groups.. Eight pregnancies had an acute cause of fetal death (e.g. cord complication or placental abruption), eight pregnancies had a chronic cause (intrauterine growth restriction or erythroblastosis) and in five pregnancies the cause of fetal death could not be determined. In all eight pregnancies with an acute cause of fetal death, AF erythropoietin levels were normal (< 20 mU/mL). In contrast, six of the eight pregnancies with a chronic cause had AF erythropoietin levels above normal (range from 49.9 mU/mL to 391 mU/mL). In the five pregnancies with an unknown cause of fetal death, AF erythropoietin levels were normal in three and elevated in two.. Elevated AF erythropoietin levels, identified after fetal death, suggest that the fetus died from a chronic hypoxic event, whereas normal AF erythropoietin levels suggest that the fetus died from an acute event.

Topics: Acute Disease; Amniotic Fluid; Body Temperature; Cause of Death; Chronic Disease; Erythropoietin; Female; Fetal Death; Fetal Diseases; Humans; In Vitro Techniques; Pregnancy; Time Factors

The study was designed to examine the impact of anemia on the antitumor efficacy of photodynamic therapy (PDT) in a murine colon-26 adenocarcinoma model syngeneic with BALB/c mice.. Acute hemolytic anemia was induced by a single i.p. injection of phenylhydrazine hydrochloride (150 mg/kg). Anemia induced by i.p. administration of carboplatin (100 mg/kg) was corrected by s.c. treatment with recombinant human erythropoietin (1000 units/kg/day). The effectiveness of PDT (10 mg/kg Photofrin, 150 J/cm2 laser dose) was evaluated by measurements of the footpad edema and tumor volume. All of the RBC-related parameters were measured from the tail vein.. Phenylhydrazine hydrochloride injection resulted in a blunted response of normal tissues to Photofrin-mediated PDT-induced edema formation. Similarly, the antitumor response in mice with hemolytic anemia was nearly completely abrogated. The antitumor effectiveness of PDT was also significantly diminished in a more realistic clinical situation when anemia was induced by administration of carboplatin. Importantly, administration of recombinant human erythropoietin completely restored the sensitivity of the tumor to PDT in carboplatin-treated mice.. These results indicate that anemia can negatively influence the therapeutic effectiveness of PDT. For optimal antitumor response anemia should be corrected before PDT procedure.

Topics: Acute Disease; Anemia; Anemia, Hemolytic; Animals; Antineoplastic Agents; Carboplatin; Disease Models, Animal; Erythropoietin; Humans; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms, Experimental; Phenylhydrazines; Photochemotherapy; Recombinant Proteins; Tumor Cells, Cultured

We measured blood erythropoietin (EPO) concentration, arterial O(2) saturation (Sa(O(2))), and urine PO(2) in 48 subjects (32 men and 16 women) at sea level and after 6 and 24 h at simulated altitudes of 1,780, 2,085, 2,454, and 2,800 m. Renal blood flow (Doppler) and Hb were determined at sea level and after 6 h at each altitude (n = 24) to calculate renal O(2) delivery. EPO increased significantly after 6 h at all altitudes and continued to increase after 24 h at 2,454 and 2,800 m, although not at 1,780 or 2,085 m. The increase in EPO varied markedly among individuals, ranging from -41 to 400% after 24 h at 2,800 m. Similar to EPO, urine PO(2) decreased after 6 h at all altitudes and returned to baseline by 24 h at the two lowest altitudes but remained decreased at the two highest altitudes. Urine PO(2) was closely related to EPO via a curvilinear relationship (r(2) = 0.99), although also with prominent individual variability. Renal blood flow remained unchanged at all altitudes. Sa(O(2)) decreased slightly after 6 h at the lowest altitudes but decreased more prominently at the highest altitudes. There were only modest, albeit statistically significant, relationships between EPO and Sa(O(2)) (r = 0.41, P < 0.05) and no significant relationship with renal O(2) delivery. These data suggest that 1) the altitude-induced increase in EPO is "dose" dependent: altitudes > or =2,100-2,500 m appear to be a threshold for stimulating sustained EPO release in most subjects; 2) short-term acclimatization may restore renal tissue oxygenation and restrain the rise in EPO at the lowest altitudes; and 3) there is marked individual variability in the erythropoietic response to altitude that is only partially explained by "upstream" physiological factors such as those reflecting O(2) delivery to EPO-producing tissues.

Topics: Acute Disease; Adult; Altitude; Arteries; Atmospheric Pressure; Erythropoietin; Female; Humans; Hypoxia; Male; Oxygen; Renal Circulation

Topics: Acute Disease; Adult; Antibodies; Diagnosis, Differential; Erythropoietin; Female; Humans; Lupus Erythematosus, Systemic; Red-Cell Aplasia, Pure

Myelodysplastic syndrome (MDS) is characterised by ineffective erythropoiesis and poor progenitor response to erythropoietin (Epo). The aim of this study was to determine the role of the Epo-R mediated signalling in the rise of MDS and whether alteration of signalling pathways contribute to the leukeamogenesis from MDS to acute leukaemia. We analysed Epo and GM-CSF induced ERK1/2 activation, c-Fos expression, STAT-5 and AP-1 DNA binding activities in mononuclear cells of umbilical cord blood (UCBMNC), normal marrow (NBMMNC) or marrow with MDS, AML with prior MDS and de novo AML. In UCBMNC and NBMMNC, Epo and GM-CSF induced the activation of STAT-5 DNA binding and ERK 1/2 activation (n = 6). In contrast, in MDS RA, both signalling pathways were activated only by GM-CSF but not by Epo (n = 7). In acute leukaemia, elevated basal activity of STAT-5 DNA binding appeared in 8/8 cases, which was independent of Epo or GM-CSF treatment. In normal and MDS samples, c-Fos and Egr-1 proteins were not detectable and the expression levels were not increased by Epo or GM-CSF treatment. In contrast, we found an elevated level of c-Fos expression in 5/8 acute leukemia cases, which was not further increased in the presence of Epo or GM-CSF. The elevated c-Fos expression was accompanied by an extremely high blast number in 5/5 cases. These results suggest that impaired ERK/MAPK activation, similarly to impaired STAT-5 activation in Epo-R signalling, may be responsible for the apoptotic process and the block of maturation in MDS RA. The results also suggest that the appearance of the constitutively activated STAT-5 DNA binding and c-Fos expression may be used as a predictor of the blastic transformation.

Topics: Acute Disease; Adolescent; Adult; Aged; Bone Marrow Cells; Case-Control Studies; DNA-Binding Proteins; Enzyme Activation; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia; Male; Middle Aged; Milk Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myelodysplastic Syndromes; Phenotype; Proto-Oncogene Proteins c-fos; Signal Transduction; STAT5 Transcription Factor; Trans-Activators

Anemia is an important complication of malaria, and its pathogenesis is not well understood. To gain insight into potential age-related relationships between tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10), erythropoietin, and anemia during acute malaria, 273 children of ages 12 to 120 months presenting with acute, uncomplicated malaria in Kampala, Uganda, were monitored at enrollment and 3 and 7 days later. Younger children had higher geometric mean erythropoietin, TNF-alpha, and alpha(1)-acid glycoprotein (AGP) concentrations than older children. Univariate regression analysis revealed that age, log(10) erythropoietin levels, IL-10/TNF-alpha ratio, and AGP levels were each significantly associated with hemoglobin levels at baseline. Hemoglobin concentrations were inversely correlated with the log(10) erythropoietin level at all three visits. For the older age groups, higher levels of TNF-alpha were significantly associated with higher IL-10 levels at all three visits, but this relationship was significant only at baseline for younger children. These data suggest that younger children do not maintain IL-10 production in response to the inflammatory process, and this mechanism may contribute to the more severe anemia found in younger children. Acute malaria is an illness whose incidence and severity are largely age dependent. Further studies are needed to understand the relationships between age-related immune responses to malaria and their role in the pathogenesis of malarial anemia.

Topics: Acute Disease; Age Factors; Anemia; Child; Child, Preschool; Erythropoietin; Humans; Infant; Interleukin-10; Longitudinal Studies; Malaria, Falciparum; Regression Analysis; Severity of Illness Index; Tumor Necrosis Factor-alpha; Uganda

We have studied paired peripheral blood progenitor cells (PBPC) and bone marrow (BM) samples from 12 acute myeloid leukaemia (AML) patients following intensive chemotherapy, and assessed direct granulocyte-macrophage colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), megakaryocyte CFU (CFU-Mk) numbers and the production of CD61+ (platelet glycoprotein IIIa) cells in suspension culture in response to various haemopoietic growth factor combinations. We found that CFU-GM and BFU-E numbers per 105 mononuclear cells were similar in both AML PBPC and BM harvests; CFU-Mk numbers, however, were significantly higher in PBPC than BM. In addition, the higher total white cell count of the PBPC harvests meant that PBPC have much higher numbers of total progenitors per collection. CD61+ cell numbers in suspension cultures of AML PBPC and BM were lower than those of harvested normal marrow. However, response to pegylated recombinant human megakaryocyte growth and development factor (PEGrHuMGDF) both alone and in combination with other growth factors was qualitatively similar to that of normal BM. As with normal BM, response to PEGrHuMGDF alone did not increase further with addition of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin 6 (IL-6) or erythropoietin (EPO) in the AML PBPC and BM. Further responses over PEGrHuMGDF alone were seen when added with stem cell factor (SCF) or with a combination of SCF + IL-3 + EPO in both AML PBPC and BM cultures; however, the magnitude of the response was greater in the PBPC cultures. Response to PEGrHuMGDF + IL-3 was seen in the PBPC cultures but not in the AML BM. These data suggest that, in AML patients, there are proportionally more megakaryocyte progenitor cells in the mobilized PBPC than in the BM harvests, which would explain the more rapid platelet recovery following PBPC autografts.

Topics: Acute Disease; Adult; Antigens, CD; Blood Platelets; Bone Marrow Cells; Cell Count; Cell Division; Cells, Cultured; Chemokine CXCL12; Chemokines, CXC; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Growth Substances; Hematopoiesis; Humans; Integrin beta3; Interleukin-3; Interleukin-6; Leukemia, Myeloid; Macrophages; Megakaryocytes; Middle Aged; Platelet Membrane Glycoproteins; Polyethylene Glycols; Recombinant Proteins; Stem Cells; Thrombopoietin

We studied the influence of cytokine mixes on the survival of acute myeloid leukemia (AML) bone-marrow (BM) cells in a 14-day culture assay in vitro. Southern-blot analysis using a panel of different probes in combination with densitometry and flow cytometry were used to detect and compare the amount of clonal or CD34-positive BM cells before and after the culturing procedure. A significant reduction of CD34-positive cells after incubation with a cytokine mix [interleukin (IL)-1beta, IL-3, IL-6, stem cell factor (SCF), erythropoietin (EP) with granulocyte macrophage/colony-stimulating factor (GM-CSF, Cytok1) could be achieved in all 16 cases with a CD34-positive blast phenotype studied at diagnosis (P<0.001), in 3 of 10 cases at relapse, and in 8 of 18 cases in complete remission. In healthy donors, an increase of CD34-positive cells was demonstrated in 5 of 5 samples. A reduction of clonal DNA through incubation with Cytok1 was achieved in 5 of 5 (100%) cases studied at diagnosis, in 1 of 4 (25%) cases at relapse, and in 7 of 9 cases (78%) in complete remission. Cytokine cocktails with GM-CSF (Cytok1) were more efficient in reducing (clonal) CD34-positive cells than cocktails without GM-CSF (Cytok2). AML patients at diagnosis and in complete remission had a better survival probability if their CD34-positive or clonal cells could be reduced in vitro by cytokine cultivation (P<0.05). Vitality of BM cells was not influenced by 14-day cytokine treatment; however, the total cell count could be increased by Cytok1 and Cytok2 by 55-174%, but not by the control medium. Our data show that: (1) clonal cell populations can be regularly detected at diagnosis, during complete remission, and at relapse; (2) CD34-positive cells in AML can be demonstrated to be clonal, gene-rearranged cells; (3) incubation of AML BM-cells with Cytokl leads to a reduction of the CD34-positive, clonal cell load in all cases at diagnosis and in 78% of the cases in complete remission of AML, but in only 25% of the cases at relapse; (4) in all healthy BM samples, proportions of 'healthy' CD34-positive cells were increased. Moreover, absolute cell counts were increased by cytokine incubation of cells obtained at diagnosis, relapse, or complete remission of AML and from healthy donors indicating a selective stimulation of healthy, but not of leukemic CD34-positive cells; (5) cytokine cocktails containing GM-CSF are more efficient in reducing leukemic cells than cocktails without GM-CSF; and (6

Topics: Acute Disease; Antigens, CD34; Bone Marrow Cells; Cell Count; Cell Division; Clone Cells; Cytokines; Erythropoietin; Gene Rearrangement; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Interleukin-3; Interleukin-6; Leukemia, Myeloid; Prognosis; Recurrence; Remission Induction; Stem Cell Factor

Topics: Acute Disease; Biomarkers; Erythropoietin; Humans; Hypoxia; Leukemia, Myeloid; Neovascularization, Pathologic

Acute Trypanosoma congolense infection induced moderate, transient anemia in N'Dama cattle (trypanotolerant) and severe anemia in Boran cattle (trypanosusceptible). Erythropoietin receptor (EpoR) was cloned and sequenced from the two breeds of cattle. A single position mutation of Tyr in the Boran to His in the N'Dama predicted amino acid sequence was revealed. The mRNA transcription of erythropoietin (Epo) in kidneys and EpoR in the bone marrow of infected cattle was determined by competitive reverse transcription and the polymerase chain reaction (RT-PCR). Though Epo mRNA transcription increased in the kidneys during infection, the increase was not significantly different (p>0.05) between the two breeds of infected cattle. The level of EpoR transcripts in the bone marrow of infected N'Damas was significantly higher (p<0.05) than that detected in the marrows from infected Boran cattle. While infection seem to increase levels of transcription of IL-1alpha and beta, and TNFalpha in kidneys from both Boran and N'Dama cattle, no significant difference was detected in the level of mRNAs of these cytokines in the kidney from the two breed of cattle. The amount of IFNgamma mRNA transcripts were not changed with infection in N'Dama cattle, while on the contrary a significant higher levels of IFNgamma was found in kidneys from infected Boran cattle as compared to the other groups. A significant (p<0.05) increase in the levels of IL-1alpha and beta, and IFNgamma mRNA transcripts were detected in the marrows of infected Borans as compared to the infected N'Dama cattle. In this study the increase in the level of TNFalpha mRNA in the marrows of the two infected breeds was not different. This implies there is no negative effect of TNFalpha on hematopoiesis during acute infection. These findings suggest that the levels of Epo and EpoR in the infected Boran cattle were inadequate for their degree of anemia, which might be due in part to high expression of IFNgamma during acute infection with T. congolense.

Topics: Acute Disease; Amino Acid Sequence; Animals; Blood Cell Count; Bone Marrow; Cattle; Cell Count; DNA, Complementary; Erythropoietin; Female; Gene Expression; Interferon-gamma; Interleukin-1; Kidney; Male; Molecular Sequence Data; Parasitemia; Receptors, Erythropoietin; RNA, Messenger; Sequence Analysis, DNA; Trypanosoma congolense; Trypanosomiasis, African; Tumor Necrosis Factor-alpha

P39/Tsugane is a myelomonocytoid cell line derived from a patient with myelodysplastic syndrome (MDS). The cells readily undergo apoptosis in response to various agents, and the cell line has been suggested as a useful model to study apoptosis in MDS. The aims of the present study were to assess differentiation and apoptosis induced with all-trans retinoic acid (ATRA) and etoposide, to characterize the mode of apoptosis in these two model systems, and to assess the influence of granulocyte colony-stimulating factor (G-CSF), which in combination with erythropoietin has been shown to inhibit apoptosis in MDS. ATRA induced differentiation and apoptosis in a concentration- and time-dependent manner. Differentiated cells were partially rescued (by 50%) from apoptosis with G-CSF. Etoposide induced apoptosis in a concentration- and time-dependent manner, but no signs of preceding maturation or G-CSF rescue were detected. ATRA- and etoposide-induced apoptosis were both mediated through the caspase pathway and were partially blocked with the general caspase inhibitor zVAD-fmk. Simultaneous treatment with G-CSF and zVAD-fmk additively blocked ATRA-induced apoptosis. However, the two pathways differed in terms of substrate cleavage during apoptosis. ATRA-induced apoptosis caused actin cleavage, which was not affected by G-CSF, and Bcl-2 downregulation. Etoposide induced a caspase-dependent cleavage of Bcl-2, while actin remained intact. The Fas system did not seem to play a major role in any of these apoptotic pathways. Our results may provide new tools to study the mechanisms of apoptosis in MDS.

Topics: Actins; Acute Disease; Amino Acid Chloromethyl Ketones; Antibodies, Monoclonal; Apoptosis; Blast Crisis; Caspase Inhibitors; Caspases; Cell Differentiation; Cysteine Proteinase Inhibitors; Cytoskeleton; Erythropoietin; Etoposide; fas Receptor; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Myelodysplastic Syndromes; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tretinoin; Tumor Cells, Cultured

Topics: Acute Disease; Erythropoietin; Heart Transplantation; Humans; Immunocompromised Host; Male; Middle Aged; Parvoviridae Infections; Parvovirus B19, Human; Postoperative Complications

Many different cell types, coordinated by proinflammatory mediators, take part in the acute inflammatory reaction, but there is a lack of evidence regarding the role of erythroid cells in such conditions. In this study, changes in bone marrow, splenic, and peripheral blood erythroid cells and in erythropoietin (Epo) blood levels were investigated up to 72 hours after polyvinylpyrrolidone (PVP)-induced sterile inflammation in male Wistar rats (two intraperitoneal injections of 15 mL 3.5% PVP at 18-hour intervals). Transient changes within progenitor erythroid cells were observed in the bone marrow. Significant increases in the number of splenic immature erythroid progenitors (BFU-E) 6 hours and mature erythroid progenitors (CFU-E), erythroblasts, and orthochromatic erythroblasts 48 and 72 hours after the induction of inflammation pointed to stimulated splenic erythropoiesis. This was confirmed by semiquantitative assessment of splenic smears, which demonstrated expansion of erythroid cells at hours 48 and 72. The changes observed in the bone marrow and spleen indicated that during acute inflammation erythropoiesis was stimulated and that the spleens of PVP-treated rats were favorable to erythroid development. The significant increase in the percentage of peripheral blood reticulocytes 48 and 72 hours after PVP-induced inflammation provided evidence that effective erythropoiesis occurred. In spite of the stimulated erythropoiesis, serum levels of Epo remained unchanged, implying that other non-Epo regulatory molecules may be responsible for erythroid cellular changes.

Topics: Acute Disease; Animals; Bone Marrow Cells; Cell Differentiation; Erythropoiesis; Erythropoietin; Inflammation; Male; Povidone; Rats; Rats, Wistar; Spleen; Time Factors

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Humans; Iron; Leukemia

Our aim was to test the hypothesis that, in leukemic children, serum erythropoietin (EPO) levels vary inversely with hemoglobin.. Twenty-four children (15 males, nine females) with an age range of 1-16 years (mean, 7.7 years) diagnosed with acute leukemia (22 acute lymphocytic, two acute myeloid) were studied over 4 months. Serum EPO and hemoglobin were measured simultaneously at multiple time points in the course of their disease, and a multiple regression analysis was performed to describe the EPO-hemoglobin relationship.. In a model adjusted for individual subject, there was a significant correlation between hemoglobin and logEPO in these leukemic children (r = -0.55, P < .01, n = 100). When measurements at hemoglobins less than 10.0 were analyzed the correlation increased significantly (r = -0.88, P < .01, n = 21). However, approximately 20% of the observations fell into one of two groups: an inappropriately low EPO for hemoglobin or an inappropriately elevated EPO for hemoglobin. The clinical characteristics of the children at each of these determinations were not different in any manner from the determinations which fell within the 95% confidence intervals for predicted mean EPO value: each of the outlying points came from a patient who at other times had an appropriate EPO for hemoglobin.. There existed a significant inverse relationship between hemoglobin and EPO, suggesting that the feedback mechanism for EPO is intact. Reasons for inappropriately high or low EPO, for level of hemoglobin, are not clear and may be reflective of other aspects of bone marrow or EPO metabolism.

Topics: Acute Disease; Biomarkers; Child; Child, Preschool; Erythropoietin; Female; Hemoglobins; Humans; Infant; Leukemia, Myeloid; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma

RAS mutations arise at high frequency (20-40%) in both acute myeloid leukemia and myelodysplastic syndrome (which is considered to be a manifestation of preleukemic disease). In each case, mutations arise predominantly at the N-RAS locus. These observations suggest a fundamental role for this oncogene in leukemogenesis. However, despite its obvious significance, little is known of how this key oncogene may subvert the process of hematopoiesis in human cells. Using CD34+ progenitor cells, we have modeled the preleukemic state by infecting these cells with amphotropic retrovirus expressing mutant N-RAS together with the selectable marker gene lacZ. Expression of the lacZ gene product, beta-galactosidase, allows direct identification and study of N-RAS-expressing cells by incubating infected cultures with a fluorogenic substrate for beta-galactosidase, which gives rise to a fluorescent signal within the infected cells. By using multiparameter flow cytometry, we have studied the ability of CD34+ cells expressing mutant N-RAS to undergo erythroid differentiation induced by erythropoietin. By this means, we have found that erythroid progenitor cells expressing mutant N-RAS exhibit a proliferative defect resulting in an increased cell doubling time and a decrease in the proportion of cells in S + G2M phase of the cell cycle. This is linked to a slowing in the rate of differentiation as determined by comparative cell-surface marker analysis and ultimate failure of the differentiation program at the late-erythroblast stage of development. The dyserythropoiesis was also linked to an increased tendency of the RAS-expressing cells to undergo programmed cell death during their differentiation program. This erythroid lineage dysplasia recapitulates one of the most common features of myelodysplastic syndrome, and for the first time provides a causative link between mutational activation of N-RAS and the pathogenesis of preleukemia.

Topics: Acute Disease; Antigens, CD34; Apoptosis; Cell Differentiation; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Genes, ras; Genes, Reporter; Humans; Leukemia, Myeloid; Mutation; Myelodysplastic Syndromes; Preleukemia

We have established an erythropoietin-dependent human leukemia cell line, AS-E2, from a patient with acute myeloid leukemia. These cells have many characteristics of late erythroid progenitor cells, they are positive for CD36, Glycophorin A, and CD71 but negative for CD41, and positive for benzidine and PAS staining. These cells express GATA-1 and have low affinity erythropoietin (EPO) receptor on their surface. Interestingly, AS-E2 cells are strictly dependent on EPO for their growth and survival; other cytokines including GM-CSF, stem cell factor, or IL-3 cannot support the growth of this cell line. These features are similar to late erythroid lineage cells, like normal BFU-E or CFU-E, and we have demonstrated that EPO stimulation induces the tyrosine phosphorylation of several proteins in AS-E2 cells including the EPO receptor and JAK2 kinase. This new cell line is a useful reagent to study biological and molecular events during the late stages of erythropoiesis, and to understand transforming events in human erythroid cells.

Topics: Acute Disease; Cell Division; DNA Fingerprinting; Erythropoietin; Humans; Karyotyping; Leukemia, Myeloid; Male; Middle Aged; Neoplasm Proteins; Phosphorylation; Receptors, Erythropoietin; Tumor Cells, Cultured; Tumor Stem Cell Assay; Tyrosine

Administration of erythropoietin augmented the mitotic activity in the erythroid crown of erythroblastic islands in polycythemic as well as normal rats. The phenomenon seems to be due to activation of erythropoietic synthesis by the central macrophage in reconstructing erythroblastic islands.

Topics: Acute Disease; Anemia; Animals; Bone Marrow Cells; Cell Division; Erythroblasts; Erythropoiesis; Erythropoietin; Female; Hemorrhage; Mitosis; Polycythemia; Rats; Time Factors

Topics: Acute Disease; Anemia; Christianity; Erythropoietin; Female; Humans; Middle Aged; Pancreatitis, Acute Necrotizing; Recombinant Proteins

The pathophysiologic backgrounds of anemia in malaria are complex and multifactorial. The purpose of the present study was to measure serum concentrations of erythropoietin (EPO) and to evaluate the adequacy of EPO production in patients suffering from acute Plasmodium falciparum malaria. Fifteen patients with complicated malaria were included in the study. Serum samples were taken on the day of admission, and days 7, 14, 21 and 28. Serum EPO concentrations were measured using an enzyme-linked immunosorbent assay. The median serum EPO concentration was 15.6 mU/ml on the day of admission (range 0.5-567) mU/ml, 10.6 mU/ml (1.2-863) on day 7, 11.8 mU/ml (0.5-72.8) on day 14, 10 mU/ml (0.5-74.6) on day 21, and 8.3 mU/ml (2.2-61.6) on day 28. Inadequate EPO production was found in 46.6% of the patients on the day of admission, which increased to 67% and 68% on days 7 and 14, and reached a maximum of 80% on day 21. Almost 54% of patients had inadequate EPO production on day 28. Our data indicate inadequate EPO production in patients suffering from acute P. falciparum malaria, which might contribute to the prolonged anemia observed in these patients.

Topics: Acute Disease; Adolescent; Adult; Anemia; Erythropoietin; Hematocrit; Humans; Malaria, Falciparum; Middle Aged

Recombinant human interferon-inducible protein-10 (rIP-10) has been recently identified, purified and shown to suppress the multiplication of normal marrow early hemopoietic progenitors. In the present study we investigated the effect of rIP-10 on different normal and acute myelogenous leukemia (AML) progenitor populations. We first studied hematologically normal bone marrow using the delta culture assay, in which marrow low-density cells were incubated in liquid culture with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) for 1 week, to allow the differentiation of mature progenitors, and thereafter cultured in methylcellulose in the presence of rGM-CSF and recombinant erythropoietin (rEPO). In this assay rIP-10 significantly inhibited the proliferation of normal marrow hemopoietic progenitors in a dose-dependent fashion. However, when fresh normal marrow cells were cultured in methylcellulose without preincubation in liquid culture, rIP-10 did not affect the growth of colony-forming cells. In contrast, when recombinant c-kit ligand (rKL) was added to rGM-CSF and rEPO, an increment in colony numbers was observed that was eliminated by rIP-10. Similar experiments performed with low-density, non-adherent, T cell-depleted AML marrow cells, obtained from 12 untreated adult AML patients, revealed qualitatively similar results: rIP-10 inhibited the proliferation of AML progenitors in the AML delta assay but did not affect the growth of rGM-CSF-responsive AML colony-forming cells when plated in semisolid media in the presence of rGM-CSF. When rKL was added to rGM-CSF during plating in an effort to recruit additional AML progenitor populations, there was an increment in leukemic blast colony numbers that was eliminated by rIP-10. As observed with normal progenitors, the effect of rIP-10 on these AML progenitors was concentration-dependent, statistically significant and reversible with a rIP-10-neutralizing antiserum. To delineate the mechanism of action of rIP-10 we used the thymidine suicide assay and found that rIP-10 significantly reduced the fraction of leukemic progenitors synthesizing DNA. Our data suggest the rIP-10 inhibits the proliferation of (probably immature) AML progenitor populations by reducing the fraction of cells undergoing DNA synthesis. Additional studies are needed to further elucidate the mechanism of this inhibition and to determine the potential clinical benefits of rIP-10 in future therapies for AML.

Topics: Acute Disease; Aged; Antigens, CD; Antigens, CD34; Antigens, Differentiation, Myelomonocytic; CD13 Antigens; Cell Cycle; Cell Division; Cells, Cultured; Chemokine CXCL10; Chemokines, CXC; Colony-Forming Units Assay; Cytokines; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Inhibitors; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; Male; Middle Aged; Neoplastic Stem Cells; Recombinant Proteins; Sialic Acid Binding Ig-like Lectin 3; Stem Cell Factor; Tumor Stem Cell Assay

A 34-year-old man with acute myelocytic leukemia (AML: MO) and a 32-year-old woman with AML: M2 developed pure red cell aplasia (PRCA) after receiving a major ABO incompatible bone marrow transplant (BMT). The first patient responded to recombinant human erythropoietin (rhEPO) therapy, while the second did not. The second patient also received methylprednisolone (m-PSL) but developed reticulocytosis and hemolysis after the administration of m-PSL. Plasmapheresis was then performed and the patient promptly recovered from hemolysis and PRCA. We conclude that close attention must be paid when treating PRCA following major ABO-incompatible BMT with rhEPO and m-PSL, as there is always the potential for massive hemolysis.

Topics: ABO Blood-Group System; Acute Disease; Adult; Blood Group Incompatibility; Bone Marrow Transplantation; Erythropoietin; Female; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Models, Immunological; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission Induction; Transplantation, Homologous

Ineffective hematopoiesis with associated cytopenias and potential evolution to acute myeloid leukemia (AML) characterize patients with myelodysplastic syndrome (MDS). We evaluated levels of apoptosis and of apoptosis-related oncoproteins (c-Myc, which enhances, and Bcl-2, which diminishes apoptosis) expressed within CD34+ and CD34- marrow cell populations of MDS patients (n = 24) to determine their potential roles in the abnormal hematopoiesis of this disorder. Marrow cells were permeabilized and CD34+ and CD34- cells were separately analyzed by FACS to detect: (1) a subdiploid (sub-G1) DNA population, and (2) expression of Bcl-2 and c-Myc oncoproteins. Within the CD34+ subset, a significantly increased percentage of cells demonstrated apoptotic/sub-G1 DNA content in early (ie. refractory anemia) MDS patients compared with normal individuals and AML patients (mean values: 9.1% > 2.1% > 1.2%). Correlated with these findings, the ratio of expression of c-Myc to Bcl-2 oncoproteins among CD34+ cells was significantly increased for MDS patients compared to those from normal and AML individuals (mean values: 1.6 > 1.2 > 0.9). Bcl-2 and c-Myc oncoprotein levels were maturation stage-dependent, with high levels expressed within CD34+ marrow cells, decreasing markedly with myeloid maturation. Treatment of seven MDS patients with the cytokines granulocyte colony-stimulating factor plus erythropoietin was associated with decreased levels of apoptosis within CD34+ marrow cells and may contribute to the enhanced hematopoiesis in vivo that was shown. These findings are consistent with the hypothesis that altered balance between cell-death (eg, c-Myc) and cell-survival (eg, Bcl-2) programs were associated with the increased degrees of apoptosis present in MDS hematopoietic precursors and may contribute to the ineffective hematopoiesis in this disorder, in contrast to decreased apoptosis and enhanced leukemic cell survival in AML.

Topics: Acute Disease; Adult; Aged; Apoptosis; Bone Marrow; Cell Cycle; Cell Transformation, Neoplastic; Disease Progression; DNA, Neoplasm; Erythropoietin; Female; Gene Expression Regulation; Genes, bcl-2; Genes, myc; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Leukemia, Myeloid; Male; Middle Aged; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Recombinant Proteins

Erythropoietin (Epo) production during acute inflammation induced by s. c. turpentine administration in experimental Long-Evans rats increased in response to reduced erythropoiesis. A close correlation was found between decreased haematocrit (Hct) and increased levels of tumour necrosis factor-alpha (TNF alpha) in this experimental system. The Epo response was not different between rats with acute inflammation and anaemia and control animals with a comparable degree of anaemia. It is concluded that Epo is not an acute phase reactant, and that the Epo response in acute experimental inflammation in rats is explained by the associated development of anaemia.

Topics: Acute Disease; Anemia; Animals; Asepsis; Erythropoiesis; Erythropoietin; Inflammation; Kinetics; Male; Rats

A 20-year-old Jehovah's witness patient experienced a femur fracture, with a section of the femoral artery and vein. On admission, haemoglobin concentration was 5.6 g.dL-1 and haematocrit 17%. Because of aponevrotomy, blood losses persisted. As the patient refused blood transfusion, recombinant human erythropoietin and parenteral iron were administered, associated with mild hypothermia, sedation and mechanical ventilation. After 21 days, the haemoglobin concentration increased to 10.9 g.dL-1 and haematocrit to 33% Recombinant human erythropoietin and parenteral iron may provide an alternative safe and effective therapy in life-threatening anaemia when blood transfusions are not accepted by the patient.

Topics: Acute Disease; Adult; Anemia, Hypochromic; Blood Loss, Surgical; Christianity; Erythropoietin; Femoral Artery; Femoral Fractures; Femoral Vein; Hemoglobins; Humans; Male; Recombinant Proteins; Time Factors

To assess the risk for acute and chronic fetal hypoxia in twin pregnancies.. We investigated 50 sets of twins (24-38 weeks' gestation, 660-3200 g birth weight) admitted consecutively to our neonatal intensive care unit. Seventy-six infants were appropriate for gestational age (AGA; tenth to 90th percentile), 20 were small for gestational age (SGA; below the tenth percentile), and four were large for gestational age (above the 90th percentile). Twenty-six singleton AGA term newborns served as controls. Umbilical arterial pH was used as a marker for acute and umbilical venous erythropoietin concentration for chronic fetal hypoxia. The results are given as median followed by quartiles.. We identified 40 sets of diamniotic-dichorionic twins and ten sets of diamniotic-monochorionic twins with transplacental vascular shunts. In the second-born twin, umbilical arterial pH was lower (7.29, 7.23-7.33) than in the firstborn (7.31, 7.25-7.34) (P = .03), and the incidence of a low pH (less than 7.20) was higher (19 versus 11%). Two second-born twins and none of the firstborn twins had an umbilical arterial pH less than 7.05. In SGA twins, the erythropoietin concentration was elevated (34.8, 22.8-325 mU/mL) compared with that in AGA twins (16.2, 8.2-26.6 mU/mL) (P < .01). In AGA twins, erythropoietin concentration did not differ from that in AGA singleton newborns (19.6, 14.7-31.6 mU/mL). In 12 of 17 twin sets with weight discordancy greater than 15% and in all five twin sets with weight difference greater than 25%, erythropoietin concentration was higher in the smaller twin. The proportion of infants and of complete sets with elevated erythropoietin levels was higher (P < .01) in monochorionic than in dichorionic pregnancies.. The second-born twin is at increased risk for acute birth asphyxia. Fetal growth restriction in twin pregnancies is associated with chronic fetal hypoxia. Monochorionic twins are at higher risk for chronic fetal hypoxia than are dichorionic twins.

Topics: Acute Disease; Chronic Disease; Erythropoietin; Fetal Hypoxia; Humans; Infant, Newborn; Infant, Newborn, Diseases; Risk Factors; Twins, Dizygotic; Twins, Monozygotic

Since renal allograft rejection is frequently associated with a blunted erythropoiesis, we investigated erythropoietin (EPO) serum concentrations in 17 patients with acute rejection, eight patients with chronic rejection, and 18 transplant recipients with stable graft function. All rejection episodes were proven by biopsy. Erythropoietin serum levels were significantly reduced in patients with chronic rejection (6.2 +/- 3.4 mU/mL; P < 0.01) compared with individuals with acute rejection (35.6 +/- 33.9 mU/mL) or stable graft function (24.0 +/- 19.7 mU/mL). Suppressed EPO levels were associated with marked anemia in chronic rejection patients. In a subgroup of patients with acute rejection and bad responses to an intensified immunosuppressive regimen or with transplant failure, we found significantly suppressed EPO levels (11.6 +/- 6.1 mU/mL) compared with a subgroup of patients with a beneficial acute rejection outcome (57.0 +/- 34.2 mU/mL; P < 0.01). A correlation between histologic parameters of acute rejection and hormone levels showed that signs of moderate glomerulitis were associated with elevated EPO levels, whereas lesions of moderate tubulitis were associated with low values. We conclude that serum EPO may have prognostic value for rejection outcome in renal transplant recipients.

Topics: Acute Disease; Anemia; Biopsy; Chronic Disease; Erythropoietin; Female; Graft Rejection; Humans; Kidney; Kidney Transplantation; Male; Prognosis

Using clonogenic assay we investigated the effect of stem cell factor (SCF) on the in vitro growth of clonogenic precursor cells from acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in the presence or absence of recombinant human erythropoietin (rhEpo) or recombinant human granulocyte colony-stimulating factor (rhG-CSF). SCF as a single factor did not induce significant colony formation, and even in the presence of rhEPO or rhG-CSF it very weakly stimulated erythroid colony formation and was rarely capable of inducing myeloid colony formation by clonogenic leukemic cells. In culture dishes supplemented with SCF, both myeloid and erythroid colony formations were dramatically enhanced in MDS, regarding both colony number and size. Colony-formation abilities by MDS progenitors were improved following costimulation with SCF and rhEpo. These results suggest that SCF may have a therapeutic role in restoring hematopoiesis in patients with MDS.

Topics: Acute Disease; Bone Marrow Cells; Cell Division; Cells, Cultured; Drug Synergism; Erythropoietin; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; In Vitro Techniques; Leukemia, Myeloid; Myelodysplastic Syndromes; Neoplastic Stem Cells; Stem Cell Factor

A preterm baby, whose mother received chemotherapy for acute leukaemia during pregnancy, required intensive care because of profound anaemia and neutropenia. Haemopoietic progenitor cell studies showed fetal marrow suppression. Those caring for such mothers and babies should know the possible serious effects chemotherapy for malignancies can have on a developing fetus. Long term follow up of the baby is imperative.

Topics: Acute Disease; Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Infant, Newborn; Infant, Premature, Diseases; Leukemia, Myeloid; Neutropenia; Pregnancy; Pregnancy Complications, Neoplastic; Prenatal Exposure Delayed Effects

Studies were performed to reexamine the response of erythropoietin (Epo) production to acute hypoxic stimuli in patients with end-stage renal disease (ESRD). In the absence of acute bleeding or hypoxia, the serum Epo level in ESRD was similar to that of normal subjects despite severe anemia. In 11 dialysis patients with acute bleeding, the decrease in the Hb level from 8.9 to 5.8 g/dL provoked a significant increase in serum Epo up to 52.2 times the normal value. The increase in serum Epo was associated with a significant increase in corrected reticulocyte. Systemic hypoxemia (PaO2 < 65 mm Hg) in 8 dialysis patients provoked a significant elevation in the serum Epo level up to 24.6 times the normal level. There was an inverse relationship between serum Epo and arterial PaO2 (r = -0.715). The serum Epo level in these patients declined to or near the normal value after recovery from acute hypoxic stress. These data suggest that the ability of the Epo production is well preserved in ESRD, indicating that acute hypoxic stimuli provoke a significant increase in serum Epo.

Topics: Acute Disease; Adult; Aged; Anemia, Iron-Deficiency; Erythropoietin; Female; Hemoglobins; Hemorrhage; Humans; Hypoxia; Kidney Failure, Chronic; Male; Middle Aged; Oxygen; Partial Pressure; Renal Dialysis

Altitude hypoxia induces an increase in erythropoiesis. Some of the factors involved in the control of altitude polycythemia were studied. Ten subjects (4 women, 6 men) were exposed for 3 wk to extreme altitude (6,542 m). Blood was withdrawn in normoxia (N) and after 1 wk (H1), 2 wk (H2), or 3 wk (H3) at 6,542 m for the measurement of serum erythropoietin (EPO), blood hemoglobin (Hb), hematocrit (Hct), intraerythrocyte folate (Fol), and plasma ferritin (Fer) concentrations. Renal blood flow (RBF) and absolute proximal reabsorption rate (APR) were measured by the p-aminohippuric acid and lithium clearance, respectively, in N and H2 conditions. O2 supply to the kidneys was calculated using RBF and arterial O2 content (CaO2). After an initial sharp increase in EPO, it decreased at H2 and H3. Hct and Hb increased from N to H1 and H2 and then unexpectedly decreased from H2 to H3. Mean corpuscular Hb content (MCHC = Hb/Hct) was lower in all H than in N conditions. Increase in EPO at H1 varied from 3- to 134-fold among individuals. Women showed a smaller increase in Hct and Hb and a greater decrease in MCHC. Two women showed a large increase in EPO without increase in Hb. Fol was not modified by altitude hypoxia. Fer showed a marked decrease in H1 and H3 compared with N. Hb was positively related to Fer in hypoxia. Iron intake in food was markedly decreased during the 2-wk ascent to 6,542 m. EPO was inversely related to CaO2 and positively related to APR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adult; Altitude; Altitude Sickness; Erythropoiesis; Erythropoietin; Female; Hormones; Humans; Hypoxia; Kidney; Male; Severity of Illness Index; Sex Characteristics; Time Factors

To examine the endogenous erythropoietin response in critically ill children with acute anemia or acute hypoxemia.. A prospective case study of critically ill acutely anemic, and acutely hypoxemic pediatric patients compared with control groups of critically ill nonanemic and nonhypoxemic patients and with a hemoglobin and age-matched, chronically anemic patient group.. Multidisciplinary, tertiary, pediatric intensive care unit (ICU).. Critically ill patients admitted to the pediatric ICU during an 11-month period between February 1992 and March 1993 with acute anemia (n = 21), acute hypoxemia (n = 18), or neither anemia nor hypoxemia (n = 10). Outpatients with chronic anemia (n = 21) and no acute illness were also studied as a comparison group.. None.. Ages were equivalent among the groups and averaged 57.4 +/- 47.2 months (range 1 to 144). Acutely hypoxemic and critically ill control patients had normal hemoglobin levels. Acutely anemic patients had a hemoglobin level equivalent to chronically anemic outpatients, but lower (p < .001) hemoglobin levels than acutely hypoxemic and critically ill control patients. The serum erythropoietin concentrations in the acutely anemic group were significantly lower than erythropoietin values in the chronically anemic group (39.3 +/- 62.2 vs. 861 +/- 758 mU/mL, p < .001) and similar to erythropoietin concentrations in the critically ill control (13.5 +/- 10.5 mU/mL) and acutely hypoxemic (5.2 +/- 3.3 mU/mL) patient groups. Only ten of 49 critically ill patients had an erythropoietin concentration above normal, compared with 20 of 21 chronically anemic patients, whose erythropoietin concentrations were above normal.. The erythropoietin response to known physiologic stimuli is blunted in critically ill children. This blunted erythropoietin response may result in increased transfusion requirements.

Topics: Acute Disease; Analysis of Variance; Anemia; Blood Transfusion; Case-Control Studies; Child; Child, Preschool; Chronic Disease; Critical Illness; Erythropoietin; Hemoglobins; Humans; Hypoxia; Infant; Infant, Newborn; Intensive Care Units, Pediatric; Matched-Pair Analysis; Outpatients; Prospective Studies; Severity of Illness Index

To analyze the relationship between serum erythropoietin levels and hemoglobin levels in elderly patients with anemia of chronic disorders related to cancer or acute infection when compared with anemic patients with iron deficiency.. Prospective survey with comparison groups.. Tertiary care center.. An elderly group aged 70 and above (mean 84, range 70-96) was divided into subgroups of 45 with anemia of chronic disorders (23 with cancer and 22 with acute infection), 24 with iron-deficiency anemia, and 27 with no anemia. Thirty non-anemic younger adults were also studied.. Serum erythropoietin (radioimmunoassay), complete blood count, serum iron, B12, folate and ferritin, liver and kidney function tests, blood gas analyses, and bacteriological and radiological tests.. The serum erythropoietin levels were significantly lower in the elderly non-anemic hospitalized group than in the healthy younger group. A significant negative relationship between the log serum erythropoietin and hemoglobin levels was found in patients with iron deficiency, but not in the other groups. For any given hemoglobin level, the response of erythropoietin was significantly higher in anemic patients with iron deficiency when compared with the neoplastic and infectious group.. Erythropoietin response to anemia is blunted in elderly patients with anemia of chronic disorders related to cancer or acute infection. Erythropoietin level is lower in non-anemic elderly inpatients than in healthy younger persons.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Anemia; Anemia, Hypochromic; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Hemoglobins; Hospitalization; Humans; Infections; Male; Neoplasms; Prospective Studies

The risks inherent in the use of homologous blood products have increased efforts toward identifying alternatives to transfusion. We have previously shown that the administration of recombinant human erythropoietin (rhEpo) enhances the erythropoietic response to acute blood loss. Recombinant human interleukin-3 (rh-IL-3) is a hematopoietic growth factor that has been shown to act synergistically with rhEpo in accelerating erythropoiesis in vitro. The purpose of this study in a primate model was to determine if the administration of rhIL-3 in combination with rhEpo could augment the erythropoietic response to acute blood loss more than rhEpo therapy alone. Twenty-four adult male baboons were randomized into four groups. The induction of acute normovolemic anemia to a hematocrit of 20% was accomplished via exchange-transfusion with 6% hetastarch. The groups were then treated for 7 consecutive days with the following growth factors: group I (n = 7), no growth factors; group II (n = 5), rhIL-3 alone (100 micrograms/kg/d); group III (n = 6), rhEpo alone (1000 U/kg/d); group IV (n = 6), rhEpo (1000 U/kg/d) plus rhIL-3 (100 micrograms/kg/d). All animals received folate, vitamin B12, and intravenous iron-dextran immediately following the exchange-transfusion. Response to therapy was monitored for 35 days. There were no adverse reactions following growth factor administration. The analysis of erythropoietic rates between study days 1 through 11, as determined via linear regression analysis, revealed that hematocrits increased significantly faster in the groups receiving rhEpo compared to controls. The administration of rhIL-3, however, did not increase the rate of erythropoiesis when compared to controls, nor did it augment response when added to the rhEpo regimen. The results of this study demonstrate that the administration of rhIL-3 alone had no significant effect on erythropoiesis in this setting of acute blood loss. Further, despite promising in vitro data, rhIL-3 provided no additional stimulation of erythropoiesis in animals receiving rhEpo. Nevertheless, the study confirms that the pharmacologic acceleration of erythropoiesis by rhEpo alone remains an attractive alternative to homologous transfusion.

Topics: Acute Disease; Analysis of Variance; Anemia; Animals; Blood Cell Count; Disease Models, Animal; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Interleukin-3; Male; Papio; Recombinant Proteins

A favorable prognosis and a low rate of leukemic transformation has been attributed to the 5q- syndrome, a myelodysplastic syndrome (MDS) characterized by macrocytic anemia, hypolobulated micromegakaryocytic hyperplasia, and an interstitial deletion of chromosome 5. We examined the characteristics and outcome of 43 consecutive patients in our institution strictly defined by morphologic criteria and a solitary 5q- cytogenetic defect. The median age at diagnosis was 68 years, with a clear female predominance (7:3). Eighty percent of the patients were red blood cell transfusion-dependent at diagnosis and all untransfused patients had macrocytic indexes. In contrast, significant neutropenia or thrombocytopenia was rare. The French-American-British (FAB) class distributions were RA (72%), RARS (7%), RAEB (16%), and RAEB-IT (5%). At a median follow-up of 31 months, 56% of the patients survive, with a projected median survival of 63 months. The incidence of acute leukemia was 16% and was uniformly fatal. Clinical hemosiderosis occurred in 28% of the patients, resulting in two deaths. Neither survival nor the risk of leukemic transformation was predictable from initial clinical parameters, including FAB classification, Bournemouth score, and degree of aneuploidy. The lack of significant neutropenia and thrombocytopenia seemed to account for a very low incidence of infection and bleeding resulting in a prognosis equal or superior to historical patients with MDS. Therapeutic endeavors, including the use of corticosteroids, androgens, cis-retinoic acid, pyridoxine, and danazol, were largely unsuccessful.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blood Transfusion; Bone Marrow; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 5; Erythropoietin; Female; Gene Deletion; Humans; Leukemia; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis

In all mammalian species studied the haematocrit (hct) declines after birth in the absence of any known nutritional deficiencies. The glycoprotein hormone, erythropoietin (Epo), is essential for normal red blood cell production. The aims of this study were 1) to investigate the changes in plasma Epo during the normal post-natal decrease in hct in lambs; 2) to compare the effects of chronic and acute haemorrhage in neonatal lambs; and 3) to test the hypothesis that the Epo response to haemorrhage is blunted in the neonatal period. Twenty-one lambs (0-9 weeks of age) were studied; group I (n = 8) were used to document normal post-natal changes (98 samples); group II (n = 7) lambs were haemorrhaged repetitively during weeks 3-6 (95 samples); group III (n = 6) lambs were bled once in the first 3-week period. In the group I (control lambs) the hct decreased from 30.6 +/- 1.3 (weeks 1 & 2) to a nadir of 23.2 +/- 0.8 (75.8% of initial value) in the 6th week, and the plasma Epo declined from 25.7 +/- 4.9 (week 1) to 12.3 +/- 1.0 mU/ml (week 6). In group II, the lambs were bled repetitively, a total of 510 +/- 32 ml blood being removed during weeks 3-6, the hct was 18.7 +/- 0.8 (81% of hct at nadir in controls) in week 6, and Epo was 26.9 +/- 13.3 in week 3, 23.4 +/- 3.6 mU/ml in week 6.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adrenocorticotropic Hormone; Animals; Animals, Newborn; Carbon Dioxide; Chronic Disease; Erythropoietin; Globins; Hematocrit; Hemorrhage; Hydrocortisone; Oxygen; Reference Values; Sheep

Erythropoietin (EPO) mRNA levels were measured by ribonuclease (RNase) protection in organs from unstimulated rats and from animals after normobaric hypoxia or hemorrhagic anemia. Both liver and kidney responded to stimulation with large increases in EPO mRNA, but the response characteristic to graded stimulation was different. The liver responded poorly to mild normobaric hypoxia, accounting for only 2 +/- 1% of total EPO mRNA at 11% O2, but hepatic EPO mRNA levels increased steeply with more severe hypoxia so that at 7.5% O2 the liver contributed to 33 +/- 7% of the total. After hemorrhagic anemia, the liver also responded more strongly to more severe stimulation, but at all points it accounted for a significant proportion of total EPO mRNA, contributing 18 +/- 6% after removal of 2.5 ml (hematocrit 37.2 +/- 1.3%), increasing to 37 +/- 14% after venesection of 10.5 ml (hematocrit 15.8 +/- 0.8%). Studies of EPO mRNA in other organs confirmed that EPO production outside the liver and kidney were quantitatively insignificant in stimulated animals. However, the hypoxia-induced increases in EPO mRNA in brain, testis, and spleen suggest the existence of an oxygen-sensing mechanism at other sites.

Topics: Acute Disease; Anemia; Animals; Erythropoietin; Feedback; Hemorrhage; Hypoxia; Kidney; Liver; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tissue Distribution

The acute rejection of kidney transplant is accompanied by kidney ischaemia which in turn is a triggering factor for erythropoietin (EPO) synthesis. It was shown, on the other hand, that during the rejection an increase in blood serum parathormone (PTH) concentration takes place. The present study was aimed at answering the question what is the effect of acute rejection of kidney transplant on blood serum concentrations of EPO i PTH. Seventeen patients with kidney transplant participated in the study. In all the patients the investigations were carried out four times: 1--few days before rejection, 2--after ascertaining that kidney transplant is being rejected, 3--immediately after rejection, and 4--few days after completing the anti-rejection therapy. High doses of methylprednisolone were used as anti-rejection therapy. Control group consisted of 16 healthy persons. Acute rejection of kidney transplant was accompanied by a significant increase in blood serum concentrations of EPO and PTH. After methylprednisolone therapy, normalization of EPO and decrease in PTH concentration were observed in kidney transplant patients. Significant positive correlations were found between EPO and PTH concentrations in blood serum. It was concluded that acute rejection of kidney transplant is characterized by a significant increase in blood serum concentrations of EPO and PTH. Despite the existence of a significant positive correlation between blood serum concentrations of EPO and PTH in patients with kidney transplant, any pathogenic relation between the observed disturbances of secretion of the two hormones seems to be of little probability.

Topics: Acute Disease; Adult; Erythropoietin; Female; Graft Rejection; Humans; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Parathyroid Hormone

Acute rejection is characterized by renal ischaemia which in turn is a triggering factor of EPO synthesis. This fact justified our present studies which aimed to assess the influence of acute rejection (AR) on plasma EPO level in KTP. A total of 17 KTP were examined some days before AR (I), at the onset of AR (II), immediately (III) and some days after (IV) discontinued therapy of AR episodes by methylprednisolone. The control group consisted of 16 healthy subjects. KTP 2-3 weeks after renal transplantation showed relative EPO deficiency both during efficient excretory function and rejection episodes. At acute graft rejection episodes a marked increase of plasma EPO level was found. Results presented in this study suggest absence of the physiological relationship between EPO secretion and erythropoiesis 2-3 weeks after transplantation.

Topics: Acute Disease; Adult; Erythropoietin; Female; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Time Factors

Reduced oxygen tension is regarded as the primary physiologic signal for the production of erythropoietin (EPO). There is little information available about early changes of EPO production in man due to severe hypoxia. The purpose of the present study was to examine the time course of EPO in serum of patients with acute cardiogenic pulmonary edema (ACPE). In 29 patients (seventy-five +/- six years, mean age +/- SEM) who were hospitalized within two hours after onset of symptoms of ACPE, serum EPO concentrations were monitored for up to seventy-two hours. At the moment of admission all patients showed significantly increased EPO concentrations of 121 +/- 64 mU/mL (mean +/- SEM) compared with a healthy population (15-35 mU/mL). Twenty-three patients who recovered within thirty minutes (group A) exhibited a quick return of their EPO serum levels to normal. The remaining 6 patients (group B) had a protracted clinical course and their EPO concentration showed a further increase up to the end of the observation period. The comparative monitoring of concentrations of alpha-1-proteinase inhibitor, antithrombin III, C-reactive protein, fibronectin, hapotoglobin, and transerrin in serum and plasma revealed no significant changes. Thus a major contribution of fluid shifts into or from the intravascular compartment to the observed changes in EPO concentration seems to be unlikely. The data suggest that the production and release of EPO in the kidneys due to altered oxygen delivery is a fast-responding mechanism.

Topics: Acute Disease; Aged; Aged, 80 and over; Blood Proteins; Cardiovascular Diseases; Erythropoietin; Female; Humans; Hypoxia; Kidney; Male; Pulmonary Edema

Six patients with acute renal failure, in five cases due to acute crescentic glomerulonephritis and in one case due to total bilateral renal cortical necrosis, were studied. All had serum erythropoietin (EPO) concentrations in the normal range, despite a relatively severe anaemia. Half-life and plasma clearance of intravenously injected recombinant human erythropoietin (rhEPO) were determined. The results indicate that the lack of compensatory increase in serum EPO to the anaemic stimulus is not due to increased catabolism, but to decreased synthesis of the renal hormone. Two patients were treated with rhEPO (Eprex). In marked contrast to untreated controls, both patients responded with vigorous reticulocytosis and normalization of haemoglobin levels while they were still in severe renal failure. These results are similar to our previous findings in patients with acute renal failure due to tubular necrosis. Under all three conditions the defective EPO synthesis is probably the dominant pathogenetic factor for the largely aregeneratory anaemia of prolonged cases, and for the sluggish restoration of red cell mass during recovery of renal function. It is concluded that defective synthesis of EPO is not only a permanent and irreversible feature of severe chronic renal failure, but that it is also present, usually in a transient and reversible form, in different types of acute renal failure.

Topics: Acute Disease; Aged; Erythropoietin; Female; Glomerulonephritis; Hemoglobins; Humans; Kidney Cortex Necrosis; Leukocyte Count; Male; Middle Aged; Recombinant Proteins; Reticulocytes

We have evaluated the therapeutic activity of rIL-3, in comparison with recombinant granulocyte-macrophage CSF (rGM-CSF) and recombinant erythropoietin (rEpo), on a lethal form of acute anemia induced by a single injection of a monoclonal IgG1 anti-mouse RBC (MRBC) autoantibody. Continuous perfusion of rIL-3 before the administration of anti-MRBC mAb prevented animals from the death due to anemia with a rapid recovery in greater than 90% of the cases, while only partial protection (one third of the cases) was obtained by rEpo perfusion, and no protection by rGM-CSF. Since the anti-MRBC mAb induced a marked agglutination of RBC in spleens and livers, and subsequent hemodynamic failure may be an additional contributing factor to the animals' death, the activation of Fc gamma receptor-dependent phagocytosis by rIL-3, as well as the increased number of monocytes/macrophages resulting from rIL-3 perfusion, may also facilitate rapid elimination of these agglutinated RBC, resulting in the further amelioration of the animals' survival. Our results suggest that the therapeutic effect of rIL-3 on anti-MRBC autoantibody-induced anemia is achieved by: (a) its activity to promote the growth and differentiation of erythroid progenitors responsive to Epo and of monocyte/macrophage lineage; and (b) its activity to enhance the phagocytic activity of macrophages to efficiently eliminate agglutinated RBC in spleens and livers.

Topics: Acute Disease; Anemia; Animals; Antibodies, Monoclonal; Autoantibodies; Colony-Stimulating Factors; Endocytosis; Erythrocytes; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Hematocrit; Interleukin-3; Liver; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Perfusion; Receptors, Fc; Recombinant Proteins; Spleen

The effects of repeated administration of recombinant human erythropoietin (rHuEPO) were investigated in mice with haemolytic anaemia. Mice with haemolytic anaemia induced by phenylhydrazine (PHZ mice) were examined as an acute model and New Zealand black mice (NZB mice) at 13 months of age were examined as a chronic model. The plasma erythropoietin (EPO) level in PHZ mice was high and showed a strong inverse correlation with the Hb in the anaemia development period. However, it was relatively low in the recovery period from anaemia. On the other hand, the plasma EPO level in NZB mice showed a simple inverse correlation with the Hb. The rHuEPO was injected every day for a week into these mice. While a high plasma EPO level was maintained in PHZ mice, no significant effect was observed by injection with rHuEPO at dose of 600 IU/kg. However, in the recovery period from anaemia, RBC and haemoglobin in PHZ mice were increased by the rHuEPO treatment and recovered more quickly to their normal levels. In NZB mice, RBC and haemoglobin were also increased by treatment with rHuEPO at dose of 600 IU/kg. Anti-RBC autoantibodies and anti-EPO antibodies did not increase, while RBC and plasma EPO levels were increased by the rHuEPO treatment. These results suggest that some types of haemolytic anaemia are not always combined with high endogenous EPO levels and that exogenous rHuEPO may be effective for use in the treatment of haemolytic anaemia.

Topics: Acute Disease; Anemia, Hemolytic; Animals; Antibodies; Blood Group Antigens; Chronic Disease; Erythropoietin; Female; Hemoglobins; Male; Mice; Mice, Inbred NZB; Phenylhydrazines; Recombinant Proteins

In situ hybridization was used to quantitate the cells that produce erythropoietin (EP) in the renal cortices of mice with varying severities of acute anemia and of mice recovering from severe, acute anemia. The number of EP-producing cells in the renal cortex increased in an exponential manner as hematocrit was decreased. Individual EP-producing cells had very similar densities of silver grains in autoradiograms regardless of whether they were from normal mice or from slightly, moderately or severely anemic animals. With increasingly severe anemia, total renal EP mRNA levels and serum EP concentrations showed increases that correlated with the number of renal EP-producing cells. These results indicate that as mice become more anemic, additional cells are recruited to produce EP rather than the cells already producing EP being stimulated to increase their individual production. In mildly and moderately anemic animals, small clusters of EP-producing cells were found in the inner cortex with large areas of cortex containing no EP-producing cells. In severely anemic mice, EP-producing cells were found throughout the inner cortex with only a very few found scattered in the outer cortex and outer medulla. The data indicate that only a subset of total renal interstitial cells produce EP. During recovery from severe, acute anemia, the numbers of EP-producing cells decreased exponentially as hematocrits rose and correlated with decreases in total renal EP mRNA and serum EP concentrations. These results suggest that following an acute blood loss and during the recovery from a blood loss, the capacity to deliver oxygen, as represented by hematocrit, is the major regulator of EP production.

Topics: Acute Disease; Anemia; Animals; Blotting, Northern; Cell Count; Erythropoietin; Hematocrit; Kidney; Mice; Mice, Inbred BALB C; Nucleic Acid Hybridization; RNA, Messenger

A comparative study of renin and erythropoietin content in the blood serum of rats with "endocrine" kidneys and changes in their activity following the action of specific erythropoietic stimulus (4-hour hypoxia) has been conducted. The presence of "endocrine" kidneys increased renin and erythropoietin activity in such animals. Acute hypoxia produced further increase in erythropoietin titre in the blood serum, with renin remaining at the same level. Possible differences in the mechanisms of renin and erythropoietin biogenesis in the kidneys are considered.

Topics: Acute Disease; Air Pressure; Animals; Aorta, Abdominal; Erythropoietin; Hypoxia; Kidney; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Rats; Rats, Inbred Strains; Renin; Time Factors

Topics: Acute Disease; Adult; Anemia; Cell Cycle; Chronic Disease; Erythropoiesis; Erythropoietin; Fetal Hemoglobin; Humans; Recombinant Proteins

The bone marrow of a patient with acute undifferentiated leukemia developed unique colonies after a 14-day culture in erythropoietin (EPO)-containing methylcellulose. The colonies consisted of 20 to 200 nonhemoglobinized large blast cells. Cytogenetic analysis of single colonies revealed hypotetraploid karyotypes with several marker chromosomes that were identical to those found in directly sampled bone marrow. The concurrently formed erythroid bursts showed only normal karyotypes. No leukemic colony formation was observed in other culture systems with either colony-stimulating activity (CSA) or phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM). The leukemic colonies exhibited a complete EPO-dose dependency similar to that of the patient's normal BFU-E. Although cytochemical and immunologic marker studies of the bone marrow cells failed to clarify the cell lineage of the leukemic cells with extraordinarily large cell size, ultrastructural study revealed erythroid differentiation such as siderosome formation in the cytoplasm and ferritin particles in the rhophecytosis invaginations. These findings indicate that the patient had poorly differentiated erythroid leukemia and that some of the clonogenic cells might respond to EPO in vitro. Corresponding to this biological feature, the leukemic cells were markedly decreased in number in response to repeated RBC transfusions, and partial remission was obtained. These observations suggest that erythroid leukemia distinct from erythroleukemia (M6) with a myeloblastic component, can develop as a minor entity of human acute leukemia.

Topics: Acute Disease; Blast Crisis; Cells, Cultured; Erythropoietin; Hematopoietic Stem Cells; Humans; Karyotyping; Leukemia; Male; Microscopy, Electron; Middle Aged

The effect of prostaglandin synthetase inhibitors, aspirin and indomethacin, salt overload and salt depletion, as well as renomedullary dissection on serum Ep level in rats exposed to acute hypoxia was studied. Male rats were given aspirin or saline for seven days prior to the exposure to hypoxia. Other group of animals was fed salt free diet for the same period of time. Indomethacin was given on two consecutive days and renomedullary dissection was performed three weeks before exposure to hypoxia. Ep level was indirectly determined by measuring the 48 h 59Fe incorporation into RBC of mice with posthypoxic polycythemia. Hypoxia induced Ep production was diminished after blocking the PG synthesis using PG synthesis inhibitors. Salt overload, procedure known to decrease PG synthesis, had the same effect. Further on, dissection of the renal medulla, the main source of renal PG, decreased Ep production. The results indicate that PG are part of the mechanism which controls Ep production.

Topics: Acute Disease; Animals; Aspirin; Cyclooxygenase Inhibitors; Dissection; Erythropoietin; Hypoxia; Indomethacin; Kidney Medulla; Male; Organic Chemicals; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Strains; Sodium Chloride

Topics: Acute Disease; Anesthesia; Animals; Erythropoietin; Female; Hemoglobins; Hydrogen-Ion Concentration; Hypercapnia; Hypoxia; Lactates; Male; Mice; Oxygen; Oxygen Consumption; Phosphates; Rabbits; Time Factors

Although severe hematologic and immunologic disorders occur in several viral infections, insight into the mechanisms by which viruses may affect hemopoietic tissues is poor. The previous demonstration of distinct immunohemopoietic lesions in mice with acute lymphocytic choriomeningitis (LCM) virus infection has led us to investigate the function of hemopoietic precursor cells in the course of this experimental infection. During the first week of infection, there was profound suppression of pluripotential stem cell (CFU) and in vitro colony-forming cell (CFU) compartments, and of 59Fe uptake into hemopoietic tissues. During the same period, we found enhanced activity of colony-stimulating factor, lack of responsiveness to erythropoietin, and appreciable titers of interferon in blood and spleen. After day 10 post infection, there was a striking increase in CFU and 59Fe uptake confined to spleen and blood. Restoration of bone marrow, however, was markedly delayed. With reference to recent studies on interferon, and the findings in mice with persistent LCM virus infection, we suggest that interferon may be the comprehensive suppressor of the hemopoietic precursor cells in the first stage of acute LCM virus infection, and that these cells in the recovery period are directed preferentially into erythropoiesis.

Topics: Acute Disease; Animals; Bone Marrow Cells; Colony-Stimulating Factors; Erythropoiesis; Erythropoietin; Hematocrit; Hematopoiesis; Interferons; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mice; Mice, Inbred C3H; Spleen

Erythropoietin level in the serum and urine of adult patients with acute leukaemia (AML, ALL, MML) was estimated by polycythaemic mouse bioassay in order to obtain more information about the associated anaemia. In AML and ALL patients the serum erythropoietin level as found to be increased and in a negative correlation with the blood haemoglobin concentration. In ALL patients erythropoietin in urine was increased regularly while in AML patients it was not. No correlation between the serum level and the urinary excretion of ESF, or between the blood Hb and the serum ESF, was found in MML patients. The results show that anaemia in leukaemia is not due to the low ESF level.

Topics: Acute Disease; Adult; Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Iron; Leukemia; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Mice; Mice, Inbred CBA

The mechanism of erythropoietin (Ep) production after acute haemorrhage has been thought to be due to a reduction in blood volume and tissue perfusion leading to tissue hypoxia. In the present study we have evaluated the effect of acute haemorrhage in the rat on the acid-base status, the red cell affinity for oxygen in vivo, and Ep production. Within a few hours after acute blood loss there was a respiratory alkalosis with an increase in blood pH, a decrease in pCO2 and an increase in the red cell affinity of Hb for oxygen in vivo that was temporally related to an increase in Ep production. Within 24 h after the acute haemorrhage, the blood pH AND PCO2, red cell affinity for oxygen in vivo, and Ep level returned towards normal. The decrease in in vivo red cell affinity for oxygen was associated with an increase in red cell 2,3-DPG levels and a decrease in Ep production.

Topics: Acid-Base Imbalance; Acute Disease; Alkalosis, Respiratory; Animals; Diphosphoglyceric Acids; Erythrocytes; Erythropoietin; Female; Hemorrhage; Oxyhemoglobins; Partial Pressure; Rats

Topics: Acute Disease; Erythropoietin; Feeding and Eating Disorders; Heart Failure; Hemorrhagic Disorders; Humans; Hypertension; Peripheral Nervous System Diseases; Renin; Uremia; Vomiting

Topics: Acute Disease; Acute Kidney Injury; Animals; Erythropoiesis; Erythropoietin; Male; Rats; Uremia

Topics: Acute Disease; Adolescent; Child; Child, Preschool; Erythropoiesis; Erythropoietin; Hodgkin Disease; Humans; Infant; Leukemia; Leukemia, Myeloid

Topics: Acute Disease; Child; Chronic Disease; Erythropoietin; Glomerulonephritis; Humans

Topics: Acute Disease; Anemia, Aplastic; Child; Erythropoietin; Hemoglobins; Humans; Leukemia

Topics: Acute Disease; Animals; Disease Models, Animal; Erythropoietin; Hypoxia; Male; Pituitary Gland; Rats

Topics: Acute Disease; Adult; Anuria; Blood Cell Count; Blood Transfusion; Bone Marrow Examination; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Hypertension, Malignant; Male; Nephrectomy; Pyelonephritis; Renal Dialysis; Reticulocytes; Urea; Uremia

Topics: Acute Disease; Anemia, Aplastic; Animals; Biological Assay; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Erythropoiesis; Erythropoietin; gamma-Globulins; Hodgkin Disease; Humans; Iron Isotopes; Leukemia; Mediastinal Neoplasms; Mice; Osteosarcoma; Thymoma