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Sample records for carbamylated erythropoietin protects

  1. Effect of carbamylated erythropoietin on retinopathy of diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Lin Jiang

    2017-01-01

    Objective:To study the effect of carbamylated erythropoietin (CEPO) on retinopathy of diabetic rats.Methods: Male SD rats were selected as experimental animals and randomly divided into control group, DM group and CEPO group, and diabetic animal models were established and then given CEPO intervention. 2 weeks after intervention, the retina was collected to detect the expression of angiogenesis molecules, apoptosis molecules and oxidative stress pathway molecules.Results: HIF-1α, VEGF, Ang-1, Bax, Caspase-3, Nrf-2, ARE, HO-1 and NQO-1 mRNA expression in retina of DM group were significantly higher than those of control group while TKLK, PEDF, Bcl-2 and Survivin mRNA expression were significantly lower than those of control group; HIF-1α, VEGF, Ang-1, TKLK and PEDF mRNA expression in retina of CEPO group were not significantly different from those of DM group, Bcl-2, Survivin, Nrf-2, ARE, HO-1 and NQO-1 mRNA expression were significantly higher than those of DM group, and Bax and Caspase-3 mRNA expression were significantly lower than those of DM group.Conclusion:CEPO can reduce the apoptosis and oxidative stress injury of the retina tissue in diabetic rats without affecting the angiogenesis.

  2. Pharmacological Effects of Erythropoietin and its Derivative Carbamyl erythropoietin in Cerebral White Matter Injury

    Science.gov (United States)

    Liu, Wei

    Periventricular leukomalacia (PVL) is the predominant form of brain injury in the premature infant and the most common cause of cerebral palsy, yet no therapy currently exists for this serious human disorder. As PVL often occurs in preterm infants suffering from cerebral hypoxia/ischemia with or without prior exposure to maternal-fetal infection/inflammation, we used hypoxia/ischemia with or without lipopolysaccharide (LPS) injection, to produce clinically relevant PVL-like lesions in the white matter in postnatal day six (P6) mice. We studied the white matter pathology under different conditions, such as different durations of hypoxia and different doses of LPS, to evaluate the effects of those etiological factors on neonatal white matter injury. Distinct related pathological events were investigated at different time points during the progression of PVL. We used immunohistochemistry, histological analysis, and electron microscopy (EM) to study demylination that occurs in the white matter area, which is consistent with the pathology of human PVL. Previous studies have shown that erythropoietin (EPO) and its derivative carbamylated EPO (CEPO) are neuroprotective in various experimental models of brain injury. However, none of these studies investigated their efficacy against white matter injury using appropriate animal models of PVL. We produced unilateral or bilateral white matter injury in P6 mice using unilateral carotid ligation (UCL) followed by hypoxia (6% oxygen, 35 min) or by UCL/hypoxia plus LPS injection, respectively. We administered a single intraperitoneal (i.p.) dose of EPO or CEPO (5000 IU/kg) immediately after the insult, and found both drugs to provide significant protection against white matter injury in PVL mice compared to vehicle-treated groups. In addition, EPO and CEPO treatments attenuated neurobehavioral dysfunctions in an acute manner after PVL injury. EPO and CEPO have relatively few adverse effects, and thus may be a therapeutic agent

  3. Erythropoietin and carbamylated erythropoietin promote histone deacetylase 5 phosphorylation and nuclear export in rat hippocampal neurons

    International Nuclear Information System (INIS)

    Jo, Hye-Ryeong; Kim, Yong-Seok; Son, Hyeon

    2016-01-01

    Erythropoietin (EPO) produces neurotrophic effects in animal model of neurodegeneration. However, clinical use of EPO is limited due to thrombotic risk. Carbamylated EPO (cEPO), devoid of thrombotic risk, has been proposed as a novel neuroprotective and neurotrophic agent although the molecular mechanisms of cEPO remain incomplete. Here, we show a previously unidentified role of histone deacetylase 5 (HDAC5) in the actions of EPO and cEPO. EPO and cEPO regulate the HDAC5 phosphorylation at two critical sites, Ser259 and Ser498 through a protein kinase D (PKD) dependent pathway. In addition, EPO and cEPO rapidly stimulates nuclear export of HDAC5 in rat hippocampal neurons which expressing HDAC5-GFP. Consequently, EPO and cEPO enhanced the myocyte enhancer factor-2 (MEF2) target gene expression. Taken together, our results reveal that EPO and cEPO mediate MEF2 target gene expression via the regulation of HDAC5 phosphorylation at Ser259/498, and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of EPO and cEPO.

  4. Erythropoietin and carbamylated erythropoietin promote histone deacetylase 5 phosphorylation and nuclear export in rat hippocampal neurons

    Energy Technology Data Exchange (ETDEWEB)

    Jo, Hye-Ryeong [Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering (Korea, Republic of); Kim, Yong-Seok [Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering (Korea, Republic of); Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791 (Korea, Republic of); Son, Hyeon, E-mail: hyeonson@hanyang.ac.kr [Department of Biomedical Sciences, Graduate School of Biomedical Science and Engineering (Korea, Republic of); Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791 (Korea, Republic of)

    2016-01-29

    Erythropoietin (EPO) produces neurotrophic effects in animal model of neurodegeneration. However, clinical use of EPO is limited due to thrombotic risk. Carbamylated EPO (cEPO), devoid of thrombotic risk, has been proposed as a novel neuroprotective and neurotrophic agent although the molecular mechanisms of cEPO remain incomplete. Here, we show a previously unidentified role of histone deacetylase 5 (HDAC5) in the actions of EPO and cEPO. EPO and cEPO regulate the HDAC5 phosphorylation at two critical sites, Ser259 and Ser498 through a protein kinase D (PKD) dependent pathway. In addition, EPO and cEPO rapidly stimulates nuclear export of HDAC5 in rat hippocampal neurons which expressing HDAC5-GFP. Consequently, EPO and cEPO enhanced the myocyte enhancer factor-2 (MEF2) target gene expression. Taken together, our results reveal that EPO and cEPO mediate MEF2 target gene expression via the regulation of HDAC5 phosphorylation at Ser259/498, and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of EPO and cEPO.

  5. High-dose erythropoietin for tissue protection

    DEFF Research Database (Denmark)

    Lund, Anton; Lundby, Carsten; Olsen, Niels Vidiendal

    2014-01-01

    BACKGROUND: The discovery of potential anti-apoptotic and cytoprotective effects of recombinant human erythropoietin (rHuEPO) has led to clinical trials investigating the use of high-dose, short-term rHuEPO therapy for tissue protection in conditions such as stroke and myocardial infarction....... Experimental studies have been favourable, but the clinical efficacy has yet to be validated. MATERIALS AND METHODS: We have reviewed clinical studies regarding the use of high-dose, short-term rHuEPO therapy for tissue protection in humans with the purpose to detail the safety and efficacy of r...... no effect of rHuEPO therapy on measures of tissue protection. Five trials including 1025 patients reported safety concerns in the form of increased mortality or adverse event rates. No studies reported reduced mortality. CONCLUSIONS: Evidence is sparse to support a tissue-protective benefit of r...

  6. Role of Carbamylated Biomolecules in Human Diseases.

    Science.gov (United States)

    Badar, Asim; Arif, Zarina; Alam, Khursheed

    2018-04-01

    Carbamylation (or carbamoylation) is a non-enzymatic modification of biomolecules mediated by cyanate, a dissociation product of urea. Proteins are more sensitive to carbamylation. Two major sites of carbamylation reaction are: N α -amino moiety of a protein N-terminus and the N ɛ -amino moiety of proteins' lysine residues. In kidney diseases, urea accumulates and the burden of carbamylation increases. This may lead to alteration in the structure and function of many important proteins relevant in maintenance of homeostasis. Carbamylated proteins namely, carbamylated-haemoglobin and carbamylated-low density lipoprotein (LDL) have been implicated in hypoxia and atherosclerosis, respectively. Furthermore, carbamylation of insulin, oxytocin, and erythropoietin have caused changes in the action of these hormones vis-à-vis the metabolic pathways they control. In this short review, authors have compiled the data on role of carbamylated proteins, enzymes, hormones, LDL, and so on, in human diseases. © 2018 IUBMB Life, 70(4):267-275, 2018. © 2018 International Union of Biochemistry and Molecular Biology.

  7. Erythropoietin

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Vinberg, Maj; Harmer, Catherine J

    2012-01-01

    Current pharmacological treatments for depression have a significant treatment-onset-response delay, an insufficient efficacy for many patients and fail to reverse cognitive dysfunction. Erythropoietin (EPO) has neuroprotective and neurotrophic actions and improves cognitive function in animal mo...

  8. Erythropoietin protects the retinal pigment epithelial barrier against ...

    African Journals Online (AJOL)

    O2-induced hyperpermeability. H Zhang, Y Gong, X Wu, Y Shi, L Yin, Y Qiu. Abstract. Erythropoietin (EPO) is not limited to hematopoiesis; it may act as a protective cytokine. In this study, the retinal pigment epithelial (RPE) cell viability, cell ...

  9. No evidence for protective erythropoietin alpha signalling in rat hepatocytes

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    Frede Stilla

    2009-04-01

    Full Text Available Abstract Background Recombinant human erythropoietin alpha (rHu-EPO has been reported to protect the liver of rats and mice from ischemia-reperfusion injury. However, direct protective effects of rHu-EPO on hepatocytes and the responsible signalling pathways have not yet been described. The aim of the present work was to study the protective effect of rHu-EPO on warm hypoxia-reoxygenation and cold-induced injury to hepatocytes and the rHu-EPO-dependent signalling involved. Methods Loss of viability of isolated rat hepatocytes subjected to hypoxia/reoxygenation or incubated at 4°C followed by rewarming was determined from released lactate dehydrogenase activity in the absence and presence of rHu-EPO (0.2–100 U/ml. Apoptotic nuclear morphology was assessed by fluorescence microscopy using the nuclear fluorophores H33342 and propidium iodide. Erythropoietin receptor (EPOR, EPO and Bcl-2 mRNAs were quantified by real time PCR. Activation of JAK-2, STAT-3 and STAT-5 in hepatocytes and rat livers perfused in situ was assessed by Western blotting. Results In contrast to previous in vivo studies on ischemia-reperfusion injury to the liver, rHu-EPO was without any protective effect on hypoxic injury, hypoxia-reoxygenation injury and cold-induced apoptosis to isolated cultured rat hepatocytes. EPOR mRNA was identified in these cells but specific detection of the EPO receptor protein was not possible due to the lack of antibody specificity. Both, in the cultured rat hepatocytes (10 U/ml for 15 minutes and in the rat liver perfused in situ with rHu-EPO (8.9 U/ml for 15 minutes no evidence for EPO-dependent signalling was found as indicated by missing effects of rHu-EPO on phosphorylation of JAK-2, STAT-3 and STAT-5 and on the induction of Bcl-2 mRNA. Conclusion Together, these results indicate the absence of any protective EPO signalling in rat hepatocytes. This implies that the protection provided by rHu-EPO in vivo against ischemia-reperfusion and

  10. Endogenous erythropoietin protects neuroretinal function in ischemic retinopathy.

    Science.gov (United States)

    Mowat, Freya M; Gonzalez, Francisco; Luhmann, Ulrich F O; Lange, Clemens A; Duran, Yanai; Smith, Alexander J; Maxwell, Patrick H; Ali, Robin R; Bainbridge, James W B

    2012-04-01

    Because retinal ischemia is a common cause of vision loss, we sought to determine the effects of ischemia on neuroretinal function and survival in murine oxygen-induced retinopathy (OIR) and to define the role of endogenous erythropoietin (EPO) in this model. OIR is a reproducible model of ischemia-induced retinal neovascularization; it is used commonly to develop antiangiogenic strategies. We investigated the effects of ischemia in murine OIR on retinal function and neurodegeneration by electroretinography and detailed morphology. OIR was associated with significant neuroretinal dysfunction, with reduced photopic and scotopic ERG responses and reduced b-wave/a-wave ratios consistent with specific inner-retinal dysfunction. OIR resulted in significantly increased apoptosis and atrophy of the inner retina in areas of ischemia. EPO deficiency in heterozygous Epo-Tag transgenic mice was associated with more profound retinal dysfunction after OIR, indicated by a significantly greater suppression of ERG amplitudes, but had no measurable effect on the extent of retinal ischemia, preretinal neovascularization, or neuroretinal degeneration in OIR. Systemic administration of recombinant EPO protected EPO-deficient mice against this additional suppression, but EPO supplementation in wild-type animals with OIR did not rescue neuroretinal dysfunction or degeneration. Murine OIR offers a valuable model of ischemic neuroretinal dysfunction and degeneration in which to investigate adaptive tissue responses and evaluate novel therapeutic approaches. Endogenous EPO can protect neuroretinal function in ischemic retinopathy. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  11. Carbamylation of proteins – mechanism, causes and consequences

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    Anna Pieniążek

    2016-05-01

    Full Text Available Carbamylation (carbamoylation is a post-translational modification resulting from the nonenzymatic reaction between isocyanic acid and free functional groups of proteins, in particular with the free amino groups. This reaction alters structural and functional properties of proteins and results in faster aging of proteins.Urea present in the body can be transformed into cyanate and its more reactive form, isocyanic acid. High concentration of urea is associated with some diseases, especially with chronic renal failure and atherosclerosis. In human tissues, urea and cyanate are in equilibrium in aqueous solutions. Surprisingly, concentration of isocyanate in the body is much lower than it would appear from the kinetic parameters of urea decomposition. The low concentration of isocyanic acid results from its high reactivity and short half-life.In this review we describe the biochemical mechanism of carbamylation of proteins and freeamino acids. We summarize the literature data for carbamylation of hemoglobin, lipoproteins,albumin, membrane proteins and erythropoietin in chronic renal failure.In summary, the carbamylation of proteins may have a negative impact on their biologicalactivity and may contribute to the deterioration of patients with chronic renal failure.

  12. Ethanol extract of Portulaca oleracea L. protects against hypoxia-induced neuro damage through modulating endogenous erythropoietin expression.

    Science.gov (United States)

    Wanyin, Wang; Liwei, Dong; Lin, Jia; Hailiang, Xin; Changquan, Ling; Min, Li

    2012-04-01

    In addition to its role in erythropoiesis, erythropoietin is also appreciated for its neuroprotective effects, and it has been suggested for treatment of some ischemic-hypoxic neurovascular diseases. The protective effects of endogenous erythropoietin in the brain give rise to the hypothesis that modulating erythropoietin expression might be a better way for treatment of ischemia-hypoxia neurovascular diseases. We have found that ethanol extract of Portulaca oleracea L. (EEPO) could increase erythropoietin expression in hypoxic mouse brain in our previous study. The present study is to investigate whether EEPO exerts its neuroprotective effects against hypoxia injury through regulating endogenous erythropoietin expression. The results demonstrated that EEPO decreased the serum neuron specific enolase level in hypoxia mice and the activity of caspase-3 in neuron, increased the neuron viability and attenuated the pathological damages caused by the hypoxia condition. Importantly, we also found that EEPO stimulated the endogenous erythropoietin expression at both mRNA and protein levels. Using the conditioned medium containing soluble erythropoietin receptor, we found that the neuroprotective effects of EEPO were dependent, at least partly, on erythropoietin expression. Although EEPO did not affect transcription of hypoxia inducible factor-1α (HIF-1α), it did stabilize expression of HIF-1α. It is concluded that EEPO has neuroprotective effects against hypoxia injury, which is at least partly through stimulating endogenous erythropoietin expression by stabilizing HIF-1α. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Protective effects of erythropoietin against cuprizone-induced oxidative stress and demyelination in the mouse corpus callosum

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    Iraj Ragerdi Kashani

    2017-08-01

    Full Text Available Objective(s: Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of multiple sclerosis. The aim of the present work is to investigate the protective effects of erythropoietin against cuprizone-induced oxidative stress. Materials and Methods: Adult male C57BL/6J mice were fed a chow containing 0.2 % cuprizone for 6 weeks. After 3 weeks, mice were simultaneously treated with erythropoietin (5,000 IU/ kg body weight by daily intraperitoneal injections. Results: Our results showed that cuprizone induced oxidative stress accompanied with down-regulation of subunits of the respiratory chain complex and demyelination of corpus callosum. Erythropoietin antagonized these effects. Biochemical analysis showed that oxidative stress induced by cuprizone was regulated by erythropoietin. Similarly, erythropoietin induced the expression of subunits of the respiratory chain complex over normal control values reflecting a mechanism to compensate cuprizone-mediated down-regulation of these genes. Conclusion: The data implicate that erythropoietin abolishes destructive cuprizone effects in the corpus callosum by decreasing oxidative stress and restoring mitochondrial respiratory enzyme activity.

  14. Perioperative erythropoietin protects the CNS against ischemic lesions in patients after open heart surgery.

    Science.gov (United States)

    Lakič, Nikola; Mrak, Miha; Šušteršič, Miha; Rakovec, Peter; Bunc, Matjaž

    2016-12-01

    The aim of this study was to establish erythropoietin as a protective factor against brain ischemia during open heart surgery. A total of 36 consecutive patients scheduled for revascularization heart surgery were included in the study. Of the patients 18 received 3 intravenous doses of recombinant human erythropoietin (rHuEpo, 24,000 IU) and 18 patients received a placebo. Magnetic resonance imaging (MRI) to detect new brain ischemic lesions was performed. Additionally, S100A, S100B, neuron-specific enolase A and B (NSE-A and B) and the concentration of antibodies against N‑methyl-D-aspartate receptors (NMDAR) to identify new neurological complications were determined. Patients who received rHuEpo showed no postoperative ischemic changes in the brain on MRI images. In the control group 5 (27.8 %) new ischemic lesions were found. The NMDAR antibody concentration, S100A, S100B and NSE showed no significant differences between the groups for new cerebral ischemia. High levels of lactate before and after external aortic compression (p = 0.022 and p = 0.048, respectively) and duration of operation could predict new ischemic lesions (p = 0.009). The addition of rHuEpo reduced the formation of lesions detectable by MRI in the brain and could be used clinically as neuroprotection in cardiac surgery.

  15. Neurobehavioral and cytotoxic effects of vanadium during oligodendrocyte maturation: a protective role for erythropoietin.

    Science.gov (United States)

    Mustapha, Oluwaseun; Oke, Bankole; Offen, Nils; Sirén, Anna-Leena; Olopade, James

    2014-07-01

    Vanadium exposure has been known to lead to lipid peroxidation, demyelination and oligodendrocytes depletion. We investigated behaviour and glial reactions in juvenile mice after early neonatal exposure to vanadium, and examined the direct effects of vanadium in oligodendrocyte progenitor cultures from embryonic mice. Neonatal pups exposed to vanadium via lactation for 15 and 22 days all had lower body weights. Behavioural tests showed in most instances a reduction in locomotor activity and negative geotaxis. Brain analyses revealed astrocytic activation and demyelination in the vanadium exposed groups compared to the controls. In cell culture, exposure of oligodendrocytes to 300 μM sodium metavanadate significantly increased cell death. Expression of the oligodendrocyte specific proteins, 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and oligodendrocyte specific protein (OSP/Claudin) were reduced upon vanadium treatment while simultaneous administration of erythropoietin (EPO; 4-12 U/ml) counteracted vanadium-toxicity. The data suggest that oligodendrocyte damage may explain the increased vulnerability of the juvenile brain to vanadium and support a potential for erythropoietin as a protective agent against vanadium-toxicity during perinatal brain development and maturation. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Carbamylation of N-terminal proline.

    Science.gov (United States)

    Olajuyigbe, Folasade M; Demitri, Nicola; Ajele, Joshua O; Maurizio, Elisa; Randaccio, Lucio; Geremia, Silvano

    2010-09-09

    Protein carbamylation is of great concern both in vivo and in vitro. Here, we report the first structural characterization of a protein carbamylated at the N-terminal proline. The unexpected carbamylation of the α-amino group of the least reactive codified amino acid has been detected in high-resolution electron density maps of a new crystal form of the HIV-1 protease/saquinavir complex. The carbamyl group is found coplanar to the proline ring with a trans conformation. The reaction of N-terminal with cyanate ion derived from the chaotropic agent urea was confirmed by mass spectra analysis on protease single crystals. Implications of carbamylation process in vitro and in vivo are discussed.

  17. Erythropoietin-derived nonerythropoietic peptide ameliorates experimental autoimmune neuritis by inflammation suppression and tissue protection.

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    Yuqi Liu

    Full Text Available Experimental autoimmune neuritis (EAN is an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system. Erythropoietin (EPO has been known to promote EAN recovery but its haematopoiesis stimulating effects may limit its clinic application. Here we investigated the effects and potential mechanisms of an EPO-derived nonerythropoietic peptide, ARA 290, in EAN. Exogenous ARA 290 intervention greatly improved EAN recovery, improved nerve regeneration and remyelination, and suppressed nerve inflammation. Furthermore, haematopoiesis was not induced by ARA 290 during EAN treatment. ARA 290 intervention suppressed lymphocyte proliferation and altered helper T cell differentiation by inducing increase of Foxp3+/CD4+ regulatory T cells and IL-4+/CD4+ Th2 cells and decrease of IFN-γ+/CD4+ Th1 cells in EAN. In addition, ARA 290 inhibited inflammatory macrophage activation and promoted its phagocytic activity. In vitro, ARA 290 was shown to promote Schwann cell proliferation and inhibit its inflammatory activation. In summary, our data demonstrated that ARA 290 could effectively suppress EAN by attenuating inflammation and exerting direct cell protection, indicating that ARA 290 could be a potent candidate for treatment of autoimmune neuropathies.

  18. Comparison of the Protective Effects of Erythropoietin and Melatonin on Renal Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Banaei, Shokofeh; Ahmadiasl, Nasser; Alihemmati, Alireza

    2016-07-01

    Renal ischemia-reperfusion (IR) contributes to the development of acute renal failure (ARF). Oxygen free radicals are considered to be the principal components involved in the pathophysiological tissue alterations observed during renal IR. In this study, we compared the effects of melatonin (MEL) and erythropoietin (EPO), both known antioxidant and anti-inflammatory agents, on IR-induced renal injury in rats. Wistar albino rats were unilaterally nephrectomized and then subjected to 45 minutes of renal pedicle occlusion followed by 24 hours of reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to the onset of ischemia. After 24 hours of reperfusion and following decapitation, blood samples were collected for the determination of the hemoglobin (Hb) and hematocrit (Hct) levels. Additionally, renal samples were taken for histological evaluation. Ischemia-reperfusion significantly decreased the observed Hb and Hct values. The histopathological findings in the IR group confirmed that there was an increase in the hyaline cast and thickening of the Bowman capsule basement membrane. Treatment with EPO or MEL significantly increased the Hb and Hct values. In the MEL + IR group, the histopathological changes were lower than those found in the EPO + IR group. Treatment with EPO and MEL had a beneficial effect on renal IR injury. The results may also indicate that MEL protects against morphological damage better than EPO in renal IR injury.

  19. Neuronal erythropoietin overexpression is protective against kanamycin-induced hearing loss in mice.

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    Bächinger, David; Horvath, Lukas; Eckhard, Andreas; Goosmann, Madeline M; Honegger, Tim; Gassmann, Max; Vogel, Johannes; Naldi, Arianne Monge

    2018-07-01

    Aminoglycosides have detrimental effects on the hair cells of the inner ear, yet these agents indisputably are one of the cornerstones in antibiotic therapy. Hence, there is a demand for strategies to prevent aminoglycoside-induced ototoxicity, which are not available today. In vitro data suggests that the pleiotropic growth factor erythropoietin (EPO) is neuroprotective against aminoglycoside-induced hair cell loss. Here, we use a mouse model with EPO-overexpression in neuronal tissue to evaluate whether EPO could also in vivo protect from aminoglycoside-induced hearing loss. Auditory brainstem response (ABR) thresholds were measured in 12-weeks-old mice before and after treatment with kanamycin for 15 days, which resulted in both C57BL/6 and EPO-transgenic animals in a high-frequency hearing loss. However, ABR threshold shifts in EPO-transgenic mice were significantly lower than in C57BL/6 mice (mean difference in ABR threshold shift 13.6 dB at 32 kHz, 95% CI 3.8-23.4 dB, p = 0.003). Correspondingly, quantification of hair cells and spiral ganglion neurons by immunofluorescence revealed that EPO-transgenic mice had a significantly lower hair cell and spiral ganglion neuron loss than C57BL/6 mice. In conclusion, neuronal overexpression of EPO is protective against aminoglycoside-induce hearing loss, which is in accordance with its known neuroprotective effects in other organs, such as the eye or the brain. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Protective effect of bone marrow mesenchymal stem cells combined with erythropoietin therapy on spinal cord injury rat model

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    Peng Xie

    2016-01-01

    Full Text Available Objective: To study the protective effect of bone marrow mesenchymal stem cells combined with erythropoietin therapy on spinal cord injury rat model. Methods: SD rats were selected as experimental animals, spinal cord injury rat model was built by striking spinal cord with Hatteras Instruments PCI3000, and model rats were divided into control group, bone marrow mesenchymal stem cells (BMSCs group, erythropoietin (EPO group and BMSCs combined with EPO group according to different treatment methods. Then number of apoptotic cells in spinal cord tissue, contents of neural markers and neurotrophic factors as well as expression of apoptosis and injury molecules was detected. Results: Number of apoptotic cells as well as mRNA contents of Caspase-3 and c-fos of BMSCs group, EPO group and BMSCs+EPO group was lower than those of control group, and number of apoptotic cells as well as mRNA contents of Caspase-3 and c-fos of BMSCs+EPO group were lower than those of BMSCs group and EPO group; mRNA contents of NF-200 and MBP as well as protein contents of NGF and BDNF in spinal cord tissue of BMSCs group, EPO group and BMSCs+EPO group were higher than those of control group, and mRNA contents of NF-200 and MBP as well as protein contents of NGF and BDNF in spinal cord tissue of BMSCs+EPO group were higher than those of BMSCs group and EPO group. Conclusions: Bone marrow mesenchymal stem cells combined with erythropoietin therapy can inhibit cell apoptosis in the injured spinal cord tissue, increase neurotrophic factor levels and inhibit apoptosis and injury molecule expression; it has protective effect on spinal cord injury.

  1. Erythropoietin protects against rhabdomyolysis-induced acute kidney injury by modulating macrophage polarization

    Science.gov (United States)

    Wang, Shuo; Zhang, Chao; Li, Jiawei; Niyazi, Sidikejiang; Zheng, Long; Xu, Ming; Rong, Ruiming; Yang, Cheng; Zhu, Tongyu

    2017-01-01

    Erythropoietin (EPO) is a well-known hormone that is clinically used for the treatment of anemia. Very recently, an increasing body of evidence showed that EPO could still regulate bioactivities of macrophages. However, the details about the immunomodulatory effect of EPO on macrophages are not fully delineated, particularly in the setting of renal damages. Therefore, in the present study, we determined whether EPO could exert an impact on the dynamics of macrophages in a well-established model of rhabdomyolysis-induced acute kidney injury and explored the potential mechanisms. EPO was found to ameliorate kidney injuries by reducing macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. It was also confirmed that EPO could directly suppress pro-inflammatory responses of M1 macrophages and promote M2 marker expression in vitro. Data indicated the possible involvement of Jak2/STAT3/STAT6 pathway in the augmentation of EPO on M2 polarization. These results improved the understanding of the immunoregulatory capacity of EPO on macrophages, which might optimize the therapeutic modalities of EPO. PMID:28383559

  2. Neuronal erythropoietin overexpression protects mice against age-related hearing loss (presbycusis).

    Science.gov (United States)

    Monge Naldi, Arianne; Belfrage, Celina; Jain, Neha; Wei, Eric T; Canto Martorell, Belén; Gassmann, Max; Vogel, Johannes

    2015-12-01

    So far, typical causes of presbycusis such as degeneration of hair cells and/or primary auditory (spiral ganglion) neurons cannot be treated. Because erythropoietin's (Epo) neuroprotective potential has been shown previously, we determined hearing thresholds of juvenile and aged mice overexpressing Epo in neuronal tissues. Behavioral audiometry revealed in contrast to 5 months of age, that 11-month-old Epo-transgenic mice had up to 35 dB lower hearing thresholds between 1.4 and 32 kHz, and at the highest frequencies (50-80 kHz), thresholds could be obtained in aged Epo-transgenic only but not anymore in old C57BL6 control mice. Click-evoked auditory brainstem response showed similar results. Numbers of spiral ganglion neurons in aged C57BL6 but not Epo-transgenic mice were dramatically reduced mainly in the basal turn, the location of high frequencies. In addition, there was a tendency to better preservation of inner and outer hair cells in Epo-transgenic mice. Hence, Epo's known neuroprotective action effectively suppresses the loss of spiral ganglion cells and probably also hair cells and, thus, development of presbycusis in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Protective Effects of Erythropoietin and N-Acetylcysteine on Methotrexate-Induced Lung Injury in Rats

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    Hasan Kahraman

    2013-03-01

    Full Text Available Objective: Methotrexate (MTX is known to have deleterious side effects on lung tissue. We aimed to investigate the effects of erythropoietin (EPO and N-acetyl-cysteine (NAC on MTX-induced lung injury in rats. Study Design: Animal experiment. Material and Methods: Twenty-six female Sprague-Dawley rats were divided into 4 groups. Sham group, 0.3 mL saline; MTX group, 5 mg/kg MTX; EPO group, 5mg/kg MTX and 2000 IU/kg EPO; NAC group, 5 mg/kg MTX and 200 mg/kg NAC were administered once daily for 4 consecutive days. Malondialdehyde (MDA, superoxide dismutase (SOD, catalase (CAT and inflammation and congestion scores in lung tissues were evaluated. Results: In MTX group MDA were significantly higher, CAT and SOD were significantly lower than in sham, EPO and NAC groups (p0.005. In group MTX both scores were significantly higher than in sham (p<0.005. The congestion score of group MTX was significantly higher than those of group EPO and NAC (p<0.005. Conclusion: EPO and NAC have significant preventive effects on MTX-induced lung injury in rats. Decreased antioxidant capacity and increased MDA level may cause the oxidative damage in MTX group. Also, higher antioxidant capacity and lower MDA level may be a response to oxidative stress in EPO and NAC groups.

  4. Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles.

    Science.gov (United States)

    Hojman, Pernille; Brolin, Camilla; Gissel, Hanne; Brandt, Claus; Zerahn, Bo; Pedersen, Bente Klarlund; Gehl, Julie

    2009-06-12

    Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (Pincrease in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles.In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles.

  5. Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles.

    Directory of Open Access Journals (Sweden)

    Pernille Hojman

    Full Text Available Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (P<0.01 in EPO transfected obese mice; thus the mice weighed 21.9+/-0.8 g (control, normal diet, 21.9+/-1.4 g (EPO, normal diet, 35.3+/-3.3 g (control, high-fat diet and 28.8+/-2.6 g (EPO, high-fat diet. Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass.The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance in the high-fat fed mice. EPO expression also induced a 14% increase in muscle volume and a 25% increase in vascularisation of the EPO transfected muscle. Muscle force and stamina were not affected by EPO expression. PCR array analysis revealed that genes involved in lipid metabolism, thermogenesis and inflammation were increased in muscles in response to EPO expression, while genes involved in glucose metabolism were down-regulated. In addition, muscular fat oxidation was increased 1.8-fold in both the EPO transfected and contralateral muscles.In conclusion, we have shown that EPO when expressed in supra-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles.

  6. Carbamylated albumin is one of the target antigens of anti-carbamylated protein antibodies.

    Science.gov (United States)

    Nakabo, Shuichiro; Hashimoto, Motomu; Ito, Shinji; Furu, Moritoshi; Ito, Hiromu; Fujii, Takao; Yoshifuji, Hajime; Imura, Yoshitaka; Nakashima, Ran; Murakami, Kosaku; Kuramoto, Nobuo; Tanaka, Masao; Satoh, Junko; Ishigami, Akihito; Morita, Satoshi; Mimori, Tsuneyo; Ohmura, Koichiro

    2017-07-01

    Anti-carbamylated protein (anti-CarP) antibodies are detected in RA patients. Fetal calf serum is used as an antigen source in anti-CarP ELISA, and the precise target antigens have not been found. We aimed to identify the target antigens of anti-CarP antibodies. Western blotting of anti-CarP antibodies was conducted. Anti-carbamylated human albumin (CarALB) antibody was detected by in-house ELISA for 493 RA patients and 144 healthy controls (HCs). An inhibition ELISA of anti-CarP antibodies by CarALB and citrullinated albumin (citALB) was performed using eight RA patients' sera. Serum CarALB was detected by liquid chromatography-tandem mass spectroscopy (LC/MS/MS), and the serum MPO concentration was measured by ELISA. We focused on carbamylated albumin because it corresponded to the size of the thickest band detected by western blotting of anti-CarP antibodies. Anti-CarALB antibody was detected in 31.4% of RA patients, and the correlation of the titres between anti-CarALB and anti-CarP was much closer than that between anti-citALB and anti-CCP antibodies (ρ = 0.59 and ρ = 0.16, respectively). The inhibition ELISA showed that anti-CarP antibodies were inhibited by CarALB, but not by citALB. CarALB was detected in sera from RA patients by LC/MS/MS. The serum MPO concentration was correlated with disease activity and was higher in RA patients with anti-CarALB antibody than in those without. We found that carbamylated albumin is a novel target antigen of anti-CarP antibodies, and it is the first reported target antigen that has not been reported as the target of ACPA. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  7. Quantification of carbamylated albumin in serum based on capillary electrophoresis.

    Science.gov (United States)

    Delanghe, Sigurd; Moerman, Alena; Pletinck, Anneleen; Schepers, Eva; Glorieux, Griet; Van Biesen, Wim; Delanghe, Joris R; Speeckaert, Marijn M

    2017-09-01

    Protein carbamylation, a nonenzymatic posttranslational modification promoted during uremia, is linked to a poor prognosis. In the present study, carbamylation of serum albumin was assayed using the symmetry factor on a capillary electrophoresis instrument (Helena V8). The symmetry factor has been defined as the distance from the center line of the peak to the back slope, divided by the distance from the center line of the peak to the front slope, with all measurements made at 10% of the maximum peak height. Serum albumin, creatinine, and urea concentrations were assayed using routine methods, whereas uremic toxins were determined using HPLC. In vitro carbamylation induced a marked albumin peak asymmetry. Reference values for the albumin symmetry factor were 0.69-0.92. In kidney patients, albumin peak asymmetry corresponded to the chronic kidney disease stage (p < 0.0001). The symmetry factor correlated well with serum urea (r = -0.5595, p < 0.0001) and creatinine (r = -0.5986, p < 0.0001) concentrations. Several protein-bound uremic toxins showed a significant negative correlation with the symmetry factor. Morphology of the albumin fraction was not affected by presence of glycated albumin and protein-bound antibiotics. In conclusion, the presented method provides a simple, practical way for monitoring protein carbamylation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Erythropoietin: a multimodal neuroprotective agent

    OpenAIRE

    Byts, Nadiya; Sir?n, Anna-Leena

    2009-01-01

    Abstract The tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brain cells during brain development and upregulated in the adult brain after injury. Peripherally administered EPO crosses the blood-brain barrier and activates in the brain anti-apoptotic, anti-oxidant and anti-inflammatory signaling in neurons, glial and cerebrovascular endothelial cells and ...

  9. The Nasal Route as a Potential Pathway for Delivery of Erythropoietin in the Treatment of Acute Ischemic Stroke in Humans

    Directory of Open Access Journals (Sweden)

    Julio Cesar García-Rodríguez

    2009-01-01

    Full Text Available Intranasal delivery provides a practical, noninvasive method of bypassing the blood-brain barrier (BBB in order to deliver therapeutic agents to the brain. This method allows drugs that do not cross the BBB to be delivered to the central nervous system in a few minutes. With this technology, it will be possible to eliminate systemic administration and its potential side effects. Using the intranasal delivery system, researchers have demonstrated neuroprotective effects in different animal models of stroke using erythropoietin (EPO as a neuroprotector or other different types of EPO without erythropoiesis-stimulating activity. These new molecules retain their ability to protect neural tissue against injury and they include Asialoerythropoietin (asialoEPO carbamylated EPO (CEPO, and rHu-EPO with low sialic acid content (Neuro-EPO. Contrary to the other EPO variants, Neuro-EPO is not chemically modified, making it biologically similar to endogenous EPO, with the advantage of less adverse reactions when this molecule is applied chronically. This constitutes a potential benefit of Neuro-EPO over other variants of EPO for the chronic treatment of neurodegenerative illnesses. Nasal administration of EPO is a potential, novel, neurotherapeutic approach. However, it will be necessary to initiate clinical trials in stroke patients using intranasal delivery in order to obtain the clinical evidence of its neuroprotectant capacity in the treatment of patients with acute stroke and other neurodegenerative disorders. This new therapeutic approach could revolutionize the treatment of neurodegenerative disorders in the 21st century.

  10. Erythropoietin radioimmunoassay studies

    International Nuclear Information System (INIS)

    Garcia, J.F.

    1982-01-01

    A highly sensitive radioimmunoassay capable of measuring erythropoietin concentrations in very small amounts of serum as been developed. After establishing normal human values on a large series of serum samples, serum samples from patients with polycythemia vera and patients with secondary polycythemia were obtained and the erythropoietin concentrations measured

  11. Radioimmunoassay of erythropoietin

    Energy Technology Data Exchange (ETDEWEB)

    Goldwasser, E; Sherwood, J B [Chicago Univ., IL (USA). Dept. of Biochemistry

    1981-07-01

    A brief review of the historical development of the radioimmunoassay (RIA) for serum erythropoietin is given. It has been shown that there is reasonable agreement between the results obtained by RIA and those obtained by the previously used bioassay. By RIA, a mean normal serum titre of 18 mu/ml erythropoietin has been determined in a study of 445 individuals. Serum erythropoietin results for patients with polycythaemia vera have not been shown to be significantly different from normal values but in patients with secondary polycythaemia, serum titres averaging 94 mu/ml have been found. The predicted physiological changes in erythropoietin titre have also been demonstrated in humans using the RIA; increasing after bleeding and decreasing after red cell administration. Studies of erythropoietin levels in experimental animals have shown that, with the particular antiserum used, the sensitivity of the RIA is markedly reduced.

  12. Protein Carbamylation in Peritoneal Dialysis and the Effect of Low Glucose Plus Amino Acid Solutions.

    Science.gov (United States)

    Trottier, Caitlin; Perl, Jeffrey; Freeman, Megan; Thadhani, Ravi; Berg, Anders; Kalim, Sahir

    2018-01-01

    Protein carbamylation is a post-translational urea-driven protein modification associated with mortality. Free amino acids (AAs) competitively inhibit protein carbamylation and parenteral AA therapy reduces carbamylation in hemodialysis (HD) patients. Peritoneal dialysis (PD) yields differences in urea clearance and AA balance compared with HD, but the influence of PD and intraperitoneal AA solutions on carbamylation is unclear. Thus, we first measured carbamylated albumin (C-Alb; a marker of carbamylation load) in 100 diabetic HD patients frequency-matched by age, sex, and race to 98 diabetic PD subjects from the IMPENDIA trial, which originally compared the metabolic effects of low-glucose PD solutions (incorporating icodextrin and AAs) to a control group (dextrose-only solutions). We then determined the effects of the AA-enriched PD solutions by measuring the 6-month change in C-Alb within the IMPENDIA cohort by treatment allocation (48 treated vs 50 controls). Peritoneal dialysis patients, when compared with HD patients, had higher baseline urea and higher C-Alb. Among IMPENDIA participants, there was no difference in C-Alb change in either arm, but treated subjects showed a trend towards increased carbamylation. Treated subjects also demonstrated an increase in urea, possibly explaining the carbamylation trend. In summary, carbamylation levels in PD patients appeared higher than in matched HD patients. A regimen of AA and low-glucose PD solutions did not reduce C-Alb in IMPENDIA subjects. Copyright © 2018 International Society for Peritoneal Dialysis.

  13. Neuroprotective properties of a novel, non-haematopoietic agonist of the erythropoietin receptor

    DEFF Research Database (Denmark)

    Pankratova, Stanislava; Kiryushko, Dar'Ya; Sonn, Katrin

    2010-01-01

    they are involved in tissue protection. However, the use of erythropoietin as a neuroprotective agent may be hampered by its erythropoietic activity. Therefore, developing non-haematopoietic erythropoietin mimetics is important. Based on the crystal structure of the complex of erythropoietin and its receptor, we...... attenuated seizures, decreased mortality and reduced neurodegeneration in an in vivo model of kainic acid-induced neurotoxicity. In contrast to erythropoietin, Epotris did not stimulate erythropoiesis upon chronic administration. Thus, Epotris is a novel neuroprotective non-haematopoietic erythropoietin...

  14. Protein Carbamylation: A Marker Reflecting Increased Age-Related Cell Oxidation

    Directory of Open Access Journals (Sweden)

    Julia Carracedo

    2018-05-01

    Full Text Available Carbamylation is a post-translational modification of proteins that may partake in the oxidative stress-associated cell damage, and its increment has been recently proposed as a “hallmark of aging”. The molecular mechanisms associated with aging are related to an increased release of free radicals. We have studied whether carbamylated proteins from the peripheral blood of healthy subjects are related to oxidative damage and aging, taking into account the gender and the immune profile of the subjects. The study was performed in healthy human volunteers. The detection of protein carbamylation and malondialdehyde (MDA levels was evaluated using commercial kits. The immune profile was calculated using parameters of immune cell function. The results show that the individuals from the elderly group (60–79 years old have increased carbamylated protein and MDA levels. When considered by gender, only men between 60 and 79 years old showed significantly increased carbamylated proteins and MDA levels. When those subjects were classified by their immune profile, the carbamylated protein levels were higher in those with an older immune profile. In conclusion, the carbamylation of proteins in peripheral blood is related to age-associated oxidative damage and to an aging functional immunological signature. Our results suggest that carbamylated proteins may play an important role at the cellular level in the aging process.

  15. Does erythropoietin augment noise induced hearing loss?

    DEFF Research Database (Denmark)

    Frederiksen, Birgitte Lidegaard; Cayé-Thomasen, Per; Lund, Søren Peter

    2007-01-01

    Noise-induced hearing loss may result from excessive release of glutamate, nitrogen oxide and reactive oxygen species. The effects of these factors on the inner ear may potentially be prevented or reduced by erythropoietin (EPO), as indicated by previously demonstrated neuro-protective effects of...

  16. Hepatic erythropoietin response in cirrhosis

    DEFF Research Database (Denmark)

    Risør, Louise M; Fenger, Mogens; Olsen, Niels Vidiendal

    2016-01-01

    The main function of erythropoietin (EPO) is to maintain red blood cell mass, but in recent years, increasing evidence has suggested a wider biological role not solely related to erythropoiesis, e.g. angiogenesis and tissue protection. EPO is produced in the liver during fetal life, but the main...... production shifts to the kidney after birth. The liver maintains a production capacity of up to 10% of the total EPO synthesis in healthy controls, but can be up-regulated to 90-100%. However, the hepatic EPO synthesis has been shown not to be adequate for correction of anemia in the absence of renal......, which lead to arterial hypotension, hepatic nephropathy and anemia. An increase in EPO due to renal hypoperfusion, hypoxia and anemia or an EPO-mediated hepato-protective and regenerative mechanism is plausible. However, poor hepatic synthesis capacity, a decreasing co-factor level and inflammatory...

  17. Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles

    DEFF Research Database (Denmark)

    Hojman, Pernille; Brolin, Camilla; Gissel, Hanne

    2009-01-01

    patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo.At 12 weeks, EPO expression resulted in a 23% weight reduction (Pobese mice; thus the mice weighed 21.9+/-0.8 g (control, normal diet,) 21.9+/-1.4 g (EPO, normal diet), 35.......3+/-3.3 g (control, high-fat diet) and 28.8+/-2.6 g (EPO, high-fat diet). Correspondingly, DXA scanning revealed that this was due to a 28% reduction in adipose tissue mass.The decrease in adipose tissue mass was accompanied by a complete normalisation of fasting insulin levels and glucose tolerance......-physiological levels has substantial metabolic effects including protection against diet-induced obesity and normalisation of glucose sensitivity associated with a shift to increased fat metabolism in the muscles....

  18. Erythropoietin and radiotherapy; Erythropoietine et radiotherapie

    Energy Technology Data Exchange (ETDEWEB)

    Le Fur, E.; Albarghach, M.N.; Pradier, O. [CHU de Morvan, Dept. de radiotherapie, 29 - Brest (France)

    2010-01-15

    Erythropoietin (E.P.O.) is a glycoprotein hormone. This hormone is a growth factor for red blood cells precursors in the bone marrow. The decrease of oxygen partial pressure, a reduced number of erythrocytes caused by bleeding or excessive destruction, or increased tissues oxygen requirements lead to increased secretion of E.P.O.. Its action takes place on bone marrow erythroblastic cells through specific receptors. E.P.O. stimulates the proliferation of red cell precursors stem cells in the bone marrow, thus increasing their production in one to two weeks. The effectiveness of E.P.O. at increasing haemoglobin and improving patients quality of life has been demonstrated by several studies. However, its use in radiotherapy remains controversial. While tumour hypoxia caused by anaemia is a factor of radio resistance and thus a source of local failure, tumour expression of E.P.O. receptors presents a significant risk for tumour progression and neo-angiogenesis, which would be increased during the administration of E.P.O.. The purpose of this article is to answer the question: is there a place for E.P.O. in combination with radiotherapy in the management of cancer?

  19. [Overview of erythropoietin].

    Science.gov (United States)

    Lacombe, C; Mayeux, P; Casadevall, N

    1991-01-01

    Erythropoietin (Epo) is a glycoprotein that promotes the proliferation and differentiation of erythrocyte precursors. The major site of Epo production is the kidney and the liver is the main extra renal site of Epo production. Epo producing cells were identified by in situ hybridization, in the kidney, they are peritubular cells, most likely endothelial cells of the cortex and outer medulla; in the liver, they are mainly hepatocytes. The Epo secretion is stimulated by hypoxia, which is detected by an oxygen sensor. The Epo receptor is a multimeric protein, one chain which binds Epo has been cloned. However the structure of the Epo receptor is still puzzling, and one or more accessory chains remain to be identified. Since the clonage of the Epo gene, recombinant Epo has been available and allowed the treatment of patients with renal diseases with a constant efficacy.

  20. Role of Erythropoietin in Renal Anemia Therapy

    African Journals Online (AJOL)

    of erythropoietin and others drugs in renal anemia treatment, as well as the cause of erythropoietin resistance. .... mouth health, atrophy prevention, prevention of artery hardening ... Secondary hyperthyroidism can lead to osteitis fibrosa ...

  1. Erythropoietin in radiotherapy

    International Nuclear Information System (INIS)

    Guttenburger, R.

    2003-01-01

    A high blood hemoglobin level is an independent factor for good prognosis as demonstrated in retrospective and prospective studies in a number of cancer sites. However, there is still debate on how hemoglobin affects outcome after radiotherapy. The issues are: 1. How about the predictive power and the magnitude of effect in various tumor entities? 2. Are all potential mechanisms for the hemoglobin effect considered? 3. Do EPO receptors found on tumor and normal cells outside the bone marrow play a role? Experimental and clinical data on anemia and its treatment have been extensively discussed. So far, the means to manipulate the hemoglobin level, their indication and administration are to be clarified. The issues are: 1. Why does transfusion not improve prognosis? 2. What have we learned from trials using EPO to stimulate endogenous Hb production? 3. What are the potential pitfalls of correcting anemia with EPO? 4. What is the optimal design of EPO-RT trials? Although there are still more questions than answers, the therapeutic potential of erythropoietin is of considerable interest to radiation oncologists. This report gives a summary reviewing the topic and ends on a note of caution: Mild anemia in cancer patients is no indication to use EPO outside clinical trials

  2. Erythropoietin and radiotherapy

    International Nuclear Information System (INIS)

    Le Fur, E.; Albarghach, M.N.; Pradier, O.

    2010-01-01

    Erythropoietin (E.P.O.) is a glycoprotein hormone. This hormone is a growth factor for red blood cells precursors in the bone marrow. The decrease of oxygen partial pressure, a reduced number of erythrocytes caused by bleeding or excessive destruction, or increased tissues oxygen requirements lead to increased secretion of E.P.O.. Its action takes place on bone marrow erythroblastic cells through specific receptors. E.P.O. stimulates the proliferation of red cell precursors stem cells in the bone marrow, thus increasing their production in one to two weeks. The effectiveness of E.P.O. at increasing haemoglobin and improving patients quality of life has been demonstrated by several studies. However, its use in radiotherapy remains controversial. While tumour hypoxia caused by anaemia is a factor of radio resistance and thus a source of local failure, tumour expression of E.P.O. receptors presents a significant risk for tumour progression and neo-angiogenesis, which would be increased during the administration of E.P.O.. The purpose of this article is to answer the question: is there a place for E.P.O. in combination with radiotherapy in the management of cancer?

  3. Biology of erythropoietin.

    Science.gov (United States)

    Lacombe, C; Mayeux, P

    1998-08-01

    Erythropoietin (Epo) controls the proliferation, differentiation and survival of the erythroid progenitors. This cytokine was cloned in 1985 and rapidly became used for treatment of anemia of renal failure, opening the way to the first clinical trials of a hematopoietic growth factor. The clonage of one chain of the Epo receptor followed in 1989, thereby opening the research on intracellular signal transduction induced by Epo. Epo is synthesized mainly by the kidney and the liver and sequences required for tissue-specific expression have been localized in the Epo gene. A 3'enhancer is responsible for hypoxia-inducible Epo gene expression. HIF-1 alpha and beta proteins bind to this enhancer. Gene regulation by hypoxia is widespread in many cells and involves numerous genes in addition to the Epo gene. The Epo receptor belongs to the cytokine receptor family and includes a p66 chain which is dimerized upon Epo activation; two accessory proteins defined by cross-linking remain to be characterized. Epo binding induces the stimulation of Jak2 tyrosine kinase. Jak2 activation leads to the tyrosine phosphorylation of several proteins including the Epo receptor itself. As a result, different intracellular pathways are activated: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. However, the exact mechanisms by which the proliferation and/or the differentiation of erythroid cells are regulated after Epo stimulation are not known. Furthermore, target disruption of both Epo and Epo receptor showed that Epo was not involved in the commitment of the erythroid lineage and seemed to act mainly as a survival factor.

  4. Studies on Erythropoietin Bioassay Method

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Kyoung Sam; Ro, Heung Kyu; Lee, Mun Ho [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1975-09-15

    It is the purpose of this paper to design the most preferable method of erythropoietin bioassay in Korea. Bioassay utilizing polycythemic mice are currently in general use for the indirect determination of erythropoietin. Assay animals are usually prepared either by transfusion or by exposure to reduced oxygen tension in specially constructed chamber. We prepared the polycythemic mice by the specially constructed hypobaric chamber. We observed weights and hematocrits of the mice in the hypobaric chamber, then hematocrits and 72 hours {sup 59}Fe red cell uptake ratio of the polycythemic mice induced by hypoxia after removal from the hypobaric chamber. We designed the method of erythropoietin bioassay according to the results obtained by above experiments. Then we measured the 72 hours {sup 59}Fe red cell uptake ratio of the polycythemic mice with normal saline, normal plasma and anemic plasma according to the method we designed. The results are followed:1) The hematocrits of the mice in hypobaric chamber increased to 74% in 11 days. It is preferable to maintain the pressure of the chamber to 400 mmHg for first 4 days then 300 mmHg for last 10 days to reduce the death rate and time consuming in hypobaric chamber. 2) After removal from the hypobaric chamber, the 72 hours {sup 59}Fe red cell uptake ratio decreased rapidly and maintained the lowest level from the fourth day to tenth day. 3) We design the method of erythropoietin bioassay according to the results of above experiment and to the half life of erythropoietin. 4) The Korean product {sup 59}Fe is mixture of {sup 55}Fe and {sup 59}Fe. And the {sup 59}Fe red cell uptake ratio in normal mice was far less with Korean product {sup 59}Fe than with pure {sup 59}Fe of foreign product. So it is desirable to use pure {sup 59}Fe in this method of erythropoietin bioassay. 5) Considering the cost, the technique, the time consuming and the sensitivity it is the most preferable method of erythropoietin bioassay in Korea

  5. Metabolites related to renal function, immune activation, and carbamylation are associated with muscle composition in older adults.

    Science.gov (United States)

    Lustgarten, Michael S; Fielding, Roger A

    2017-12-15

    Reduced skeletal muscle density in older adults is associated with insulin resistance, decreased physical function, and an increased all-cause mortality risk. To elucidate mechanisms that may underlie the maintenance of skeletal muscle density, we conducted a secondary analysis of previously published muscle composition and serum metabolomic data in 73 older adults (average age, 78y). Multivariable-adjusted linear regression was used to examine associations between 321 metabolites with muscle composition, defined as the ratio between normal density (NDM) with low density (LDM) thigh muscle cross sectional area (NDM/LDM). Sixty metabolites were significantly (p≤0.05 and qMetabolites that were significantly associated with muscle composition were then tested for their association with circulating markers of renal function (blood urea nitrogen, creatinine, uric acid), and with the immune response (neutrophils/lymphocytes) and activation (kynurenine/tryptophan). 43 significant NDM/LDM metabolites (including urea) were co-associated with at least 1 marker of renal function; 23 of these metabolites have been previously identified as uremic solutes. The neutrophil/lymphocyte ratio was significantly associated with NDM/LDM (β±SE: -0.3±0.1, p=0.01, q=0.04). 35 significant NDM/LDM metabolites were co-associated with immune activation. Carbamylation (defined as homocitrulline/lysine) was identified as a pathway that may link renal function and immune activation with muscle composition, as 29 significant NDM/LDM metabolites were co-associated with homocitrulline/lysine, with at least 2 markers of renal function, and with kynurenine/tryptophan. When considering that elevated urea and uremic metabolites have been linked with an increased systemic microbial burden, that antimicrobial defense can be reduced in the presence of carbamylation, and that adipocytes can promote host defense, we propose the novel hypothesis that the age-related increase in adipogenesis within muscle

  6. 21 CFR 864.7250 - Erythropoietin assay.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Erythropoietin assay. 864.7250 Section 864.7250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7250 Erythropoietin...

  7. The Relationship of Erythropoietin Receptor Expression and ...

    African Journals Online (AJOL)

    2018-04-04

    Apr 4, 2018 ... brain tumor characterized with poor prognosis and short survival. In addition to the standard treatment protocols, targeted molecular treatment options are under trial. In the recent trials, erythropoietin and erythropoietin receptor were found to be linked with the progression of GBM cells. Aim: In this study, we.

  8. Effect of two doses of carbamylated allergoid extract of dust mite on nasal reactivity.

    Science.gov (United States)

    Scalone, G; Compalati, E; Bruno, M E; Mistrello, G

    2013-11-01

    Background and Objective. Single SLIT studies with native allergen extracts support a dose-response effect for clinical and immunological outcomes. Conversely for carbamylated allergoids this dose-response effects is less evident, likely because the threshold for efficacy is more easily reached through the enhanced bioavailability of the extract consequent to the selective chemical modification. Thus this pilot study investigates the dose-response effect on nasal specific reactivity and safety of two unusual doses of carbamylated allergoid in patients mono-sensitized to house dust mites. Methods. A prospective open randomized study involved 6-65 year-old Italian patients with clinically relevant sensitization to house dust mites and positive response to nasal provocation challenge. Monomeric carbamylated allergoid was delivered once daily at the dose of 1000 AU or 2000 AU from June to September 2009, during the lowest level of mites exposure. Primary outcomes were the change of the threshold of allergen concentration for a positive nasal provocation test (NPT) before and after the treatment and the product safety. Secondary outcome was the change  in the mean percentage fall of peak nasal inspiratory flow (PNIF) following nasal challenge. Results. Thirty-four patients were enrolled. Fifteen in group 1 and 14 in group 2 concluded the study. After 12 weeks all patients treated in group 1 and all but one in group 2 showed an increase in the threshold dose provoking a positive NPT. Those with no symptoms onset with the highest dose delivered were 80% in group 1 and 78.6% in group 2 (p=0.92). From first to second challenge, the mean percentage fall of PNIF  was reduced with no statistical difference between groups (p=0.95), and with no difference between the final mean percentage falls (p=0.65). No serious adverse reactions occurred and the frequency of events, all mild, was similar in the two groups. Conclusions. Twelve weeks of carbamylated sublingual allergoid

  9. Use of carbamylated charge standards for testing batches of ampholytes used in two-dimensional elecrophoresis

    Energy Technology Data Exchange (ETDEWEB)

    Tollaksen, S L; Edwards, J J; Anderson, N G

    1981-01-01

    A method of testing batches of ampholytes is presented. By using carbamylated charge standards to co-electrophorese with the protein sample in the first-dimension isoelectric focusing gel, one can monitor, after running and staining the second-dimension sodium dodecyl sulfate (SDS) slab gel, the continuity of the pH gradient. Charge standards can also be used to check the reproducibility of the pH gradient among batches of ampholytes and to modify the new batch with a small amount of a narrow range ampholyte to assure reproducibility of experiments. Ampholytes for comparison were obtained from three major manufacturers. 5 figures.

  10. Recombinant human erythropoietin in sports: a review

    Directory of Open Access Journals (Sweden)

    Rafael Maia de Almeida Bento

    2003-06-01

    Full Text Available Erythropoietin is an endogenous hormone of glicoproteic nature secreted by the kidneys and is the main regulator of the erythropoiesis. An alteration in its production generates a disturbance in the plasmatic concentration giving rise to several types of pathologies related to the hematopoietic system. The recombinant forms of erythropoietin have indiscriminately been used by athletes, mainly in endurance sports, by increasing the erythrocytes concentration, generating a better delivery of oxygen to the muscle tissue. The administration of recombinant erythropoietin was prohibited by the International Olympic Committee and its use considered as doping. This review has the intention to describe the physical, biological and pharmacokinetic properties of the endogenous erythropoietin, as well as its recombinant form, describing also its use in sports and the process of searching methodologies for its detection in doping control.

  11. Erythropoietin in Cardiorenal Anemia Syndrome

    Directory of Open Access Journals (Sweden)

    Emir Fazlibegović

    2008-11-01

    Full Text Available Incidents of heart and renal failure (HF, RF together, are increasing in our country and all over the world, so a great attention has been dedicated to this problem recently. These diseases together have shown bad results because of the process of accelerated arteriosclerosis, structural changes of myocardium, oxidative stress, inflammation, increased activities of sympathetic nervous system (SNS, increased activities of a renin-angiotensin-aldosterone system (RAAS. These factors are crucial in the development of patho-physiological process and consequential development of anemia, that together with heart and renal failure through interaction, cause serious disorder that we call the cardio-renal anemia syndrome. We examined effects of erythropoietin (Epoetin beta at 90 (60 men and 30 women pre-dialysed and dialysed patients with HF signs during a period of three years in individual dozes of 2000-6000 units subcutaneous (sc weekly. Using computer S PLUS and SAS multiple variant analysis we have got correlations by Pearson. Epoetin beta significantly develops anemiaparameters: number of erythrocytes (r=0.51779; p<0.0001, hemoglobin (r=0.38811; p<0.0002, MCV (r=0.59876; p<0.0001 at patients with HF. Positive effects are seen at NYHA class (r=0.59906; p<0.0001, on quality of life before and after prescribing medicine. Parameters of renal functions are improving: more urea (r =0.45557; p<0.0001 than creatinine (r=0.26397; p<0.00119 and potassium values K(+ are not changed significantly (r=0.02060; p<0.8471. Epoetin beta has been useful in treatment of pre-dialysed and dialysed patients with HF and anemia by improving functional ability of myocardium and quality of life.

  12. Disease Activity and Conversion into Multiple Sclerosis after Optic Neuritis Is Treated with Erythropoietin

    Directory of Open Access Journals (Sweden)

    Kurt-Wolfram Sühs

    2016-09-01

    Full Text Available Changes in cerebral lesion load by magnetic resonance imaging (MRI in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095 were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU of recombinant human erythropoietin (IV daily for three days, or a placebo, as an add-on to methylprednisolone. Of 35 patients, we investigated changes in cerebral lesion load in MRIs obtained at baseline and at weeks 4, 8, and 16. In 5 of the 35 patients, we found conversion into multiple sclerosis (MS based on MRI progression only. These five patients had received the placebo. Another five patients showed MRI progression together with relapses. Three of these patients had received erythropoietin, and two the placebo. Yet, analyzing the change in absolute numbers of periventricular, juxtacortical, and infratentorial lesions including gadolinium-enhancing lesions, there were no significant differences between the groups. Although effective in terms of retinal nerve fiber layer protection, erythropoietin treatment of acute isolated optic neuritis did not influence further evolution of MRI lesions in the brain when comparing absolute numbers. However, early conversion from clinically isolated syndrome to MS assessed by MRI activity seemed to occur more frequently in the placebo-treated group.

  13. Therapeutic implications of recombinant human erythropoietin in ...

    African Journals Online (AJOL)

    AJB SERVER

    2006-12-29

    Dec 29, 2006 ... quence of both, RHUEPO has achieved the highest annual sales ... analysis of the US Medicare database (Ma et al., 1999) ... blood transfusions and improves quality of life (Eschbach, ... Large doses of EPO results increase in blood pressure .... human erythropoietin was obtained from human genomic.

  14. Erythropoietin: ready for prime-time cardioprotection.

    NARCIS (Netherlands)

    Riksen, N.P.; Hausenloy, D.J.; Yellon, D.

    2008-01-01

    To improve clinical outcomes in patients presenting with an acute myocardial infarction, new strategies to limit infarct size and postinfarct remodelling are warranted. Recent animal studies have revealed that erythropoietin has the potential to achieve both these goals. Even more intriguing is the

  15. Erythropoietin receptor signaling is membrane raft dependent

    NARCIS (Netherlands)

    K.L. McGraw (Kathy); G.M. Fuhler (Gwenny); J.O. Johnson (Joseph); J.A. Clark (Justine); G.C. Caceres (Gisela); L. Sokol (Lubomir); A.F. List (Alan)

    2012-01-01

    textabstractUpon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling

  16. Dose-finding study of carbamylated monomeric allergoid tablets in grass-allergic rhinoconjunctivitis patients.

    Science.gov (United States)

    Mösges, Ralph; Rohdenburg, Christina; Eichel, Andrea; Zadoyan, Gregor; Kasche, Elena-Manja; Shah-Hosseini, Kija; Lehmacher, Walter; Schmalz, Petra; Compalati, Enrico

    2017-11-01

    To determine the optimal effective and safe dose of sublingual immunotherapy tablets containing carbamylated monomeric allergoids in patients with grass pollen-induced allergic rhinoconjunctivitis. In this prospective, randomized, double-blind, active-controlled, multicenter, Phase II study, four different daily doses were applied preseasonally for 12 weeks. Of 158 randomized adults, 155 subjects (safety population) received 300 units of allergy (UA)/day (n = 36), 600 UA/day (n = 43), 1000 UA/day (n = 39), or 2000 UA/day (n = 37). After treatment, 54.3, 47.6, 59.0 and 51.4% of patients, respectively, ceased to react to the highest allergen concentration in a conjunctival provocation test. Furthermore, the response threshold improved in 70.4, 62.9, 76.7 and 66.7% of patients, respectively. No serious adverse events occurred. This study found 1000 UA/day to be the optimal effective and safe dose.

  17. The Effect of Erythropoietin on S100 Protein Expression in Cochlea After Acoustic Overstimulation: An Experimental Study

    Directory of Open Access Journals (Sweden)

    Gulsen Gurgen

    2014-03-01

    Full Text Available Aim: To investigate the effect of Erythropoietin on acoustically overstimulated rat spiral ganglion neurons (SGNs using S100 protein immunostaining.Material and Method: Twenty-two Wistar albino rats were divided into three groups: healthy control group (n=7, Saline solution (n=7 and Erythropoietin injection groups (n=8. Saline solution and Erythropoietin injection groups received white noise (100 dB SPL for 3 hours. Cochlear sections were stained by silver staining technique and immunostained by S100 antibody. Results: Histochemical analysis of silver staining sections revealed normal structure and a weak staining in SGNs of healthy control group. However, dark-black cytoplasmic staining, cellular shrinkage and degeneration were detected in saline injection group. On the other hand, a few weakly stained neurons were observed in erythropoietin injection group. S100 staining demonstrated strong reaction in Schwann cells and myelin sheaths of SGNs in healthy control group (p<0.05. In saline solution injection group, Schwann cells showed moderate S100 reaction and other regions of SGNs showed weak reaction (p<0.05. In erythropoietin injection group, strong S100 expression almost similar to the healthy control group was determined, although there was an occasional decrease. Discussion: Erythropoetin may prevent noise induced SGN degeneration via protecting the Schwann cells in rat cochlea.

  18. Use of Recombinant Human Erythropoietin in Renal Anemia in Children

    Directory of Open Access Journals (Sweden)

    Habibur Rahman

    2009-11-01

    Full Text Available Erythropoietin is a hormone highly effective as like as natural erythropoietin to maintain target hemoglobin and hematocrit level in renal anemia. Its advantage over blood transfusion has been proved by improving the quality of life and decreasing morbidity and mortality in ESRD patients. Effectiveness of r-erythropoietin depends on absences of infection, inflammation and vitamin deficiency and iron status. Iron supplementation is needed before r-erythropoietin administration and sub-cutaneous rout is better in renal anemia because of slow and sustained releases of r-erythropoietin from the site of administration. Target hemoglobin level is 11-12.5 gm/dl and hematocrit is 33% which can be achieved by this hormone therapy. Key words- Recombinant erythropoietin, renal anemia, end stage renal disease.DOI: 10.3329/bsmmuj.v2i1.3713 BSMMU J 2009; 2(1: 50-53  

  19. Polycythemia in transgenic mice expressing the human erythropoietin gene

    International Nuclear Information System (INIS)

    Semenza, G.L.; Traystman, M.D.; Gearhart, J.D.; Antonarakis, S.E.

    1989-01-01

    Erythropoietin is a glycoprotein hormone that regulates mammalian erythropoiesis. To study the expression of the human erythropoietin gene, EPO, 4 kilobases of DNA encompassing the gene with 0.4 kilobase of 5' flanking sequence and 0.7 kilobase of 3' flanking sequence was microinjected into fertilized mouse eggs. Transgenic mice were generated that are polycythemic, with increased erythrocytic indices in peripheral blood, increased numbers of erythroid precursors in hematopoietic tissue, and increased serum erythropoietin levels. Transgenic homozygotes show a greater degree of polycythemia than do heterozygotes as well as striking extramedullary erythropoiesis. Human erythropoietin RNA was found not only in fetal liver, adult liver, and kidney but also in all other transgenic tissues analyzed. Anemia induced increased human erythropoietin RNA levels in liver but not kidney. These transgenic mice represent a unique model of polycythemia due to increased erythropoietin levels

  20. Accuracy of erythropoietin determination in the dialysate of CAPD patients

    NARCIS (Netherlands)

    Struijk, D. G.; Koomen, G. C.; Krediet, R. T.; Arisz, L.

    1990-01-01

    In vitro experiments were performed to analyze problems with the determination of erythropoietin in dialysate. Human recombinant erythropoietin (EPO; 4000 U/L) was added to several fluids, to glass or polystyrene tubes with or without addition of bovine serum albumin (BSA) and to dialysate bags. The

  1. Hypoxia and the initiation of erythropoietin production. [Rats

    Energy Technology Data Exchange (ETDEWEB)

    Schooley, J.C.; Mahlmann, L.J.

    1975-01-01

    The initiation of erythropoietin production in rats by hypoxia is dependent upon the magnitude of the hypoxic exposure, the position of the oxygen dissociation curve at the time of the hypoxic exposure, and the animal's endocrine status. Normal male rats produce more erythropoietin and elevate their intraerythrocytic 2,3-DPG levels more than female rats exposed to the same degree of hypoxia. Hypophysectomized rats produce erythropoietin following severe hypoxic exposure, but do not elevate their 2,3-DPG levels above control values. Respiratory acidosis in rats produced by breathing 10 percent CO/sub 2/ or by the injection of acetazolamide inhibits the initiation of erythropoietin production by hypoxic environments, but this inhibition is minimal in animals with metabolic acidosis produced by ureterligation. Changes in serum erythropoietin levels and the in vitro P/sub 50/ appear to be two separate but interrelated physiological events which occur during the adaptation of animals to hypoxic environments.

  2. An abnormally glycosylated isoform of erythropoietin in hemangioblastoma is associated with polycythemia.

    Science.gov (United States)

    Delanghe, Sigurd E; Dierick, Jan; Maenhout, Thomas M; Zabeau, Lennart; Tavernier, Jan; Claes, Kathleen; Bleyen, Joris; Delanghe, Joris R

    2015-01-01

    Hemangioblastomas express erythropoietin and the patients often present with polycythemia. Serum erythropoietin was measured using a commercial immunoassay, a functional erythropoietin assay and iso-electric focusing. Despite the polycythemia, serum erythropoietin remained low, while a functional erythropoietin-assay showed a 4-5 higher activity in serum compared to the immunoassay. Iso-electric focusing of serum erythropoietin indicated overrepresentation of highly sialylated erythropoietin isoforms produced by the tumor. As a result, altered affinity of the monoclonal antibody used in the immunoassay for the hypersialylated isoforms was suggested. Analysis of erythropoietin isoforms may be helpful in distinguishing the ectopic erythropoietin isoforms from normally glycosylated erythropoietin. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Erythropoiesis and erythropoietin in hypo- and hyperthyroidism.

    Science.gov (United States)

    Das, K C; Mukherjee, M; Sarkar, T K; Dash, R J; Rastogi, G K

    1975-02-01

    Qualitative and quantitative studies of erythropoiesis in 23 patients with hypothyroidism and 21 patients with hyperthryoidism included routine hematologic evaluation, bone marrow morphology, status of serum iron, B12 and folate red blood cell mass and plasma volume by radioisotope methods, erythrokinetics and radiobioassay of plasma erythropoietin. A majority of patients with the hypothyroid state had significant reduction in red blood cell mas per kg of body weight. The presence of anemia in many of these patients was not evident from hemoglobin and hematocrit values due to concomitant reduction of plasma volume. The erythrokinetic data in hypothyroid patients provided evidence of significant decline of the erythropoietic activity of the bone marrow. Erythroid cells in the marrow were depleted and also showed reduced proliferative activity as indicated by lower 3H-thymidine labeling index. Plasma erythropoietin levels were reduced, often being immeasurable by the polycythemic mouse bioassay technique. These changes in erythropoiesis in the hypothyroid state appear to be a part of physiological adjustment to the reduced oxygen requirement of the tissues due to diminished basal metabolic rate. Similar investigations revealed mild erythrocytosis in a significant proportion of patients with hyperthyroidism. Failure of erythrocytosis to occur in other patients of this group was associated with impaired erythropoiesis due to a deficiency of hemopoietic nutrients such as iron, vitamin B12 and folate. The mean plasma erythropoietin level of these patients was significantly elevated; in 4 patients the levels were in the upper normal range whereas in the rest, the values were above the normal range. The bone marrow showed erythyroid hyperplasia in all patients with hyperthyroidism. The mean 3H-thymidine labeling index of the erythroblasts was also significantly higher than normal in hyperthyroidism; in 8 patients the index was within the normal range whereas in the

  4. Autosomal dominant familial erythrocytosis due to autonomous erythropoietin production

    International Nuclear Information System (INIS)

    Distelhorst, C.W.; Wagner, D.S.; Goldwasser, E.; Adamson, J.W.

    1981-01-01

    A family is described in which four members spanning three consecutive generations have erythrocytosis associated with a normal hemoglobin oxygen affinity. When bone marrow from one affected family member was cultured in vitro, erythroid colonies formed only when erythropoietin was added to the culture. Serum erythropoietin, measured by radioimmunoassay, was significantly elevated above normal in each of the affected family members. Bioassayable erythropoietin was detected in the urine of two of the three affected family members. In two of the affected family members, erythropoietin was measured in serum by radioimmunoassay and in urine by bioassay before and for 4 days following an isovolemic phlebotomy, which reduced the red cell mass by 20%. Neither serum nor urinary erythropoietin levels changed following phlebotomy. The erythrocytosis in this family appears to be secondary to inappropriately increased erythropoietin production unassociated with a decrease in the blood oxygen-carrying capacity. This is the first instance in which autonomous erythropoietin production appears to be inherited on an autosomal dominant basis

  5. Erythropoietin in stroke therapy: friend or foe.

    Science.gov (United States)

    Souvenir, Rhonda; Doycheva, Desislava; Zhang, John H; Tang, Jiping

    2015-01-01

    Recombinant human erythropoietin (rhEPO), over the past decade, was hailed as an auspicious therapeutic strategy for various types of brain injuries. The promising results from experiments conducted in animal models of stroke led to a hurried clinical trial that was swiftly aborted in Phase II. The multiple neuroprotective modalities of rhEPO failed to translate smoothly to human adult ischemic brain injury and provided limited aid to neonates. In light of the antithetical results, several questions were raised as to why and how this clinical trial failed. There was bolstering evidence from the preliminary studies that pointed to a bright future. Therefore, the objective of this review is to address these questions by discussing the signaling pathways of rhEPO that are reported to mediate the neuroprotective effect in various animal models of brain injury. Major biomedical bibliographical databases (MEDLINE, ISI, PubMed, and Cochrane Library) were searched with the use of keywords such as erythropoietin, stroke, neonatal hypoxia ischemia, intracerebral hemorrhage, etc. This article will discuss the confounding factors that influence the efficacy of rhEPO treatment hence challenging its clinical translatability. Lastly, rhEPO may still be a promising therapeutic candidate for neonates in spite of its shortcoming in clinical trial if caution is taken with the dose and duration of its administration.

  6. Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.

    LENUS (Irish Health Repository)

    Presneill, Jeffrey

    2014-01-01

    The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes.

  7. The Impact of Tumor Expression of Erythropoietin Receptors and Erythropoietin on Clinical Outcome of Esophageal Cancer Patients Treated With Chemoradiation

    International Nuclear Information System (INIS)

    Rades, Dirk; Golke, Helmut; Schild, Steven E.; Kilic, Ergin

    2008-01-01

    Background: To investigate the impact of tumor erythropoietin receptors (Epo-R) and erythropoietin (Epo) expression in 64 patients with Stage III esophageal cancer receiving or not receiving erythropoietin during chemoradiation. Materials and Methods: The impact of tumor Epo-R expression, Epo expression, and 10 additional factors (age, Karnofsky-Performance-Score [KPS], tumor length, T and N stage, histology and grading, hemoglobin during radiotherapy, erythropoietin administration, surgery) on overall survival (OS) and locoregional control (LC) was evaluated. Results: Improved OS was associated with low (≤20%) Epo expression (p = 0.049), KPS >80 (p 0.008), T3 stage (p = 0.010), hemoglobin ≥12 g/dL (p < 0.001), and surgery (p = 0.010). Erythropoietin receptor expression showed a trend (p = 0.09). Locoregional control was associated with T stage (p = 0.005) and hemoglobin (p < 0.001), almost with erythropoietin administration (p = 0.06). On multivariate analyses, OS was associated with KPS (p = 0.045) and hemoglobin (p = 0.032), LC with hemoglobin (p < 0.001). Patients having low expression of both Epo-R and Epo had better OS (p = 0.003) and LC (p = 0.043) than others. Two-year OS was nonsignificantly better (p = 0.25) in patients with low Epo-R expression receiving erythropoietin (50%) than in those with higher Epo-R expression receiving erythropoietin (21%), low Epo-R expression/no erythropoietin administration (29%), or higher Epo-R expression/no erythropoietin administration (18%). Two-year LC rates were, respectively, 65%, 31%, 26%, and 29% (p = 0.20). Results for Epo expression were similar. Conclusions: Higher Epo-R expression or Epo expression seemed to be associated with poorer outcomes. Patients with low expression levels receiving erythropoietin seemed to do better than patients with higher expression levels or not receiving erythropoietin. The data need to be confirmed in a larger series of patients

  8. Fetal plasma erythropoietin concentration in severe growth retardation.

    Science.gov (United States)

    Snijders, R J; Abbas, A; Melby, O; Ireland, R M; Nicolaides, K H

    1993-02-01

    The aim of this study was to determine whether hypoxemia induces an increase in plasma erythropoietin concentration in human fetal life and, if so, whether this response stimulates fetal erythropoiesis. The plasma erythropoietin concentration in blood samples from 33 small-for-gestational-age fetuses at 26 to 38 weeks' gestation was measured. Measurements were compared with the reference range for gestation, and associations with PO2, pH, and erythroblast and erythrocyte counts were examined. The mean plasma erythropoietin concentration in the small-for-gestational-age fetuses was significantly increased, and the degree of increase was significantly associated both with fetal acidemia and, more strongly, with fetal erythroblastosis. Erythropoietin production in response to tissue hypoxia occurs from at least 26 weeks' gestation with measurable physiologic effects on erythropoiesis. Furthermore, more accurate assessment of tissue oxygenation may be obtained by measuring the erythroblast count rather than the blood pH.

  9. Cytoprotective effect of glutaraldehyde erythropoietin on HEK293 kidney cells after silver nanoparticle exposure

    Directory of Open Access Journals (Sweden)

    Sooklert K

    2016-02-01

    Full Text Available Kanidta Sooklert,1,2 Supreecha Chattong,3 Krissanapong Manotham,3 Chawikan Boonwong,1 I-yanut Klaharn,1 Depicha Jindatip,4 Amornpun Sereemaspun1,4 1Nanobiomedicine Laboratory, Department of Anatomy, Faculty of Medicine, 2Inter-Department Program of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, 3Renal Unit, Department of Medicine, Lerdsin General Hospital, 4Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, ThailandAbstract: The toxic effects from exposure to silver nanoparticles (AgNPs, which are broadly present in many consumer products, have long raised concerns. Many studies have focused on the mechanisms of nanosilver, which cause toxicity in human cells, but little is known about prevention of this type of injury. This study investigated the in vitro effects of glutaraldehyde erythropoietin (GEPO, a cytoprotective compound derived from erythropoietin, in terms of cell protection against AgNP-induced injury. HEK293 cells were pretreated with or without GEPO before administration of AgNPs. The protective effects of GEPO in this cell line were assessed by the percentage of viable cells, alterations of cell morphology, and the proliferative capability of the cells. In addition, we assessed the role of GEPO in lowering cellular oxidative stress and regulating expression of the anti-apoptotic protein Bcl2. The results showed rescue effects on the percentage of viable and proliferative cells among GEPO pretreated cells. Pretreatment with GEPO maintained the normal cell shape and ultrastructural morphology. Moreover, GEPO reduced the generation of reactive oxygen species in cells and activated expression of Bcl2, which are the major mechanisms in protection against cellular toxicity induced by AgNPs. In conclusion, our study showed that the cytotoxic effects from exposure to AgNPs can be prevented by GEPO. Keywords: glutaraldehyde erythropoietin, silver nanoparticles, cytoprotection

  10. Basic conditions for radioimmunoassay of erythropoietin, and plasma levels of erythropoietin in normal subjects and anemic patients

    Energy Technology Data Exchange (ETDEWEB)

    Mizoguchi, Hideaki; Ohta, Kazuo; Suzuki, Toshiaki; Murakami, Akihiko; Ueda, Masatsugu; Sasaki, Ryuzou; Chiba, Hideo

    1987-02-01

    We have developed a specific and sensitive radioimmunoassay for erythropoietin. The sensitivity of our assay is 0.5 mU or 5 mU/ml and is sufficient to detect normal plasma erythropoietin levels. The mean plasma erythropoietin titer of normal Japanese with our radioimmunoassay was found to be 21.9 +- 12.0 mU/ml (n = 199). The validity of the method was further confirmed by the observations that the plasma erythropoietin titers were inversely related to hemoglobin levels in patients with nonuremic anemias, lower in uremic patients than in patients with nonuremic anemias with similar hemoglobin levels, markedly elevated in patients with aplastic anemia and pure red cell aplasia, and in a low normal range in patients with polycythemia vera.

  11. Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of Cisplatin-induced neuropathy

    Directory of Open Access Journals (Sweden)

    Egensperger Rupert

    2009-07-01

    Full Text Available Abstract Background Cisplatin mediates its antineoplastic activity by formation of distinct DNA intrastrand cross links. The clinical efficacy and desirable dose escalations of cisplatin are restricted by the accumulation of DNA lesions in dorsal root ganglion (DRG cells leading to sensory polyneuropathy (PNP. We investigated in a mouse model by which mechanism recombinant erythropoietin (rhEPO protects the peripheral nervous system from structural and functional damage caused by cisplatin treatment with special emphasis on DNA damage burden. Results A cumulative dose of 16 mg cisplatin/kg resulted in clear electrophysiological signs of neuropathy, which were significantly attenuated by concomitant erythropoietin (cisplatin 32,48 m/s ± 1,68 m/s; cisplatin + rhEPO 49,66 m/s ± 1,26 m/s; control 55,01 m/s ± 1,88 m/s; p Conclusion The protective effect of recombinant erythropoietin is not mediated by reducing the burden of DNA platination in the target cells, but it is likely to be due to a higher resistance of the target cells to the adverse effect of DNA damage. The increased frequency of intact mitochondria might also contribute to this protective role.

  12. Anti-carbamylated Protein Antibody Levels Correlate with Anti-Sa (Citrullinated Vimentin) Antibody Levels in Rheumatoid Arthritis.

    Science.gov (United States)

    Challener, Gregory J; Jones, Jonathan D; Pelzek, Adam J; Hamilton, B JoNell; Boire, Gilles; de Brum-Fernandes, Artur José; Masetto, Ariel; Carrier, Nathalie; Ménard, Henri A; Silverman, Gregg J; Rigby, William F C

    2016-02-01

    The presence of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) indicates a breach in immune tolerance. Recent studies indicate that this breach extends to homocitrullination of lysines with the formation of anti-carbamylated protein (anti-CarP) antibodies. We analyzed the clinical and serologic relationships of anti-CarP in 2 RA cohorts. Circulating levels of immunoglobulin G anti-CarP antibodies were determined by ELISA in established (Dartmouth-Hitchcock Medical Center) and early (Sherbrooke University Hospital Center) cohorts and evaluated for anticyclic citrullinated peptide antibodies (anti-CCP), specific ACPA, and rheumatoid factor (RF) levels using the Student t test and correlation analysis. We identified elevated anti-CarP antibodies titers in 47.0% of seropositive patients (Dartmouth, n = 164), with relationships to anti-CCP (p < 0.0001) and IgM-RF (p = 0.001). Similarly, 38.2% of seropositive patients from the Sherbrooke cohort (n = 171) had elevated anti-CarP antibodies; titers correlated to anti-CCP (p = 0.01) but not IgM-RF (p = 0.09). A strong correlation with anti-Sa was observed: 47.9% anti-Sa+ patients were anti-CarP antibodies+ versus only 25.4% anti-Sa- in the Sherbrooke cohort (p = 0.0002), and 62.6% anti-Sa+ patients versus 26.9% anti-Sa- were anti-CarP antibodies+ in Dartmouth (p < 0.0001). We found a more variable response for reactivity to citrullinated fibrinogen or to citrullinated peptides from fibrinogen and α enolase. In 2 North American RA cohorts, we observed a high prevalence of anti-CarP antibody positivity. We also describe a surprising and unexpected association of anti-CarP with anti-Sa antibodies that could not be explained by cross-reactivity. Further, considerable heterogeneity exists between anti-CarP reactivity and other citrullinated peptide reactivity, raising the question of how the pathogenesis of antibody responses for carbamylated proteins and citrullinated proteins may be linked in vivo.

  13. Studying of the standardization principles of pharmacological activity of recombinant erythropoietin preparations

    OpenAIRE

    A. K. Yakovlev; L. A. Gayderova; N. A. Alpatova; T. N. Lobanova; E. L. Postnova; E. I. Yurchikova; T. A. Batuashvili; R. A. Volkova; V. N. Podkuiko; Yu. V. Olefir

    2016-01-01

    Analysis of the publications devoted to the structure, functions, mechanism of action of erythropoietin is given in the article. Erythropoietin preparations derived from recombinant DNA technology are a mixture of isoforms with different biological activity, which determine the biological properties pharmacological activity, pharmacokinetics, efficacy and safety of medicinal product. Erythropoietin preparations derived by using recombinant DNA technology are a mixture of isoforms with differe...

  14. Erythropoietin Receptor Signaling Is Membrane Raft Dependent

    Science.gov (United States)

    McGraw, Kathy L.; Fuhler, Gwenny M.; Johnson, Joseph O.; Clark, Justine A.; Caceres, Gisela C.; Sokol, Lubomir; List, Alan F.

    2012-01-01

    Upon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling receptor signal fidelity. Here we show a critical role for membrane raft (MR) microdomains in creation of discrete signaling platforms essential for Epo-R signaling. Treatment of UT7 cells with Epo induced MR assembly and coalescence. Confocal microscopy showed that raft aggregates significantly increased after Epo stimulation (mean, 4.3±1.4(SE) vs. 25.6±3.2 aggregates/cell; p≤0.001), accompanied by a >3-fold increase in cluster size (p≤0.001). Raft fraction immunoblotting showed Epo-R translocation to MR after Epo stimulation and was confirmed by fluorescence microscopy in Epo stimulated UT7 cells and primary erythroid bursts. Receptor recruitment into MR was accompanied by incorporation of JAK2, Lyn, and STAT5 and their activated forms. Raft disruption by cholesterol depletion extinguished Epo induced Jak2, STAT5, Akt and MAPK phosphorylation in UT7 cells and erythroid progenitors. Furthermore, inhibition of the Rho GTPases Rac1 or RhoA blocked receptor recruitment into raft fractions, indicating a role for these GTPases in receptor trafficking. These data establish a critical role for MR in recruitment and assembly of Epo-R and signal intermediates into discrete membrane signaling units. PMID:22509308

  15. Serum erythropoietin levels by radioimmunoassay in polycythaemia

    Energy Technology Data Exchange (ETDEWEB)

    Birgegaard, G.; Miller, O.; Caro, J.; Erslev, A. (Cardeza Foundation for Hematological Research, Jefferson University, Philadelphia, Pa.)

    1982-01-01

    A radioimmunoassay (RIA) method for erythropoietin (Epo) was developed and validated against the polycythaemic mouse assay. The correlation was good, with a r=0.94. Several other criteria of specificity were also filled by the RIA, which had a lower detection limit of 5 mU/ml. The mean serum-Epo level in 6 patients with secondary polycythaemia, 50.2 +- 26.2 mU/ml, was significantly higher than in a group of 11 normal subjects, 28.7 +- 7.2 mU/ml (P<0.0002). However, the Epo level in 31 polycythaemia vera (PV) patients, M = 21.9 +- 6.6 mU/ml, was not significantly different from normal (P = 0.006). Since previous studies with bioassay of heat-treated and concentrated plasma samples have shown a decreased serum-Epo level in PV, Epo levels were measured before and after heat treatment and concentration of samples from normals and polycythaemics. It was found that the levels of immunoreactive material increased after heat treatment and 40 times concentration in samples from normals and patients with secondary polycythaemias, but decreased in PV. We conclude that the Epo levels in serum in the low range measured by our and previous RIA:s probably are not true Epo levels but are partly due to an unspecific serum effect, that was removed by heat treatment.

  16. Erythropoietin abuse and erythropoietin gene doping: detection strategies in the genomic era.

    Science.gov (United States)

    Diamanti-Kandarakis, Evanthia; Konstantinopoulos, Panagiotis A; Papailiou, Joanna; Kandarakis, Stylianos A; Andreopoulos, Anastasios; Sykiotis, Gerasimos P

    2005-01-01

    The administration of recombinant human erythropoietin (rhEPO) increases the maximum oxygen consumption capacity, and is therefore abused as a doping method in endurance sports. The detection of erythropoietin (EPO) abuse is based on direct pharmacological and indirect haematological approaches, both of which have several limitations. In addition, current detection methods cannot cope with the emerging doping strategies of EPO mimicry, analogues and gene doping, and thus novel detection strategies are urgently needed. Direct detection methods for EPO misuse can be either pharmacological approaches that identify exogenous substances based on their physicochemical properties, or molecular methods that recognise EPO transgenes or gene transfer vectors. Since direct detection with molecular methods requires invasive procedures, it is not appropriate for routine screening of large numbers of athletes. In contrast, novel indirect methods based on haematological and/or molecular profiling could be better suited as screening tools, and athletes who are suspect of doping would then be submitted to direct pharmacological and molecular tests. This article reviews the current state of the EPO doping field, discusses available detection methods and their shortcomings, outlines emerging pharmaceutical and genetic technologies in EPO misuse, and proposes potential directions for the development of novel detection strategies.

  17. Central nervous system frontiers for the use of erythropoietin

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    2003-01-01

    Recombinant human erythropoietin (r-HuEPO; epoetin alfa) is well established as safe and effective for the treatment of anemia. In addition to the erythropoietic effects of endogenous erythropoietin (EPO), recent evidence suggests that it may elicit a neuroprotective effect in the central nervous...... system (CNS). Preclinical studies have demonstrated the presence of EPO receptors in the brain that are up-regulated under hypoxic or ischemic conditions. Intracerebral and systemic administration of epoetin alfa have been demonstrated to elicit marked neuroprotective effects in multiple preclinical...

  18. Erythropoietin in the treatment of carbon monoxide neurotoxicity in rat.

    Science.gov (United States)

    Moallem, Seyed Adel; Mohamadpour, Amir Hooshang; Abnous, Khalil; Sankian, Mojtaba; Sadeghnia, Hamid Reza; Tsatsakis, Aristidis; Shahsavand, Shabnam

    2015-12-01

    Erythropoietin (EPO) plays a critical role in the development of the nervous system. In this study, the effects of EPO in carbon monoxide (CO) neurotoxicity were examined. Rats were exposed to 3000 ppm CO for 1 h and then different doses of EPO were administrated intraperitoneally. After 24 h, glial fibrillary acidic protein (GFAP) levels in the serum were determined and water content of brain and the extravasation of a tracer (Evans blue) were measured. Brain lipid peroxidation, myeloperoxidase activity Myelin basic protein (MBP) and BAX/BcL2 protein relative expressions were determined. Cation exchange chromatography was used to evaluate MBP alterations. Seven days after exposure, pathological assessment was performed after Klüver-Barrera staining. EPO reduced malondialdehyde levels at all doses (2500, 5000 and 10,000 u/kg). Lower doses of EPO (625, 1250, 2500 u/kg) significantly decreased the elevated serum levels of GFAP. EPO could not reduce the water content of the edematous poisoned brains. However, at 5000 and 10,000 u/kg it protected the blood brain barrier against integrity loss as a result of CO. EPO could significantly decrease the MPO activity. CO-mediated oxidative stress caused chemical alterations in MBP and EPO could partially prevent these biochemical changes. Fewer vacuoles and demyelinated fibers were found in the EPO-treated animals. EPO (5000 u/kg) could restore the MBP density. CO increased brain BAX/Bcl-2 ratio 38.78%. EPO reduced it 38.86%. These results reveal that EPO could relatively prevent different pathways of neurotoxicity by CO poisoning and thus has the potential to be used as a novel approach to manage this poisoning. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. The potential protective effects of erythropoietin and estrogen on ...

    African Journals Online (AJOL)

    Noha I. Hussien

    2015-12-30

    Dec 30, 2015 ... Kit to measure NO production following reduction of nitrate to nitrite using ..... tion of endothelial NO may eventually lead to the destruction of tubular ..... quent renal ischemia and reperfusion injury in mice. Am J Physiol.

  20. Erythropoietin protects the retinal pigment epithelial barrier against ...

    African Journals Online (AJOL)

    zhanghongmei

    2011-05-09

    May 9, 2011 ... Results showed that, EPO increased the viability of H2O2-treated RPE cells, the disruption of .... in RPE damage that occurs in AMD and other retinal diseases of aging ..... However, preventing the cellular effects of ROIs in the.

  1. Erythropoietin in Treatment of Methanol Optic Neuropathy.

    Science.gov (United States)

    Pakdel, Farzad; Sanjari, Mostafa S; Naderi, Asieh; Pirmarzdashti, Niloofar; Haghighi, Anousheh; Kashkouli, Mohsen B

    2018-06-01

    Methanol poisoning can cause an optic neuropathy that is usually severe and irreversible and often occurs after ingestion of illicit or homemade alcoholic beverages. In this study, we evaluated the potential neuroprotective effect of erythropoietin (EPO) on visual acuity (VA) in patients with methanol optic neuropathy. In a prospective, noncomparative interventional case series, consecutive patients with methanol optic neuropathy after alcoholic beverage ingestion were included. All patients initially received systemic therapy including metabolic stabilization and detoxification. Treatment with intravenous recombinant human EPO consisted of 20,000 units/day for 3 successive days. Depending on clinical response, some patients received a second course of EPO. VA, funduscopy, and spectral domain optical coherence tomography were assessed during the study. Main outcome measure was VA. Thirty-two eyes of 16 patients with methanol optic neuropathy were included. Mean age was 34.2 years (±13.3 years). The mean time interval between methanol ingestion and treatment with intravenous EPO was 9.1 days (±5.56 days). Mean follow-up after treatment was 7.5 months (±5.88 months). Median VA in the better eye of each patient before treatment was light perception (range: 3.90-0.60 logMAR). Median last acuity after treatment in the best eye was 1.00 logMAR (range: 3.90-0.00 logMAR). VA significantly increased in the last follow-up examination (P optic neuropathy and may represent a promising treatment for this disorder.

  2. Garlic accelerates red blood cell turnover and splenic erythropoietic gene expression in mice: evidence for erythropoietin-independent erythropoiesis.

    Directory of Open Access Journals (Sweden)

    Bünyamin Akgül

    2010-12-01

    Full Text Available Garlic (Allium sativum has been valued in many cultures both for its health effects and as a culinary flavor enhancer. Garlic's chemical complexity is widely thought to be the source of its many health benefits, which include, but are not limited to, anti-platelet, procirculatory, anti-inflammatory, anti-apoptotic, neuro-protective, and anti-cancer effects. While a growing body of scientific evidence strongly upholds the herb's broad and potent capacity to influence health, the common mechanisms underlying these diverse effects remain disjointed and relatively poorly understood. We adopted a phenotype-driven approach to investigate the effects of garlic in a mouse model. We examined RBC indices and morphologies, spleen histochemistry, RBC half-lives and gene expression profiles, followed up by qPCR and immunoblot validation. The RBCs of garlic-fed mice register shorter half-lives than the control. But they have normal blood chemistry and RBC indices. Their spleens manifest increased heme oxygenase 1, higher levels of iron and bilirubin, and presumably higher CO, a pleiotropic gasotransmitter. Heat shock genes and those critical for erythropoiesis are elevated in spleens but not in bone marrow. The garlic-fed mice have lower plasma erythropoietin than the controls, however. Chronic exposure to CO of mice on garlic-free diet was sufficient to cause increased RBC indices but again with a lower plasma erythropoietin level than air-treated controls. Furthermore, dietary garlic supplementation and CO treatment showed additive effects on reducing plasma erythropoietin levels in mice. Thus, garlic consumption not only causes increased energy demand from the faster RBC turnover but also increases the production of CO, which in turn stimulates splenic erythropoiesis by an erythropoietin-independent mechanism, thus completing the sequence of feedback regulation for RBC metabolism. Being a pleiotropic gasotransmitter, CO may be a second messenger for garlic

  3. Effects of Erythropoietin Administration on Adrenal Glands of Landrace/Large White Pigs after Ventricular Fibrillation

    Directory of Open Access Journals (Sweden)

    Armando Faa

    2016-01-01

    Full Text Available Aim. To evaluate the effects of erythropoietin administration on the adrenal glands in a swine model of ventricular fibrillation and resuscitation. Methods. Ventricular fibrillation was induced via pacing wire forwarded into the right ventricle in 20 female Landrace/Large White pigs, allocated into 2 groups: experimental group treated with bolus dose of erythropoietin (EPO and control group which received normal saline. Cardiopulmonary resuscitation (CPR was performed immediately after drug administration as per the 2010 European Resuscitation Council (ERC guidelines for Advanced Life Support (ALS until return of spontaneous circulation (ROSC or death. Animals who achieved ROSC were monitored, mechanically ventilated, extubated, observed, and euthanized. At necroscopy, adrenal glands samples were formalin-fixed, paraffin-embedded, and routinely processed. Sections were stained with hematoxylin-eosin. Results. Oedema and apoptosis were the most frequent histological changes and were detected in all animals in the adrenal cortex and in the medulla. Mild and focal endothelial lesions were also detected. A marked interindividual variability in the degree of the intensity of apoptosis and oedema at cortical and medullary level was observed within groups. Comparing the two groups, higher levels of pathological changes were detected in the control group. No significant difference between the two groups was observed regarding the endothelial changes. Conclusions. In animals exposed to ventricular fibrillation, EPO treatment has protective effects on the adrenal gland.

  4. Haemostatic aspects of recombinant human erythropoietin in colorectal surgery

    DEFF Research Database (Denmark)

    Poulsen, K A; Qvist, N; Winther, K

    1998-01-01

    OBJECTIVE: To find out whether recombinant human erythropoietin (r-HuEPO) given perioperatively has any effect on haemostatic activity in patients undergoing elective colorectal resection. DESIGN: A placebo-controlled double-blind study. SETTING: Odense university hospital, Denmark. SUBJECTS: 24...

  5. Study the relationship of erythropoietin and chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    R.I. El-Korashy

    2012-07-01

    It also appeared that response to erythropoietin in COPD is probably blunted especially with increased severity of the condition. This might be considered as a contributing factor in the development of anemia in COPD which is considered as anemia of chronic disease.

  6. Reduction in central venous pressure enhances erythropoietin synthesis

    DEFF Research Database (Denmark)

    Montero, D.; Rauber, S.; Gøtze, Jens Peter

    2016-01-01

    AIMS: Erythropoiesis is a tightly controlled biological event, but its regulation under non-hypoxic conditions, however, remains unresolved. We examined whether acute changes in central venous blood pressure (CVP) elicited by whole-body tilting affect erythropoietin (EPO) concentration according...

  7. Protein kinase C alpha controls erythropoietin receptor signaling.

    NARCIS (Netherlands)

    M.M. von Lindern (Marieke); M. Parren-Van Amelsvoort (Martine); T.B. van Dijk (Thamar); E. Deiner; B. Löwenberg (Bob); E. van den Akker (Emile); S. van Emst-de Vries (Sjenet); P.J. Willems (Patrick); H. Beug (Hartmut)

    2000-01-01

    textabstractProtein kinase C (PKC) is implied in the activation of multiple targets of erythropoietin (Epo) signaling, but its exact role in Epo receptor (EpoR) signal transduction and in the regulation of erythroid proliferation and differentiation remained elusive. We

  8. Protein kinase C alpha controls erythropoietin receptor signaling

    NARCIS (Netherlands)

    von Lindern, M.; Parren-van Amelsvoort, M.; van Dijk, T.; Deiner, E.; van den Akker, E.; van Emst-de Vries, S.; Willems, P.; Beug, H.; Löwenberg, B.

    2000-01-01

    Protein kinase C (PKC) is implied in the activation of multiple targets of erythropoietin (Epo) signaling, but its exact role in Epo receptor (EpoR) signal transduction and in the regulation of erythroid proliferation and differentiation remained elusive. We analyzed the effect of PKC inhibitors

  9. Treatment of anemia of nephrotic syndrome with recombinant erythropoietin

    NARCIS (Netherlands)

    Gansevoort, RT; Vaziri, ND; deJong, PE

    Nephrotic syndrome has been recently shown to cause erythropoietin (EPO) deficiency in humans and experimental models. However, efficacy and safety of recombinant EPO (rEPO) in the treatment of the associated anemia has not been previously investigated. We report a patient with nephrotic syndrome

  10. Prognostic significance of erythropoietin in pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Thilo Welsch

    Full Text Available BACKGROUND: Erythropoietin (Epo administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC. METHODOLOGY: The clinico-pathological relevance of hemoglobin (Hb, n = 150, serum Epo (sEpo, n = 87 and tissue expression of Epo/Epo receptor (EpoR, n = 104 was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. RESULTS: Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05 and PDAC (p<0.001, reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46, 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99 but not in PDAC (O/P = 0.85. Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml were not significantly different in M0 (20% and M1 (30% groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05. The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. CONCLUSION/SIGNIFICANCE: Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold

  11. Circulating levels of carbamylated protein and neutrophil extracellular traps are associated with periodontitis severity in patients with rheumatoid arthritis: A pilot case-control study.

    Science.gov (United States)

    Kaneko, Chihiro; Kobayashi, Tetsuo; Ito, Satoshi; Sugita, Noriko; Murasawa, Akira; Nakazono, Kiyoshi; Yoshie, Hiromasa

    2018-01-01

    An interrelationship between rheumatoid arthritis (RA) and periodontitis has been suggested due to their common pathogenic mechanisms. Protein carbamylation and neutrophil extracellular traps (NETs) formation have been shown to be related to autoimmune conditions, including RA, but their association with periodontitis has not been elucidated. Therefore, we assessed whether or not circulating levels of carbamylated protein (CarP) and NETs are associated with periodontitis severity and influenced by periodontal treatment. We conducted a retrospective case-control study that included 40 patients with RA and periodontitis, 30 patients with periodontitis, and 43 systemically and periodontally healthy controls to assess the circulating levels of CarP and NETs and rheumatologic and periodontal conditions. The same assessments were also performed in 22 patients with RA and periodontitis after 2 months of periodontal treatment, including oral hygiene instruction and full-mouth supragingival scaling. Patients with RA and periodontitis showed significantly higher serum levels of CarP and NETs than the control group (P = 0.04 and P periodontitis. Multiple logistic regression analyses also revealed significantly positive associations between the serum levels of CarP and NETs and moderate to severe periodontitis (P = 0.03 and P = 0.001, respectively). Furthermore, periodontal treatment significantly decreased the serum levels of CarP and NETs in patients with RA and periodontitis (P = 0.03 and P = 0.02). The circulating levels of CarP and NETs are associated with periodontitis severity and influenced by periodontal treatment in patients with RA.

  12. Evaluation of functional erythropoietin receptor status in skeletal muscle in vivo

    DEFF Research Database (Denmark)

    Christensen, Britt; Lundby, Carsten; Jessen, Niels

    2012-01-01

    Background: Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle. Methodology/Principal Findings: The protocols...... involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well...... as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle...

  13. Evaluation of functional erythropoietin receptor status in skeletal muscle in vivo

    DEFF Research Database (Denmark)

    Christensen, Britt; Lundby, Carsten; Jessen, Niels

    2012-01-01

    as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle......Background: Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle. Methodology/Principal Findings: The protocols...... involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well...

  14. CNS hypoxia is more pronounced in murine cerebral than noncerebral malaria and is reversed by erythropoietin

    DEFF Research Database (Denmark)

    Hempel, Casper; Combes, Valery; Hunt, Nicholas Henry

    2011-01-01

    observed in mice without CM, and hypoxia seemed to be confined to neuronal cell somas. PARP-1-deficient mice were not protected against CM, which argues against a role for cytopathic hypoxia. Erythropoietin therapy reversed the development of CM and substantially reduced the degree of neural hypoxia......Cerebral malaria (CM) is associated with high mortality and risk of sequelae, and development of adjunct therapies is hampered by limited knowledge of its pathogenesis. To assess the role of cerebral hypoxia, we used two experimental models of CM, Plasmodium berghei ANKA in CBA and C57BL/6 mice....... These findings demonstrate cerebral hypoxia in malaria, strongly associated with cerebral dysfunction and a possible target for adjunctive therapy....

  15. Erythropoietin and vascular endothelial growth factor as risk markers for severe hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P L; Pedersen-Bjergaard, U; Schalkwijk, C

    2010-01-01

    OBJECTIVE: Circulating erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increase during hypoglycaemia and may represent protective hormonal counter-regulatory responses. We tested the hypothesis that low levels of EPO and VEGF are associated with a higher frequency of severe....... Plasma EPO and serum VEGF levels were measured at baseline with ELISA. Events of severe hypoglycaemia defined by third party assistance were recorded and validated in telephone interviews within 24 h. RESULTS: Totally 235 episodes of severe hypoglycaemia (1.1 episodes per patient-year) were reported...... mass index, HbAlc, C-peptide level or hypoglycaemia awareness status. The levels of VEGF were positively associated with age and female sex. CONCLUSIONS: Although several studies suggest that VEGF and EPO may affect brain function during hypoglycaemia, this study does not support random VEGF or EPO...

  16. Systemic administration of erythropoietin inhibits retinopathy in RCS rats.

    Directory of Open Access Journals (Sweden)

    Weiyong Shen

    Full Text Available OBJECTIVE: Royal College of Surgeons (RCS rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO on retinopathy in RCS rats. METHODS: Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR, pro-neurotrophin 3 (pro-NT3, tumour necrosis factor-α (TNFα, pigment epithelium derived factor (PEDF and vascular endothelial growth factor-A (VEGF-A, the production of CD34(+ cells and mobilization of CD34(+/VEGF-R2(+ cells as well as recruitment of CD34(+ cells into the retina were examined after EPO treatment. RESULTS: RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34(+ cells along with effective mobilization of CD34(+/VEGF-R2(+ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. CONCLUSIONS: Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple

  17. Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution

    DEFF Research Database (Denmark)

    Aachmann-Andersen, Niels Jacob; Just Christensen, Søren; Lisbjerg, Kristian

    2014-01-01

    The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross......-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13); high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13); or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N......-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3) % (mean (SD)). High-dose Epoetin beta decreased PMI...

  18. Cytoprotective effect of recombinant human erythropoietin produced in transgenic tobacco plants.

    Directory of Open Access Journals (Sweden)

    Farooqahmed S Kittur

    Full Text Available Asialo-erythropoietin, a desialylated form of human erythropoietin (EPO lacking hematopoietic activity, is receiving increased attention because of its broader protective effects in preclinical models of tissue injury. However, attempts to translate its protective effects into clinical practice is hampered by unavailability of suitable expression system and its costly and limit production from expensive mammalian cell-made EPO (rhuEPO(M by enzymatic desialylation. In the current study, we took advantage of a plant-based expression system lacking sialylating capacity but possessing an ability to synthesize complex N-glycans to produce cytoprotective recombinant human asialo-rhuEPO. Transgenic tobacco plants expressing asialo-rhuEPO were generated by stably co-expressing human EPO and β1,4-galactosyltransferase (GalT genes under the control of double CaMV 35S and glyceraldehyde-3-phosphate gene (GapC promoters, respectively. Plant-produced asialo-rhuEPO (asialo-rhuEPO(P was purified by immunoaffinity chromatography. Detailed N-glycan analysis using NSI-FTMS and MS/MS revealed that asialo-rhuEPO(P bears paucimannosidic, high mannose-type and complex N-glycans. In vitro cytoprotection assays showed that the asialo-rhuEPO(P (20 U/ml provides 2-fold better cytoprotection (44% to neuronal-like mouse neuroblastoma cells from staurosporine-induced cell death than rhuEPO(M (21%. The cytoprotective effect of the asialo-rhuEPO(P was found to be mediated by receptor-initiated phosphorylation of Janus kinase 2 (JAK2 and suppression of caspase 3 activation. Altogether, these findings demonstrate that plants are a suitable host for producing cytoprotective rhuEPO derivative. In addition, the general advantages of plant-based expression system can be exploited to address the cost and scalability issues related to its production.

  19. Erythropoietin enhances hippocampal response during memory retrieval in humans

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla; O'Sullivan, Ursula; Harmer, Catherine J

    2007-01-01

    Although erythropoietin (Epo) is best known for its effects on erythropoiesis, recent evidence suggests that it also has neurotrophic and neuroprotective properties in animal models of hippocampal function. Such an action in humans would make it an intriguing novel compound for the treatment....... This is consistent with upregulation of hippocampal BDNF and neurotrophic actions found in animals and highlights Epo as a promising candidate for treatment of psychiatric disorders....

  20. Clinical trial experience using erythropoietin during radiation therapy

    International Nuclear Information System (INIS)

    Lavey, R.S.

    1998-01-01

    Oncologists have several reasons for trying to maintain or increase hemoglobin levels in their patients during therapy. Relief of the symptoms of anemia, including fatigue and dyspnea, are traditional, well-accepted indications. A newer rationale is to enhance the efficacy of radiation therapy and/or chemotherapy in controlling tumors. A laboratory animal study found that administration of recombinant human erythropoietin (rHuEPO) increased intratumoral median oxygen levels and diminished the proportion of measurements in the very low ( [de

  1. Does erythropoietin cause hemoglobin variability--is it 'normal'?

    Directory of Open Access Journals (Sweden)

    Ashwani K Gupta

    Full Text Available Hemoglobin variability (Hb-var in patients with chronic kidney disease has been stipulated to be a result of exogenous treatment with erythropoiesis stimulating agents (ESA and has been related to mortality in dialysis patients. We hypothesized the existence of Hb-var independent of ESA administration and compared it to that in healthy adults using data from the Scripps-Kaiser and NHANES III databases. We studied the Hb-var in 1571 peritoneal dialysis patients which included 116 patients not requiring treatment with erythropoietin. We systematically studied the differences between the groups that needed ESA therapy and those who did not. White race and male sex were significant predictors of need for erythropoietin therapy. We found peritoneal dialysis patients to exhibit significantly increased Hb-var independent of treatment with exogenous erythropoietin (0.99 gm/dL vs. 1.17 gm/dL, p-value60 years peritoneal dialysis patients was similar to that seen in healthy elders, suggesting similarity with anemia of aging. We conclude that exogenous ESA administration does not explain Hb-var entirely but may enhance it. Intrinsic factors affecting erythropoiesis including age may be the major determinants of Hb-var.

  2. The potential of erythropoietin to treat asphyxia in newborns

    Directory of Open Access Journals (Sweden)

    Pet GC

    2014-11-01

    Full Text Available Gillian C Pet, Sandra E Juul Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, WA, USA Abstract: Perinatal asphyxia is a cause of significant neonatal morbidity worldwide. Lack of oxygenation and perfusion to the neonatal brain leads to energy failure and cell death. Currently, therapeutic hypothermia is the standard of care for term infants with hypoxic-ischemic encephalopathy, but as it has shown only modest effects on survival and morbidity, additional neuroprotective agents are needed. Erythropoietin has been extensively studied as a neuroprotective agent for infants who suffer a hypoxic-ischemic brain injury. It has multiple mechanisms of action, in both preventing cell death and promoting tissue repair. Studies have progressed over time from in vitro to in vivo studies, first in animals and now in humans, with several Phase I/II trials completed and Phase III trials underway. As therapeutic hypothermia has become the standard of care in treating term infants with hypoxic-ischemic encephalopathy, studies must now evaluate other neuroprotective agents, including erythropoietin, used in concert with therapeutic hypothermia. Erythropoietin has shown promise as a neuroprotective agent in animal and human models, both alone and together with hypothermia. Keywords: neonate, brain injury

  3. Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution.

    Directory of Open Access Journals (Sweden)

    Niels Jacob Aachmann-Andersen

    Full Text Available The membrane-assisted isoform immunoassay (MAIIA quantitates erythropoietin (EPO isoforms as percentages of migrated isoforms (PMI. We evaluated the effect of recombinant human EPO (rhEPO on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13; high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13; or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3 % (mean (SD. High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2% (p<0.00001 and 45.2 (7.3% (p<0.00001. Low-dose Epoetin beta decreased PMI on days 4 and 11 to 46.0 (12.8% (p<0.00001 and 46.1 (10.4% (p<0.00001. In both rhEPO groups, PMI on day 25 was still decreased (high-dose Epoetin beta: 72.9 (19.4% (p=0.029; low-dose Epoetin beta: 73.1 (17.8% (p=0.039. In conclusion, Epoetin beta leaves a footprint in the plasma-EPO isoform pattern. MAIIA can detect changes in EPO isoform distribution up til at least three weeks after administration of Epoetin beta even though the total EPO concentration has returned to normal.

  4. The effect of erythropoietin on platelet function and fibrinolysis in chronic renal failure

    DEFF Research Database (Denmark)

    Stenver, Doris Irene; Jeppesen, L; Nielsen, B

    1994-01-01

    The influence of erythropoietin therapy on platelet function and fibrinolysis was evaluated in 12 anemic hemodialysis patients. Six months of therapy with human erythropoietin (50 to 80 IU/kg initially) raised the hemoglobin level to 10.8 g/dl but did not increase platelet activity in vivo as mea...

  5. Therapy with recombinant human erythropoietin in patients with myelodysplastic syndromes.

    Science.gov (United States)

    Stone, R M; Bernstein, S H; Demetri, G; Facklam, D P; Arthur, K; Andersen, J; Aster, J C; Kufe, D

    1994-10-01

    We conducted a Phase I-II trial of recombinant human erythropoietin-beta (rhEPO) in patients with myelodysplastic syndrome (MDS). Patients with anemia and pathologically confirmed MDS were eligible for the study. Treatment consisted of rhEPO by subcutaneous injection thrice weekly for 6 weeks at one of three dose levels (100 U/kg (three patients), 200 U/kg (three patients) and 400 U/kg (14 patients)). Ferrous sulfate (325 mg po tid) was also administered if the transferrin saturation was below 30% (two patients). Patients were monitored with weekly CBC, white cell differential, and reticulocyte counts. Bone marrow examinations were performed at the conclusion of the treatment period and after a 2 week washout period. Patients who responded to therapy were continued on rhEPO at the same dose for 6 additional months. Response criteria included: 50% reduction in transfusion requirements compared with the 6 week pre-study period; doubling of reticulocyte count that was maintained on two determinations at least 1 week apart; or an increase in hemoglobin by at least 1.2 gm/dl without transfusions. Pre-treatment factors potentially predictive of response were analyzed by univariate analysis and in a multivariate fashion by classification and regression trees. Seven of the twenty patients sustained an untransfused rise in serum hemoglobin > or = 1.2 gm/dl. Four of the sixteen patients (including three of seven patients experiencing a rise in serum hemoglobin) who were transfusion-dependent prior to the study achieved a reduction or elimination of their transfusion requirements. Five of thirteen patients who received rhEPO during the extension phase had a continued response. A low baseline erythropoietin level (< 50 mU/ml) was the best predictor of hemoglobin response when controlling for other variables. rhEPO has a role in the treatment of certain patients with MDS, particularly in those whose endogenous serum erythropoietin levels are not markedly elevated.

  6. Biological evaluation of recombinant human erythropoietin in pharmaceutical products

    Directory of Open Access Journals (Sweden)

    Ramos A.S.

    2003-01-01

    Full Text Available The potencies of mammalian cell-derived recombinant human erythropoietin pharmaceutical preparations, from a total of five manufacturers, were assessed by in vivo bioassay using standardized protocols. Eight-week-old normocythemic mice received a single subcutaneous injection followed by blood sampling 96 h later or multiple daily injections with blood sampling 24 h after the last injection. Reticulocyte counting by microscopic examination was employed as the end-point using the brilliant cresyl blue or selective hemolysis methods, together with automated flow cytometry. Different injection schedules were investigated and dose-response curves for the European Pharmacopoeia Biological Reference Preparation of erythropoietin were compared. Manual and automated methods of reticulocyte counting were correlated with respect to assay validity and precision. Using 8 mice per treatment group, intra-assay precision determined for all of the assays in the study showed coefficients of variation of 12.1-28.4% for the brilliant cresyl blue method, 14.1-30.8% for the selective hemolysis method and 8.5-19.7% for the flow cytometry method. Applying the single injection protocol, a combination of at least two independent assays was required to achieve the precision potency and confidence limits indicated by the manufacturers, while the multiple daily injection protocol yielded the same acceptable results within a single assay. Although the latter protocol using flow cytometry for reticulocyte counting gave more precise and reproducible results (intra-assay coefficients of variation: 5.9-14.2%, the well-characterized manual methods provide equally valid alternatives for the quality control of recombinant human erythropoietin therapeutic products.

  7. Hemopoietic cell precursor responses to erythropoietin in plasma clot cultures

    Energy Technology Data Exchange (ETDEWEB)

    Kennedy, W.L.

    1979-01-01

    The time dependence of the response of mouse bone marrow cells to erythropoietin (Ep) in vitro was studied. Experiments include studies on the Ep response of marrow cells from normal, plethoric, or bled mice. Results with normal marrow reveal: (1) Not all erythroid precursors (CFU-E) are alike in their response to Ep. A significant number of the precursors develop to a mature erythroid colony after very short Ep exposures, but they account for only approx. 13% of the total colonies generated when Ep is active for 48 hrs. If Ep is active more than 6 hrs, a second population of erythroid colonies emerges at a nearly constant rate until the end of the culture. Full erythroid colony production requires prolonged exposure to erythropoietin. (2) The longer erythropoietin is actively present, the larger the number of erythroid colonies that reach 17 cells or more. Two distinct populations of immediate erythroid precursors are also present in marrow from plethoric mice. In these mice, total colony numbers are equal to or below those obtained from normal mice. However, the population of fast-responding CFU-E is consistently decreased to 10 to 20% of that found in normal marrow. The remaining colonies are formed from plethoric marrow at a rate equal to normal marrow. With increasing Ep exposures, the number of large colonies produced increases. From the marrow of bled mice, total erythroid colony production is equal to or above that of normal marrow. Two populations of colony-forming cells are again evident, with the fast-responding CFU-E being below normal levels. The lack of colonies from this group was compensated in bled mice by rapid colony production in the second population. A real increase in numbers of precursors present in this pool increased the rate of colony production in culture to twice that of normal marrow. The number of large colonies obtained from bled mice was again increased as the Ep exposure was lengthened. (ERB)

  8. Pharmacokinetics of erythropoietin in intact and anephric dogs

    International Nuclear Information System (INIS)

    Fu, J.S.; Lertora, J.J.; Brookins, J.; Rice, J.C.; Fisher, J.W.

    1988-01-01

    The present studies were performed to determine the pharmacokinetic parameters of erythropoietin in intact and anephric dogs by use of unlabeled crude native erythropoietin (nEp) and iodine 125-labeled purified recombinant erythropoietin (rEp) given by intravenous infusion for 15 minutes. Sephadex G-75 gel filtration was used to confirm that the 125I-rEp molecule remained iodinated in dog plasma during the 24-hour period of these studies. The plasma disappearance of erythropoietin conformed to a biexponential equation for both nEp and 125I-rEp, with the central compartment being larger than the peripheral compartment. The mean distribution half-life of 75.3 +/- 21.2 minutes for nEp was significantly (p less than 0.05) longer than that of 125I-rEp (23.7 +/- 5.0 minutes) in intact dogs. The intercompartmental clearance (CIic) for nEp (0.018 +/- 0.006 L/kg/hr) was significantly smaller than that of 125I-rEp (0.068 +/- 0.018 L/kg/hr) in intact dogs (p less than 0.05). There were no significant differences in apparent volume of distribution, elimination half-life, and elimination clearance (CIe) for nEp and rEp in intact dogs. The mean elimination half-life for 125I-rEp in intact dogs (9.0 +/- 0.6 hours) and anephric dogs (13.8 +/- 1.4 hours) was significantly different (p less than 0.05). The CIe for 125I-rEp in anephric dogs (0.008 +/- 0.001 L/kg/hr) was significantly (p less than 0.05) smaller than that of 125I-rEp in intact dogs (0.011 +/- 0.001 L/kg/hr). There were no significant differences in apparent volume of distribution, distribution half-life, and CIic for 125I-rEp in intact and anephric dogs

  9. Development of a VHH-Based Erythropoietin Quantification Assay

    DEFF Research Database (Denmark)

    Kol, Stefan; Beuchert Kallehauge, Thomas; Adema, Simon

    2015-01-01

    Erythropoietin (EPO) quantification during cell line selection and bioreactor cultivation has traditionally been performed with ELISA or HPLC. As these techniques suffer from several drawbacks, we developed a novel EPO quantification assay. A camelid single-domain antibody fragment directed against...... human EPO was evaluated as a capturing antibody in a label-free biolayer interferometry-based quantification assay. Human recombinant EPO can be specifically detected in Chinese hamster ovary cell supernatants in a sensitive and pH-dependent manner. This method enables rapid and robust quantification...

  10. The effect of erythropoietin on healing of obstructive vs nonobstructive left colonic anastomosis: an experimental study

    Directory of Open Access Journals (Sweden)

    Renda Nurten

    2007-05-01

    Full Text Available Abstract Background Anastomotic leakage is an important problem following primary resection in the left colon and is even more prominent when obstruction is present. We aimed to evaluate the possible effects of erythropoietin on the healing of anastomosis under both obstructive and non-obstructive states. Methods Forty male Wistar albino rats were divided into four groups. In group I, two cm left colonic resection and primary anastomosis were done. In group II, left colon were completely ligated and 24 hours later animals were re-operated for segmental resection. The same procedures were performed for rats in group III and IV in respect to group I and II and, 500 IU/kg a day erythropoietin were given in the latter two groups for seven days. For the quantative description of anastomotic healing mechanical, biochemical and histopathological parameters were employed on the seventh day and the animals were sacrificied. Results Although erythropoietin had positive effects on bursting pressure in group IV when compared to group II, it has no effect in group III. Despite the increased tissue hydroxyproline levels in group IV, erythropoietin failed to show any effects in group III. Erythropoietin had positive effects on neovascularization, fibroblast proliferiation and storage of collagen in group IV. Conclusion We failed to find any direct and evident effects of erythropoietin on healing of left colonic anastomosis. On the other hand, erythropoietin might prevent negative effects of obstruction on healing.

  11. Predominance of granulocytopoiesis in bone marrow grafts in the omenta of mice treated with erythropoietin

    International Nuclear Information System (INIS)

    Meck, R.A.; Laissue, J.A.

    1977-01-01

    The effects of erythropoietin on the differentiation of murine bone marrow injected into the omenta of x-irradiated mice were investigated. Experimental hosts were injected with 2.5 units of erythropoietin on days 0-7 and sacrificed on day 10. Control hosts were injected with saline or sheep serum. After 10 days the grafts were > 95% granulocytic regardless of host treatment. Since these grafts contain multipotent hematopoietic stem cells and the experimental hosts were exposed to large doses of erythropoietin, the results of this experiment indicate that a specialized microenvironment is required for murine erythropoiesis in vivo. (author)

  12. Skeletal muscle alterations and exercise performance decrease in erythropoietin-deficient mice: a comparative study

    Directory of Open Access Journals (Sweden)

    Mille-Hamard Laurence

    2012-06-01

    Full Text Available Abstract Background Erythropoietin (EPO is known to improve exercise performance by increasing oxygen blood transport and thus inducing a higher maximum oxygen uptake (VO2max. Furthermore, treatment with (or overexpression of EPO induces protective effects in several tissues, including the myocardium. However, it is not known whether EPO exerts this protective effect when present at physiological levels. Given that EPO receptors have been identified in skeletal muscle, we hypothesized that EPO may have a direct, protective effect on this tissue. Thus, the objectives of the present study were to confirm a decrease in exercise performance and highlight muscle transcriptome alterations in a murine EPO functional knock-out model (the EPO-d mouse. Methods We determined VO2max peak velocity and critical speed in exhaustive runs in 17 mice (9 EPO-d animals and 8 inbred controls, using treadmill enclosed in a metabolic chamber. Mice were sacrificed 24h after a last exhaustive treadmill exercise at critical speed. The tibialis anterior and soleus muscles were removed and total RNA was extracted for microarray gene expression analysis. Results The EPO-d mice’s hematocrit was about 50% lower than that of controls (p  1.4 and 115 were strongly down-regulated (normalized ratio  Conclusions Our results showed that the lack of functional EPO induced a decrease in the aerobic exercise capacity. This decrease was correlated with the hematocrit and reflecting poor oxygen supply to the muscles. The observed alterations in the muscle transcriptome suggest that physiological concentrations of EPO exert both direct and indirect muscle-protecting effects during exercise. However, the signaling pathway involved in these protective effects remains to be described in detail.

  13. The use of /sup 125/I recombinant DNA/sub 125/ derived human erythropoietin (R-HuEPO) as a replacement for /sup 125/I human urinary epo as tracer antigen in a radioimmunoassay for human epo

    International Nuclear Information System (INIS)

    Cotes, P.M.; Tam, R.C.; GainesDas, R.E.

    1987-01-01

    This paper represents evidence that in a radioimmunoassay for human erythropoietin, recombinant DNA derived human erythropoietin can replace highly purified human urinary erythropoietin in the preparation of radioiodinated tracer antigen

  14. [Correction of anemia in hemodialysis, effect of intravenous iron without erythropoietin].

    Science.gov (United States)

    Alvo, Miriam; Elgueta, Leticia; Aragón, Henry; Cotera, Alejandro

    2002-08-01

    In the last two decades, the use of erythropoietin for the correction of anemia in hemodialysis patients has been recommended. In Chile, only 10% of hemodialysis patients use erythropoietin, therefore, the correction of iron deficiency must be optimized. To report the effects of intravenous iron without erythropoietin in the management of anemia in hemodialysis patients. Retrospective analysis of 42 patients that received intravenous ferrous sacharate in doses of 100 mg/week during 5 weeks and 100 mg bimonthly during six months. These patients did not receive erythropoietin. Thirty six patients had iron deficiency. Basal ferritin was 137 +/- 22 micrograms/l and increased to 321 +/- 28 micrograms/l after treatment. Packed red cell volume increased from 24 +/- 2% to 29 +/- 3%. No adverse effects were reported. Iron deficiency is frequent in hemodialyzed patients. Intraveineous iron is safe and effective in the treatment of iron deficiency in these patients.

  15. Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial.

    LENUS (Irish Health Repository)

    Nichol, Alistair

    2015-02-08

    Traumatic brain injury is a leading cause of death and disability worldwide. Laboratory and clinical studies demonstrate a possible beneficial effect of erythropoietin in improving outcomes in the traumatic brain injury cohort. However, there are concerns regarding the association of erythropoietin and thrombosis in the critically ill. A large-scale, multi-centre, blinded, parallel-group, placebo-controlled, randomised trial is currently underway to address this hypothesis.

  16. High-dose phenobarbital or erythropoietin for the treatment of perinatal asphyxia in term newborns.

    Science.gov (United States)

    Avasiloaiei, Andreea; Dimitriu, Cristina; Moscalu, Mihaela; Paduraru, Luminita; Stamatin, Maria

    2013-10-01

    The aim of this study was to compare two neuroprotective strategies to supportive care in the treatment of perinatal asphyxia. A total of 67 term newborns with perinatal asphyxia were included and randomized into three groups: one group received supportive treatment; another group received a single dose of 40 mg/kg phenobarbital; and the third received three daily doses of 1000 IU/kg erythropoietin. The following parameters were analyzed: gestational age, birthweight, Apgar scores, cord blood pH, total serum antioxidant status (TAS), superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). The newborns were included in the follow-up program and examined up to 18 months of age. TAS was higher in the erythropoietin group than in the other groups. SOD and GPx were lower for infants treated with phenobarbital or erythropoietin compared to control infants. MDA was lower in the erythropoietin group compared to the other groups, although the difference was not statistically significant (P > 0.05). The mortality rate was lower in the phenobarbital and erythropoietin groups (both 4.6%) than in the control group (17.4%). Long-term neurologic follow up showed a high incidence of sequelae in the control group compared to the phenobarbital and erythropoietin groups. Follow-up results were better in the phenobarbital group than in the erythropoietin group for motor and cognitive function at 3 and 6 months and worse for expressive language. At 18 months, however, the differences between these two groups were not significant. High-dose phenobarbital or erythropoietin along with supportive treatment has a positive influence on the outcome of newborns with perinatal asphyxia. Phenobarbital has the advantage of low cost and simplicity. © 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.

  17. Discrete β-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia.

    Science.gov (United States)

    Hasan, Shirin; Mosier, Michael J; Szilagyi, Andrea; Gamelli, Richard L; Muthumalaiappan, Kuzhali

    2017-10-01

    Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin-independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by β1/β2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin-independent late maturation stages and the effect of β1/β2, β-2, or β-3 blockade in burn mediated erythropoietin-resistant anemia. Burn mice were randomized to receive daily injections of propranolol (nonselective β1/β2 antagonist), nadolol (long-acting β1/β2 antagonist), butoxamine (selective β2 antagonist), or SR59230A (selective β3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Ter119, and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells. Although propranolol improved early and late erythroblasts, only butoxamine and selective β3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, β1/β2 antagonism increased the early erythroblasts through commitment stages via β2 specific MafB regulation. β3 antagonism was more effective in improving overall red blood cells through late maturation stages. The study unfolds novel β2 and β3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively. Copyright © 2017

  18. Erythropoietin Action in Stress Response, Tissue Maintenance and Metabolism

    Directory of Open Access Journals (Sweden)

    Yuanyuan Zhang

    2014-06-01

    Full Text Available Erythropoietin (EPO regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR, suggest the potential for EPO response in metabolism and disease.

  19. High-dose erythropoietin in patients with progressive multiple sclerosis

    DEFF Research Database (Denmark)

    Schreiber, Karen; Magyari, Melinda; Sellebjerg, Finn

    2017-01-01

    BACKGROUND: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). OBJECTIVE: To evaluate a treatment effect of EPO on progressive MS. METHODS: This was a single-center, randomized......, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6......: This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS....

  20. Is erythropoietin gene a modifier factor in amyotrophic lateral sclerosis?

    Science.gov (United States)

    Ghezzi, Serena; Del Bo, Roberto; Scarlato, Marina; Nardini, Martina; Carlesi, Cecilia; Prelle, Alessandro; Corti, Stefania; Mancuso, Michelangelo; Briani, Chiara; Siciliano, Gabriele; Murri, Luigi; Bresolin, Nereo; Comi, Giacomo Pietro

    2009-05-01

    To investigate the role of erythropoietin (EPO) as genetic determinant in the susceptibility to sporadic amyotrophic lateral sclerosis (SALS). We sequenced a 259-bp region spanning the 3'hypoxia-responsive element of the EPO gene in 222 Italian SALS patients and 204 healthy subjects, matched for age and ethnic origin. No potentially causative variation was detected in SALS subjects; in addition, two polymorphic variants (namely C3434T and G3544T) showed the same genotype and haplotype frequencies in patients and controls. Conversely, a weak but significant association between G3544T and age of disease onset was observed (p=0.04). Overall, our data argue against the hypothesis of EPO as a genetic risk factor for motor neuron dysfunction, at least in Italian population. However, further studies on larger cohort of patients are needed to confirm the evidence of EPO gene as modifier factor.

  1. Effect of erythropoietin on acoustically traumatized rat cochlea: an immunohistochemical study.

    Science.gov (United States)

    Gürgen, Oğuzhan; Gürgen, Seren Gülşen; Kirkim, Günay; Kolatan, Efsun; Gürkan, Selhan; Güvenç, Yeşim; Eskiizmir, Görkem

    2014-08-01

    To investigate the audiological and histopathological effects of erythropoietin on acoustic overstimulation in rats. Twenty-two male Wistar albino rats were divided into 3 groups: sham group (n = 7), erythropoietin injection group (n = 8), and saline injection group (n = 7). Both erythropoietin and saline injection groups were exposed to white noise (100 decibel [dB] sound pressure level [SPL]) for 3 hours. Auditory brainstem responses were measured before, immediately after, and on the 7th day of noise exposure. All animals were sacrificed on the 7th day and temporal bones were collected. The serial sections of the cochleae were stained by caspase-3 and caspase-9 immunostaining and by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method in order to detect apoptotic cells. In the saline group statistically significant differences were detected between the baseline and immediate postacoustic overstimulation thresholds of click and 6 kHz stimuli. However, when the baseline and immediate postacoustic overstimulation thresholds of click and 6 kHz stimuli were compared in the erythropoietin injection group, no statistically significant difference was determined. Histopathologic evaluations demonstrated that erythropoietin decreased the amount of apoptotic cells in the cochlea. Erythropoietin is likely to prevent the acute threshold changes and decrease the amount of apoptosis in cochlea after acoustic overstimulation in rats.

  2. Blood leptin levels and erythropoietin requirement in Iranian hemodialysis patients

    Directory of Open Access Journals (Sweden)

    Rahimi A

    2008-12-01

    Full Text Available "nBackground: Anemia is a common complication accompanied by high morbidity and mortality in hemodialysis patients. Considering the fact that the reduction of erythropoietin (EPO synthesis is the main cause of uremic anemia, receiving recombinant human erythropoietin (rHuEPO can improve the condition in these patients. Some of these hemodialysis patients, however, have acceptable hemoglobin levels without any need to EPO. Higher BMI, higher albumin and leptin plasma levels and longer durations of hemodialysis are possible factors contributing to the reduced need for rHuEPO in these patients. The present study is designed to asses the relationship between the plasma levels of leptin and the reduced EPO need. "nMethods: Fifty eligible hemodialysis patients with hemoglobin levels higher than 11 mg/dl were enrolled in the cross-sectional study. The information on age, sex, hemodialysis duration and the cause of renal dysfunction were extracted from the files. The baseline plasma levels of Leptin and albumin were measured. The patients BMI and the weekly need for rHuEPO were also calculated. "nResults: There was no correlation between the weekly need for rHuEPO and sex, BMI, the cause of renal dysfunction and the plasma levels of albumin and leptin; it, however, was related with age and the duration of dialysis. While age negatively influences the weekly need, the duration of dialysis has a positive effect on the need. "nConclusion: The plasma levels of leptin are not directly correlated with the required amounts of rHuEPO, indicating that leptin is not an effective factor in erythropoiesis. Conversely, older age and shorter hemodialysis durations are accompanied by reduced need for rHuEPO.

  3. Recombinant erythropoietin and analogues: a challenge for doping control.

    Science.gov (United States)

    Pascual, J A; Belalcazar, V; de Bolos, C; Gutiérrez, R; Llop, E; Segura, J

    2004-04-01

    Erythropoietin (EPO) increases the number of circulating erythrocytes and thus muscle oxygenation. The availability of the recombinant protein (rEPO) has increased the risk of its illegal use in sports, its detection being a difficult challenge. Five different hematopoietic parameters were initially chosen as indirect markers of rEPO abuse: concentration of serum EPO, concentration of serum-soluble transferrin receptors (sTFr), hematocrit, percentage of reticulocytes, and percentage of macrocytes. New models considering only hemoglobin, serum EPO concentration, and percentage of reticulocytes are simpler and seem to be more sensitive when low doses of rEPO are used. A more direct method of urine analysis (isoelectrofocusing, double blotting, and chemiluminescent detection) based on the charge differences between rEPO and endogenous EPO, related to their carbohydrate composition, provides proof of rEPO use. Furthermore, this approach permits the detection of darbepoetin, a direct analogue of EPO also known as NESP ("new erythropoiesis stimulating protein"). Recently a protein conjugate, "synthetic erythropoiesis protein" (SEP), containing precision-length, monodisperse, negatively charged polymers instead of oligosaccharides has been synthesized. Finally, EPO-mimetics are molecules capable of acting as EPO in dimerizing the EPO receptor. Two kinds of EPO-mimetics have been described: peptides and nonpeptides. The enhancement of oxygen availability to muscles by rEPO, analogues, and mimetics constitutes one of the main challenges to doping control. Major steps have already been developed for detection ofrEPO and some analogues. In the near future, the transfection to an athlete's body of genes that code for erythropoietin might be an emerging doping issue, and sports authorities have incorporated "gene doping" among the prohibited practices.

  4. Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin.

    Science.gov (United States)

    Ohls, Robin K; Cannon, Daniel C; Phillips, John; Caprihan, Arvind; Patel, Shrena; Winter, Sarah; Steffen, Michael; Yeo, Ronald A; Campbell, Richard; Wiedmeier, Susan; Baker, Shawna; Gonzales, Sean; Lowe, Jean

    2016-03-01

    We previously reported improved neurodevelopmental outcomes at 2 years among infants treated with the erythropoiesis-stimulating agents (ESAs) darbepoetin alfa (darbepoetin) or erythropoietin. Here we characterize 4-year outcomes. Former preterm infants randomly assigned to receive darbepoetin (10 μg/kg, once per week), erythropoietin (400 U/kg, 3 times/week), or placebo through 35 weeks' postconceptual age were evaluated at 3.5 to 4 years of age. For comparison, healthy children formerly delivered full term (term controls [TCs]) were also recruited. All participants were assessed by using measures of full-scale IQ (FSIQ) and general language from the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, and an overall measure of executive function, on the basis of tests evaluating inhibitory control and spatial working memory. Rates of neurodevelopmental impairment were compared across groups. Multivariate analysis of variance compared children randomly assigned to ESAs (n = 39), placebo (n =14), and TCs (n = 24). FSIQ and performance IQ were significantly higher in the ESA group than in the placebo group (FSIQ: 91.1 ± 17.5 vs 79.2 ± 18.5, P = .036; performance IQ: 93.0 ± 17.0 vs 79.5 ± 19.5, P = .018). Follow-up analyses revealed that the children receiving ESAs performed better than those who received placebo on executive function tasks. The ESA group's performance was below that of TCs, but the results did not reach significance on executive function. The incidence of neurodevelopmental impairment was greater in the placebo group than in the ESA group. ESA-treated infants had better cognitive outcomes and less developmental impairment at 3.5 to 4 years of age compared with placebo-treated infants. ESAs show promise in improving long-term cognitive outcomes of infants born prematurely. Copyright © 2016 by the American Academy of Pediatrics.

  5. CLINICAL APPLICATION OF RECOMBINANT ERYTHROPOIETIN IN BETA-THALASSAEMIA INTERMEDIA.

    Science.gov (United States)

    Asadov, Ch; Alimirzoyeva, Z; Hasanova, M; Mammadova, T; Shirinova, A

    2016-06-01

    Research objective is to study the efficacy of recombinant erythropoietin (epoetin alfa) as alternative method of treatment beta-thalassemia intermedia. Study involved 58 patients with beta-thalassemia intermedia (23 women and 35 men). In all observed patients was defined levels of hemoglobin (Hb), red blood cells (RBC), erythrocyte indexes (MCV, MCH, MCHC), hemoglobin fractions (HbA, HbA2, HbF), serum ferritin, serum erythropoietin before and after administrated rEPO. All patients received rEPO during 6 month at the dose - 10000 IU subcutaneously. The majority of patients - 39 (67%) had a good response to rEPO (increase in hemoglobin level more than 20 g/l); 16 patients (28%) had a mean response (increase in Hb 10 - 20 g/l); in 3 (5%) patients occurred poor response to rEPO therapy (increase in Hb intermedia patients there was a statistically significant change in the number of RBC, levels of HbF and sEPO. The evaluation of interdependence between the indices of the baseline sEPO and increased Hb values in patients after rEPO treatment revealed the presence of the reverse direct relationship (r=-0.67). Based on the results, it can be concluded that the use of rEPO in complex therapy of beta-thalassemia intermedia leads to increased levels of Hb and consequently reducing the need for blood transfusions, and accordingly expected to prevent severe complications of blood transfusion (alloimmunization, hypersplenism, iron overload, contamination transmissible infections) facilitating normal growth and development, and a better quality of life.

  6. Erythropoietin Attenuates the Memory Deficits in Aging Rats by Rescuing the Oxidative Stress and Inflammation and Promoting BDNF Releasing.

    Science.gov (United States)

    Jia, Zhankui; Xue, Rui; Ma, Shengli; Xu, Jingjing; Guo, Si; Li, Songchao; Zhang, Erwei; Wang, Jun; Yang, Jinjian

    2016-10-01

    Aging is a natural process accompanied with many disorders, including the memory decline. The underlying mechanisms for the age-related memory decline are complicated. Previous work suggested that oxidative stress, inflammatory disturbance, and the neurotropic absence play important roles in the age-related disorders. Thus, to seek a drug to target those abnormalities might be a possible protective approach for aging. Here, we reported that supplements with exogenous erythropoietin (EPO) for 4 weeks could partially rescue the spatial and fear memory impairments in aged rats. The EPO treatment also suppresses the oxidative stress and inflammatory response. Most importantly, EPO supplement restores the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), the critical neurotropic factor for synaptic plasticity and memory. Our study strongly suggests the potential usage of EPO in an anti-aging agent clinically.

  7. PRAS40 is an integral regulatory component of erythropoietin mTOR signaling and cytoprotection.

    Directory of Open Access Journals (Sweden)

    Zhao Zhong Chong

    Full Text Available Emerging strategies that center upon the mammalian target of rapamycin (mTOR signaling for neurodegenerative disorders may bring effective treatment for a number of difficult disease entities. Here we show that erythropoietin (EPO, a novel agent for nervous system disorders, prevents apoptotic SH-SY5Y cell injury in an oxidative stress model of oxygen-glucose deprivation through phosphatidylinositol-3-kinase (PI 3-K/protein kinase B (Akt dependent activation of mTOR signaling and phosphorylation of the downstream pathways of p70 ribosomal S6 kinase (p70S6K, eukaryotic initiation factor 4E-binding protein 1 (4EBP1, and proline rich Akt substrate 40 kDa (PRAS40. PRAS40 is an important regulatory component either alone or in conjunction with EPO signal transduction that can determine cell survival through apoptotic caspase 3 activation. EPO and the PI 3-K/Akt pathways control cell survival and mTOR activity through the inhibitory post-translational phosphorylation of PRAS40 that leads to subcellular binding of PRAS40 to the cytoplasmic docking protein 14-3-3. However, modulation and phosphorylation of PRAS40 is independent of other protective pathways of EPO that involve extracellular signal related kinase (ERK 1/2 and signal transducer and activator of transcription (STAT5. Our studies highlight EPO and PRAS40 signaling in the mTOR pathway as potential therapeutic strategies for development against degenerative disorders that lead to cell demise.

  8. Tratamiento con eritropoyetina humana recombinante Human recombinant erythropoietin therapy

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    Hugo Donato

    2006-02-01

    Full Text Available La eritropoyetina recombinante (rHuEPO se ha transformado en la citoquina más utilizada terapéuticamente en el mundo. Luego del éxito obtenido en pacientes con insuficiencia renal terminal, se pudo establecer la utilidad de la terapia con rHuEPO para mejorar otras anemias, incluso en pacientes pediátricos y neonatos. El tratamiento o la prevención de la anemia del prematuro mediante el uso de rHuEPO llevó a una significativa reducción en cantidad de transfusiones y en exposición a dadores. Aún debe establecerse una clara definición sobre cuáles niños prematuros deben recibir tratamiento rutinariamente. Otras indicaciones en período neonatal incluyen anemias hiporregenerativas y hemolíticas. La eficacia de la rHuEPO en niños mayores, con excepción de la insuficiencia renal crónica, no ha sido tan exhaustivamente evaluada como en adultos. Mientras que durante los últimos años se han realizado gran cantidad de estudios en adultos con anemia asociada al cáncer o a infección por HIV, permitiendo establecer conclusiones claras sobre su eficacia, sólo escasa cantidad de estudios con pequeño número de pacientes han sido realizados en niños. Hasta la fecha, los resultados sugieren que la terapia con rHuEPO en niños es tan útil como en adultos, pero la realización de estudios aleatorizados prospectivos incluyendo gran número de pacientes es esencial para alcanzar conclusiones definitivas. Los resultados de estudios dirigidos a evaluar la eficacia de la rHuEpo para mantener una dosis adecuada de ribavirina en pacientes en tratamiento por hepatitis C son alentadores. La utilización potencial de los efectos no hemopoyéticos de la rHuEPO en neonatos es un terreno novedoso y apasionante. El rol de la Epo como citoprotector para sistema nervioso central y mucosa intestinal está bajo investigación exhaustiva.Recombinant human erythropoietin (rHuEpo has become the most widely used cytokine in the world. Following the success of

  9. Recovery of the Erythropoietin-Sensitive Stem-Cell Population following Total-Body X-Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Byron, J. W. [Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (United Kingdom)

    1968-08-15

    Erythropoietin acts upon haemopoietic stem cells to initiate their differentiation into the erythroid series. This effect may be used in polycythaemic mice to estimate changes in the erythropoietin-sensitive stem-cell population following total-body irradiation (TBR). Generally, single doses of erythropoietin, less than that needed for maximum stem-cell response, are used to estimate changes in the stem-cell population. The validity of results using this test is based upon accepting several assumptions regarding erythropoietin kinetics. These are: (a) the contribution of endogenous erythropoietin is always negligible; (b) the origin of the dose-response curve to erythropoietin alters only because of changes in stem-cell numbers; (c) the proportion of stem cells responding to a given concentration of erythropoietin is independent of stem-cell numbers; (d) the slope of the dose-response curve does not alter; and (e) competition between erythropoietin and other factors for the stem cells remains unchanged. The studies to be reported indicate that some of these assumptions m a y not always be valid. Following 150 rad TBR, changes in erythropoietin dose-response curves were not always due to changes in the size of the stem-cell population, but also due to changes in erythropoietin kinetics. Changes in erythropoietin kinetics could be corrected for by using doses of erythropoietin which at any particular time after TBR gave maximum stem-cell response; through full dose-response studies, the nature of changes in erythropoietin kinetics following TBR could be established. These studies appear to explain discrepancies in results obtained in different laboratories using the erythropoietin test. The effect of 150 rad TBR on the erythropoietin-sensitive stem-cell population is an initial depression within 30 min to 20% of normal followed by a second depression (post-irradiation dip) at about 12 h. Twenty-four hours after TBR there is a recovery to the initial depression. This

  10. Erythropoietin during hypoglycaemia in type 1 diabetes: relation to basal renin-angiotensin system activity and cognitive function

    DEFF Research Database (Denmark)

    Kristensen, Peter Lommer; Høi-Hansen, Thomas; Olsen, Niels Vidiendal

    2009-01-01

    diabetes with high and nine with low activity in RAS were studied. Hypoglycaemia was induced using a standardized insulin-infusion. RESULTS: Overall, erythropoietin concentrations increased during hypoglycaemia. In the high RAS group erythropoietin rose 29% (p=0.032) whereas no significant response...... was observed in the low RAS group (7% increment; p=0.43). Independently, both hypoglycaemia and high RAS activity were associated with higher levels of erythropoietin (p=0.02 and 0.04, respectively). Low plasma erythropoietin at baseline was associated with poorer cognitive performance during hypoglycaemia...

  11. Erythropoietin and a nonerythropoietic peptide analog promote aortic endothelial cell repair under hypoxic conditions: role of nitric oxide

    Directory of Open Access Journals (Sweden)

    Heikal L

    2016-08-01

    Full Text Available Lamia Heikal,1 Pietro Ghezzi,1 Manuela Mengozzi,1 Blanka Stelmaszczuk,2 Martin Feelisch,2 Gordon AA Ferns1 1Brighton and Sussex Medical School, Falmer, Brighton, 2Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton, UK Abstract: The cytoprotective effects of erythropoietin (EPO and an EPO-related nonerythropoietic analog, pyroglutamate helix B surface peptide (pHBSP, were investigated in an in vitro model of bovine aortic endothelial cell injury under normoxic (21% O2 and hypoxic (1% O2 conditions. The potential molecular mechanisms of these effects were also explored. Using a model of endothelial injury (the scratch assay, we found that, under hypoxic conditions, EPO and pHBSP enhanced scratch closure by promoting cell migration and proliferation, but did not show any effect under normoxic conditions. Furthermore, EPO protected bovine aortic endothelial cells from staurosporine-induced apoptosis under hypoxic conditions. The priming effect of hypoxia was associated with stabilization of hypoxia inducible factor-1α, EPO receptor upregulation, and decreased Ser-1177 phosphorylation of endothelial nitric oxide synthase (NOS; the effect of hypoxia on the latter was rescued by EPO. Hypoxia was associated with a reduction in nitric oxide (NO production as assessed by its oxidation products, nitrite and nitrate, consistent with the oxygen requirement for endogenous production of NO by endothelial NOS. However, while EPO did not affect NO formation in normoxia, it markedly increased NO production, in a manner sensitive to NOS inhibition, under hypoxic conditions. These data are consistent with the notion that the tissue-protective actions of EPO-related cytokines in pathophysiological settings associated with poor oxygenation are mediated by NO. These findings may be particularly relevant to atherogenesis and postangioplasty restenosis. Keywords

  12. Neuroprotective effect of erythropoietin against pressure ulcer in a mouse model of small fiber neuropathy.

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    Aurore Danigo

    Full Text Available An increased risk of skin pressure ulcers (PUs is common in patients with sensory neuropathies, including those caused by diabetes mellitus. Recombinant human erythropoietin (rhEPO has been shown to protect the skin against PUs developed in animal models of long-term diabetes. The aim of this work was to determine whether rhEPO could prevent PU formation in a mouse model of drug-induced SFN. Functional SFN was induced by systemic injection of resiniferatoxin (RTX, 50 µg/kg, i.p.. RhEPO (3000 UI/kg, i.p. was given the day before RTX injection and then every other day. Seven days after RTX administration, PUs were induced by applying two magnetic plates on the dorsal skin. RTX-treated mice expressed thermal and mechanical hypoalgesia and showed calcitonin gene-related peptide (CGRP and substance P (SP depletion without nerve degeneration or vascular dysfunction. RTX mice developed significantly larger stage 2 PUs than Vehicle mice. RhEPO prevented thermal and mechanical hypoalgesia and neuropeptide depletion in small nerve fibers. RhEPO increased hematocrit and altered endothelium-dependent vasodilatation without any effect on PU formation in Vehicle mice. The characteristics of PUs in RTX mice treated with rhEPO and Vehicle mice were found similar. In conclusion, RTX appeared to increased PU development through depletion of CGRP and SP in small nerve fibers, whereas systemic rhEPO treatment had beneficial effect on peptidergic nerve fibers and restored skin protective capacities against ischemic pressure. Our findings support the evaluation of rhEPO and/or its non-hematopoietic analogs in preventing to prevent PUs in patients with SFN.

  13. "Erythropoietin Utilization Evaluation And Two Brand Products Comparison, Eprex and Eposim "

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    H. Khalili

    2006-06-01

    Full Text Available Background and Aim: Anemia is one of the common problems in patients with chronic renal impairment. The most common cause of anemia in this patients is a decreased in erythropoietin hormone excretion, however other common cause include low life of red blood cells, loss of blood during dialysis, frequent blood sampling, uremia, iron, vitamin B12 and folic acid deficiency. Until introduction of erythropoietin in 1982, blood transfusion was an alternative for correction and maintaining hematocrit in normal range in dialyze patients. In current date, any dialyzed patient take rh-erythropoietin . Materials and Methods: The goal of this study is to evaluate erythropoietin utilization and comparing the effectiveness of the commercial product in the Iranian drugs market. The study was performed at nephrology and dialyze ward of Immam Khomeini hospital in a one year period. Results and Conclusion: Of the 30 patients' subject of study, 13 patients received eprex and 17 received epocim. Average dose of erythropoietin 2000IU was three times per week. The average plasma hemoglobin and hematocrit of patients prior to the treatment were 9.38 g/dl and 28% respectively. Increase in the hemoglobin and hematocrit in the group who received eprex was significantly higher than epocim group (p=0.001 and p=0.026 respectively. The incidents of side effects including hypertension, headache, pain at injection site, and influenza-like in eposim group were considerably higher than eprex.

  14. Increased preoperative collection of autologous blood with recombinant human erythropoietin therapy in tertiary care hospitals of Jammu

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    Kumkum Sharma

    2013-01-01

    Full Text Available Introduction: To study whether the administration of recombinant human erythropoietin increases the amount of autologous blood that can be collected before orthopaedic surgery. Materials and Methods: We conducted a randomized controlled trial of recombinant human erythropoietin in 68 adults scheduled for elective orthopedic procedures. The patients received either erythropoietin 600 units/kg of body weight or placebo intravenously every 5 th day prior to each phlebotomy for 21 days during which time up to 5 units of blood was collected. Patients were excluded from donation when their hematocrit values were less than 33%. All patients received iron sulphate 325mg orally 3 times daily. The mean number of units collected per patient was 4.33 ± 0.4 for erythropoietin group and 3.05± 0.71 for the placebo group. Results: The mean packed red cell volume donated by patients who received erythropoietin was 32% greater than that donated by patients who received placebo (196.3 vs. 169.4 ml, p<0.05. 68% in the placebo group and 9% of patients treated with erythropoietin were unable to donate ≥4 units. No adverse effects were attributed to erythropoietin. While participating in the study, complications developed in 2 patients one in each group necessitating their removal from the study. Conclusion: We conclude that recombinant human erythropoietin increases the ability of the patients about to undergo elective surgery to donate autologous blood units.

  15. Clinical applications of measurement of serum immunoreactive levels of erythropoietin

    International Nuclear Information System (INIS)

    Miller, M.E.; Chandra, M.; Garcia, J.F.

    1985-01-01

    The purification of erythropoietin (Ep) in 1977 enabled investigators to more clearly define the role of this hormone in erythropoiesis in man. Radioimmunoassays were rapidly developed. Undoubtedly differences between levels of immunoreactive and biologically active Ep will be found but the resolution of these discrepancies will expand our understanding of the erythron. Recently others described a monoclonal antibody against Ep. Because of this breakthrough, large quantities of pure hormone should soon be available to a larger number of investigators than currently have access to it. The major clinical use of this hormone will probably be in the treatment of the anemia of chronic renal disease. In the relatively few years since the radioimmunoassay (RIA) was developed, measurements of the levels of this hormone have been made in several disease states as well as in normal man. Most of the findings to date confirm the predictions that have been made over the years based on studies done using the rather crude bioassay for Ep. In the present study the authors shall review and expand on what is known about subjects with chronic lung and renal disease

  16. Antioxidants may Attenuate Plasma Erythropoietin Decline after Hyperbaric Oxygen Diving.

    Science.gov (United States)

    Mutzbauer, T S; Schneider, M; Neubauer, B; Weiss, M; Tetzlaff, K

    2015-11-01

    According to previous studies, plasma erythropoietin (EPO) may decrease after hyperbaric oxygen exposure due to oxidative stress. It is hypothesized that the decrease of EPO can be attenuated by oxygen free radical scavengers.The aim of the present study was to evaluate whether EPO plasma levels can be influenced by oral application of vitamin C and E before repeated hyperbaric oxygen exposure during diving. 16 healthy male police task force divers performed 3 morning dives on oxygen within a regular diving schedule on 3 consecutive days. They were randomized into either the placebo group or the vitamin group, receiving 1 g ascorbic acid and 600 IU D-α-tocopherol orally 60 min before the dive. Blood samples for EPO measurement were taken on days 1, 2, and 3 at T1, T3 and T5 60 min before and at T2, T4 and T6 60 min after each dive, respectively. A moderate decrease of EPO was observed beginning at T3 until T6 in the placebo group. The EPO concentrations in the vitamin group did not show relevant variations compared to baseline. Radical scavenging vitamins C and D may counteract hyperbaric oxygen related mechanisms reducing EPO production in hyperbaric oxygen exposure during diving. © Georg Thieme Verlag KG Stuttgart · New York.

  17. Stability of erythropoietin repackaging in polypropylene syringes for clinical use

    Directory of Open Access Journals (Sweden)

    Angela Marsili

    2017-02-01

    Full Text Available Introduction: Epoetin alfa (Eprex® is a subcutaneous, injectable formulation of short half-life recombinant human erythropoietin (rHuEPO. To current knowledge there are no published studies regarding the stability of rHuEPO once repackaging occurs (r-EPO for clinical trial purposes. Materials and methods: We assessed EPO concentration in Eprex® and r-EPO syringes at 0, 60, 90, and 120 days after repackaging in polypropylene syringes. R-EPO was administered to 56 patients taking part in a clinical trial in Friedreich Ataxia. Serum EPO levels were measured at baseline and 48 h after r-EPO administration. Results: No differences were found between r-EPO and Eprex® syringes, but both globally decreased in total EPO content during storage at 4 °C. Patients receiving r-EPO had similar levels in EPO content as expected from previous trials in Friedreich Ataxia and from pharmacokinetics studies in healthy volunteers. Discussion: We demonstrate that repackaging of EPO does not alter its concentration if compared to the original product (Eprex®. This is true both for repackaging procedures and for the stability in polypropylene tubes. The expiration date of r-EPO can be extended from 1 to 4 months after repackaging, in accordance with pharmacopeia rules.

  18. Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

    Energy Technology Data Exchange (ETDEWEB)

    Feder, D.; Rugollini, M.; Santomauro, A. Jr; Oliveira, L.P.; Lioi, V.P. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Santos, R. dos; Ferreira, L.G.; Nunes, M.T.; Carvalho, M.H. [Universidade de São Paulo, Instituto de Ciências Biomédicas, São Paulo, SP (Brazil); Delgado, P.O.; Carvalho, A.A.S. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Fonseca, F.L.A. [Faculdade de Medicina do ABC, Santo André, SP (Brazil); Universidade Federal de São Paulo, Ambientais e Farmacêuticas, Instituto de Ciências Químicas, Diadema, SP (Brazil)

    2014-09-05

    Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16) and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle.

  19. Erythropoietin enhances hippocampal long-term potentiation and memory

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    El-Kordi Ahmed

    2008-09-01

    Full Text Available Abstract Background Erythropoietin (EPO improves cognition of human subjects in the clinical setting by as yet unknown mechanisms. We developed a mouse model of robust cognitive improvement by EPO to obtain the first clues of how EPO influences cognition, and how it may act on hippocampal neurons to modulate plasticity. Results We show here that a 3-week treatment of young mice with EPO enhances long-term potentiation (LTP, a cellular correlate of learning processes in the CA1 region of the hippocampus. This treatment concomitantly alters short-term synaptic plasticity and synaptic transmission, shifting the balance of excitatory and inhibitory activity. These effects are accompanied by an improvement of hippocampus dependent memory, persisting for 3 weeks after termination of EPO injections, and are independent of changes in hematocrit. Networks of EPO-treated primary hippocampal neurons develop lower overall spiking activity but enhanced bursting in discrete neuronal assemblies. At the level of developing single neurons, EPO treatment reduces the typical increase in excitatory synaptic transmission without changing the number of synaptic boutons, consistent with prolonged functional silencing of synapses. Conclusion We conclude that EPO improves hippocampus dependent memory by modulating plasticity, synaptic connectivity and activity of memory-related neuronal networks. These mechanisms of action of EPO have to be further exploited for treating neuropsychiatric diseases.

  20. Diurnal variations of serum erythropoietin at sea level and altitude

    DEFF Research Database (Denmark)

    Klausen, T; Poulsen, T D; Fogh-Andersen, N

    1996-01-01

    in 2, 3 diphosphoglycerate. After 64 h at altitude, six of the nine subjects had down-regulated their serum-EPO concentrations so that median values were three times above those at sea level. These six subjects had significant diurnal variations of serum-EPO concentration at sea level; the nadir......This study tested the hypothesis that the diurnal variations of serum-erythropoietin concentration (serum-EPO) observed in normoxia also exist in hypoxia. The study also attempted to investigate the regulation of EPO production during sustained hypoxia. Nine subjects were investigated at sea level...... and during 4 days at an altitude of 4350 m. Median sea level serum-EPO concentration was 6 (range 6-13) U.l-1. Serum-EPO concentration increased after 18 and 42 h at altitude, [58 (range 39-240) and 54 (range 36-340) U.l-1, respectively], and then decreased after 64 and 88 h at altitude [34 (range 18...

  1. Erythropoietin reduces the expression of myostatin in mdx dystrophic mice

    International Nuclear Information System (INIS)

    Feder, D.; Rugollini, M.; Santomauro, A. Jr; Oliveira, L.P.; Lioi, V.P.; Santos, R. dos; Ferreira, L.G.; Nunes, M.T.; Carvalho, M.H.; Delgado, P.O.; Carvalho, A.A.S.; Fonseca, F.L.A.

    2014-01-01

    Erythropoietin (EPO) has been well characterized as a renal glycoprotein hormone regulating red blood cell production by inhibiting apoptosis of erythrocyte progenitors in hematopoietic tissues. EPO exerts regulatory effects in cardiac and skeletal muscles. Duchenne muscular dystrophy is a lethal degenerative disorder of skeletal and cardiac muscle. In this study, we tested the possible therapeutic beneficial effect of recombinant EPO (rhEPO) in dystrophic muscles in mdx mice. Total strength was measured using a force transducer coupled to a computer. Gene expression for myostatin, transforming growth factor-β1 (TGF-β1), and tumor necrosis factor-α (TNF-α) was determined by quantitative real time polymerase chain reaction. Myostatin expression was significantly decreased in quadriceps from mdx mice treated with rhEPO (rhEPO=0.60±0.11, control=1.07±0.11). On the other hand, rhEPO had no significant effect on the expression of TGF-β1 (rhEPO=0.95±0.14, control=1.05±0.16) and TNF-α (rhEPO=0.73±0.20, control=1.01±0.09). These results may help to clarify some of the direct actions of EPO on skeletal muscle

  2. Topical erythropoietin promotes wound repair in diabetic rats.

    Science.gov (United States)

    Hamed, Saher; Ullmann, Yehuda; Masoud, Muhannad; Hellou, Elias; Khamaysi, Ziad; Teot, Luc

    2010-01-01

    Wound healing in diabetic patients is slower than in healthy individuals. Erythropoietin (EPO) has non-hemopoietic targets in the skin, and systemically administered EPO promotes wound healing in experimental animals. This study investigated the effect of topical EPO treatment on defective wound repair in the skin of diabetic rats. Full-thickness excisional skin wounds were made in 38 rats, of which 30 had diabetes. The wounds were then treated topically with a cream that contained either vehicle, 600 IU ml(-1) EPO (low dose), or 3,000 IU ml(-1) (high dose) EPO. We assessed the rate of wound closure during the 12-day treatment period, and microvascular density (MVD), vascular endothelial growth factor (VEGF), and hydroxyproline (HP) contents, and the extent of apoptosis in wound tissues at the end of the 12-day treatment period. Topical EPO treatment significantly reduced the time to final wound closure. This increased rate of closure of the two EPO-treated wounds in diabetic rats was associated with increased MVD, VEGF, and HP contents, and a reduced extent of apoptosis. In light of our finding that topical EPO treatment promotes skin wound repair in diabetic rats, we propose that topical EPO treatment is a therapeutically beneficial method of treating chronic diabetic wounds.

  3. Modulation of erythropoietin concentrations by manipulation of hypercarbia

    Energy Technology Data Exchange (ETDEWEB)

    Miller, M.E.; Howard, D.

    1979-01-01

    The present studies were done to determine whether preventing the respiratory alkalosis, which is known to occur with acute hypoxic stimuli, would lead to alterations in plasma concentrations of erythropoietin (Ep). Rats were subjected to two acute stresses, hypoxia and blood loss, separately and in combination, with and without the added stress of hypercarbia. Hypercarbia in all experimental groups was associated with a decrease in plasma concentrations of Ep. This reduction in plasma Ep with hypercarbia could not be fully explained by the higher arterial pO/sub 2/s or p50s of the hypercarbic rats. Hypercarbia may have indirectly suppressed Ep production by increasing blood flow to the site of Ep production. Alternatively, the cell of origin of Ep could be sensitive to changes in pH and/or pCO/sub 2/. It was further demonstrated that neither the onset nor the degree of reticulocytosis could be predicted by the plasma Ep concentrations. It is likely that the removal of red blood cells led to a decrease in marrow transit time with the early emergence of reticulocytes after acute blood loss.

  4. Radioimmunoassay of erythropoietin: analytical performance and clinical use in hematology.

    Science.gov (United States)

    Schlageter, M H; Toubert, M E; Podgorniak, M P; Najean, Y

    1990-10-01

    We report here the performance of a recently commercialized radioimmunoassay kit for determining erythropoietin (EPO) in serum or plasma. The lower detection limit of the method was 3 U/L. Precision, analyzed by the variation coefficients between different assay runs and in the same experiment, was always less than 10%; accuracy was assessed by recovery and dilution tests. In anemic patients (hematocrit 18-39%), the concentration of EPO was logarithmically related to hematocrit. A relatively large dispersion of the results was noted, as reported by others with various RIAs. Patients with severe renal failure demonstrated a very low EPO value, whatever the degree of their anemia. In some chronic anemias resulting from malignancy, EPO concentrations were also relatively low. In the polycythemia vera group, the EPO mean was below normal for greater than 95% of the patients, whatever their clinical stage (first evaluation, relapse, or remission). In contrast, 91% of the patients with pure erythrocytosis had a normal or increased EPO value, even when the etiology was unknown. Measurement of EPO concentration may be useful for the clinical differentiation of myeloproliferative disorders and, subsequently, for their prognosis and choice of treatment.

  5. Functional significance of erythropoietin in renal cell carcinoma

    International Nuclear Information System (INIS)

    Morais, Christudas; Johnson, David W; Vesey, David A; Gobe, Glenda C

    2013-01-01

    One of the molecules regulated by the transcription factor, hypoxia inducible factor (HIF), is the hypoxia-responsive hematopoietic factor, erythropoietin (EPO). This may have relevance to the development of renal cell carcinoma (RCC), where mutations of the von Hippel-Lindau (VHL) gene are major risk factors for the development of familial and sporadic RCC. VHL mutations up-regulate and stabilize HIF, which in turn activates many downstream molecules, including EPO, that are known to promote angiogenesis, drug resistance, proliferation and progression of solid tumours. HIFs typically respond to hypoxic cellular environment. While the hypoxic microenvironment plays a critical role in the development and progression of tumours in general, it is of special significance in the case of RCC because of the link between VHL, HIF and EPO. EPO and its receptor, EPOR, are expressed in many cancers, including RCC. This limits the use of recombinant human EPO (rhEPO) to treat anaemia in cancer patients, because the rhEPO may be stimulatory to the cancer. EPO may also stimulate epithelial-mesenchymal transition (EMT) in RCC, and pathological EMT has a key role in cancer progression. In this mini review, we summarize the current knowledge of the role of EPO in RCC. The available data, either for or against the use of EPO in RCC patients, are equivocal and insufficient to draw a definitive conclusion

  6. Does Erythropoietin Regulate TRPC Channels in Red Blood Cells?

    Directory of Open Access Journals (Sweden)

    Jens Danielczok

    2017-03-01

    Full Text Available Background: Cation channels play an essential role in red blood cells (RBCs ion homeostasis. One set of ion channels are the transient receptor potential channels of canonical type (TRPC channels. The abundance of these channels in primary erythroblasts, erythroid cell lines and RBCs was associated with an increase in intracellular Ca2+ upon stimulation with Erythropoietin (Epo. In contrast two independent studies on Epo-treated patients revealed diminished basal Ca2+ concentration or reduced phosphatidylserine exposure to the outer membrane leaflet. Methods: To resolve the seemingly conflicting reports we challenged mature human and mouse RBCs of several genotypes with Epo and Prostaglandin E2 (PGE2 and recorded the intracellular Ca2+ content. Next Generation Sequencing was utilised to approach a molecular analysis of reticulocytes. Results/Conclusions: Our results allow concluding that Epo and PGE2 regulation of the Ca2+ homeostasis is distinctly different between murine and human RBCs and that changes in intracellular Ca2+ upon Epo treatment is a primary rather than a compensatory effect. In human RBCs, Epo itself has no effect on Ca2+ fluxes but inhibits the PGE2-induced Ca2+ entry. In murine mature RBCs functional evidence indicates TRPC4/C5 mediated Ca2+ entry activated by Epo whereas PGE2 leads to a TRPC independent Ca2+ entry.

  7. Recombinant human erythropoietin therapy in critically ill Jehovah's Witnesses.

    Science.gov (United States)

    Ball, Amanda M; Winstead, P Shane

    2008-11-01

    Blood transfusions and blood products are often given as a life-saving measure in patients with critical illness. However, some patients, such as Jehovah's Witnesses, may refuse their administration due to religious beliefs. Jehovah's Witnesses accept most available medical treatments, but not blood transfusions or blood products due to their religion's interpretation of several passages from the Bible. Since recombinant human erythropoietin (rHuEPO) became available, several cases have been reported in which rHuEPO was successfully administered to critically ill Jehovah's Witnesses. Administration of rHuEPO in combination with other blood conservation techniques has been shown to increase hemoglobin levels and survival in patients who experienced trauma, burns, general surgery, or gastrointestinal hemorrhage. We performed a literature search of the MEDLINE and International Pharmaceutical Abstracts databases of rHuEPO therapy in the Jehovah's Witness population. Fourteen cases were identified in which rHuEPO was administered to Jehovah's Witnesses who required the drug for critical care resuscitation as an alternative to blood products. In each clinical situation, rHuEPO enhanced erythropoiesis; however, time to the start of treatment, dosages, route of administration, and treatment duration varied widely. Supplementation with adjunctive agents, such as iron, folic acid, and vitamin B12, was also beneficial. Use of rHuEPO in Jehovah's Witnesses may provide an alternative to blood transfusions or blood products. Other alternatives, such as hemoglobin-based oxygen carriers and perfluorocarbons, are also being explored.

  8. Erythropoietin treatment does not compromise cardiovascular function in chronic renal failure

    DEFF Research Database (Denmark)

    Haedersdal, C; Mehlsen, J; Stenver, Doris Irene

    1994-01-01

    The anemia in patients with chronic renal failure can be corrected through treatment with recombinant human erythropoietin treatment. This correction is associated with changes in the rheologic variables, which could explain the changes in hemodynamics found by many investigators. The authors have...... followed up 11 patients with chronic renal failure on hemodialysis before and during six months of therapy with erythropoietin. The measurements were made before treatment, after four months of therapy, and after six months of therapy. The measurements included hematocrit, osmotic resistance of the red...... were unchanged. The conclude that, in spite of changes in rheologic variables, increasing viscosity of the blood and thus possibly increasing the peripheral resistance, these had no effect on the cardiovascular state. Erythropoietin treatment improves the subjective well-being in patients on chronic...

  9. Erythropoietin between therapy and doping : Two sides of the same coin

    Directory of Open Access Journals (Sweden)

    Ostojić Ana

    2016-01-01

    Full Text Available Erythropoietin is a hormone that promotes the formation of red blood cells by the bone marrow. In adults it is mainly produced by the kidneys as a response to hypoxia. Besides its main role, it also acts as antiapoptotic, anti-inflammatory and cytoprotective agent. Furthermore, it is produced in many non-hematopoietic tissues where it acts locally, stimulating angiogenesis. Erythropoietin binds cytokine receptors on target cells, such as erythrocyte precursor cells, neurons, glial and endothelial cells, cardiomyocytes, myocytes etc. The discovery of synthetic erythropoietin forms, in the late eighties of the last century, has significantly improved treatment outcome of patients with anaemia related to chronic diseases, especially chronic renal failure. Renal anaemia is multifactorial, but predominantly a consequence of erythropoietin deficiency. Today, three generations of erythropoiesis stimulating agents are available, differing in glycosylation pattern, molecular size, half-life and modes of administration and dosage. In anaemic patients this therapy significantly improves their quality of life, but may also have serious, potentially dangerous adverse effects. Synthesis of recombinant human erythropoietin, on the other hand, has improved possibilities for manipulations in sport, in the field of blood doping. Erythropoietin administration in athletes increases their maximum oxygen consumption capacity, improves endurance and performance, especially in aerobic exercise. This seriously undermines the spirit of sport, and also endangers athletes' health. Different anti-doping tests have been developed and used, still with limited success. At the same time, new illicit ways of malpractice are developing, such as variuos models of gene doping. Therefore, providing new models of anti-doping tests and strategies, together with better health control of athletes, still remains a considerable challenge.

  10. Caveat oncologist: clinical findings and consequences of distributing counterfeit erythropoietin in the United States.

    Science.gov (United States)

    Qureshi, Zaina P; Norris, Leann; Sartor, Oliver; McKoy, June M; Armstrong, John; Raisch, Dennis W; Garg, Vishvas; Stafkey-Mailey, Dana; Bennett, Charles Lee

    2012-03-01

    Counterfeit pharmaceuticals pose risks domestically. Because of their cost, cancer pharmaceuticals are vulnerable. We review findings from a domestic counterfeiting episode involving erythropoietin and outline anticounterfeiting recommendations for policy makers, patients, and health care professionals. Information was obtained on patients who received counterfeit erythropoietin, its distribution, and criminal investigations into counterfeiting networks. Interview sources included a physician, an attorney, employees of the Florida Department of Health and Human Services and the US Food and Drug Administration's (FDA) Office of Criminal Investigation, manufacturers, and wholesalers. Other sources included the book "Dangerous Doses," LexisNexis (search terms "counterfeit" and "erythropoietin") and the FDA database. Counterfeit product consisted of 2,000 U vials with counterfeit labels denoting 40,000 U. The counterfeiters, in collaboration with a Miami pharmacy, purchased 110,000 erythropoietin 2,000 U vials and affixed counterfeit labels to each vial. Products were then sold via the pharmaceutical "gray market" to wholesalers, then pharmacy chains. Investigations by Florida government officials implicated 17 persons, all of whom were found guilty of trafficking in counterfeit pharmaceuticals. Despite the large size of the operation, the FDA received reports of only 12 patients who had received counterfeit erythropoietin and detailed information for only two individuals. A 17-year-old liver transplant recipient and a 61-year-old patient with breast cancer experienced loss of efficacy after receiving counterfeit erythropoietin. Wider use of FDA anticounterfeit initiatives, limiting pharmaceutical suppliers to reputable distributors, and educating providers and patients about signs of counterfeit drugs can improve the safety of cancer pharmaceuticals.

  11. FGF23 modulates the effects of erythropoietin on gene expression in renal epithelial cells

    Directory of Open Access Journals (Sweden)

    Yashiro M

    2018-04-01

    Full Text Available Mitsuru Yashiro,1 Masaki Ohya,1 Toru Mima,1 Yumi Ueda,2 Yuri Nakashima,1 Kazuki Kawakami,1 Yohei Ishizawa,2 Shuto Yamamoto,1 Sou Kobayashi,1 Takurou Yano,1 Yusuke Tanaka,1 Kouji Okuda,1 Tomohiro Sonou,1 Tomohiro Shoshihara,1 Yuko Iwashita,1 Yu Iwashita,1 Kouichi Tatsuta,1 Ryo Matoba,2 Shigeo Negi,1 Takashi Shigematsu1 1Department of Nephrology, Wakayama Medical University, Wakayama, Japan; 2DNA Chip Research Inc., Minato, Japan Background: FGF23 plays an important role in calcium–phosphorus metabolism. Other roles of FGF23 have recently been reported, such as commitment to myocardium enlargement and immunological roles in the spleen. In this study, we aimed to identify the roles of FGF23 in the kidneys other than calcium–phosphorus metabolism. Methods: DNA microarrays and bioinformatics tools were used to analyze gene expression in mIMCD3 mouse renal tubule cells following treatment with FGF23, erythropoietin and/or an inhibitor of ERK. Results: Three protein-coding genes were upregulated and 12 were downregulated in response to FGF23. Following bioinformatics analysis of these genes, PPARγ and STAT3 were identified as candidate transcript factors for mediating their upregulation, and STAT1 as a candidate for mediating their downregulation. Because STAT1 and STAT3 also mediate erythropoietin signaling, we investigated whether FGF23 and erythropoietin might show interactive effects in these cells. Of the 15 genes regulated by FGF23, 11 were upregulated by erythropoietin; 10 of these were downregulated following cotreatment with FGF23. Inhibition of ERK, an intracellular mediator of FGF23, reversed the effects of FGF23. However, FGF23 did not influence STAT1 phosphorylation, suggesting that it impinges on erythropoietin signaling through other mechanisms. Conclusion: Our results suggest cross talk between erythropoietin and FGF23 signaling in the regulation of renal epithelial cells. Keywords: FGF23, STAT1, PPARγ, DNA microarray

  12. Erythropoietin treatment does not compromise cardiovascular function in chronic renal failure

    DEFF Research Database (Denmark)

    Haedersdal, C; Mehlsen, J; Stenver, Doris Irene

    1994-01-01

    The anemia in patients with chronic renal failure can be corrected through treatment with recombinant human erythropoietin treatment. This correction is associated with changes in the rheologic variables, which could explain the changes in hemodynamics found by many investigators. The authors have...... followed up 11 patients with chronic renal failure on hemodialysis before and during six months of therapy with erythropoietin. The measurements were made before treatment, after four months of therapy, and after six months of therapy. The measurements included hematocrit, osmotic resistance of the red...

  13. Recombinant Erythropoietin And Blood Transfusion In Very Low Birth Weight Infants

    Directory of Open Access Journals (Sweden)

    Keramat Nouri

    2005-05-01

    Full Text Available Backgroundp: Very low birth weight infants ( <1500 g frequently require blood transfusions because of repeated blood sampling accompanied by anemia of prematurity. Methods: In an attempt to identify the effect of human recombinant erythropoietin to decrease the requirement for blood transfusions, erythropoietin was administered to 24 pre term infants less than 1500 g prospectively from September 1999 till December2000. Data about the characteristics of the population, the severity of diseases, and treatment with erythropoietin, clinical diagnosis, initial and subsequent hemoglobin, volume of blood loss, and the number of blood transfusions were recorded. These results were compared with data from the recorded information of 49 infants who did not receive erythropoietin during those past 2 years. There were no differences between the 2 groups with regard to the gestational age, birth weight, clinical diagnosis, severity of the illness, primary causes of admission, and initial hematologic parameters such as hemoglobin, hematocrit and reticulocytes. Erythropoietin was administered in a dose of 200 ill/kg three times weekly for 6-8 weeks accompanied with iron supplement 6 mg/ kg/day. Transfusions were administered according to protocol. Results: There was no significant difference between the number of blood transfusion among these 2 groups (p= 0.07. However, transfusions in the erythropoietin treated group were fewer in comparison to the other group (1.9 +1-1.6 to 3.2 +/-1.1. No difference was observed between final hemoglobin and hematocrit levels among the two groups (10.3 +1- 0.9 vs. 10.4 +1- 0.7 and 33.7 +1- 2.3 vs. 32.2 +1- 2.2. Conclusion: Very low birth weight infants receive frequent blood transfusions but a reduction in transfusion requirements was not apparent after administration of erythropoietin and iron in preterm infants in this study. However, the lack of impact on transfusion requirements fails to support routine use of

  14. Neural correlates of improved recognition of happy faces after erythropoietin treatment in bipolar disorder

    DEFF Research Database (Denmark)

    Miskowiak, K W; Petersen, N A; Harmer, C J

    2018-01-01

    -group design. Participants underwent whole-brain fMRI at 3T, mood ratings and blood tests at baseline and week 14. During fMRI, participants viewed happy and fearful faces and performed a gender discrimination task. RESULTS: Thirty-four patients had complete pre- and post-treatment fMRI data (EPO: N = 18......, saline: N = 16). Erythropoietin vs. saline increased right superior frontal response to happy vs. fearful faces. This correlated with improved happiness recognition in the EPO group. Erythropoietin also enhanced gender discrimination accuracy for happy faces. These effects were not influenced...

  15. TNF-alpha-induced apoptosis is prevented by erythropoietin treatment on SH-SY5Y cells

    International Nuclear Information System (INIS)

    Pregi, Nicolas; Wenker, Shirley; Vittori, Daniela; Leiros, Claudia Perez; Nesse, Alcira

    2009-01-01

    The growth factor erythropoietin (Epo) has shown neuronal protective action in addition to its well known proerythroid activity. Furthermore, Epo has dealt with cellular inflammation by inhibiting the expression of several proinflammatory cytokines, such as IL-1 and TNF-α. The action of TNF can have both apoptotic and antiapoptotic consequences due to altered balance between different cell signalling pathways. This work has focused on the apoptotic effects of this cytokine and the potential protective action of Epo. The model we used was neuroblastoma SH-SY5Y cells cultured in the presence of 25 ng/ml TNF-α or pretreated with 25 U/ml Epo for 12 h before the addition of TNF-α. Apoptosis was evaluated by differential cell count after Hoechst staining, analysis of DNA ladder pattern, and measurement of caspase activity. Despite its ability to induce NF-κB nuclear translocation, TNF-α induced cell death, which was found to be associated to upregulation of TNF Receptor 1 expression. On the other hand, cells activated by Epo became resistant to cell death. Prevention of death receptor upregulation and caspase activation may explain this antiapoptotic effect of Epo, which may be also favoured by the induction of a higher expression of protective factors, such as Bcl-2 and NF-κB, through mechanisms involving Jak/STAT and PI3K signalling pathways

  16. Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia.

    Science.gov (United States)

    Souvenir, Rhonda; Fathali, Nancy; Ostrowski, Robert P; Lekic, Tim; Zhang, John H; Tang, Jiping

    2011-10-01

    Previous studies have shown that erythropoietin (EPO) is neuroprotective in both in vivo and in vitro models of hypoxia ischemia. However these studies hold limited clinical translations because the underlying mechanism remains unclear and the key molecules involved in EPO-induced neuroprotection are still to be determined. This study investigated if tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and its upstream regulator signaling molecule Janus kinase-2 (JAK-2) are critical in EPO-induced neuroprotection. Hypoxia ischemia (HI) was modeled in-vitro by oxygen and glucose deprivation (OGD) and in-vivo by a modified version of Rice-Vannucci model of HI in 10-day-old rat pups. EPO treated cells were exposed to AG490, an inhibitor of JAK-2 or TIMP-1 neutralizing antibody for 2h with OGD. Cell death, phosphorylation of JAK-2 and signal transducers and activators of transcription protein-3 (STAT-3), TIMP-1 expression, and matrix metalloproteinase-9 (MMP-9) activity were measured and compared with normoxic group. Hypoxic ischemic animals were treated one hour following HI and evaluated 48 h after. Our data showed that EPO significantly increased cell survival, associated with increased TIMP-1 activity, phosphorylation of JAK-2 and STAT-3, and decreased MMP-9 activity in vivo and in vitro. EPO's protective effects were reversed by inhibition of JAK-2 or TIMP-1 in both models. We concluded that JAK-2, STAT-3 and TIMP-1 are key mediators of EPO-induced neuroprotection during hypoxia ischemia injury. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Erythropoietin and its receptors in the brainstem of adults with fatal falciparum malaria

    Directory of Open Access Journals (Sweden)

    White Nicholas J

    2009-11-01

    Full Text Available Abstract Background Facilitation of endogenous neuroprotective pathways, such as the erythropoietin (Epo pathway, has been proposed as adjuvant treatment strategies in cerebral malaria. Whether different endogenous protein expression levels of Epo or differences in the abundance of its receptor components could account for the extent of structural neuropathological changes or neurological complications in adults with severe malaria was investigated. Methods High sensitivity immunohistochemistry was used to assess the frequency, distribution and concordance of Epo and components of its homodimeric and heteromeric receptors, Epo receptor and CD131, within the brainstem of adults who died of severe malaria. The following relationships with Epo and its receptor components were also defined: (i sequestration and indicators of hypoxia; (ii vascular damage in the form of plasma protein leakage and haemorrhage; (iii clinical complications and neuropathological features of severe malaria disease. Brainstems of patients dying in the UK from unrelated non-infectious causes were examined for comparison. Results The incidence of endogenous Epo in parenchymal brain cells did not greatly differ between severe malaria and non-neurological UK controls at the time of death. However, EpoR and CD131 labelling of neurons was greater in severe malaria compared with non-neurological controls (P = .009. EpoR labelling of vessels was positively correlated with admission peripheral parasite count (P = .01 and cerebral sequestration (P P = .001. There were no significant correlations with indicators of vascular damage, neuronal chromatolysis, axonal swelling or vital organ failure. Conclusion Cells within the brainstem of severe malaria patients showed protein expression of Epo and its receptor components. However, the incidence of endogeneous expression did not reflect protection from vascular or neuronal injury, and/or clinical manifestations, such as coma. These

  18. Applications and biomonitoring issues of recombinant erythropoietins for doping control.

    Science.gov (United States)

    Tsitsimpikou, Christina; Kouretas, Demetrios; Tsarouhas, Konstantinos; Fitch, Kenneth; Spandidos, Demetrios A; Tsatsakis, Aristides

    2011-02-01

    The biochemical actions and side effects of recombinant erythropoietins (rhEPOs), their analogs and mimetics, their misuse as doping agents, and the principal analytical strategies developed to identify them in athletes' biologic fluids are reviewed. Patients who experience a range of pathologies have benefited from the administration of rhEPOs to correct severe anemia. Currently, monitoring the biologic effect of rhEPO in patients under treatment is by measuring the hemoglobin concentration. However, it may be valuable to directly monitor the actual levels of the administered drug and determine a dose-dependent correlation with any clinical adverse effect observed. This may permit the adoption of a patient-specific administration regime. Currently, the method of detecting EPO approved for doping control is an isoelectric-focusing, double-blotting, chemiluminescence assay based on charge differences between isoforms of rhEPOs and endogenous EPO in urine. The advantages and limitations of this method are presented. A new approach using sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a complementary tool to the established method is discussed. The application of matrix-assisted laser desorption/ionization mass spectrometry and liquid chromatography combined with tandem mass spectrometry for the direct detection of the rhEPO molecules may prove to be promising. Indirect evidence of rhEPO abuse by athletes is based on the analysis of blood parameters (hemoglobin hematocrit, reticulocytes, macrocytes, etc) and serum markers (concentration of EPO and serum transferrin receptors, etc). Enrichment of the screened parameters with gene or biochemical markers revealing altered erythropoiesis and adoption of longitudinal monitoring of athletes' hematologic and biochemical parameters could also be a complementary approach in the fight against doping.

  19. Erythropoietin's Beta Common Receptor Mediates Neuroprotection in Spinal Cord Neurons.

    Science.gov (United States)

    Foley, Lisa S; Fullerton, David A; Mares, Joshua; Sungelo, Mitchell; Weyant, Michael J; Cleveland, Joseph C; Reece, T Brett

    2017-12-01

    Paraplegia from spinal cord ischemia-reperfusion (SCIR) remains an elusive and devastating complication of complex aortic operations. Erythropoietin (EPO) attenuates this injury in models of SCIR. Upregulation of the EPO beta common receptor (βcR) is associated with reduced damage in models of neural injury. The purpose of this study was to examine whether EPO-mediated neuroprotection was dependent on βcR expression. We hypothesized that spinal cord neurons subjected to oxygen-glucose deprivation would mimic SCIR injury in aortic surgery and EPO treatment attenuates this injury in a βcR-dependent fashion. Lentiviral vectors with βcR knockdown sequences were tested on neuron cell cultures. The virus with greatest βcR knockdown was selected. Spinal cord neurons from perinatal wild-type mice were harvested and cultured to maturity. They were treated with knockdown or nonsense virus and transduced cells were selected. Three groups (βcR knockdown virus, nonsense control virus, no virus control; n = 8 each) were subjected to 1 hour of oxygen-glucose deprivation. Viability was assessed. βcR expression was quantified by immunoblot. EPO preserved neuronal viability after oxygen-glucose deprivation (0.82 ± 0.04 versus 0.61 ± 0.01; p neuron preservation was similar in the nonsense virus and control mice (0.82 ± 0.04 versus 0.80 ± 0.05; p = 0.77). EPO neuron preservation was lost in βcR knockdown mice compared with nonsense control mice (0.46 ± 0.03 versus 0.80 ± 0.05; p neuronal loss after oxygen-glucose deprivation in a βcR-dependent fashion. This receptor holds immense clinical promise as a target for pharmacotherapies treating spinal cord ischemic injury. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  20. Protective

    Directory of Open Access Journals (Sweden)

    Wessam M. Abdel-Wahab

    2013-10-01

    Full Text Available Many active ingredients extracted from herbal and medicinal plants are extensively studied for their beneficial effects. Antioxidant activity and free radical scavenging properties of thymoquinone (TQ have been reported. The present study evaluated the possible protective effects of TQ against the toxicity and oxidative stress of sodium fluoride (NaF in the liver of rats. Rats were divided into four groups, the first group served as the control group and was administered distilled water whereas the NaF group received NaF orally at a dose of 10 mg/kg for 4 weeks, TQ group was administered TQ orally at a dose of 10 mg/kg for 5 weeks, and the NaF-TQ group was first given TQ for 1 week and was secondly administered 10 mg/kg/day NaF in association with 10 mg/kg TQ for 4 weeks. Rats intoxicated with NaF showed a significant increase in lipid peroxidation whereas the level of reduced glutathione (GSH and the activity of superoxide dismutase (SOD, catalase (CAT, glutathione S-transferase (GST and glutathione peroxidase (GPx were reduced in hepatic tissues. The proper functioning of the liver was also disrupted as indicated by alterations in the measured liver function indices and biochemical parameters. TQ supplementation counteracted the NaF-induced hepatotoxicity probably due to its strong antioxidant activity. In conclusion, the results obtained clearly indicated the role of oxidative stress in the induction of NaF toxicity and suggested hepatoprotective effects of TQ against the toxicity of fluoride compounds.

  1. Expression of platelet-derived growth factor BB, erythropoietin and erythropoietin receptor in canine and feline osteosarcoma.

    Science.gov (United States)

    Meyer, F R L; Steinborn, R; Grausgruber, H; Wolfesberger, B; Walter, I

    2015-10-01

    The discovery of expression of the erythropoietin receptor (EPO-R) on neoplastic cells has led to concerns about the safety of treating anaemic cancer patients with EPO. In addition to its endocrine function, the receptor may play a role in tumour progression through an autocrine mechanism. In this study, the expression of EPO, EPO-R and platelet-derived growth factor BB (PDGF-BB) was analysed in five feline and 13 canine osteosarcomas using immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR). EPO expression was positive in all tumours by IHC, but EPO mRNA was only detected in 38% of the canine and 40% of the feline samples. EPO-R was expressed in all samples by quantitative RT-PCR (RT-qPCR) and IHC. EPO-R mRNA was expressed at higher levels in all feline tumours, tumour cell lines, and kidney when compared to canine tissues. PDGF-BB expression was variable by IHC, but mRNA was detected in all samples. To assess the functionality of the EPO-R on tumour cells, the proliferation of canine and feline osteosarcoma cell lines was evaluated after EPO administration using an alamarBlue assay and Ki67 immunostaining. All primary cell lines responded to EPO treatment in at least one of the performed assays, but the effect on proliferation was very low indicating only a weak responsiveness of EPO-R. In conclusion, since EPO and its receptor are expressed by canine and feline osteosarcomas, an autocrine or paracrine tumour progression mechanism cannot be excluded, although in vitro data suggest a minimal role of EPO-R in osteosarcoma cell proliferation. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. The Effect of Erythropoietin on Testosterone Levels During Ischemia Reperfusion Injury in Rats

    Directory of Open Access Journals (Sweden)

    Tsompos C.

    2016-11-01

    Full Text Available Objective: This experimental study examined the effect of erythropoietin (Epo in a rat model and particularly in an adrenal ischemia-reperfusion (IR protocol. The effect of that molecule was studied biochemically using blood mean testosterone levels (T.

  3. Expression of human erythropoietin gene in the mammary gland of a transgenic mouse

    Czech Academy of Sciences Publication Activity Database

    Mikuš, Tomáš; Malý, Petr; Poplštein, M.; Landa, Vladimír; Trefil, P.; Lidický, J.

    2001-01-01

    Roč. 47, č. 6 (2001), s. 187-195 ISSN 0015-5500 Institutional research plan: CEZ:AV0Z5052915 Keywords : erythropoietin, mammary gland, transgenic mouse Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.519, year: 2001

  4. Characterization of recombinant human erythropoietin produced in Chinese hamster ovary cells

    International Nuclear Information System (INIS)

    Davis, J.M.; Arakawa, T.; Strickland, T.W.; Yphantis, D.A.

    1987-01-01

    Physicochemical properties of recombinant human erythropoietin were examined. This protein, produced in Chinese hamster ovary cells, showed a conformation apparently identical with the natural product isolated from human urine when examined by circular dichroism, UV absorbance, and fluorescence spectroscopy. Sedimentation equilibrium experiments showed the recombinant erythropoietin preparation to be essentially a single macromolecular component with a molecular weight of 30,400 and a carbohydrate content of 39%. The Stokes radius of recombinant erythropoietin was estimated to be 32 A from gel filtration, much larger than the 20-A radius calculated for a sphere of the observed molecular weight. This difference may be ascribed to the extensive glycosylation. The fluorescence and phosphorescence spectra showed that the luminescent tryptophan(s) is (are) solvent-exposed and can be quenched by I - and acrylamide but not by Cs + . On acid titration, the recombinant erythropoietin showed a conformational transition with a midpoint of pH 4.1. This suggests that the net charges on the protein moiety rather than on the whole molecule play a role in protein structure stability

  5. [Recombinant erythropoietin as treatment for hyporegenerative anemia following hemolytic disease of the newborn].

    Science.gov (United States)

    Donato, Hugo; Bacciedoni, Viviana; García, Cecilia; Schvartzman, Gabriel; Vain, Néstor

    2009-04-01

    The aim of the study is to report results of erythropoietin treatment for late hyporegenerative anemia in the hemolytic disease of the newborn (HDN). Reports previously published concern only a few cases, with controversial results. Case series report concerning 50 neonates with HDN due to Rh, ABO or KpA antigens, aged more than 7 days. Erythropoietin treatment started when hematocrit dropped to levels requiring transfusion, with an inappropriate reticulocyte response (Reticulocyte Production Index <1). At start of treatment mean age was 24.3 +/- 12.0 days (range 8-65 days), hematocrit 24.1 +/- 2.8% (range 18-30%), and Reticulocyte Production Index 0.34 +/- 0.25 (range 0.05-0.98). Hematocrit and Reticulocyte Production Index showed significant increases after 7 and 14 days of treatment (p <0.001). No difference was observed either between infants with Rh-HDN and ABO-HDN or between Rh-HDN patients with or without intrauterine transfusions. Seven infants (14%) required one packed RBC transfusion during erythropoietin therapy, 2 of them within 72 hours from starting treatment. The percentage of transfused infants showed no difference either between ABO-HDN and Rh-HDN or between Rh-HDN with and without intrauterine transfusions. Moderate, short-lasting neutropenia, not associated to infections, was observed in 11 patients. No other adverse effect was observed. The administration of erythropoietin appears to be a safe and useful therapy. Its efficacy should be confirmed by randomized studies.

  6. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...

  7. Erythropoietin deficiency in acute crescentic glomerulonephritis and in total bilateral renal cortical necrosis

    DEFF Research Database (Denmark)

    Thaysen, J H; Nielsen, O J; Brandi, L

    1991-01-01

    -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...

  8. Lentivirus administration to rat muscle provides efficient sustained expression of erythropoietin

    NARCIS (Netherlands)

    Seppen, J.; Barry, S. C.; Harder, B.; Osborne, W. R.

    2001-01-01

    A lentivirus pseudotyped with vesicular stomatitis virus G protein (VSV-G) encoding rat erythropoietin (EPO) complementary DNA was administered to rat skeletal muscle and red blood cell production was serially monitored. After a single intramuscular injection hematocrit values increased and reached

  9. Therapeutic levels of erythropoietin (EPO) achieved after gene electrotransfer to skin in mice

    DEFF Research Database (Denmark)

    Gothelf, A; Hojman, P; Gehl, Julie

    2010-01-01

    Gene electrotransfer refers to gene transfection by electroporation and is an effective non-viral method for delivering naked DNA into cells and tissues. This study presents data from gene electrotransfer with erythropoietin (EPO) to mouse skin. Nine-week-old female NMRI mice received one, two...

  10. Carbon monoxide in chronic uraemia related to erythropoietin treatment and smoking habits

    DEFF Research Database (Denmark)

    Thunedborg, P; Nielsen, A L; Brinkenfeldt, H

    1995-01-01

    In 69 patients on chronic haemodialysis, blood sampled randomly during dialysis was analyzed for carboxyhaemoglobin (COHb). The median value was 1.40% (range 0.9-2.3) in non-smoking patients and (1.4-7.5) in smokers. In non-smokers treated with erythropoietin (EPO) correlation was found between C...

  11. Erythropoietin in the cerebrospinal fluid of patients with aneurysmal subarachnoid haemorrhage originates from the brain

    DEFF Research Database (Denmark)

    Springborg, Jacob Bertram; Sonne, Bjarne; Frederiksen, Hans Jørgen

    2003-01-01

    Recent years' research has revealed a specific, neuroprotective erythropoietin (EPO) system in the central nervous system (CNS) that is upregulated by hypoxia. The presence and dynamics of EPO in the cerebrospinal fluid (CSF) of patients with subarachnoid haemorrhage (SAH) has not been investigated...

  12. Tyrosine kinase receptor RON functions downstream of the erythropoietin receptor to induce expansion of erythroid progenitors

    NARCIS (Netherlands)

    van den Akker, Emile; van Dijk, Thamar; Parren-van Amelsvoort, Martine; Grossmann, Katja S.; Schaeper, Ute; Toney-Earley, Kenya; Waltz, Susan E.; Löwenberg, Bob; von Lindern, Marieke

    2004-01-01

    Erythropoietin (EPO) is required for cell survival during differentiation and for progenitor expansion during stress erythropoiesis. Although signaling pathways may couple directly to docking sites on the EPO receptor (EpoR), additional docking molecules expand the signaling platform of the

  13. Control of erythropoiesis by erythropoietin and stem cell factor: a novel role for Bruton's tyrosine kinase

    NARCIS (Netherlands)

    von Lindern, Marieke; Schmidt, Uwe; Beug, Hartmut

    2004-01-01

    Erythropoietin (Epo) and stem cell factor (SCF) are essential factors in the control of survival, expansion and differentiation of erythroid progenitors. Upon activation, their receptors, the EpoR and c-Kit, initiate multiple signalling pathways that control many cellular processes. To control

  14. Erythropoietin Receptor in Human Tumor Cells: Expression and Aspects Regarding Functionality

    NARCIS (Netherlands)

    T.A. Knoch (Tobias); G. Westphal; E. Niederberger; C. Blum; Y. Wollman; W. Rebel; J. Debus; E. Friedrich

    2001-01-01

    textabstractRecombinant human erythropoietin (Epo)and granu l o cy t e - c o l o ny - s t i mulating factor (G-CSF) are used to stimulate hematopoiesis in patients with malignant dise a s e s . These cytokines transduce their biological signal via the Epo receptor (EpoR) and G-CSF receptor (G-CSF-R)

  15. Active Smoking and Hematocrit and Fasting Circulating Erythropoietin Concentrations in the General Population

    NARCIS (Netherlands)

    Eisenga, Michele F.; Kieneker, Lyanne M.; Touw, Daan J.; Nolte, Ilja M.; van der Meer, Peter; Huls, Gerwin; Gaillard, Carlo A. J. M.; Bakker, Stephan J. L.

    Cigarette smoking continues to be one of the major risk factors for increased morbidity and mortality worldwide. Among many adverse health effects, smoking can induce erythrocytosis, which is commonly believed to result from elevated serum erythropoietin (EPO) levels. Currently, however, this notion

  16. Comparison of Hemoglobin Levels Before and After Hemodialysis and Their Effects on Erythropoietin Dosing and Cost

    OpenAIRE

    Sagheb; Fallahzadeh; Moaref; Fallahzadeh; Dormanesh

    2016-01-01

    Background Hemoglobin levels measured after hemodialysis, as compared to hemoglobin levels measured before hemodialysis, are suggested to be a more accurate reflection of the hemoglobin levels between hemodialysis sessions, and to be a better reference point for adjusting erythropoietin dosing. Objectives The aim of this study was to compare the hemoglobin levels before and after hemodialysis, to calculate the required erythropoie...

  17. Increased serum erythropoietin activity in rats following intrarenal injection of nickel subsulfide

    International Nuclear Information System (INIS)

    Hopfer, S.M.; Sunderman, F.W. Jr.; Fredrickson, T.N.; Morse, E.E.

    1979-01-01

    To investigate the pathopysiologic mechanisms of nickel-induced erythocytosis, serum erythropoietin activities were measured in (a) pooled serum from rats at 2 wk after intrarenal injection of αNi 3 S 2 (5 mg/rat), and (b) pooled serum from control rats at 2 wk after intrarenal injection of sterile NaCl vehicle (0.4 ml/rat). A sensitive erythropoietin bioassay was employed, which entailed repetitive administration of test serums to post-hypoxic polycythemic mice in divided doses (12 s.c. injections of 0.5 ml of serum at 6 h intervals for 3 da; total dose = 6 ml of serum/mouse). The erythropoietin detection limit was approx. = 20 I.U./liter of serum. In mice which received pooled serum from αNi 3 S 2 -treated rats, erythrocyte 59 Fe-uptake averaged 28% (S.D. +- 5) (vs 3.7 +- 1.1% in control rats; P 3 S 2 -treated rats averaged 130 I.U./liter (S.D. +- 18) (vs 27 +- 6 I.U./liter in control rats; P 3 S 2 is mediated by increased serum erythropoietin activity

  18. Study of the erythropoiesis activity of nano-encapsulated forms of erythropoietin

    Directory of Open Access Journals (Sweden)

    Zhanagul Khasenbekova

    2014-01-01

    Full Text Available Introduction: The recombinant human erythropoietin (rhEPO is used in the treatment of anemia. In order to improve its pharmacokinetic properties, nanoparticles of biodegradable polymers of natural or synthetic origin were used. The aim of this study was to investigate the effect of new nano-encapsulated forms of recombinant human erythropoietin for oral use on the erythropoiesis in the cyclophosphamide immunosuppression model. Material and methods: The CHOpE immortalized cells culture (a primary producer of rhEPO "Vector" in Russia was used. The following biodegradable polymers were chosen: 0.05% and 0.005% carbopol, 0.05% and 0.005% kollidon, and 0.05% and 0.005% pectin. Immunosuppression was obtained by a single dose of i.p. injection of cyclophosphamide (250 mg/kg in white mice (18-20 g. During the next 5 days, the nano-encapsulated erythropoietin (100 ED/mouse was administered orally to each mouse. After 5 and 10 days, the cell count of the number of blood reticulocytes and the myelogram of bone marrow were performed. The control group of mice received injections of Eprex. Results: On the 5th day of the experiment, the highest level of reticulocyte was observed in the samples of erythropoietin with kollidon (0.05% and pectin (0.005% nanoparticles. On the 10th day, the highest activity was observed in the samples of erythropoietin substance with pectin at 0.05% and 0.005% concentrations. The levels of reticulocytes in these groups reached 13.53% and 14.55%, respectively. The results of the myelogram during immunosuppression showed some activity of erythropoietin in conjunction with both concentrations of pectin when a two-fold increase in the number of erythroblasts was observed on the 5th day. High degrees of erythrokaryocytes in the state of mitosis were observed in the 0.05% pectin samples. Similar results were observed in equivalent groups of control animals on the 10th day of the experiment, which is compatible with the data on Eprex

  19. Aberrant phenotypes of transgenic mice expressing dimeric human erythropoietin

    Directory of Open Access Journals (Sweden)

    Yun Seong-Jo

    2012-01-01

    Full Text Available Abstract Background Dimeric human erythropoietin (dHuEPO peptides are reported to exhibit significantly higher biological activity than the monomeric form of recombinant EPO. The objective of this study was to produce transgenic (tg mice expressing dHuEPO and to investigate the characteristics of these mice. Methods A dHuEPO-expressing vector under the control of the goat beta-casein promoter, which produced a dimer of human EPO molecules linked by a 2-amino acid peptide linker (Asp-Ile, was constructed and injected into 1-cell fertilized embryos by microinjection. Mice were screened using genomic DNA samples obtained from tail biopsies. Blood samples were obtained by heart puncture using heparinized tubes, and hematologic parameters were assessed. Using the microarray analysis tool, we analyzed differences in gene expression in the spleens of tg and control mice. Results A high rate of spontaneous abortion or death of the offspring was observed in the recipients of dHuEPO embryos. We obtained 3 founder lines (#4, #11, and #47 of tg mice expressing the dHuEPO gene. However, only one founder line showed stable germline integration and transmission, subsequently establishing the only transgenic line (#11. We obtained 2 F1 mice and 3 F2 mice from line #11. The dHuEPO protein could not be obtained because of repeated spontaneous abortions in the tg mice. Tg mice exhibited symptoms such as short lifespan and abnormal blood composition. The red blood cell count, white blood cell count, and hematocrit levels in the tg mice were remarkably higher than those in the control mice. The spleens of the tg mice (F1 and F2 females were 11- and -21-fold larger than those of the control mice. Microarray analysis revealed 2,672 spleen-derived candidate genes; more genes were downregulated than upregulated (849/764. Reverse transcriptase-polymerase chain reaction (RT-PCR and quantitative real-time PCR (qRT-PCR were used for validating the results of the microarray

  20. Caveat Oncologist: Clinical Findings and Consequences of Distributing Counterfeit Erythropoietin in the United States

    Science.gov (United States)

    Qureshi, Zaina P.; Norris, LeAnn; Sartor, Oliver; McKoy, June M.; Armstrong, John; Raisch, Dennis W.; Garg, Vishvas; Stafkey-Mailey, Dana; Bennett, Charles Lee

    2012-01-01

    Purpose: Counterfeit pharmaceuticals pose risks domestically. Because of their cost, cancer pharmaceuticals are vulnerable. We review findings from a domestic counterfeiting episode involving erythropoietin and outline anticounterfeiting recommendations for policy makers, patients, and health care professionals. Materials and Methods: Information was obtained on patients who received counterfeit erythropoietin, its distribution, and criminal investigations into counterfeiting networks. Interview sources included a physician, an attorney, employees of the Florida Department of Health and Human Services and the US Food and Drug Administration's (FDA) Office of Criminal Investigation, manufacturers, and wholesalers. Other sources included the book “Dangerous Doses,” LexisNexis (search terms “counterfeit” and “erythropoietin”) and the FDA database. Results: Counterfeit product consisted of 2,000 U vials with counterfeit labels denoting 40,000 U. The counterfeiters, in collaboration with a Miami pharmacy, purchased 110,000 erythropoietin 2,000 U vials and affixed counterfeit labels to each vial. Products were then sold via the pharmaceutical “gray market” to wholesalers, then pharmacy chains. Investigations by Florida government officials implicated 17 persons, all of whom were found guilty of trafficking in counterfeit pharmaceuticals. Despite the large size of the operation, the FDA received reports of only 12 patients who had received counterfeit erythropoietin and detailed information for only two individuals. A 17-year-old liver transplant recipient and a 61-year-old patient with breast cancer experienced loss of efficacy after receiving counterfeit erythropoietin. Conclusion: Wider use of FDA anticounterfeit initiatives, limiting pharmaceutical suppliers to reputable distributors, and educating providers and patients about signs of counterfeit drugs can improve the safety of cancer pharmaceuticals. PMID:23077434

  1. Animal experiment studies on biological and chemical radiation protection - the combined effects of serotonin and erythropoletin

    International Nuclear Information System (INIS)

    Sasse, U.

    1975-01-01

    The influence of a prophylactic combination treatment with serotonin and erythropoietin on the inhibited erythropoiesis of whole-body irradiated mice (500 R) was studied. Both erythropoietin and serotonin turned out to compensate the radiation-induced inhibition of the formation rate for erythrocytes to a small extent. However, only the enhancement of erythropoiesis due to serotonin indicated significant values. Yet the combined application of the named substances yielded a distinct and significant effect in radiation protection which even exceeded the simple addition of the protective effect yielded by serotonin and erythropoietin alone. But despite of this considerable success the radiation damage in the erythropoietic system was not even half compensated for. (orig./MG) [de

  2. Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla; Inkster, Becky; O'Sullivan, Ursula

    2008-01-01

    Erythropoietin (Epo) has neuroprotective and neurotrophic effects and improves cognitive function in animal models of neurodegenerative and neuropsychiatric illness. In humans, weekly Epo administration over 3 months improves cognitive function in schizophrenia. The neural underpinnings and time...

  3. Comparison of erythropoietic response to erythropoietin-secreting stimuli in mice following polycythemia induced by transfusion or hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Alippi, R.M.; Barcelo, A.C.; Bozzini, C.E.

    1985-03-01

    The erythropoietic response, measured as RBC-/sup 59/Fe uptake, in response to either 24-h exposure to hypoxia or administration of dexamethasone, isoproterenol, testosterone, or erythropoietin, was determined in both posthypoxic (PH) and hypertransfused (HT) polycythemic mice. Highly significant differences between PH and HT mice exposed to hypoxia or injected with dexamethasone, isoproterenol, or testosterone were observed, isotope incorporation being always higher in PH than in HT mice. On the other hand, the response to erythropoietin did not show a significant difference between PH and HT mice. These results suggest that PH mice have been preconditioned by exposure to hypoxia in a way that makes them more sensitive to at least some kinds of erythropoietic stimuli. Since these stimuli have been shown by others to increase erythropoietin production, the results support the hypothesis that hypoxia induces sensitization of the erythropoietin- producing organ(s).

  4. Carbamylated monomeric allergoids as a therapeutic option for sublingual immunotherapy of dust mite- and grass pollen-induced allergic rhinoconjunctivitis: a systematic review of published trials with a meta-analysis of treatment using Lais® tablets.

    Science.gov (United States)

    Mösges, R; Ritter, B; Kayoko, G; Allekotte, S

    2010-10-01

    Lais® allergoid tablets contain allergens that are modified by carbamylation. Due to their modified chemical structure, they are suitable for sublingual immunotherapy (SLIT) (13, 16, 17, 24). Based on their small molecule size of 12 to 40 kDa, they can be easily absorbed via the oral mucosa (1). In this review, we studied the efficacy of SLIT with carbamylated monomeric allergoid tablets in the treatment of grass pollen- and dust mite-induced allergic rhinoconjunctivitis on the basis of symptom and medication score improvements. Following a selective internet and databank search, six trials-some placebo-controlled-regarding the treatment of grass pollen- (n = 266) and dust mite-induced (n = 241) allergic rhinoconjunctivitis were used to draw conclusions regarding the clinical efficacy of allergoid tablets. The primary endpoints in these trials were decreases in the need for allergy medications and/or reductions in the occurrence of rhinoconjunctivitis symptoms. Data was recorded from patient diaries regarding their symptoms and medications used and conclusions were then drawn about the effectiveness and tolerabieity of Lais® tablets. The average improvement in symptom score in three trials of grass pollen allergy treatment was 34% in comparison to the placebo group. The treatment of dust mite-induced rhinoconjunctivitis produced an average symptom score improvement of 22% compared to the placebo or control groups. The intake of symptomatic rescue medication during allergoid tablet therapy declined. Treatment of grass pollen allergies and dust mite-induced rhinoconjunctivitis showed an average medication score improvement of 49% and 24%, respectively. Few side effects were documented in the trials and predominantly local effects were observed. Severe systemic side effects did not occur. On the basis of the trial results summarized in this review, we suggest that SLIT using Lais® sublingual tablets is an effective and well-tolerated form of treatment.

  5. Activating mitochondrial function and haemoglobin expression with EH-201, an inducer of erythropoietin in neuronal cells, reverses memory impairment

    OpenAIRE

    Horng, Lin-Yea; Hsu, Pei-Lun; Chen, Li-Wen; Tseng, Wang-Zou; Hsu, Kai-Tin; Wu, Chia-Ling; Wu, Rong-Tsun

    2015-01-01

    Background and Purpose Memory impairment can be progressive in neurodegenerative diseases, and physiological ageing or brain injury, mitochondrial dysfunction and oxidative stress are critical components of these issues. An early clinical study has demonstrated cognitive improvement during erythropoietin treatment in patients with chronic renal failure. As erythropoietin cannot freely cross the blood?brain barrier, we tested EH-201 (2,3,5,4?-tetrahydroxystilbene-2-O-?-d-glucoside, also known ...

  6. Incorporation of Ortho- and Meta-Tyrosine Into Cellular Proteins Leads to Erythropoietin-Resistance in an Erythroid Cell Line

    Directory of Open Access Journals (Sweden)

    Esztella Mikolás

    2014-04-01

    Full Text Available Background/Aims: Erythropoietin-resistance is an unsolved concern in the treatment of renal anaemia. We aimed to investigate the possible role of ortho- and meta-tyrosine - the hydroxyl free radical products of L-phenylalanine - in the development of erythropoietin-resistance. Methods: TF-1 erythroblast cell line was used. Cell concentration was determined on day 1; 2 and 3 by two independent observers simultaneously in Bürker cell counting chambers. Protein concentration was determined with colorimetric method. Para-, ortho- and meta-tyrosine levels were measured using reverse phase-HPLC with fluorescence detection. Using Western blot method activating phosphorylation of STAT5 and ERK1/2 were investigated. Results: We found a time- and concentration-dependent decrease of erythropoietin-induced proliferative activity in case of ortho- and meta-tyrosine treated TF-1 erythroblasts, compared to the para-tyrosine cultured cells. Decreased erythropoietin-response could be regained with a competitive dose of para-tyrosine. Proteins of erythroblasts treated by ortho- or meta-tyrosine had lower para-tyrosine and higher ortho- or meta-tyrosine content. Activating phosphorylation of ERK and STAT5 due to erythropoietin was practically prevented by ortho- or meta-tyrosine treatment. Conclusion: According to this study elevated ortho- and meta-tyrosine content of erythroblasts may lead to the dysfunction of intracellular signaling, resulting in erythropoietin-hyporesponsiveness.

  7. Erythropoietin may reduce the risk of germ cell loss in boys with cryptorchidism

    DEFF Research Database (Denmark)

    Cortes, D; Visfeldt, J; Thorup, J M

    2001-01-01

    of infertility. In order to increase the number of germ cells, and thereby the fertility potential, additional hormonal therapy has been attempted before surgery. In a study, small doses of the gonadotropin-releasing hormone analogue buserelin before orchiopexy caused higher values. Others have found......: Erythropoietin (Eprex) 100 IU/kg were administered subcutaneously weekly for 3 months prior to surgery in two cryptorchid boys, 6 months old and 1 year 9 months old, respectively, with renal function impairment. RESULTS: The number of spermatogonia per tubular cross-section in testicular biopsies was unusually...... that hormonal treatment with human chorionic gonadotropin or gonadotropin releasing hormone analogue may harm the germ cells in cryptorchidism. The aim of the study is to demonstrate that additional hormonal therapy with erythropoietin has a positive effect on the number of germ cells. MATERIALS AND METHODS...

  8. Effects of prolonged recombinant human erythropoietin administration on muscle membrane transport systems and metabolic marker enzymes

    DEFF Research Database (Denmark)

    Juel, C; Thomsen, J J; Rentsch, R L

    2007-01-01

    on the expression of muscle membrane transport proteins. Likewise, improvements in performance may involve upregulation of metabolic enzymes. Since Epo is known to augment performance we tested the effect of rHuEpo on some marker enzymes that are related to aerobic capacity. For these purposes eight subjects...... performance by approximately 54%. Membrane transport systems and carbonic anhydrases involved in pH regulation remained unchanged. Of the Na(+), K(+)-pump isoforms only the density of the alpha2 subunit was decreased (by 22%) after treatment. The marker enzymes cytochrom c and hexokinase remained unchanged......Adaptations to chronic hypoxia involve changes in membrane transport proteins. The underlying mechanism of this response may be related to concomitant occurring changes in erythropoietin (Epo) levels. We therefore tested the direct effects of recombinant human erythropoietin (rHuEpo) treatment...

  9. Erythropoietin resistance in end-stage renal disease patient with gastric antral vascular ectasia

    Directory of Open Access Journals (Sweden)

    Desiree Ji Re Lee

    2015-09-01

    Full Text Available AbstractWe observed a case of recombinant human erythropoietin resistance caused by Gastric Antral Vascular Ectasia in a 40-year-old female with ESRD on hemodialysis. Some associated factors such as autoimmune disease, hemolysis, heart and liver disease were discarded on physical examination and complementary tests. The diagnosis is based on the clinical history and endoscopic appearance of watermelon stomach. The histologic findings are fibromuscular proliferation and capillary ectasia with microvascular thrombosis of the lamina propria. However, these histologic findings are not necessary to confirm the diagnosis. Gastric Antral Vascular Ectasia is a serious condition and should be considered in ESRD patients on hemodialysis with anemia and resistance to recombinant human erythropoietin because GAVE is potentially curable with specific endoscopic treatment method or through surgical procedure.

  10. Form CMS-2728 data versus erythropoietin claims data: implications for quality of care studies.

    Science.gov (United States)

    Beaubrun, Anne C; Kanda, Eiichiro; Bond, T Christopher; McClellan, William M

    2013-01-01

    Medical Evidence Report Form CMS-2728 data is frequently used to study US dialysis patients, but the validity of these data have been called into question. We compared predialysis erythropoietin use as recorded on Form CMS-2728 with claims data as part of an assessment of quality of care among hemodialysis patients. Medicare claims were linked to Form CMS-2728 data for 18,870 patients. Dialysis patients, 67 years old or older, who started dialysis from 1 June 2005 to 31 May 2007 were eligible. Logistic and multivariate regressions were used to compare the use of either Form CMS-2728 or the corresponding claims data to predict mortality and the probability of meeting target hemoglobin levels. The sensitivity, specificity, and kappa coefficient for the predialysis erythropoietin indicator were 58.0%, 78.4%, and 0.36, respectively. Patients with a predialysis erythropoietin claim were less likely to die compared with patients without a claim (odds ratio = 0.80 and 95% confidence interval = 0.74-0.87), but there was no relationship observed between predialysis care and death using only Form CMS-2728 predictors. At the facility level, a predialysis erythropoietin claim was associated with a 0.085 increase in the rate of meeting target hemoglobin levels compared with patients without a claim (p = 0.041), but no statistically significant relationship was observed when using the Form CMS-2728 indicators. The agreement between Form CMS-2728 and claims data is poor and discordant results are observed when comparing the use of these data sources to predict health outcomes. Facilities with higher agreement between the two data sources may provide greater quality of care.

  11. Increased Levels of Erythropoietin in Nipple Aspirate Fluid and in Ductal Cells from Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Ferdinando Mannello

    2008-01-01

    Full Text Available Background: Erythropoietin (Epo is an important regulator of erythropoiesis, and controls proliferation and differentiation of both erythroid and non-erythroid tissues. Epo is actively synthesized by breast cells during lactation, and also plays a role in breast tissues promoting hypoxia-induced cancer initiation. Our aims are to perform an exploratory investigation on the Epo accumulation in breast secretions from healthy and cancer patients and its localization in breast cancer cells.

  12. Activation of erythropoietin receptors by Friend viral gp55 and by erythropoietin and down-modulation by the murine Fv-2r resistance gene

    International Nuclear Information System (INIS)

    Hoatlin, M.E.; Kozak, S.L.; Kabat, D.; Lilly, F.; Chakraborti, A.; Kozak, C.A.

    1990-01-01

    The leukemogenic membrane glycoprotein (gp55) encoded by Friend spleen focus-forming virus appears to bind to erythropoietin receptors (EpoR) to stimulate erythroblastosis. To directly compare the effects of gp55 with erythropoietin (Epo), the authors produced retrovirions that encode either gp55, Epo, or EpoR. After infection with EpoR virus, interleukin 3-dependent DA-3 cells bound 125 I-labeled Epo and grew without interleukin 3 in the presence of Epo. These latter cells, but not parental DA-3 cells, became factor-independent after superinfection either with Epo virus or with Friend spleen focus-forming virus. In addition, Epo virus caused a disease in mice that mimicked Friend erythroleukemia. Although Fv-2 r homozygotes are susceptible to all other retroviral diseases, they are resistant to both Epo viral and Friend viral erythroleukemia. These results indicate that both gp55 and Epo stimulate EpoR and that the Fv-2 gene encodes a protein that controls response to these ligands. However, the Fv-2 protein is not EpoR because the corresponding genes map to opposite ends of mouse chromosome 9. These results have important implications for understanding signal transduction by EpoR and the role of host genetic variation in controlling susceptibility to an oncogenic protein

  13. Intraosseous Erythropoietin for Acute Tissue Protection in Battlefield Casualties Suffering Hypovolemic Shock

    Science.gov (United States)

    2015-07-01

    tidal volume of 10 mL?kg21, peak flow of 60 l?min21, and FiO2 of 0.5. Respiratory rate was adjusted at baseline to maintain the end- expired PCO2 (PETCO...lactic acidosis (Table 3). Of the 12 animals that received fluids, 11 were resuscitated and remained alive at 72 hours. Of the 12 Figure 7. Metabolic...same time, substantial systemic lactic acidosis developed in series HS-65BV and series HS-65BV+VP, indicating critical reductions in oxygen delivery

  14. Intraosseous Erythropoietin for Acute Tissue Protection in Battlefield Casualties Suffering Hypovolemic Shock

    Science.gov (United States)

    2013-11-01

    Resuscitation. Universidad Católica de la Santísima Concepción, Facultad de Ciencias de la Salud . May 7-8. Concepción, Chile. 1997 Advances in CPR...Med 2003;31:2811-2812. 20. Gazmuri RJ. Editorial: Optimizando la calidad en medicina intensiva [Optimizing the quality of intensive care medicine...increase in left ventricular stroke work index and cardiac index – likely an effect on preload – that helped increase the aor- tic pressure and reduce the

  15. Prevention of contrast-induced nephropathy with single bolus erythropoietin in patients with diabetic kidney disease: A randomized controlled trial.

    Science.gov (United States)

    Shema-Didi, Lilach; Kristal, Batya; Eizenberg, Sarit; Marzuq, Nabil; Sussan, Majdy; Feldman-Idov, Yulie; Ofir, Pnina; Atar, Shaul

    2016-04-01

    Contrast-induced-nephropathy (CIN) is associated with poor outcomes, thus prevention of CIN may be of clinical value. Erythropoietin (EPO) has been shown to elicit tissue-protective effects in experimental models and in clinical studies of acute kidney injury. We therefore evaluated its effectiveness for prevention of CIN after coronary angiography (CA) ± percutaneous coronary intervention (PCI) in diabetic patients with chronic kidney disease. A prospective, randomized, controlled trial was carried out in 138 diabetic patients with eGFR <60 mL/min who underwent non-urgent CA ± PCI. Patients received normal saline and n-acetyl cysteine before CA, with or without 50,000 U of EPO administered 30 min prior to CA. CIN was defined as an increase in serum creatinine of at least 0.5 mg/dL during the first 2 days after exposure to contrast media. Primary outcome was the incidence of CIN. Secondary outcomes were the sensitivity and positive predictive value (PPV) of Cystatin C (CC) and Neutrophil-gelatinase-associated-lipocalin (NGAL) for diagnosis of CIN. The observed incidence of CIN was 8.7%, significantly lower than the expected for such high-risk population. The administration of EPO prior to CA did not reduce the incidence of CIN (9.7% vs. 7.6%, P = 0.65). CC and NGAL demonstrated a low sensitivity (16.6%) and low PPV (6.7 and 33.3%, respectively) for detecting CIN. The administration of EPO prior to CA did not reduce the incidence of CIN. Additional prospective research with a larger sample size and in other patient categories is essential to further define the potential protective effect of EPO on prevention of CIN. © 2015 Asian Pacific Society of Nephrology.

  16. Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α.

    Science.gov (United States)

    Nagaya, Yoshiaki; Aoyama, Mineyoshi; Tamura, Tetsuya; Kakita, Hiroki; Kato, Shin; Hida, Hideki; Saitoh, Shinji; Asai, Kiyofumi

    2014-12-01

    Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood-brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo. In cultured astrocytes exposed to hypoxic conditions for 6 and 12 h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  17. Activating mitochondrial function and haemoglobin expression with EH-201, an inducer of erythropoietin in neuronal cells, reverses memory impairment.

    Science.gov (United States)

    Horng, Lin-Yea; Hsu, Pei-Lun; Chen, Li-Wen; Tseng, Wang-Zou; Hsu, Kai-Tin; Wu, Chia-Ling; Wu, Rong-Tsun

    2015-10-01

    Memory impairment can be progressive in neurodegenerative diseases, and physiological ageing or brain injury, mitochondrial dysfunction and oxidative stress are critical components of these issues. An early clinical study has demonstrated cognitive improvement during erythropoietin treatment in patients with chronic renal failure. As erythropoietin cannot freely cross the blood-brain barrier, we tested EH-201 (2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside, also known as TSG), a low MW inducer of erythropoietin, for its therapeutic effects on memory impairment in models of neurodegenerative diseases, physiological ageing or brain injury. The effects of EH-201 were investigated in astrocytes and PC12 neuronal-like cells. In vivo, we used sleep-deprived (SD) mice as a stress model, amyloid-β (Aβ)-injected mice as a physiological ageing model and kainic acid (KA)-injected mice as a brain damage model to assess the therapeutic effects of EH-201. EH-201 induced expression of erythropoietin, PPAR-γ coactivator 1α (PGC-1α) and haemoglobin in astrocytes and PC12 neuronal-like cells. In vivo, EH-201 treatment restored memory impairment, as assessed by the passive avoidance test, in SD, Aβ and KA mouse models. In the hippocampus of mice given EH-201 in their diet, levels of erythropoietin, PGC-1α and haemoglobin were increased The induction of endogenous erythropoietin in neuronal cells by inducers such as EH-201 might be a therapeutic strategy for memory impairment in neurodegenerative disease, physiological ageing or traumatic brain injury. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  18. National Cooperative rHu Erythropoietin Study in patients with chronic renal failure--an interim report. The National Cooperative rHu Erythropoietin Study Group.

    Science.gov (United States)

    Levin, N W; Lazarus, J M; Nissenson, A R

    1993-08-01

    This second interim report of the National Cooperative rHu Erythropoietin Study presents data from 324 patients new to recombinant human erythropoietin (Epoetin alfa) who completed at least 12 months of study participation. Mean hematocrit levels increased to approximately 30% by month 3 in patients on hemodialysis (n = 293) and stabilized for the remainder of the study whether Epoetin alfa was administered by the intravenous (n = 250) or subcutaneous (n = 42) route. The intravenous dosage level ranged between 106.9 and 121.6 U/kg/wk; subcutaneous dosing ranged between 87.4 and 108.0 U/kg/wk; dosing levels in patients on peritoneal dialysis (n = 31) were similar, although there was a trend towards slightly higher hematocrit levels. Throughout the 12 months of the study, there was no relationship between blood pressure and either hematocrit level or Epoetin alfa dose. Approximately two thirds of the patients were receiving iron supplementation at any given time, and there was a trend towards the increased use of oral iron supplements. The incidence of adverse events in this cohort of patients was low throughout the study, and there was no relationship between the incidence of adverse events and either hematocrit level or Epoetin alfa dose. Based on an analysis of data from baseline to first follow-up, Epoetin alfa therapy resulted in improvement in several quality-of-life factors, most notable of which was vitality. Improvement occurred in all patient subgroups with some variability in the level and intensity of effect. Overall, these data demonstrate that Epoetin alfa therapy is safe and effective when used in a broad cross-section of patients on dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Favaron, Elisa; Hafizi, Sepehr

    2010-01-01

    Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The curren...... study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients.......Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The current...

  20. Recombinant human erythropoietin improves angiogenesis and wound healing in experimental burn wounds.

    Science.gov (United States)

    Galeano, Mariarosaria; Altavilla, Domenica; Bitto, Alessandra; Minutoli, Letteria; Calò, Margherita; Lo Cascio, Patrizia; Polito, Francesca; Giugliano, Giovanni; Squadrito, Giovanni; Mioni, Chiara; Giuliani, Daniela; Venuti, Francesco S; Squadrito, Francesco

    2006-04-01

    Erythropoietin interacts with vascular endothelial growth factor (VEGF) and stimulates endothelial cell mitosis and motility; thus it may be of importance in the complex phenomenon of wound healing. The purpose of this study was to investigate the effect of recombinant human erythropoietin (rHuEPO) on experimental burn wounds. Randomized experiment. Research laboratory. C57BL/6 male mice weighing 25-30 g. Mice were immersed in 80 degrees C water for 10 secs to achieve a deep-dermal second degree burn. Animals were randomized to receive either rHuEPO (400 units/kg/day for 14 days in 100 microL subcutaneously) or its vehicle alone (100 microl/day distilled water for 14 days subcutaneously). On day 14 the animals were killed. Burn areas were used for histologic examination, evaluation of neoangiogenesis by immunohistochemistry, and expression (Western blot) of the specific endothelial marker CD31 as well as quantification of microvessel density, measurement of VEGF wound content (enzyme-linked immunosorbent assay), expression (Western blot) of endothelial and inducible nitric oxide synthases, and determination of wound nitric oxide (NO) products. rHuEPO increased burn wound reepithelialization and reduced the time to final wound closure. These effects were completely abated by a passive immunization with specific antibodies against erythropoietin. rHuEPO improved healing of burn wound through increased epithelial proliferation, maturation of the extracellular matrix, and angiogenesis. The hematopoietic factor augmented neoangiogenesis as suggested by the marked increase in microvessel density and by the robust expression of the specific endothelial marker CD31. Furthermore, rHuEPO enhanced the wound content of VEGF caused a marked expression of endothelial and inducible nitric oxide synthases and increased wound content of nitric oxide products. Our study suggests that rHuEPO may be an effective therapeutic approach to improve clinical outcomes after thermal injury.

  1. Management of anemia in patients undergoing curative radiotherapy. Erythropoietin, transfusions, or better nothing?

    International Nuclear Information System (INIS)

    Dunst, J.

    2004-01-01

    Background and results: anemia is a well-known risk factor for decreased local control and survival in patients undergoing curative radiotherapy. There is clear evidence from recent clinical investigations that anemia is an independent risk factor and hemoglobin (Hb) levels during radiotherapy are important (and not pretreatment Hb levels). The most likely explanation for the prognostic impact is the association with tumor hypoxia. An ''optimal'' Hb range with regard to tumor oxygenation seems to exist, and Hb levels ∝15 g/dl impair tumor oxygenation but have (over a broader range) no significant impact on normal tissue oxygenation. There is some evidence from retrospective and prospective studies that the response to radiotherapy and the prognosis, especially in cervical cancers, might be improved if the Hb levels during radiotherapy can be maintained in the optimal range, either by transfusions or by erythropoietin. The effect of any antianemic therapy should be analyzed according to whether or not treatment was successful with regard to achieving optimal Hb levels during irradiation. Erythropoietin is probably more effective in steadily increasing and stabilizing Hb levels, but bears the risk of overcorrection of Hb levels. The clinical relevance of erythropoietin receptors on tumor cells remains questionable. Conclusions: treatment of anemia with the objective of improving local control and survival in radiotherapy patients is probably more difficult and sophisticated than coping with symptoms of anemia or improving quality of life. Nevertheless, the potential of antianemic treatment is high on the basis of experimental and clinical data, and further clinical trials are warranted. (orig.)

  2. Use of high-dose erythropoietin for repair after injury: A comparison of outcomes in heart and kidney.

    Science.gov (United States)

    Gobe, Glenda C; Morais, Christudas; Vesey, David A; Johnson, David W

    2013-07-01

    There is a need to define the exact benefits and contraindications of use of high-dose recombinant human erythropoietin (EPO) for its non-hematopoietic function as a cytokine that enhances tissue repair after injury. This review compares the outcomes from use of EPO in the injured heart and kidney, two organs that are thought, traditionally, to have intrinsically-different repair mechanisms. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. Ongoing work by us on EPO protection of ischemia-reperfusion-injured kidneys indicated, first, that EPO acutely enhanced kidney repair via anti-apoptotic, pro-regenerative mechanisms, and second, that EPO may promote chronic fibrosis in the long term. Work by others on the ischaemia-injured heart has also indicated that EPO promotes repair. Although myocardial infarcts are made up mostly of necrotic tissue, many publications state EPO is anti-apoptotic in the heart, as well as promoting healing via cell differentiation and stimulation of granulation tissue. In the case of the heart, promotion of fibrosis may be advantageous where an infarct has destroyed a zone of cardiomyocytes, but if EPO stimulates progressive fibrosis in the heart, this may promote cardiac failure. A major concern in relation to the use of EPO in a cytoprotective role is its stimulation of long-term inflammation and fibrosis. EPO usage for cytoprotection is undoubtedly advantageous, but it may need to be offset with an anti-inflammatory agent in some organs, like kidney and heart, where progression to chronic fibrosis after acute injury is often recorded.

  3. Effect of a combined treatment with erythropoietin and melatonin on renal ischemia reperfusion injury in male rats.

    Science.gov (United States)

    Ahmadiasl, Nasser; Banaei, Shokofeh; Alihemati, Alireza; Baradaran, Behzad; Azimian, Ehsan

    2014-12-01

    Renal ischemia reperfusion (IR) is an important cause of renal dysfunction. It contributes to the development of acute renal failure. Oxidative damage from reactive oxygen species is considered to be the principal component involved in the pathophysiological tissue alterations observed during IR. The purpose of this study was to evaluate the effect of a combined treatment with erythropoietin (EPO) plus melatonin (MEL), which are known anti-inflammatory and antioxidant agents, in IR-induced renal injury in rats. Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h of reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to ischemia. After 24 h of reperfusion, blood samples were collected for the determination of superoxide dismutase (SOD), glutathione peroxidase (GPx), plasma levels of total antioxidant capacity (TAC), and malondialdehyde (MDA) and serum urea level. Also, renal samples were taken for histological evaluation. Ischemia reperfusion significantly increased urea, blood SOD, and GPx levels. Histological findings of the IR group indicated that there was increase in tubular and glomerular hyaline cast, thickening of Bowman capsule basement membrane, and renal impairment in the glomerular epithelium. Treatment with EPO and MEL significantly decreased blood SOD, GPx, and urea levels and increased TAC level. In the EPO + MEL group, while the histopathological changes were lower than those in EPO group, they were the same as MEL group. EPO and MEL combination treatment exerted more nephroprotective effects than EPO treatment and nearly had protective effects similar to MEL treatment.

  4. Effects of low-dose recombinant human erythropoietin treatment on cognitive performance

    DEFF Research Database (Denmark)

    Viuff, Søren Lundgaard; Plenge, Ulla; Belhage, Bo

    2017-01-01

    , NUFI or self-reported results between the groups. CONCLUSIONS: In this small study, we found no significant effect of low-dose or micro-dose rhEpo on visual attention, cognitive performance in complex cognitive tasks or self-experienced cognitive performance compared with placebo. FUNDING: The Aase......INTRODUCTION: High-dose recombinant human erythropoietin (rhEpo) has been shown to improve cognitive performance in both healthy volunteers and in patients suffering from diseases affecting the brain. The aim of this study was to examine whether administration of low-dose and even micro-dose rh...

  5. Effects of low-dose recombinant human erythropoietin treatment on cognitive performance

    DEFF Research Database (Denmark)

    Viuff, Søren Lundgaard; Plenge, Ulla; Belhage, Bo

    2017-01-01

    -reported results between the groups. Conclusions: In this small study, we found no significant effect of low-dose or micro-dose rhEpo on visual attention, cognitive performance in complex cognitive tasks or self-experienced cognitive performance compared with placebo. Funding: The Aase and Ejnar Danielsen......Introduction: High-dose recombinant human erythropoietin (rhEpo) has been shown to improve cognitive performance in both healthy volunteers and in patients suffering from diseases affecting the brain. The aim of this study was to examine whether administration of low-dose and even micro-dose rh...

  6. Immunoreactive erythropoietin concentrations in neonatal rats and the effects of hypoxia

    International Nuclear Information System (INIS)

    Clemons, G.K.; Fitzsimmons, S.L.; DeManincor, D.

    1987-01-01

    We attempted to find answers to what are the circulating, hepatic and renal erythropoietin (Ep) levels in normal rat neonates measured daily through the first three weeks of life and when they attain sexual maturity, how are these Ep levels altered by exposure to hypoxia, and whether can it be transferred to the nursing neonatal animals? Since we established earlier that in the fetal rat the liver is the main Ep producing tissue, we attempted to determine the age at which the switch from liver to kidney occurred in both the normal and the hypoxic neonatal rat. 2 figs

  7. New insights for identification of doping with recombinant human erythropoietin micro-doses after high hydration

    DEFF Research Database (Denmark)

    Martin, L.; Ashenden, M; Bejder, Jacob

    2016-01-01

    To minimize the chances of being caught after doping with recombinant human erythropoietins (rhEPO), athletes have turned to new practices using micro-doses and excess fluid ingestion to accelerate elimination and decrease the probability of detection. Our objective was to test the sensitivity...... subjects. After an injection in the evening, urine and plasma samples were collected the following morning. Half of the subjects then drank a bolus of water and new samples were collected 80 min later. Interestingly, rhEPO was detected in 100% of the samples even after water ingestion. A second similar...

  8. [Renal cell carcinoma producing erythrocytosis due to inappropriate production of erythropoietin].

    Science.gov (United States)

    Villanueva-Gimeno, M M; Vicario-Bermúdez, J M; Fonseca-López, Ch; Caballero-Castro, J P; Zabala-López, S I; Sánchez-Elipe, M A; González-Gómez, N

    2013-01-01

    Erythrocytosis, or polycythaemia, is an increase, in absolute terms, of the erythrocyte mass. The most common solid tumour related to this phenomenon is renal cell carcinoma, which can produce erythrocytosis by increasing erythropoietin production. About 30% of symptomatic renal cell carcinomas are diagnosed due to the appearance of a paraneoplastic syndrome. Polycythaemia is one of these. Surgery, (radical or partial nephrectomy), is the treatment of choice in renal cell carcinoma and helps to keep the erythrocytosis situation under control. Copyright © 2011 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

  9. Erythropoietin as an add-on treatment for cognitive side effects of electroconvulsive therapy

    DEFF Research Database (Denmark)

    Schmidt, Lejla Sjanic; Petersen, Jeff Zarp; Vinberg, Maj

    2018-01-01

    trial investigates (1) whether short-term add-on treatment with erythropoietin (EPO) can reduce the cognitive side -effects of ECT and (2) whether such effects are long-lasting. Further, structural and functional magnetic resonance imaging (MRI) will be used to explore the neural underpinnings...... cognitive benefits of EPO are investigated with structural and functional MRI after the final EPO/saline infusion. The primary outcome is change from baseline to after EPO treatment (3 days after eight ECT sessions) in a cognitive composite score spanning attention, psychomotor speed, and executive...... of covariance. Functional MRI data will be preprocessed and analyzed using the FMRIB Software Library....

  10. Erythropoietin--en ny terapi ved cerebral iskaemi?

    DEFF Research Database (Denmark)

    Kalialis, Louise Vennegaard; Olsen, Niels Vidiendal

    2003-01-01

    as an anti-inflammatory and neuroprotective drug. EPO and its receptor are expressed in neurons, glial cells and brain capillary endothelial cells, and the system is upregulated in conditions of cerebral ischaemia and hypoxia. Animal studies have now established that intracerebroventricular administration...... of recombinant EPO exerts neuroprotection in models of stroke. The mechanisms appear to involve an upregulation of specific anti-apoptotic and anti-inflammatory pathways. In addition, neurotrophic and angiogenetic effects of EPO may contribute in a long latency protection. Interestingly, also systemic...... administration of recombinant EPO ameliorates neuronal damage after brain ischaemia, and prevents the loss of autoregulation of cerebral blood flow following experimental subarachnoid haemorrhage. Recombinant human EPO is a safe and non-toxic drug, and clinical studies are currently investigating...

  11. Anemia in kidney transplants without erythropoietic agents: levels of erythropoietin and iron parameters.

    Science.gov (United States)

    Florit, E A; Hadad, F; Rodriguez Cubillo, B; De la Flor, J C; Valga, F; Perez Flores, I; Calvo Romero, N; Valero San Cecilio, R; Barrientos Guzman, A; Sanchez Fructuoso, A

    2012-11-01

    To study the association between hemoglobin, endogenous erythropoietin (EPO) levels and ferric parameters in kidney recipients not treated with EPO-stimulating agents. Transverse study of 219 kidney transplant outpatients. The median time after transplantation was 54 months (P(25-75), 23-107). We assessed blood counts, ferric parameters, EPO levels, renal function (MDRD-4), and adjuvant treatment. We performed a linear regression analysis to predict hemoglobin. Median EPO values were 14.05 mUI/mL (P(25-75) = 10.2-19.7). Applying the formulas described by Beguin, kidney transplant recipients showed a low observed/expected ratio of erythropoietin and of transferrin. Considering anemia to be an hemoglobin of calculate hemoglobin was: hemoglobin = 11829-0909 log (EPG level) - 0455 (if female) + 0.010 0.013 transferrin + 0.013 creatinine clearance (r = .424, P < .001). Treatment with ACEI and/or ARBs seemed to produce a defect in the synthesis of EPO, while those treated with mTORi, a hyporesponsive state. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. The effect of erythropoietin on calcium levels during hypoxia reoxygenation injury in rats

    Directory of Open Access Journals (Sweden)

    Constantinos Tsompos

    2016-04-01

    Full Text Available This experimental study examined the effect of erythropoietin (Epo on rat model and particularly in a hypoxia-reoxygenation protocol. The effect of that molecule was studied biochemically using blood mean calcium levels (Ca++. Forty rats of mean weight 247.7 g were used in the study. Ca++ levels were measured at 60 min (groups A and C and at 120 min (groups B and D of reoxygenation. Erythropoietin was administered only in groups C and D. Epo administration non-significantly decreased the Ca++ levels by 0.56%±1.13% (P=0.5761. Reoxygenation time non-significantly increased the Ca++ levels by 0.65%±1.12% (P=0.5281. However, Epo administration and reoxygenation time together non-significantly decreased the Ca++ levels by 0.34%±0.68% (P=0.6095. Epo administration whether it interacted or not with reoxygenation time had non-significant decreasing short-term effects on calcium levels. Perhaps, a longer study time than 2 h or a higher Epo dose may reveal more significant effects.

  13. Erythropoietin combined with liposomal amphotericin b improves outcome during disseminated aspergillosis in mice

    Directory of Open Access Journals (Sweden)

    nathalie erousseau

    2014-10-01

    Full Text Available Disseminated aspergillosis is responsible for a high mortality rate despite the use of antifungal drugs. Adjuvant therapies are urgently needed to improve the outcome. The aim of this study was to demonstrate that the cytoprotective effect of erythropoietin combined to amphotericin b can reduce the mortality rate in a murine model of disseminated aspergillosis. After infection with Aspergillus fumigatus, neutropenic mice were randomized to receive vehicle or 7,5 mg/Kg of Liposomal Amphotericin B (LAmB or 7,5 mg/Kg of LAmB combined with 1000 IU/Kg of EPO (16 mice per group. Aspergillus galactomannan and organ cultures were performed to evaluate fungal burden at day 5. Cumulative long-term survival was analyzed at day 12 post-infection according to the Kaplan-Meier method. At day 5, fungal burden was similar between non-treated and treated groups. At day 12, mortality rates were 75 %, 62.5 % and 31 % in control group, LAmB group and EPO/LAmB group, respectively. We observed a significant decreased in mortality using EPO/LAmB combination compared to control group (p < 0.01. LAmB single treatment did not improve the survival rate compared to control group (p = 0.155.Our results provided the first evidence that erythropoietin improved the outcome of mice presenting disseminated aspergillosis when combined with amphotericin b.

  14. Investigation of Genetic Disturbances in Oxygen Sensing and Erythropoietin Signaling Pathways in Cases of Idiopathic Erythrocytosis

    Directory of Open Access Journals (Sweden)

    Carla Luana Dinardo

    2013-01-01

    Full Text Available Background. Idiopathic erythrocytosis is the term reserved for cases with unexplained origins of abnormally increased hemoglobin after initial investigation. Extensive molecular investigation of genes associated with oxygen sensing and erythropoietin signaling pathways, in those cases, usually involves sequencing all of their exons and it may be time consuming. Aim. To perform a strategy for molecular investigation of patients with idiopathic erythrocytosis regarding oxygen sensing and erythropoietin signaling pathways. Methods. Samples of patients with idiopathic erythrocytosis were evaluated for the EPOR, VHL, PHD2, and HIF-2α genes using bidirectional sequencing of their hotspots. Results. One case was associated with HIF-2α mutation. Sequencing did not identify any pathogenic mutation in 4 of 5 cases studied in any of the studied genes. Three known nonpathogenic polymorphisms were found (VHL p.P25L, rs35460768; HIF-2α p.N636N, rs35606117; HIF-2α p.P579P, rs184760160. Conclusion. Extensive molecular investigation of cases considered as idiopathic erythrocytosis does not frequently change the treatment of the patient. However, we propose a complementary molecular investigation of those cases comprising genes associated with erythrocytosis phenotype to meet both academic and genetic counseling purposes.

  15. Hemoglobin and hematocrit at the end of hemodialysis: a better way to adjust erythropoietin dose?

    Science.gov (United States)

    Rangel, Erika B; Andreoli, Maria Claudia; Matos, Ana Cristina C; Guimarães-Souza, Nadia K; Mallet, Ana Cláudia; Carneiro, Fabiana D; Santos, Bento C

    2010-04-01

    A severe disadvantage of administration of recombinant human erythropoietin to hemodialysis patients has been reported. A significant correlation has been shown with hemoglobin values determined online by use of the blood volume monitor (BVM) and by laboratory measurement. Online hemoglobin and hematocrit were measured by use of the BVM during hemodialysis session. Data were analyzed by t test and statistical significance was defined as a P of hemoglobin and hematocrit from 11.6 +/- 1.9 to 13.9 +/- 2.4 g/dL (17.4 +/- 7.1%, P = 0.02) and from 34.4 +/- 6.8 to 42 +/- 8.3% (20.6 +/- 8.8%, P = 0.022), respectively, were observed from the beginning to the end of dialysis. We hypothesize that a new strategy for adjusting erythropoietin dose may be based on hemoglobin and hematocrit values evaluated at the end of hemodialysis, when patients are no longer hypervolemic. Inadvertent high levels of hemoglobin could be one explanation why patients present higher rates of cardiovascular and access-related events, especially when monitored online by use of the BVM to achieve the dry weight.

  16. Distribution of 131I-labeled recombinant human erythropoietin in maternal and fetal organs following intravenous administration in pregnant rats

    International Nuclear Information System (INIS)

    Yilmaz, O.; Lambrecht, F.Y.; Durkan, K.; Gokmen, N.; Erbayraktar, S.

    2007-01-01

    The aim of the present study was to demonstrate the possible transplacental transmission of 131 I labeled recombinant human erythropoietin ( 131 I-rh-EPO) in pregnant rats and its distribution through maternal and fetal organs. Six Wistar Albino Rats in their pregnancy of 18 days were used 131 I labeled recombinant human erythropoietin (specific activity = 2.4 μCi/IU) was injected into the tail vein of rats. After 30 minutes labeled erythropoietin infusion maternal stomach, kidney, lung, liver, brain and heart as well as fetus were removed. Then, the same organs were removed from each fetus. Measuring weight of maternal and fetal organs as well as placenta were followed by radioactivity count via Cd(Te) detector. 131 I labeled recombinant human erythropoietin was found to be able to pass rat placenta and its distribution order in fetal organs was similar to those of maternal organs. Besides, as measurements were performed closer to cornu uteri, uptakes were decreasing in every fetus and its corresponding placenta. (author)

  17. Effects of an 8-weeks erythropoietin treatment on mitochondrial and Whole body fat oxidation capacity during exercise in healthy males

    DEFF Research Database (Denmark)

    Guadalupe Grau, Amelia; Plenge, Ulla; Bønding, Signe Helbo

    2015-01-01

    fat oxidation were measured. Biopsies of the vastus lateralis muscle were obtained before and after the intervention. Recombinant erythropoietin treatment increased mitochondrial O2 flux during ADP stimulated state 3 respiration in the presence of complex I and II substrates (malate, glutamate...

  18. Determinants of Red Cell Distribution Width (RDW) in Cardiorenal Patients : RDW is Not Related to Erythropoietin Resistance

    NARCIS (Netherlands)

    Emans, Mireille E.; van der Putten, Karien; van Rooijen, Karlijn L.; Kraaijenhagen, Rob J.; Swinkels, Dorine; van Solinge, Wouter W.; Cramer, Maarten J.; Doevendans, Pieter A. F. M.; Braam, Branko; Gaillard, Carlo A. J. M.

    Background: Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity,

  19. Generation and phenotypic analysis of a transgenic line of rabbits secreting active recombinant human erythropoietin in the milk

    Czech Academy of Sciences Publication Activity Database

    Mikuš, Tomáš; Poplštein, M.; Sedláková, J.; Landa, Vladimír; Jeníková, Gabriela; Trefil, P.; Lidický, J.; Malý, Petr

    2004-01-01

    Roč. 13, č. 5 (2004), s. 487-498 ISSN 0962-8819 R&D Projects: GA ČR GA304/03/0090 Institutional research plan: CEZ:AV0Z5052915 Keywords : erythropoietin, mammary gland, transgenic rabbit Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.107, year: 2004

  20. Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin

    DEFF Research Database (Denmark)

    Robach, Paul; Recalcati, Stefania; Girelli, Domenico

    2009-01-01

    healthy volunteers were treated with recombinant erythropoietin (rhEpo) for 1 month. As expected, the treatment efficiently increased erythropoiesis and stimulated bone marrow iron use. It was also associated with a prompt and considerable decrease in urinary hepcidin and a slight transient increase...

  1. Recombinant human erythropoietin and blood transfusion in low-birth weight preterm infants under restrictive transfusion guidelines

    International Nuclear Information System (INIS)

    Badiee, Z.; Pourmirzaiee, Mohmmad A.; Naseri, F.; Kelishadi, R.

    2006-01-01

    To compare the number and volume of red blood cell transfusions (RBCTs) in very low birth weight infants under restrictive red blood cell transfusion guidelines with and without erythropoietin administration. In a controlled clinical trial conducted at the neonatal intensive care unit of Alzahra Hospital, Isfahan, Iran, between April 2002 to April 2004, 60 premature infants with gestational age up to 34 weeks, birth weight up to 1500 g, and postnatal age between 8 and 14 days were included. The newborns were randomized into 2 groups: Group 1 received 3 doses of 400 IU/kg erythropoietin per week for 6 weeks, and Group 2 received no treatment aside from their conventional medications. The 2 groups did not differ significantly with respect to their mean gestational age, birth weight and hematocrit at the study entry. Fewer transfusions were administered to those receiving erythropoietin (26.7% versus 50%, p=0.03), but there was no statistically significant difference between groups with respect to volume of transfusion. Compared with the placebo group, the infants receiving erythropoietin had a higher mean hematocrit (34% +/- 4.3 versus 29% +/- 5.9, p<0.001) and absolute reticulocyte count (57 +/- 19 versus 10 +/- 4.8 x 106, p<0.001) at the end of the study. We found no significant difference in the incidence of thrombocytopenia and leukopenia between the 2 groups. We conclude that when the restrictive RBCT guidelines were followed, treatment with erythropoietin can be useful in reduction of the number of RBCTs. (author)

  2. Improvement in performance status after erythropoietin treatment in lung cancer patients undergoing concurrent chemoradiotherapy

    International Nuclear Information System (INIS)

    Casas, Francesc; Vinolas, Nuria; Ferrer, Ferran; Farrus, Blanca; Gimferrer, Josep Maria; Agusti, Carles; Belda, Josep; Luburich, Patricio

    2003-01-01

    Purpose: A prospective Phase II trial was carried out to evaluate the effectiveness of erythropoietin in improving or maintaining performance status as determined by the Karnofsky performance status (KPS) score and hemoglobin (Hb) levels in lung cancer patients treated with concurrent chemoradiation (CH-RT). Methods and Materials: A total of 51 patients with lung cancer (11 with small-cell, limited stage and 40 with non-small-cell disease, 17 with Stage IIIA and 23 with Stage IIIB), who underwent three different concurrent CH-RT protocols were enrolled. Baseline Hb and KPS values were recorded, as were the nadir Hb and KPS values before concurrent CH-RT. The final Hb and KPS values were recorded the last week of concurrent CH-RT. An Hb level of ≤11 g/dL before concurrent CH-RT was required before receiving erythropoietin. Prognostic factors for KPS improvement and survival were assessed by univariate and multivariate studies. Results: Of the 51 patients, 47 (92.3%) were men (mean age 63.6 years, range 40-75). The median baseline KPS score was 80, and the mean baseline Hb was 12.2 ± 1.76 g/dL (range 9-16.9). The mean nadir and final Hb value was 9.98±0.67 g/dL (range 8.6-11) and 11.33±1.59 g/dL (range 6.9-14.4), respectively. A significant increase was seen in the Hb and KPS score (p<0.05) in the final measurements. Differences were found between the final and nadir Hb in the predictive value for differences in performance status (p=0.001). On univariate study, pathologic findings (p=0.0234), weight loss (p=0.0049), baseline Hb (p=0.0057), and final Hb improvement (p=0.0237) were prognostic factors for survival. Nadir Hb (p=0.027), final Hb improvement (p=0.0069), pathologic findings (p = 0.0006), and weight loss (p=0.0001) had significant prognostic value for survival in multivariate analysis. Conclusion: In this study, erythropoietin appears to have a significant, beneficial impact on the KPS and Hb of patients undergoing concurrent CH-RT

  3. Erythropoietin receptor in human skeletal muscle and the effects of acute and long-term injections with recombinant human erythropoietin on the skeletal muscle

    DEFF Research Database (Denmark)

    Lundby, Carsten; Hellsten, Ylva; Jensen, Mie B. F.

    2008-01-01

    The presence and potential physiological role of the erythropoietin receptor (Epo-R) were examined in human skeletal muscle. In this study we demonstrate that Epo-R is present in the endothelium, smooth muscle cells, and in fractions of the sarcolemma of skeletal muscle fibers. To study...... the potential effects of Epo in human skeletal muscle, two separate studies were conducted: one to study the acute effects of a single Epo injection on skeletal muscle gene expression and plasma hormones and another to study the effects of long-term (14 wk) Epo treatment on skeletal muscle structure. Subjects...... was studied in subjects (n = 8) who received long-term Epo administration, and muscle biopsies were obtained before and after. Epo treatment did not alter mean fiber area (0.84 +/- 0.2 vs. 0.72 +/- 0.3 mm(2)), capillaries per fiber (4.3 +/- 0.5 vs. 4.4 +/- 1.3), or number of proliferating endothelial cells...

  4. The glucocorticoid receptor cooperates with the erythropoietin receptor and c-Kit to enhance and sustain proliferation of erythroid progenitors in vitro

    NARCIS (Netherlands)

    von Lindern, M.; Zauner, W.; Mellitzer, G.; Steinlein, P.; Fritsch, G.; Huber, K.; Löwenberg, B.; Beug, H.

    1999-01-01

    Although erythropoietin (Epo) is essential for the production of mature red blood cells, the cooperation with other factors is required for a proper balance between progenitor proliferation and differentiation. In avian erythroid progenitors, steroid hormones cooperate with tyrosine kinase receptors

  5. Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system

    DEFF Research Database (Denmark)

    Aachmann-Andersen, Niels J.; Christensen, Soren J.; Lisbjerg, Kristian

    2018-01-01

    The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt...... that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect...... of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system....

  6. Erythropoietin levels in patients with sleep apnea: a meta-analysis.

    Science.gov (United States)

    Zhang, Xiao-Bin; Zeng, Yi-Ming; Zeng, Hui-Qing; Zhang, Hua-Ping; Wang, Hui-Ling

    2017-06-01

    Currently available data regarding the blood levels of erythropoietin (EPO) in sleep apnea (SA) patients are contradictory. The aim of the present meta-analysis was to evaluate the EPO levels in SA patients via quantitative analysis. A systematic search of Pubmed, Embase, and Web of Science were performed. EPO levels in SA group and control group were extracted from each eligible study. Weight mean difference (WMD) or Standard mean difference (SMD) with 95% confidence interval (CI) was calculated by using fixed-effects or random effect model analysis according to the degree of heterogeneity between studies. A total of 9 studies involving 407 participants were enrolled. The results indicated that EPO levels in SA group were significantly higher than that in control group (SMD 0.61, 95% CI 0.11-1.11, p = 0.016). Significantly higher EPO levels were found in patients with body mass index analysis (both p analysis.

  7. Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

    DEFF Research Database (Denmark)

    Kästner, Anne; Grube, Sabrina; El-Kordi, Ahmed

    2012-01-01

    -term memory readouts, with one particular combination of genotypes superior to all others (p 800), these associations were confirmed. A matching preclinical study with mice demonstrated cognitive processing speed and memory enhanced upon transgenic......Erythropoietin (EPO) improves cognitive performance in clinical studies and rodent experiments. We hypothesized that an intrinsic role of EPO for cognition exists, with particular relevance in situations of cognitive decline, which is reflected by associations of EPO and EPO receptor (EPOR......) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5' upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPORSTR(GA)(n). Associations of these variants were obtained for cognitive processing speed, fine motor skills and short...

  8. Satellite cell response to erythropoietin treatment and endurance training in healthy young men

    DEFF Research Database (Denmark)

    Hoedt, Andrea; Christensen, Britt; Nellemann, Birgitte

    2016-01-01

    KEY POINT: Erythropoietin (Epo) treatment may induce myogenic differentiation factor (MyoD) expression and prevent apoptosis in satellite cells (SCs) in murine and in vitro models. Endurance training stimulates SC proliferation in vivo in murine and human skeletal muscle. In the present study, we......-receptor interaction. Moreover, endurance training, but not Epo treatment, increases the SC content in type II myofibres, as well as the content of MyoD(+) SCs. Collectively, our results suggest that Epo treatment can regulate human SCs in vivo, supported by Epo receptor mRNA expression in human SCs. In effect, long......-term Epo treatment during disease conditions involving anaemia may impact SCs and warrants further investigation. Satellite cell (SC) proliferation is observed following erythropoitin treatment in vitro in murine myoblasts and endurance training in vivo in human skeletal muscle. The present study aimed...

  9. Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders

    DEFF Research Database (Denmark)

    Miskowiak, K W; Macoveanu, J; Vinberg, M

    2016-01-01

    MRI at 3T, mood ratings, and blood tests at baseline and week 14. During fMRI, participants performed a picture encoding task followed by postscan recall. RESULTS: Sixty-two patients had complete data (EPO: N = 32, saline: N = 30). EPO improved picture recall and increased encoding-related activity......OBJECTIVE: Erythropoietin (EPO) improves verbal memory and reverses subfield hippocampal volume loss across depression and bipolar disorder (BD). This study aimed to investigate with functional magnetic resonance imaging (fMRI) whether these effects were accompanied by functional changes in memory...... in dorsolateral prefrontal cortex (dlPFC) and temporo-parietal regions, but not in hippocampus. Recall correlated with activity in the identified dlPFC and temporo-parietal regions at baseline, and change in recall correlated with activity change in these regions from baseline to follow-up across the entire...

  10. Synthesis and biological evaluation of 125I-erythropoietin as a potential radiopharmaceutical agent for tumours

    International Nuclear Information System (INIS)

    Clemente, Goncalo dos Santos; Duarte, Vera Lucia Serra

    2011-01-01

    Erythropoietin (EPO) is a glycoprotein hormone responsible for regulating erythropoiesis. Expression of EPO and EPO receptors (EPOr) has recently been demonstrated in some neoplastic cell lines and tumours, suggesting a potential new target for therapy. In this work, EPO was labeled with iodine-125 using the lactoperoxidase method, known to prevent damage to protein during radioiodination, and labeling conditions were optimized. In vitro stability studies have shown that 125 I-EPO is radiochemically stable for 20 days after radiolabeling. In vitro cell binding studies have demonstrated very low binding ( 125 I-EPO. In mice with induced melanoma, only a residual fixation in the tumour was evident. Further studies are warranted on other tumoral cell lines to better understand the binding process and internalization into cells. Studies on EPO labeled with carbon-11 could be valuable, since there is a greater chance of preserving the biological activity of the protein using this method. (author)

  11. Generation of a transplantable erythropoietin-producer derived from human mesenchymal stem cells.

    Science.gov (United States)

    Yokoo, Takashi; Fukui, Akira; Matsumoto, Kei; Ohashi, Toya; Sado, Yoshikazu; Suzuki, Hideaki; Kawamura, Tetsuya; Okabe, Masataka; Hosoya, Tatsuo; Kobayashi, Eiji

    2008-06-15

    Differentiation of autologous stem cells into functional transplantable tissue for organ regeneration is a promising regenerative therapeutic approach for cancer, diabetes, and many human diseases. Yet to be established, however, is differentiation into tissue capable of producing erythropoietin (EPO), which has a critical function in anemia. We report a novel EPO-producing organ-like structure (organoid) derived from human mesenchymal stem cells. Using our previously established relay culture system, a human mesenchymal stem cell-derived, human EPO-competent organoid was established in rat omentum. The organoid-derived levels of human EPO increased in response to anemia induced by rapid blood withdrawal. In addition, the presence of an organoid in rats suppressed for native (rat) EPO production enhanced recovery from anemia when compared with control animals lacking the organoid. Together these results confirmed the generation of a stem cell-derived organoid that is capable of producing EPO and sensitive to physiological regulation.

  12. Effects of erythropoietin administration on cerebral metabolism and exercise capacity in men

    DEFF Research Database (Denmark)

    Rasmussen, Peter; Foged, Eva M; Krogh-Madsen, Rikke

    2010-01-01

    administration of EPO. We recorded exercise capacity, transcranial ultrasonography-derived middle cerebral artery blood velocity, and arterial-internal jugular venous concentration differences of glucose and lactate. In addition, cognitive function, ratings of perceived exertion, ventilation and voluntary......Recombinant human erythropoietin (EPO) increases exercise capacity by stimulating erythropoiesis and subsequently enhancing oxygen delivery to the working muscles. In a large dose, EPO cross the blood brain barrier and may reduce central fatigue and improve cognition. In turn, this would augment...... exercise capacity independent of erythropoiesis. To test this hypothesis, 15 healthy young males (18-34 yo., 74 +/- 7 kg) received either 3 days of high dose (30,000 IU day(-1), N=7) double-blinded placebo controlled or 3 months of low dose (5,000 IU week(-1), N=8) counter-balanced open but controlled...

  13. Erythropoietin reduces neural and cognitive processing of fear in human models of antidepressant drug action

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla; O'Sullivan, Ursula; Harmer, Catherine J

    2007-01-01

    with reduced attention to fear. Erythropoietin additionally reduced recognition of fearful facial expressions without affecting recognition of other emotional expressions. These actions occurred in the absence of changes in hematological parameters. CONCLUSIONS: The present study demonstrates that Epo directly......) versus saline on the neural processing of happy and fearful faces in 23 healthy volunteers. Facial expression recognition was assessed outside the scanner. RESULTS: One week after administration, Epo reduced neural response to fearful versus neutral faces in the occipito-parietal cortex consistent...... study aimed to explore the effects of Epo on neural and behavioral measures of emotional processing relevant for depression and the effects of conventional antidepressant medication. METHODS: In the present study, we used functional magnetic resonance imaging to explore the effects of Epo (40,000 IU...

  14. Detection of erythropoietin misuse by the Athlete Biological Passport combined with reticulocyte percentage

    DEFF Research Database (Denmark)

    Bejder, Jacob; Aachmann-Andersen, Niels Jacob; Bonne, Thomas Christian

    2016-01-01

    The sensitivity of the adaptive model of the Athlete Biological Passport (ABP) and reticulocyte percentage (ret%) in detection of recombinant human erythropoietin (rHuEPO) misuse was evaluated using both a long-term normal dose and a brief high dose treatment regime. Sixteen subjects received...... initiation. The ABP based on haemoglobin concentration ([Hb]) and OFF-hr score ([Hb] - 60×√ret%) yielded atypical profiles following both normal-dose and high-dose treatment (0 %, 31 %, 13 % vs. 21 %, 33 %, 20 % at days 4, 11, and 25 after normal and high dose, respectively). Including ret% as a stand...... will present an atypical ABP profile. Including ret% as a stand-alone parameter improves the sensitivity two-fold....

  15. [Effects of benazepril and valsartan on erythropoietin levels in patients with essential hypertension].

    Science.gov (United States)

    Guo, Lin-lin; Li, Min; Wang, Ai-hong

    2011-10-01

    To compare effects of valsartan and benazepril on erythropoietin (EPO) levels in essential hypertensive patients with normal renal function. Sixty essential hypertensive patients were randomly divided into valsartan group (n=30, valsartan 80 mg/day) and benazepril group (n=30, benazepril 10 mg/day). Plasma EPO and hemoglobin (Hb) levels were measured at the start of and at 4 and 8 weeks during the treatments. EPO and Hb levels were all in normal range in the two groups. Valsartan decreased EPO levels from 14.179∓3.214 U/L (baseline) to 12.138∓2.926 U/L (PBenazepril treatment did not resulted in any obvious changes in EPO or Hb levels (P>0.05). Valsartan may lower EPO and Hb levels in patients with essential hypertension, while benazepril does not have such effects. The safety of valsartan in anemic hypertensive patients should be further investigated.

  16. Chronic erythropoietin treatment improves diet-induced glucose intolerance in rats

    DEFF Research Database (Denmark)

    Caillaud, Corinne; Mechta, Mie; Ainge, Heidi

    2015-01-01

    Erythropoietin (EPO) ameliorates glucose metabolism through mechanisms not fully understood. In this study, we investigated the effect of EPO on glucose metabolism and insulin signaling in skeletal muscle. A 2-week EPO treatment of rats fed with a high-fat diet (HFD) improved fasting glucose levels...... and glucose tolerance, without altering total body weight or retroperitoneal fat mass. Concomitantly, EPO partially rescued insulin-stimulated AKT activation, reduced markers of oxidative stress, and restored heat-shock protein 72 expression in soleus muscles from HFD-fed rats. Incubation of skeletal muscle...... not directly activate the phosphorylation of AKT in muscle cells. We propose that the reduced systemic inflammation or oxidative stress that we observed after treatment with EPO could contribute to the improvement of whole-body glucose metabolism....

  17. Effect of recombinant erythropoietin on inflammatory markers in patients with affective disorders

    DEFF Research Database (Denmark)

    Vinberg, Maj; Weikop, Pia; Olsen, Niels Vidiendal

    2016-01-01

    Aim: This study investigated the effect of repeated infusions of recombinant human erythropoietin (EPO) on markers of inflammation in patients with affective disorders and whether any changes in inflammatory markers were associated with improvements on verbal memory. Methods: In total, 83 patients......). In both sub-studies, patients were randomised in a double-blind, parallel-group design to receive eight weekly intravenous infusions of EPO (Eprex; 40,000 IU/ml) or saline (0.9% NaCl). Plasma concentrations of interleukin 6 (IL-6), interleukin 18 (IL-18) and high sensitive c-reactive protein (hsCRP) were...... and change in verbal memory. Conclusions: Repeated EPO infusions had no effect on IL-6 and IL-18 levels but produced a modest increase in hsCRP levels in patients with TRD. Changes over time in inflammatory markers were not correlated with changes in cognition suggesting that modulation of the inflammatory...

  18. Radioimmunoassay of erythropoietin and its potential in the diagnosis of fetal hypoxia

    International Nuclear Information System (INIS)

    Fingerova, H.

    1993-01-01

    Radioimmunoassay (RIA) for erythropoietin (EPO) in the serum and amniotic fluid was set up, based on donated rabbit antibody and a commercial tracer. EPO levels obtained by means of the RIA correlated well with the results obtained by means of ELISA or a commercial RIA kit. Retrospective evaluations of EPO levels in umbilical cord serum and amniotic fluid samples obtained during 171 vaginal or Cesarean section deliveries have shown that already in the course of spontaneous vaginal delivery a moderate increase of EPO in umbilical cord serum can be detected. The marked increase of EPO levels in both cord serum and amniotic fluid was always observed in relation to a severe fetal distress. (author) 3 figs., 3 refs

  19. Diurnal levels of immunoreactive erythropoietin in normal subjects and subjects with chronic lung disease

    Energy Technology Data Exchange (ETDEWEB)

    Miller, M.E.; Garcia, J.F.; Cohen, R.A.; Cronkite, E.P.; Moccia, G.; Acevedo, J.

    1981-10-01

    Serum levels of immunoreactive erythropoietin (Ep) were measured in 48 normal male and female volunteers, ages 20-60 years, to establish a control value for Ep of 18.5 +/- 5.0 (mean +/- SD) mU/ml. Levels of the hormone were also measured sequentially over a 24 h period of time in an additional 17 normal volunteers with no diurnal variation. Diurnal levels of immunoreactive Ep were also measured in 30 subjects, with chronic lung disease. These patients, in contrast to normal subjects exhibited a diurnal variation in the level of immunoreactive Ep with peak levels occurring at midnight. The only variable measured which correlated with the serum immunoreactive Ep level in subjects with chronic lung disease was the level of carboxyhaemoglobin (P less than 0.02).

  20. Recombinant human erythropoietin stimulates angiogenesis and wound healing in the genetically diabetic mouse.

    Science.gov (United States)

    Galeano, Mariarosaria; Altavilla, Domenica; Cucinotta, Domenico; Russo, Giuseppina T; Calò, Margherita; Bitto, Alessandra; Marini, Herbert; Marini, Rolando; Adamo, Elena B; Seminara, Paolo; Minutoli, Letteria; Torre, Valerio; Squadrito, Francesco

    2004-09-01

    The effects of recombinant human erythropoietin (rHuEPO) in diabetes-related healing defects were investigated by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJ-m(+/+)Lept(db) mice (db(+)/db(+)) and their normoglycemic littermates (db(+/+)m). Animals were treated with rHuEPO (400 units/kg in 100 microl s.c.) or its vehicle alone (100 microl). Mice were killed on different days (3, 6, and 12 days after skin injury) for measurement of vascular endothelial growth factor (VEGF) mRNA expression and protein synthesis, for monitoring angiogenesis by CD31 expression, and for evaluating histological changes. Furthermore, we evaluated wound-breaking strength at day 12. At day 6, rHuEPO injection in diabetic mice resulted in an increase in VEGF mRNA expression (vehicle = 0.33 +/- 0.1 relative amount of mRNA; rHuEPO = 0.9 +/- 0.09 relative amount of mRNA; P < 0.05) and protein wound content (vehicle = 23 +/- 5 pg/wound; rHuEPO = 92 +/- 12 pg/wound; P < 0.05) and caused a marked increase in CD31 gene expression (vehicle = 0.18 +/- 0.05 relative amount of mRNA; rHuEPO = 0.98 +/- 0.21 relative amount of mRNA; P < 0.05) and protein synthesis. Furthermore, rHuEPO injection improved the impaired wound healing and, at day 12, increased the wound-breaking strength in diabetic mice (vehicle = 12 +/- 2 g/mm; rHuEPO 21 +/- 5 g/mm; P < 0.05). Erythropoietin may have a potential application in diabetes-related wound disorders.

  1. The role of erythropoietin stimulating agents in anemic patients with heart failure: solved and unresolved questions

    Directory of Open Access Journals (Sweden)

    Palazzuoli A

    2014-08-01

    Full Text Available Alberto Palazzuoli, Gaetano Ruocco, Marco Pellegrini, Carmelo De Gori, Gabriele Del Castillo, Nicola Giordano, Ranuccio NutiDepartment of Internal Medicine and Metabolic Diseases, Cardiology Section, Le Scotte Hospital, University of Siena, Siena, ItalyAbstract: Anemia is a common finding in congestive heart failure (CHF and is associated with an increased mortality and morbidity. Several conditions can cause depression of erythroid progenitor cells: reduction of iron absorption and reuptake, decreased bone marrow activity, reduced endogenous erythropoietin production, and chronic inflammatory state. Anemia’s etiology in CHF is complex and partially understood; it involves several systems including impaired hemodynamic condition, reduced kidney and bone perfusion, increased inflammatory activity, and neurohormonal overdrive. The use of erythropoiesis stimulating agents (ESAs such as erythropoietin and its derivatives is recently debated; the last interventional trial seems to demonstrate a neutral or negative effect in the active arm with darbepoetin treatment. The current data is opposite to many single blind studies and previous meta-analysis showing an improvement in quality of life, New York Heart Association class, and exercise tolerance using ESA therapy. These contrasting data raise several concerns regarding the target of hemoglobin levels needing intervention, the exact anemia classification and categorization, and the standardization of hematocrit cutoffs. Some cardiac and systemic conditions (ie, hypertension, atrial fibrillation, prothrombotic status may predispose to adverse events, and ESA administration should be avoided. To prevent the negative effects, high-dosage and chronic administration should be avoided. Clarification of these items could probably identify patients that may benefit from additional iron or ESA treatment. In this review, we discuss the interventional trials made in anemic heart failure patients, the

  2. Resuscitative therapy with erythropoietin reduces oxidative stress and inflammatory responses of vital organs in a rat severe fixed-volume hemorrhagic shock model.

    Science.gov (United States)

    Ranjbaran, Mina; Kadkhodaee, Mehri; Seifi, Behjat; Mirzaei, Reza; Ahghari, Parisa

    2018-01-01

    Hemorrhagic shock (HS) still has a high mortality rate and none of the known resuscitative regimens completely reverse its adverse outcomes. This study investigated the effects of different models of resuscitative therapy on the healing of organ damage in a HS model. Male Wistar rats were randomized into six groups: Sham, without HS induction; HS, without resuscitation; HS+Blood, resuscitation with the shed blood; HS+Blood+NS, resuscitation with blood and normal saline; HS+Blood+RL, resuscitation with blood and Ringer's lactate; EPO, erythropoietin was added to the blood and RL. Blood and urine samples were obtained 3 h after resuscitation. Kidney, liver and brain tissue samples were harvested for multiple organ failure evaluation. Survival rate was the highest in the Sham, EPO and HS+Blood+RL groups compared to others. Plasma creatinine concentration, ALT, AST, urinary NAG activity and renal NGAL mRNA expression significantly increased in the HS+Blood+RL group compared to the Sham group. There was a significant increase in tissue oxidative stress markers and pro-inflammatory cytokines in HS+Blood+RL group compared to the Sham rats. EPO had more protective effects on multiple organ failure compared to the HS+Blood+RL group. EPO, as a resuscitative treatment, attenuated HS-induced organ damage. It seems that it has a potential to be attractive for clinical trials.

  3. A role for heme oxygenase-1 in the antioxidant and antiapoptotic effects of erythropoietin: the start of a good news/bad news story?

    Science.gov (United States)

    Calò, Lorenzo A; Davis, Paul A; Piccoli, Antonio; Pessina, Achille C

    2006-01-01

    Erythropoietin (EPO) is the major regulator of erythropoiesis. EPO's actions have been shown to be antiapoptotic and dependent on JAK2 signaling and Akt phosphorylation. These effects serve as link between EPO and heme oxygenase-1 (HO-1). HO-1 is an inducible enzyme with potent antioxidant and antiapoptotic activities which are regulated by Akt signaling. EPO's ability to alter cellular systems that involve apoptosis and oxidants suggests that EPO treatments are likely to have multiple and different effects which may start a good news/bad news story. Recombinant human EPO is the recognized treatment of choice to address anemia and to stimulate erythropoiesis in chronic renal failure patients, through its antiapoptotic action which likely involves HO-1. On the other hand, EPO treatment to address anemia in cancer patients, while providing significant improvements in cancer patients' quality of life, its effects on survival are equivocal, likely due to its linkage with HO-1. Two clinical trials of EPO in patients with solid tumors have, in fact, shown specific negative effects on survival. However, EPO's effect on tumor growth and survival is not uniformily pro growth and pro survival, as EPO may act synergistically with chemotherapy to induce apoptosis. Finally, compounds have been synthesized that do not trigger EPO receptor and thus may allow experimental distinction and, therefore, at least potentially affect at the clinical level the tissue-protective effects of EPO (e.g., antiapoptosis) without provoking its other potentially detrimental effects. Copyright 2006 S. Karger AG, Basel

  4. Exercise aggravates cardiovascular risks and mortality in rats with disrupted nitric oxide pathway and treated with recombinant human erythropoietin.

    Science.gov (United States)

    Meziri, Fayçal; Binda, Delphine; Touati, Sabeur; Pellegrin, Maxime; Berthelot, Alain; Touyz, Rhian M; Laurant, Pascal

    2011-08-01

    Chronic administration of recombinant human erythropoietin (rHuEPO) can generate serious cardiovascular side effects such as arterial hypertension (HTA) in clinical and sport fields. It is hypothesized that nitric oxide (NO) can protect from noxious cardiovascular effects induced by chronic administration of rHuEPO. On this base, we studied the cardiovascular effects of chronic administration of rHuEPO in exercise-trained rats treated with an inhibitor of NO synthesis (L-NAME). Rats were treated or not with rHuEPO and/or L-NAME during 6 weeks. During the same period, rats were subjected to treadmill exercise. The blood pressure was measured weekly. Endothelial function of isolated aorta and small mesenteric arteries were studied and the morphology of the latter was investigated. L-NAME induced hypertension (197 ± 6 mmHg, at the end of the protocol). Exercise prevented the rise in blood pressure induced by L-NAME (170 ± 5 mmHg). However, exercise-trained rats treated with both rHuEPO and L-NAME developed severe hypertension (228 ± 9 mmHg). Furthermore, in these exercise-trained rats treated with rHuEPO/L-NAME, the acetylcholine-induced relaxation was markedly impaired in isolated aorta (60% of maximal relaxation) and small mesenteric arteries (53%). L-NAME hypertension induced an internal remodeling of small mesenteric arteries that was not modified by exercise, rHuEPO or both. Vascular ET-1 production was not increased in rHuEPO/L-NAME/training hypertensive rats. Furthermore, we observed that rHuEPO/L-NAME/training hypertensive rats died during the exercise or the recovery period (mortality 51%). Our findings suggest that the use of rHuEPO in sport, in order to improve physical performance, represents a high and fatal risk factor, especially with pre-existing cardiovascular risk.

  5. Erythropoietin test

    Science.gov (United States)

    ... used to help determine the cause of anemia, polycythemia (high red blood cell count) or other bone ... Increased EPO level may be due to secondary polycythemia. This is an overproduction of red blood cells ...

  6. Hypoproduction of erythropoietin contributes to anemia in chronic cadmium intoxication: clinical study on Itai-itai disease in Japan

    Energy Technology Data Exchange (ETDEWEB)

    Horiguchi, Hyogo (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Teranishi, Hidetoyo (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Niiya, Kenji (Dept. of Clinical Lab. Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Aoshima, Keiko (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Katoh, Terutaka (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Sakuragawa, Nobuo (Dept. of Clinical Lab. Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan)); Kasuya, Minoru (Dept. of Public Health, Faculty of Medicine, Toyama Medical and Pharmaceutical Univ. (Japan))

    1994-10-01

    Itai-itai disease is a condition caused by longterm exposure of the inhabitants of Toyama prefecture, Japan, to cadmium intoxication. The characteristic clinical features of this disease include renal tubular dysfunction, osteomalacia, and anemia. In order to clarify the pathogenesis of the anemia, the red blood cell count, hemoglobin concentration, hematocrit, serum iron level, total iron-binding capacity, serum ferritin level, serum erythropoietin level, creatinine clearance, fractional excretion of [beta][sub 2]-microglobulin, and bone marrow morphology were determined in ten patients with Itai-itai disease. Low serum iron or ferritin levels were not observed, and bone marrow aspiration did not reveal any specific hematological disorders. A close relationship was observed between the decrease in the hemoglobin level and the progression of renal dysfunction. Low serum erythropoietin levels were detected despite the presence of severe anemia. These results suggest an important role of renal damage in the anemia which develops in Itai-itai disease. (orig.)

  7. Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

    OpenAIRE

    van Loon, Rosa Laura E; Bartelds, Beatrijs; Wagener, Frank A D T G; Affara, Nada; Mohaupt, Saffloer; Wijnberg, Hans; Pennings, Sebastiaan W C; Takens, Janny; Berger, Rolf M F

    2015-01-01

    BACKGROUND: Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease with a high mortality, characterized by typical angio-proliferative lesions. Erythropoietin (EPO) attenuates pulmonary vascular remodeling in PAH. We postulated that EPO acts through mobilization of endothelial progenitor cells (EPCs) and activation of the cytoprotective enzyme heme oxygenase-1 (HO-1). METHODS: Rats with flow-associated PAH, resembling pediatric PAH, were treated with HO-1 inducer EPO in the pre...

  8. Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

    OpenAIRE

    van Loon, Rosa Laura E.; Bartelds, Beatrijs; Wagener, Frank A. D. T. G.; Affara, Nada; Mohaupt, Saffloer; Wijnberg, Hans; Pennings, Sebastiaan W. C.; Takens, Janny; Berger, Rolf M. F.

    2015-01-01

    Background Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease with a high mortality, characterized by typical angio-proliferative lesions. Erythropoietin (EPO) attenuates pulmonary vascular remodeling in PAH. We postulated that EPO acts through mobilization of endothelial progenitor cells (EPCs) and activation of the cytoprotective enzyme heme oxygenase-1 (HO-1). Methods Rats with flow-associated PAH, resembling pediatric PAH, were treated with HO-1 inducer EPO i...

  9. A Simple Three-Step Method for Design and Affinity Testing of New Antisense Peptides: An Example of Erythropoietin

    OpenAIRE

    Štambuk, Nikola; Manojlović, Zoran; Turčić, Petra; Martinić, Roko; Konjevoda, Paško; Weitner, Tin; Wardega, Piotr; Gabričević, Mario

    2014-01-01

    Antisense peptide technology is a valuable tool for deriving new biologically active molecules and performing peptide–receptor modulation. It is based on the fact that peptides specified by the complementary (antisense) nucleotide sequences often bind to each other with a higher specificity and efficacy. We tested the validity of this concept on the example of human erythropoietin, a well-characterized and pharmacologically relevant hematopoietic growth factor. The purpose of the work was to ...

  10. The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

    International Nuclear Information System (INIS)

    Uziel, Orit; Kanfer, Gil; Beery, Einat; Yelin, Dana; Shepshelovich, Daniel; Bakhanashvili, Mary; Nordenberg, Jardena; Lahav, Meir

    2014-01-01

    Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway

  11. Use of recombinant erythropoietin for the management of severe hemolytic disease of the newborn of a K0 phenotype mother.

    Science.gov (United States)

    Manoura, Antonia; Korakaki, Eftychia; Hatzidaki, Eleftheria; Saitakis, Emmanuel; Maraka, Sofia; Papamastoraki, Isabella; Matalliotakis, Emmanuel; Foundouli, Kaliopi; Giannakopoulou, Christine

    2007-01-01

    Very few people do not express any Kell antigens on their red blood cells (K0 phenotype). They can be immunized by transfusion or pregnancy and develop antibodies against Kell system antigens. These maternal antibodies can cause severe hemolytic disease of the fetus/newborn, as a result of the suppression of erythropoiesis and hemolysis. Multiple intrauterine transfusions in the management of severe hemolytic disease have been shown to cause erythropoietic suppression as well. Recombinant erythropoietin has been successfully used in the management of late anemia of infants with Rh hemolytic disease and in 1 case of KEL1 (Kell)-associated hemolytic disease. The authors present the case of severe hemolytic disease of a newborn due to KEL5 (Ku) isoimmunization of his K0 phenotype mother. Regular intrauterine transfusions were performed to manage the severe fetal anemia (Hb 3 g/dL). A male infant was born at the 36th week of gestation having normal hemoglobin (15.8 g/dL) and developed only mild hyperbilirubinemia. On the 15th day of life, the infant's hematocrit had fallen to 27.3%, with low reticulocyte count and low erythropoietin level. The infant was managed successfully with recombinant erythropoietin.

  12. A Simple Three-Step Method for Design and Affinity Testing of New Antisense Peptides: An Example of Erythropoietin

    Directory of Open Access Journals (Sweden)

    Nikola Štambuk

    2014-05-01

    Full Text Available Antisense peptide technology is a valuable tool for deriving new biologically active molecules and performing peptide–receptor modulation. It is based on the fact that peptides specified by the complementary (antisense nucleotide sequences often bind to each other with a higher specificity and efficacy. We tested the validity of this concept on the example of human erythropoietin, a well-characterized and pharmacologically relevant hematopoietic growth factor. The purpose of the work was to present and test simple and efficient three-step procedure for the design of an antisense peptide targeting receptor-binding site of human erythropoietin. Firstly, we selected the carboxyl-terminal receptor binding region of the molecule (epitope as a template for the antisense peptide modeling; Secondly, we designed an antisense peptide using mRNA transcription of the epitope sequence in the 3'→5' direction and computational screening of potential paratope structures with BLAST; Thirdly, we evaluated sense–antisense (epitope–paratope peptide binding and affinity by means of fluorescence spectroscopy and microscale thermophoresis. Both methods showed similar Kd values of 850 and 816 µM, respectively. The advantages of the methods were: fast screening with a small quantity of the sample needed, and measurements done within the range of physicochemical parameters resembling physiological conditions. Antisense peptides targeting specific erythropoietin region(s could be used for the development of new immunochemical methods. Selected antisense peptides with optimal affinity are potential lead compounds for the development of novel diagnostic substances, biopharmaceuticals and vaccines.

  13. The effects of erythropoietin signaling on telomerase regulation in non-erythroid malignant and non-malignant cells

    Energy Technology Data Exchange (ETDEWEB)

    Uziel, Orit, E-mail: Oritu@clalit.org.il [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Kanfer, Gil [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Beery, Einat [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Yelin, Dana; Shepshelovich, Daniel [Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Bakhanashvili, Mary [Unit of Infectious Diseases, Sheba Medical Center, Tel-Hashomer (Israel); Nordenberg, Jardena [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Dep. of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Endocrinology Laboratory, Beilinson Medical Center, Petah-Tikva (Israel); Lahav, Meir [Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel); Medicine A, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv (Israel)

    2014-07-18

    Highlights: • We assumed that some of erythropoietin adverse effects may be mediated by telomerase activity. • EPO administration increased telomerase activity, cells proliferation and migration. • The inhibition of telomerase modestly repressed the proliferative effect of erythropoietin. • Telomere shortening caused by long term inhibition of the enzyme totally abolished that effect. • This effect was mediated via the Lyn–AKT axis and not by the canonical JAK2–STAT pathway. - Abstract: Treatment with erythropoietin (EPO) in several cancers is associated with decreased survival due to cancer progression. Due to the major importance of telomerase in cancer biology we hypothesized that some of these effects may be mediated through EPO effect on telomerase. For this aim we explored the possible effects of EPO on telomerase regulation, cell migration and chemosensitivity in non-erythroid malignant and non-malignant cells. Cell proliferation, telomerase activity (TA) and cell migration increased in response to EPO. EPO had no effect on cancer cells sensitivity to cisplatinum and on the cell cycle status. The inhibition of telomerase modestly repressed the proliferative effect of EPO. Telomere shortening caused by long term inhibition of the enzyme abolished the effect of EPO, suggesting that EPO effects on cancer cells are related to telomere dynamics. TA was correlated with the levels of Epo-R. The increase in TA was mediated post-translationally through the Lyn-Src and not the canonical JAK2 pathway.

  14. Autologous blood transfusion with recombinant erythropoietin treatment in anaemic patients with rheumatoid arthritis.

    Science.gov (United States)

    Tanaka, N; Ito, K; Ishii, S; Yamazaki, I

    1999-01-01

    The aim of this study was to determine the conditions under which a sufficient preoperative amount of autologous blood could be obtained with administration of rHuEPO (recombinant human erythropoietin) in anaemic patients with rheumatoid arthritis (RA). Thirty-one patients (29 female, two male) with RA who were unable to donate any autologous blood owing to a haemoglobin level of less than 11 g/dl were recruited for this study. Their mean age at the time of operation was 59.3 years. The study protocol for preoperative autologous blood donations started 2.7 weeks before surgery. All patients received 6000 IU rHuEPO intravenously three times a week, supplemented with 40 mg intravenous saccharated ferric oxide at each rHuEPO administration. The protocol also included the provision that 200 g of blood at the first and third donations and 400 g of blood at the second donation were collected. The patients who were able or unable to donate 800 g of blood by this protocol were regarded as having a good or poor response, respectively, to rHuEPO. Patients with a poor response to rHuEPO showed greater clinical symptoms (morning stiffness, the number of swollen joints, Ritchie index) and higher laboratory inflammation parameters (ESR, CRP, platelets, IL-6, TNFalpha, IL-1beta) than patients with a good response to rHuEPO. The poor-response group showed a significant decrease in the progression of inflammation compared with the good-response group. Before treatment with rHuEPO, anaemia in the poor-response group was the same as that in the good-response group, except for impairment of UIBC (unsaturated iron-binding capacity). The poor-response group had a higher blood loss than the good-response group. In conclusion, anaemic RA patients should be considered as candidates for aggressive blood conservation interventions that depend on erythropoietin-modulated erythropoiesis. However, it is important to determine this approach under good control of inflammation.

  15. In-vivo detection of the erythropoietin receptor in tumours using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Fuge, Felix; Doleschel, Dennis; Rix, Anne; Gremse, Felix; Lederle, Wiltrud; Kiessling, Fabian [RWTH Aachen University, Department for Experimental Molecular Imaging (ExMI), Medical Faculty, Aachen (Germany); Wessner, Axel [Roche Diagnostics GmbH, R and D RPD Protein Chemistry, Penzberg (Germany); Winz, Oliver; Mottaghy, Felix [University Clinic RWTH Aachen, Clinic for Nuclear Medicine, Aachen (Germany)

    2014-09-09

    Recombinant human erythropoietin (rhuEpo) is used clinically to treat anaemia. However, rhuEpo-treated cancer patients show decreased survival rates and erythropoietin receptor (EpoR) expression has been found in patient tumour tissue. Thus, rhuEpo application might promote EpoR{sup +} tumour progression. We therefore developed the positron emission tomography (PET)-probe {sup 68}Ga-DOTA-rhuEpo and evaluated its performance in EpoR{sup +} A549 non-small-cell lung cancer (NSCLC) xenografts. {sup 68}Ga-DOTA-rhuEpo was generated by coupling DOTA-hydrazide to carbohydrate side-chains of rhuEpo. Biodistribution was determined in tumour-bearing mice 0.5, 3, 6, and 9 h after probe injection. Competition experiments were performed by co-injecting {sup 68}Ga-DOTA-rhuEpo and rhuEpo in five-fold excess. Probe specificity was further evaluated histologically using Epo-Cy5.5 stainings. The blood half-life of {sup 68}Ga-DOTA-rhuEpo was 2.6 h and the unbound fraction was cleared by the liver and kidney. After 6 h, the highest tumour to muscle ratio was reached. The highest {sup 68}Ga-DOTA-rhuEpo accumulation was found in liver (10.06 ± 6.26%ID/ml), followed by bone marrow (1.87 ± 0.53%ID/ml), kidney (1.58 ± 0.39 %ID/ml), and tumour (0.99 ± 0.16%ID/ml). EpoR presence in these organs was histologically confirmed. Competition experiments showed significantly (p < 0.05) lower PET-signals in tumour and bone marrow at 3 and 6 h. {sup 68}Ga-DOTA-rhuEpo shows favourable pharmacokinetic properties and detects EpoR specifically. Therefore, it might become a valuable radiotracer to monitor EpoR status in tumours and support decision-making in anaemia therapy. (orig.)

  16. Effect of intravenous iron saccharate on the requirements ofErythropoietin in Hemodialysis patients

    International Nuclear Information System (INIS)

    Shaheen, F.A.M.; Akeel, N.; Souqiyye, M.Z.

    2002-01-01

    We attempt in this study to evaluate the effect of intravenous ironsaccharate (i.v. Sach) on the erythropoietin (EPO) requirements during theinitial phase of replacement therapy with recombinant human erythropoietin(r-HuEPO) in adult chronic hemodialysis (HD) patients. We evaluated 96 studypatients who completed 12 weeks of treatment with EPO. There were 69 (72%)males and 27 (28%) females with a mean age of 44+-10 years (range 24 to 74years). The patients were initiated on EPO at 50 units/kg body weightsubcutaneously post-dialysis two to three times weekly. Intravenous iron wasadministered to maintain the ferritin levels and transferrin saturation ratiowithin normal range. There were 36 (37.5%) patients who received i.v. Sach atdoses of 100 mg at the end of dialysis two or three times per week during thewhole study period (total dose 2400-3600 mg). Of the 96 study patients, 91(94.8%) responded to the EPO. The mean hemoglobin (Hb) at entry to the studywas 72+-84 g/L (range 52-88 g/L). There was significant increase of the meanHb to 108+-10 g/L (range 70-120 grams/L) at the end of study (P 0.2and ferritin 0.2 and ferritin >100ng/ml. There were 19 patients in group I (13 received i.v. Sach), 26 in groupII (16 received i.v. Sach) and 44 in group III (seven received i.v. Sach).There was a group of seven patients who had TSAT 100ng/ml, however, none received i.v. sach and they were not included in thestratification. There was no significant difference in the mean Hb betweenpatients who received and those who did not receive i.v. Sach in thesub-groups studied. However, there was a significant decrease in the meanweekly dose of EPO in the patients who received i.v. Sach. We conclude thatroutine use of i.v. iron supplementation in chronic HD patients receivingrecombinant EPO may be beneficial in the initial phase of treatment inattaining the target Hb with lower doses of EPO, regardless of the status ofthe iron indices. (author)

  17. Determining level of endogenous serum erythropoietin for differential diagnosis of polycythemia vera and symptomatic polycythemia

    Directory of Open Access Journals (Sweden)

    Kostyukevych O.M.

    2013-06-01

    Full Text Available The article deals with determining possibility of the assessment of the level of endogenous serum erythropoietin (EPO for differential diagnosis of polycythemia vera (PV and secondary erythrocytosis (SE. The determination of subnormal level of this cytokine for the diagnosis of PV has been detected. The relation between the level of endogenous erythropoietin and iron metabolism also has been analyzed. The study involved 88 patients with PV and 119 patients with SE. Statistically significant decrease in EPO concentration level has been detected in PV patients. The mean EPO level was equal to 6.38 ± 0.84 mIU/mL and 17.98 ±2.48 mIU/mL in PV and SE patients respectively. In control group of individuals EPO concentration was equal to 9,81 ±0,58 mIU/mL, the significant difference was found between all studied groups (р<0.01. According to our data, EPO was increased in 28 SE patients (23.53%, it was not observed in control group and in group of PV patients (φ*emp = 4.355, р<0.01. The decrease of EPO level in PV patients has been detected more often than in SE patients (84.09% versus 11.76% , φ*emp = 5.218, р<0.01, it has not been observed in control group. Only 14 (15.91% PV patients had normal EPO level, in contrast 77 (64.71% SE patients demonstrated normal EPO level (φ*emp = 4.578, р<0.01. The average level of ferritin was equal to 57.41 ± 9.74 ng/mL in PV patients and 199.77 ± 14.32 ng/mL in SE patients (р<0.01. Significantly more patients with PV demonstrated decrease of ferritin level (31.81% versus 7.56%, φ*emp = 4.438, р<0.01. Patients with SE more often had raised level of EPO than PV patients (15.12% versus 4.54%, φ*emp = 2.453, р<0.01. The sensitivity of test with detecting of the reduced level of EPO for the diagnosis of PV was 84.1%, specificity - 87.4%, positive predictive value - 83.1%, negative predictive value - 88.1%. Normal range of EPO significantly (rs = 0,5494 correlated with decreased levels of serum ferritin in

  18. Prognostic Impact of Erythropoietin Expression and Erythropoietin Receptor Expression on Locoregional Control and Survival of Patients Irradiated for Stage II/III Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Rades, Dirk; Setter, Cornelia; Dahl, Olav; Schild, Steven E.; Noack, Frank

    2011-01-01

    Purpose: Prognostic factors can guide the physician in selecting the optimal treatment for an individual patient. This study investigates the prognostic value of erythropoietin (EPO) and EPO receptor (EPO-R) expression of tumor cells for locoregional control and survival in non-small-cell lung cancer (NSCLC) patients. Methods and Materials: Fourteen factors were investigated in 62 patients irradiated for stage II/III NSCLC, as follows: age, gender, Karnofsky performance score (KPS), histology, grading, TNM/American Joint Committee on Cancer (AJCC) stage, surgery, chemotherapy, pack years (average number of packages of cigarettes smoked per day multiplied by the number of years smoked), smoking during radiotherapy, hemoglobin levels during radiotherapy, EPO expression, and EPO-R expression. Additionally, patients with tumors expressing both EPO and EPO-R were compared to those expressing either EPO or EPO-R and to those expressing neither EPO nor EPO-R. Results: On univariate analysis, improved locoregional control was associated with AJCC stage II cancer (p 70 (p = 0.08), an N stage of 0 to 1 (p = 0.07), and no EPO-R expression (p = 0.10). On multivariate analysis, AJCC stage II and no EPO expression remained significant. No smoking during radiotherapy was almost significant. On univariate analysis, improved survival was associated with N stage 0 to 1 (p = 0.009), surgery (p = 0.039), hemoglobin levels of ≥12 g/d (p = 0.016), and no EPO expression (p = 0.001). On multivariate analysis, N stage 0 to 1 and no EPO expression maintained significance. Hemoglobin levels of ≥12 g/d were almost significant. On subgroup analyses, patients with tumors expressing both EPO and EPO-R had worse outcomes than those expressing either EPO or EPO-R and those expressing neither EPO nor RPO-R. Conclusions: EPO expression of tumor cells was an independent prognostic factor for locoregional control and survival in patients irradiated for NSCLC. EPO-R expression showed a trend

  19. Significant association between polymorphism of the erythropoietin gene promoter and myelodysplastic syndrome

    Directory of Open Access Journals (Sweden)

    O'Brien Susan

    2010-11-01

    Full Text Available Abstract Background Myelodysplastic syndrome (MDS may be induced by certain mutagenic environmental or chemotherapeutic toxins; however, the role of susceptibility genes remains unclear. The G/G genotype of the single-nucleotide polymorphism (SNP rs1617640 in the erythropoietin (EPO promoter has been shown to be associated with decreased EPO expression. We examined the association of rs1617640 genotype with MDS. Methods We genotyped the EPO rS1617640 SNP in 189 patients with MDS, 257 with acute myeloid leukemia (AML, 106 with acute lymphoblastic leukemia, 97 with chronic lymphocytic leukemia, 353 with chronic myeloid leukemia, and 95 healthy controls. Results The G/G genotype was significantly more common in MDS patients (47/187; 25.1% than in controls (6/95; 6.3% or in patients with other leukemias (101/813; 12.4% (all P P = 0.03. Time to neutrophils recovery after therapy was significantly longer in MDS patients with the G/G genotype (P = 0.02. Conclusions These findings suggest a strong association between the rs1617640 G/G genotype and MDS. Further studies are warranted to investigate the utility of screening for this marker in individuals exposed to environmental toxins or chemotherapy.

  20. HPLC-MS/MS investigation of biochemical markers for the disclosure of erythropoietin abuse in sports

    Science.gov (United States)

    Appolonova, S. A.; Dikunets, M. A.; Rodchenkov, G. M.

    2009-04-01

    The polypeptide hormone erythropoietin (EPO), which is a forbidden doping drug, was determined by high-performance liquid chromatography combined with tandem mass spectrometry (HPLC-MS/MS). The hypothesis about the influence of EPO on the asymmetric dimethylarginine (ADMA)-dimethylargininedime-thylaminohydrolase (DDAH)-NO-synthase system was verified. Changes in this system can serve as indirect biochemical markers of the presence of the forbidden EPO drug in the organism. In the test group, the concentrations of biochemical markers varied from 10 to 40 μg/ml for ADMA and symmetrical DMA (SDMA) and from 0.5 to 10 μg/ml for arginine and citrulline. A single intravenous administration of r-HuEPO (Epocrin, 2000 ME/day) for two volunteers reliably increased ADMA, SDMA, arginine, and citrulline concentrations to 40-270 μg/ml, 40-240μg/ml, 10-60 μg/ml, and 12-140 μg/ml, respectively, with respect to the reference values. The simultaneous increase in arginine, methylarginines, and citrulline contents could be an indirect marker of EPO abuse. The method is recommended for fast screening analysis.

  1. Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders.

    Science.gov (United States)

    Miskowiak, K W; Macoveanu, J; Vinberg, M; Assentoft, E; Randers, L; Harmer, C J; Ehrenreich, H; Paulson, O B; Knudsen, G M; Siebner, H R; Kessing, L V

    2016-09-01

    Erythropoietin (EPO) improves verbal memory and reverses subfield hippocampal volume loss across depression and bipolar disorder (BD). This study aimed to investigate with functional magnetic resonance imaging (fMRI) whether these effects were accompanied by functional changes in memory-relevant neuro-circuits in this cohort. Eighty-four patients with treatment-resistant unipolar depression who were moderately depressed or BD in remission were randomized to eight weekly EPO (40 000 IU) or saline infusions in a double-blind, parallel-group design. Participants underwent whole-brain fMRI at 3T, mood ratings, and blood tests at baseline and week 14. During fMRI, participants performed a picture encoding task followed by postscan recall. Sixty-two patients had complete data (EPO: N = 32, saline: N = 30). EPO improved picture recall and increased encoding-related activity in dorsolateral prefrontal cortex (dlPFC) and temporo-parietal regions, but not in hippocampus. Recall correlated with activity in the identified dlPFC and temporo-parietal regions at baseline, and change in recall correlated with activity change in these regions from baseline to follow-up across the entire cohort. The effects of EPO were not correlated with change in mood, red blood cells, blood pressure, or medication. The findings highlight enhanced encoding-related dlPFC and temporo-parietal activity as key neuronal underpinnings of EPO-associated memory improvement. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. BET bromodomain inhibition rescues erythropoietin differentiation of human erythroleukemia cell line UT7

    International Nuclear Information System (INIS)

    Goupille, Olivier; Penglong, Tipparat; Lefèvre, Carine; Granger, Marine; Kadri, Zahra; Fucharoen, Suthat; Maouche-Chrétien, Leila; Leboulch, Philippe; Chrétien, Stany

    2012-01-01

    Highlights: ► UT7 erythroleukemia cells are known to be refractory to differentiate. ► Brief JQ1 treatment initiates the first steps of erythroid differentiation program. ► Engaged UT7 cells then maturate in the presence of erythropoietin. ► Sustained JQ1 treatment inhibits both proliferation and erythroid differentiation. -- Abstract: Malignant transformation is a multistep process requiring oncogenic activation, promoting cellular proliferation, frequently coupled to inhibition of terminal differentiation. Consequently, forcing the reengagement of terminal differentiation of transformed cells coupled or not with an inhibition of their proliferation is a putative therapeutic approach to counteracting tumorigenicity. UT7 is a human leukemic cell line able to grow in the presence of IL3, GM-CSF and Epo. This cell line has been widely used to study Epo-R/Epo signaling pathways but is a poor model for erythroid differentiation. We used the BET bromodomain inhibition drug JQ1 to target gene expression, including that of c-Myc. We have shown that only 2 days of JQ1 treatment was required to transitory inhibit Epo-induced UT7 proliferation and to restore terminal erythroid differentiation. This study highlights the importance of a cellular erythroid cycle break mediated by c-Myc inhibition before initiation of the erythropoiesis program and describes a new model for BET bromodomain inhibitor drug application.

  3. Characterization of the structure of the erythropoietin receptor by ligand blotting

    International Nuclear Information System (INIS)

    Atkins, H.L.; Broudy, V.C.; Papayannopoulou, T.

    1991-01-01

    Erythropoietin (Epo) regulates the growth and differentiation of erythroid cells by binding to a specific receptor. We characterized the native Epo receptor on erythroleukemia cell lines by ligand blotting. Solubilized cell membrane proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred onto nitrocellulose, and probed with 125I-Epo. Specificity was demonstrated by inhibition of 125I-Epo binding by unlabeled excess Epo but not other peptide growth factors and by the cellular distribution of the Epo binding protein. A single membrane protein of 61 Kd ± 4 Kd was sufficient to bind 125I Epo in both human (OCIM2, K562) and murine (GM979, Rauscher, DA-1) cell lines. This finding is consistent with the predicted size of the Epo receptor from the murine cDNA clone. However, chemical crosslinking of 125I-Epo to its receptor has identified two Epo binding proteins of 105 Kd and 85 Kd. This difference may occur because the receptor is size fractionated before Epo binding in the ligand blot, but after Epo binding in crosslinking studies. Ligand blotting demonstrates that the native Epo receptor is composed of a single 61-Kd Epo binding protein, and suggests the presence of additional proteins of 20 to 25 Kd that associate with the receptor after Epo binding

  4. Erythropoietin, 2,3 DPG, oxygen transport capacity, and altitude training in adolescent Alpine skiers.

    Science.gov (United States)

    Son, Hee Jeong; Kim, Hyo Jeong; Kim, Jin Hae; Ohno, Hideki; Kim, Chang Keun

    2012-01-01

    Rapid growth during adolescence caused by metabolic changes and their metabolic response to anaerobic and aerobic exercise differs considerably from that in adults and this is especially true in the responses to stresses, such as altitude exposure. However, there is little information on the suitability of exercise training at altitude for young athletes. Six male Korean adolescent alpine skiers (13-17 yr), with a skiing career of 3-5 yr, participated in the study. All subjects were exposed to an altitude of 2700 m (8858 ft) for 5 wk and altitude exposure consisted of 6 d/wk of training (4-5 h/d), with living quarters at 2100 m (-6890 ft) (Tignes, France). The 5 wk of ski training at altitude were maintained at the same level (the same number of slalom and giant slalom skiing trials) as at sea level. There was a significant increase in oxygen transport capacity, despite decreased erythropoietin (EPO) production (-31%) after altitude training. Red blood cell (RBC), hemoglobin (Hb), hematocrit (Hct), and 2,3 DPG concentrations increased significantly during altitude exposure and after return to sea level. Results indicate that applying altitude training in adolescent skiers may improve their endurance performance. However, EPO production during altitude training needs to be evaluated in larger future studies.

  5. Serum immunoreactive erythropoietin in high altitude natives with and without excessive erythrocytosis.

    Science.gov (United States)

    León-Velarde, F; Monge, C C; Vidal, A; Carcagno, M; Criscuolo, M; Bozzini, C E

    1991-05-01

    We report the estimation of blood hemoglobin (Hb), arterial blood oxygen saturation (SaO2), and serum immunoreactive erythropoietin (siEPO) in a group of Peruvian workers residing in Cerro de Pasco at 4300 m showing "excessive erythrocytosis" (EE, Monge's disease, chronic mountain sickness). These estimates were compared with those of humans residing either in Cerro de Pasco and showing "normal erythrocytosis" (NE) or in Lima (sea level, SL) to determine whether Hb and SaO2 are related to siEPO in high altitude (HA) natives with NE or EE. The three parameters showed statistically significant differences between HA and SL groups--the values in SL being lower. Significant differences were also found between NE and EE groups in Hb and SaO2. There was no statistical difference in siEPo between the two groups. The results indicate, therefore, that HA residents who develop EE are not distinguishable from residents who develop NE on the basis of estimates of siEPO. As a result, siEPO and Hb do not show a dose-response relationship in HA residents, and variation in EPO does not explain the striking variation in Hb at high altitudes.

  6. Human pluripotent stem cell-derived erythropoietin-producing cells ameliorate renal anemia in mice.

    Science.gov (United States)

    Hitomi, Hirofumi; Kasahara, Tomoko; Katagiri, Naoko; Hoshina, Azusa; Mae, Shin-Ichi; Kotaka, Maki; Toyohara, Takafumi; Rahman, Asadur; Nakano, Daisuke; Niwa, Akira; Saito, Megumu K; Nakahata, Tatsutoshi; Nishiyama, Akira; Osafune, Kenji

    2017-09-27

    The production of erythropoietin (EPO) by the kidneys, a principal hormone for the hematopoietic system, is reduced in patients with chronic kidney disease (CKD), eventually resulting in severe anemia. Although recombinant human EPO treatment improves anemia in patients with CKD, returning to full red blood cell production without fluctuations does not always occur. We established a method to generate EPO-producing cells from human induced pluripotent stem cells (hiPSCs) by modifying previously reported hepatic differentiation protocols. These cells showed increased EPO expression and secretion in response to low oxygen conditions, prolyl hydroxylase domain-containing enzyme inhibitors, and insulin-like growth factor 1. The EPO protein secreted from hiPSC-derived EPO-producing (hiPSC-EPO) cells induced the erythropoietic differentiation of human umbilical cord blood progenitor cells in vitro. Furthermore, transplantation of hiPSC-EPO cells into mice with CKD induced by adenine treatment improved renal anemia. Thus, hiPSC-EPO cells may be a useful tool for clarifying the mechanisms of EPO production and may be useful as a therapeutic strategy for treating renal anemia. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  7. Antidepressant-like effects of erythropoietin: a focus on behavioural and hippocampal processes.

    Science.gov (United States)

    Osborn, Meagan; Rustom, Nazneen; Clarke, Melanie; Litteljohn, Darcy; Rudyk, Chris; Anisman, Hymie; Hayley, Shawn

    2013-01-01

    Depression is a chronic and debilitating condition with a significant degree of relapse and treatment resistance that could stem, at least in part, from disturbances of neuroplasticity. This has led to an increased focus on treatment strategies that target brain derived neurotrophic factor (BDNF), synaptic plasticity and adult neurogenesis. In the current study we aimed to assess whether erythropoietin (EPO) would have antidepressant-like effects given its already established pro-trophic actions. In particular, we assessed whether EPO would diminish the deleterious effects of a social stressor in mice. Indeed, EPO induced anxiolytic and antidepressant-like responses in a forced swim test, open field, elevated-plus maze, and a novelty test, and appeared to blunt some of the negative behavioural effects of a social stressor. Furthermore, EPO promoted adult hippocampal neurogenesis, an important feature of effective antidepressants. Finally, a separate study using the mTOR inhibitor rapamycin revealed that antagonizing this pathway prevented the impact of EPO upon forced swim performance. These data are consistent with previous findings showing that the mTOR pathway and its neurogenic and synaptogenic effects might mediate the behavioral consequences of antidepressant agents. Our findings further highlight EPO as a possible adjunct treatment for affective disorders, as well as other stressor associated disorders of impaired neuroplasticity.

  8. Cost analysis of erythropoietin versus blood transfusions for cervical cancer patients receiving chemoradiotherapy

    International Nuclear Information System (INIS)

    Kavanagh, Brian D.; Fischer, Bernard A.; Segreti, Eileen M.; Wheelock, John B.; Boardman, Cecilia; Roseff, Susan D.; Cardinale, Robert M.; Benedict, Stanley H.; Goram, Adrian L.

    2001-01-01

    Purpose: Red blood cell (RBC) transfusions or erythropoietin (EPO) can be used to evade the detrimental effects of anemia during radiotherapy, but the economic consequences of selecting either intervention are not well defined. The RBC transfusion needs during chemoradiotherapy for cervix cancer were quantified to allow comparison of RBC transfusion costs with the projected cost of EPO in this setting. Methods and Materials: For patients receiving pelvic radiotherapy, weekly cisplatin, and brachytherapy, the RBC units transfused during treatment were tallied. RBC transfusion costs per unit included the blood itself, laboratory fees, and expected value (risk multiplied by cost) of transfusion-related viral illness. EPO costs included the drug itself and supplemental RBC transfusions when hemoglobin was not adequately maintained. An EPO dosage based on reported usage in cervix cancer patients was applied. Results: Transfusions were given for hemoglobin <10 g/dL. Among 12 consecutive patients, 10 needed at least 1 U of RBC before or during treatment, most commonly after the fifth week. A total of 37 U was given during treatment, for an average of 3.1 U/patient. The sum total of the projected average transfusion-related costs was $990, compared with the total projected EPO-related costs of $3869. Conclusions: Because no proven clinical advantage has been documented for EPO compared with RBC transfusions to maintain hemoglobin during cervix cancer treatment, for most patients, transfusions are an appropriate and appealingly less expensive option

  9. An integrative 'omics' solution to the detection of recombinant human erythropoietin and blood doping.

    Science.gov (United States)

    Pitsiladis, Yannis P; Durussel, Jérôme; Rabin, Olivier

    2014-05-01

    Administration of recombinant human erythropoietin (rHumanEPO) improves sporting performance and hence is frequently subject to abuse by athletes, although rHumanEPO is prohibited by the WADA. Approaches to detect rHumanEPO doping have improved significantly in recent years but remain imperfect. A new transcriptomic-based longitudinal screening approach is being developed that has the potential to improve the analytical performance of current detection methods. In particular, studies are being funded by WADA to identify a 'molecular signature' of rHumanEPO doping and preliminary results are promising. In the first systematic study to be conducted, the expression of hundreds of genes were found to be altered by rHumanEPO with numerous gene transcripts being differentially expressed after the first injection and further transcripts profoundly upregulated during and subsequently downregulated up to 4 weeks postadministration of the drug; with the same transcriptomic pattern observed in all participants. The identification of a blood 'molecular signature' of rHumanEPO administration is the strongest evidence to date that gene biomarkers have the potential to substantially improve the analytical performance of current antidoping methods such as the Athlete Biological Passport for rHumanEPO detection. Given the early promise of transcriptomics, research using an 'omics'-based approach involving genomics, transcriptomics, proteomics and metabolomics should be intensified in order to achieve improved detection of rHumanEPO and other doping substances and methods difficult to detect such a recombinant human growth hormone and blood transfusions.

  10. Influence of Erythropoietin Dose and Albumin Level on the Plasma Brain Natriuretic Peptide in Hemodialysis Patients

    Directory of Open Access Journals (Sweden)

    Alsuwaida Abdulkareem

    2006-01-01

    Full Text Available Brain natriuretic peptide (BNP levels increase in patients with congestive heart failure. Theoretically, BNP levels can be helpful in the determination of the "dry weight" of hemodialysis patients. To evaluate the effect of hemodialysis on the plasma concentration of BNP and to determine the factors that affect BNP levels during hemodialysis in patients with chronic renal failure, we studied five stable patients with chronic renal failure. A total of 15 blood samples were obtained for BNP levels at 24, 48 and 72 hours after the last hemodialysis session. The plasma BNP levels did not change significantly either with ultrafiltration volume or with time since last dialysis. However, the BNP levels correlated positively with the erythropoietin (EPO dose (r=0.98, P< 0.001 and negatively with the serum albumin levels (r = 0.94, P=0.02. Univariate analysis showed that the EPO dose (P=0.001 and the albumin level (P=0.02 were significant predictors of BNP level. Adjusted multivariate analysis showed significant interaction between the EPO dose and the albumin level (P=0.01, P=0.03 respectively. In conclusion: the plasma BNP levels were not significantly influenced by ultrafiltration volume or time since last dialysis. However, the BNP levels may be a useful prognostic parameter for assessing the risk of cardiovascular morbidity and mortality in hemodialysis patients.

  11. General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain.

    Directory of Open Access Journals (Sweden)

    Tomoharu Tanaka

    Full Text Available Erythropoietin (EPO, originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is also endogenously expressed in the central nervous system (CNS. EPO in the CNS, mainly produced in astrocytes, is induced under hypoxic conditions in a hypoxia-inducible factor (HIF-dependent manner and plays a dominant role in neuroprotection and neurogenesis. We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes.BALB/c mice were exposed to 10% oxygen with isoflurane at various concentrations (0.10-1.0%. Expression of EPO mRNA in the brain was studied, and the effects of sevoflurane, halothane, nitrous oxide, pentobarbital, ketamine, and propofol were investigated. In addition, expression of HIF-2α protein was studied by immunoblotting. Hypoxia-induced EPO mRNA expression in the brain was significantly suppressed by isoflurane in a concentration-dependent manner. A similar effect was confirmed for all other general anesthetics. Hypoxia-inducible expression of HIF-2α protein was also significantly suppressed with isoflurane. In the experiments using primary cultured astrocytes, isoflurane, pentobarbital, and ketamine suppressed hypoxia-inducible expression of HIF-2α protein and EPO mRNA.Taken together, our results indicate that general anesthetics suppress activation of HIF-2 and inhibit hypoxia-induced EPO upregulation in the mouse brain through a direct effect on astrocytes.

  12. In vitro expression of erythropoietin by transfected human mesenchymal stromal cells.

    Science.gov (United States)

    Mok, P-L; Cheong, S-K; Leong, C-F; Othman, A

    2008-01-01

    Mesenchymal stromal cells (MSC) are pluripotent progenitor cells that can be found in human bone marrow (BM). These cells have low immunogenicity and could suppress alloreactive T-cell responses. In the current study, MSC were tested for their capacity to carry and deliver the erythropoietin (EPO) gene in vitro. Expanded BM MSC was transfected with EPO-encoded plasmid pMCV1.2 and EPO-encoded MIDGE (minimalistic immunologically defined gene expression) vector by electroporation. The expressed EPO was used to induce hematopoietic stem cells (HSC) into erythroid colonies. The results showed that the MIDGE vector was more effective and stable than the plasmid (pMCV1.2) in delivering EPO gene into MSC. The supernatants containing EPO obtained from the transfected cell culture were able to induce the differentiation of HSC into erythroid colonies. MSC hold promise as a cell factory for the production of biologic molecules, and MIDGE vector is more effective and stable than the plasmid in nucleofection involving the EPO gene.

  13. THE ROLE OF ERYTHROPOIETIN IN TREATMENT OF ANEMIA IN CANCER PATIENTS

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    P. G. Berezin

    2017-01-01

    Full Text Available Malignant neoplasms are a serious pathological condition, both in terms of the course of the disease and the need for treatment, and a prognosis for the life of patients. The deterioration in the quality of life, social disadaptation (reduced physical activity, job change, fatigue, etc. is a complication of the course of the disease caused by the development of anemia, which requires a vital need for its correction. This article analyzes the efficacy of recombinant erythropoietin — Epoetin-theta in the treatment of patients with NON — myeloid tumors and CRF (chronic renal failure in cancer patients. The high efficacy and safety of drug therapy in this category of patients are demonstrated. Recommendations are given on the optimal dose of the drug in order to obtain the most pronounced clinical effect of treatment, increasing the therapeutic dose of the drug with an insufficient increase in the hemoglobin level by 100% or more allows an individual approach to the correction of anemia. The possibility of its application in routine clinical practice of the oncologist’s doctor, namely in out-patientpolyclinic conditions, has been determined.

  14. Increased red cell 2,3-diphosphoglycerate levels in haemodialysis patients treated with erythropoietin.

    Science.gov (United States)

    Horina, J H; Schwaberger, G; Brussee, H; Sauseng-Fellegger, G; Holzer, H; Krejs, G J

    1993-01-01

    The efficacy of recombinant human erythropoietin (rHuEpo) for the treatment of renal anaemia is well established. To assess the effect of rHuEpo treatment on physical performance we evaluated physical working capacity, oxygen uptake and red cell 2,3-diphosphoglycerate (DPG) values at rest and during and after exercise on a bicycle spiroergometer in eight chronically haemodialysed patients. Follow-up examination was carried out after a mean of 14 weeks (range 9-19 weeks), when mean haemoglobin had increased from 7.8 to a stable value of 13.0 g/dl in response to rHuEpo treatment (P level without rHuEpo treatment than after correction of anaemia. Therefore rHuEpo treatment results both in better oxygen transport capacity and reduced intraerythrocytic oxygen affinity, which is followed by improved oxygen delivery to tissues per unit of haemoglobin. These effects may explain the improvement of exercise capacity observed in dialysis patients after rHuEpo treatment.

  15. Blood rheology and 2,3-diphosphoglycerate levels after erythropoietin treatment.

    Science.gov (United States)

    Crowley, J P; Chazan, J A; Metzger, J B; Pono, L; Valeri, C R

    1993-01-01

    Twenty-seven transfusion dependent patients with end-stage renal disease on long-term dialysis had blood cell counts, serum chemistries, blood pressure, and whole blood viscosity measured, as well as having transfusion requirements assessed. Three months after the institution of recombinant human erythropoietin (rHU-EPO) (75 u per kg per wk), there was an 88 percent fall in transfusion requirement. After four months, the hematocrit increased from 24 +/- 3.8 to 25.6 +/- 4.2 percent, mean corpuscular volume from 93 +/- 4.9 to 97 +/- 6.6 fl, 2-3-diphosphoglycerate (2,3-DPG) from 13.2 +/- 3.2 to 15.6 +/- 4.3 microM per g of Hb. Whole blood viscosity fell from 14.1 +/- 2.1 to 12.7 +/- 2.3 seconds, and ferritin levels fell from 3282 +/- 3889 to 2131 +/- 2441 ng per ml. In eight patients in whom the dose of rHU-EPO was further increased by up to 50 units per kg three times weekly for three months, the hematocrit rose further to 29.3 +/- 3.0 percent and the rise in hematocrit was accompanied by a further increase in 2,3-DPG to 17.9 +/- 2.8 microM per g of Hb (p < 0.03). There were no major side effects or vascular complications.

  16. How bio-questionable are the different recombinant human erythropoietin copy products in Thailand?

    Science.gov (United States)

    Halim, Liem Andhyk; Brinks, Vera; Jiskoot, Wim; Romeijn, Stefan; Praditpornsilpa, Kearkiat; Assawamakin, Anunchai; Schellekens, Huub

    2014-05-01

    The high prevalence of pure red cell aplasia in Thailand has been associated with the sharp increase in number of recombinant human erythropoietin (rhEPO) copy products, based on a classical generic regulatory pathway, which have entered the market. This study aims to assess the quality of rhEPO copy products being used in Thailand. Twelve rhEPO copy products were purchased from pharmacies in Thailand, shipped under controlled cold chain conditions to the Netherlands and characterized using (1) high performance size-exclusion chromatography, (2) asymmetrical flow field-flow fractionation, (3) sodium dodecyl sulfate polyacrylamide gel electrophoresis in combination with (4) Western blotting and additionally tested for (5) host cell protein impurities as well as (6) endotoxin contamination. Some of the tested rhEPO copy products showed high aggregate levels and contained a substantial amount of protein fragments. Also, one of rhEPO copy products had a high endotoxin level, exceeding the FDA limit. Our observations show that some of the tested copy products on the Thai market differ significantly from the originator rhEPO product, Epogen®. This comparison study supports a link between the quality attributes of copy rhEPO products and their immunogenicity.

  17. BET bromodomain inhibition rescues erythropoietin differentiation of human erythroleukemia cell line UT7

    Energy Technology Data Exchange (ETDEWEB)

    Goupille, Olivier [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Penglong, Tipparat [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Thalassemia Research Center and Department of Clinical Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University (Thailand); Lefevre, Carine; Granger, Marine; Kadri, Zahra [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Fucharoen, Suthat [Thalassemia Research Center and Department of Clinical Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University (Thailand); Maouche-Chretien, Leila [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Leboulch, Philippe [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France); Genetics Division, Department of Medicine, Brigham and Women' s Hospital and Harvard Medical School, Boston, MA (United States); Chretien, Stany, E-mail: stany.chretien@cea.fr [CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (France); UMR INSERM U.962, University Paris XI, CEA, Fontenay-aux-Roses (France)

    2012-12-07

    Highlights: Black-Right-Pointing-Pointer UT7 erythroleukemia cells are known to be refractory to differentiate. Black-Right-Pointing-Pointer Brief JQ1 treatment initiates the first steps of erythroid differentiation program. Black-Right-Pointing-Pointer Engaged UT7 cells then maturate in the presence of erythropoietin. Black-Right-Pointing-Pointer Sustained JQ1 treatment inhibits both proliferation and erythroid differentiation. -- Abstract: Malignant transformation is a multistep process requiring oncogenic activation, promoting cellular proliferation, frequently coupled to inhibition of terminal differentiation. Consequently, forcing the reengagement of terminal differentiation of transformed cells coupled or not with an inhibition of their proliferation is a putative therapeutic approach to counteracting tumorigenicity. UT7 is a human leukemic cell line able to grow in the presence of IL3, GM-CSF and Epo. This cell line has been widely used to study Epo-R/Epo signaling pathways but is a poor model for erythroid differentiation. We used the BET bromodomain inhibition drug JQ1 to target gene expression, including that of c-Myc. We have shown that only 2 days of JQ1 treatment was required to transitory inhibit Epo-induced UT7 proliferation and to restore terminal erythroid differentiation. This study highlights the importance of a cellular erythroid cycle break mediated by c-Myc inhibition before initiation of the erythropoiesis program and describes a new model for BET bromodomain inhibitor drug application.

  18. Long-term erythropoietin gene expression from transduced cells in bioisolator devices.

    Science.gov (United States)

    Yanay, Ofer; Barry, Simon C; Flint, Lisa Y; Brzezinski, Margaret; Barton, Randall W; Osborne, William R A

    2003-11-20

    Recombinant erythropoietin (EPO) is widely administered for long-term treatment of anemia associated with renal failure and other chronic diseases. The ability to deliver EPO by gene therapy would have clinical and economic benefit. We compared autologous and allogeneic transduced primary vascular smooth muscle cells for their ability to provide sustained EPO gene expression when encapsulated in TheraCyte devices implanted subcutaneously (SQ) or intraperitoneally (IP) in rats. Cells were transduced with retrovirus vector LrEpSN encoding rat EPO cDNA. Rats that received either autologous or allogeneic transduced cells showed elevated hematocrits (HCTs) ranging from 50 to 79% that were sustained for more than 12 months. The HCT of control rats remained at baseline (45.8%). Rats that received second SQ implants of either autologous or allogeneic cells showed elevations in hematocrit that were sustained for up to 12 months, suggesting the absence of immunological responses to transduced cells or implant material. All experimental groups had statistically significant elevated HCT (p TheraCyte devices was well tolerated and histological evaluation of the devices up to 12 months after surgery revealed a high degree of vascularization and no evidence of host immune response. TheraCyte devices offer a simple and safe gene delivery system that provides sustained therapeutic gene expression, permit removal and implantation of new devices, and do not require immunosuppression of the host.

  19. Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients.

    Science.gov (United States)

    DeVita, M V; Frumkin, D; Mittal, S; Kamran, A; Fishbane, S; Michelis, M F

    2003-11-01

    Although clinical use of recombinant human erythropoietin (rHuEPO) since 1989 has improved anemia in most end-stage renal disease patients, there are still many hemodialysis patients unable to maintain an adequate hematocrit (HCT) without large doses of rHuEPO. This suggests that anemia is not solely a consequence of rHuEPO deficiency, but may be due to other factors including functional iron deficiency. Since the optimal prescription for iron replacement is not yet known, we evaluated the effect of intravenous iron dextran (IVFe) infusion on serum ferritin (SFer) concentration and rHuEPO dose. Our objective was to raise and maintain serum ferritin concentrations to 2 different levels above the National Kidney Foundation Dialysis Outcome Quality Initiative standard of 100 ng/ml to determine whether, and by what degree rHuEPO dose could be lowered. HD patients on i.v. rHuEPO with a SFer concentration > or = 70 ng/ml and an HCT of requirements.

  20. Erythropoietin improves the survival of fat tissue after its transplantation in nude mice.

    Directory of Open Access Journals (Sweden)

    Saher Hamed

    Full Text Available BACKGROUND: Autologous transplanted fat has a high resorption rate, providing a clinical challenge for the means to reduce it. Erythropoietin (EPO has non-hematopoietic targets, and we hypothesized that EPO may improve long-term fat graft survival because it has both pro-angiogenic and anti-apoptotic properties. We aimed to determine the effect of EPO on the survival of human fat tissue after its transplantation in nude mice. METHODOLOGY/PRINCIPAL FINDINGS: Human fat tissue was injected subcutaneously into immunologically-compromised nude mice, and the grafts were then treated with either 20 IU or 100 IU EPO. At the end of the 15-week study period, the extent of angiogenesis, apoptosis, and histology were assessed in the fat grafts. The results were compared to vascular endothelial growth factor (VEGF-treated and phosphate-buffered saline (PBS-treated fat grafts. The weight and volume of the EPO-treated grafts were higher than those of the PBS-treated grafts, whose weights and volumes were not different from those of the VEGF-treated grafts. EPO treatment also increased the expression of angiogenic factors and microvascular density, and reduced inflammation and apoptosis in a dose-dependent manner in the fat grafts. CONCLUSIONS/SIGNIFICANCE: Our data suggest that stimulation of angiogenesis by a cluster of angiogenic factors and decreased fat cell apoptosis account for potential mechanisms that underlie the improved long-term survival of fat transplants following EPO treatment.

  1. Fibronectin potentiates topical erythropoietin-induced wound repair in diabetic mice.

    Science.gov (United States)

    Hamed, Saher; Ullmann, Yehuda; Egozi, Dana; Daod, Essam; Hellou, Elias; Ashkar, Manal; Gilhar, Amos; Teot, Luc

    2011-06-01

    Diabetes mellitus disrupts all phases of the wound repair cascade and leads to development of chronic wounds. We previously showed that topical erythropoietin (EPO) can promote wound repair in diabetic rats. Fibronectin (FN) has a critical role throughout the process of wound healing, yet it is deficient in wound tissues of diabetic patients. Therefore, we investigated the effect of topical treatment of both EPO and FN (EPO/FN) on wound repair in diabetic mice. Full-thickness excisional skin wounds in diabetic and nondiabetic mice were treated with a cream containing vehicle, EPO, FN, or EPO/FN. We assessed the rate of wound closure, angiogenesis, apoptosis, and expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS) and β1-integrin, in the wound tissues. We also investigated the effect of EPO, FN, and EPO/FN on human dermal microvascular endothelial cells and fibroblasts cultured on fibrin-coated plates, or in high glucose concentrations. EPO/FN treatment significantly increased the rate of wound closure and this effect was associated with increased angiogenesis, increased eNOS and β1-integrin expression, and reduced expression of inflammatory cytokines and apoptosis. Our findings show that EPO and FN have an additive effect on wound repair in diabetic mice.

  2. Erythropoietin improves the survival of fat tissue after its transplantation in nude mice.

    Science.gov (United States)

    Hamed, Saher; Egozi, Dana; Kruchevsky, Danny; Teot, Luc; Gilhar, Amos; Ullmann, Yehuda

    2010-11-15

    Autologous transplanted fat has a high resorption rate, providing a clinical challenge for the means to reduce it. Erythropoietin (EPO) has non-hematopoietic targets, and we hypothesized that EPO may improve long-term fat graft survival because it has both pro-angiogenic and anti-apoptotic properties. We aimed to determine the effect of EPO on the survival of human fat tissue after its transplantation in nude mice. Human fat tissue was injected subcutaneously into immunologically-compromised nude mice, and the grafts were then treated with either 20 IU or 100 IU EPO. At the end of the 15-week study period, the extent of angiogenesis, apoptosis, and histology were assessed in the fat grafts. The results were compared to vascular endothelial growth factor (VEGF)-treated and phosphate-buffered saline (PBS)-treated fat grafts. The weight and volume of the EPO-treated grafts were higher than those of the PBS-treated grafts, whose weights and volumes were not different from those of the VEGF-treated grafts. EPO treatment also increased the expression of angiogenic factors and microvascular density, and reduced inflammation and apoptosis in a dose-dependent manner in the fat grafts. Our data suggest that stimulation of angiogenesis by a cluster of angiogenic factors and decreased fat cell apoptosis account for potential mechanisms that underlie the improved long-term survival of fat transplants following EPO treatment.

  3. ERYTHROPOIETIN TREATMENT FOR ANEMIA IN CHILDREN WITH CANCER – SINGLE CENTRE EXPERIENCES

    Directory of Open Access Journals (Sweden)

    Polona Mali

    2004-12-01

    Full Text Available Background. Anemia, a common complication during treatment of malignant disease in children, was frequently treated with red blood cell transfusions. Several studies have shown, that the introduction of recombinant human erythropoietin (rh EPO for treating anemia in patients has been effective in reducing the need for transfusions. Variable doses of EPO from 150 to 900 IU/kg body weight have been used usually three times weekly. Recently some studies showed equally effective once weekly administration of EPO with proposed doses for children of 450 to 600 IU/ kg body weight.Efficacy and safety of once weekly EPO therapy was tested in 8/10 children treated in our Unit for solid tumors and nonHodgkin’s lymphoma. In this article we would like to present our one year experience with EPO treatment.Patients and methods. Patients have subcutaneously received the EPO dose of 600 UI/ kg body weight once weekly. Hemoglobin response and transfusion needs before and during treatment with EPO were analyzed.Results. Response was seen in 7/8 of patient, with increased hemoglobin level and lower transfusion needs. Only one patient was poor responder at first, but responded perfect after twice weekly EPO application. No adverse reaction related to EPO therapy was observed.Conclusions. Our experience with treating anemia in pediatric cancer patients who undergo intensive and aggressive chemotherapy treatment regimens are good and promising. Once weekly dosage regimen is child friendly and acceptable way of treating anemia.

  4. Erythropoietin does not reduce plasma lactate, H+, and K+ during intense exercise

    DEFF Research Database (Denmark)

    Nordsborg, Nikolai Baastrup; Robach, P; Boushel, R

    2015-01-01

    It is investigated if recombinant human erythropoietin (rHuEPO) treatment for 15 weeks (n = 8) reduces extracellular accumulation of metabolic stress markers such as lactate, H(+) , and K(+) during incremental exhaustive exercise. After rHuEPO treatment, normalization of blood volume...... and composition by hemodilution preceded an additional incremental test. Group averages were calculated for an exercise intensity ∼80% of pre-rHuEPO peak power output. After rHuEPO treatment, leg lactate release to the plasma compartment was similar to before (4.3 ± 1.6 vs 3.9 ± 2.5 mmol/min) and remained similar...... after hemodilution. Venous lactate concentration was higher (P release to the plasma compartment after rHuEPO was similar to before (19.6 ± 5.4 vs 17.6 ± 6.0 mmol/min) and remained similar after hemodilution. Nevertheless, venous p...

  5. A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia.

    Science.gov (United States)

    Frey, Helena; Moreth, Kristin; Hsieh, Louise Tzung-Harn; Zeng-Brouwers, Jinyang; Rathkolb, Birgit; Fuchs, Helmut; Gailus-Durner, Valérie; Iozzo, Renato V; de Angelis, Martin Hrabě; Schaefer, Liliana

    2017-06-01

    Secondary polycythemia, a disease characterized by a selective increase in circulating mature erythrocytes, is caused by enhanced erythropoietin (Epo) concentrations triggered by hypoxia-inducible factor-2α (HIF-2α). While mechanisms of hypoxia-dependent stabilization of HIF-2α protein are well established, data regarding oxygen-independent regulation of HIF-2α are sparse. In this study, we generated a novel transgenic mouse model, in which biglycan was constitutively overexpressed and secreted by hepatocytes (BGN Tg ), thereby providing a constant source of biglycan released into the blood stream. We discovered that although the mice were apparently normal, they harbored an increase in mature circulating erythrocytes. In addition to erythrocytosis, the BGN Tg mice showed elevated hemoglobin concentrations, hematocrit values and enhanced total iron binding capacity, revealing a clinical picture of polycythemia. In BGN Tg mice markedly enhanced Epo mRNA expression was observed in the liver and kidney, while elevated Epo protein levels were found in liver, kidney and blood. Mechanistically, we showed that the transgenic animals had an abundance of HIF-2α protein in the liver and kidney. Finally, by transiently overexpressing circulating biglycan in mice deficient in various Toll-like receptors (TLRs), we determined that this novel function of biglycan to promote Epo synthesis was specifically mediated by a selective interaction with TLR2. Thus, we discovered a novel biological pathway of soluble biglycan inducing HIF-2α protein stabilization and Epo production presumably in an oxygen-independent manner, ultimately giving rise to secondary polycythemia.

  6. Cervical spinal erythropoietin induces phrenic motor facilitation via ERK and Akt signaling

    Science.gov (United States)

    Dale, Erica A.; Satriotomo, Irawan; Mitchell, Gordon S.

    2012-01-01

    Erythropoietin (EPO) is typically known for its role in erythropoiesis, but is also a potent neurotrophic/neuroprotective factor for spinal motor neurons. Another trophic factor regulated by Hypoxia-Inducible Factor-1, vascular endothelial growth factor (VEGF), signals via ERK and Akt activation to elicit long-lasting phrenic motor facilitation (pMF). Since EPO also signals via ERK and Akt activation, we tested the hypothesis that EPO elicits similar pMF. Using retrograde labeling and immunohistochemical techniques, we demonstrate in adult, male, Sprague-Dawley rats that EPO and its receptor, EPO-R, are expressed in identified phrenic motor neurons. Intrathecal EPO at C4 elicits long-lasting pMF; integrated phrenic nerve burst amplitude increased >90 min post-injection (63±12% baseline 90 min post-injection; pphrenic motor neurons; EPO also increased pAkt (1.6 fold vs controls; pphrenic motor neurons (p<0.05), indicating a complex interaction between these kinases. We conclude that EPO elicits spinal plasticity in respiratory motor control. Since EPO expression is hypoxia-sensitive, it may play a role in respiratory plasticity in conditions of prolonged or recurrent low oxygen. PMID:22539857

  7. Inhibition of erythropoietin siRNA on corneal neovascularization of rabbit

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    Yu-Shun Xue

    2017-03-01

    Full Text Available AIM: To observe the expression of erythropoietin(EPOon the corneal of rabbit and evaluate the inhibition effect of EPO siRNA on corneal neovascularization(CNV. METHODS: Totally 22 healthy rabbits were randomly divided into 2 groups, which were experimental group and normal control group. Both eyes of rabbits in experimental group were chosen to establish corneal neovascularization model by alkali burn. The morphologic change of corneal was observed with slit lamp microscope and the area of CNV was calculated every day. After alkali burn, the right eye of the experimental group was accepted EPO siRNA injection under the conjunctiva, and the left eye was assigned to be experimental control group. The corneal with CNV was collected for immunohistochemistry at 3d, 7d, 14d, 21d after alkali burn, and the expression of EPO was measured. RESULTS: CNV began growing at the 3d after alkali burn in experimental group, and it was vigorous growing at 7d-14d period. The result of immunohistochemistry shows that the expression of EPO increased after the operation. Compared with experimental group, the rabbits who were treated by EPO siRNA was found with less neovascularization on their corneal, and the expression of EPO decreased. There were statistical significance between the two group at different time(PCONCLUSION: EPO is likely to play an important role on CNV growth, and EPO siRNA can inhibit the growth of CNV by restraining the expression of EPO.

  8. Potency Evaluation of Recombinant Human Erythropoietin in Brazil: Assessment of Reproducibility Using a Practical Approach

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    Michele Cardoso do Nascimento

    2015-08-01

    Full Text Available In this study, we compared the results of potency determination of recombinant human erythropoietin (rhEPO obtained between 2010 and 2012 by the National Institute of Quality Control in Health (INCQS/Fiocruz, i.e., the National Control Laboratory (NCL, and by a manufacturer of rhEPO. In total, 47 different batches of commercially prepared rhEPO (alpha isoform were analyzed. All results, including those of the control and warning limits, remained within the limits recommended by European Pharmacopoeia (Ph. Eur.. All relative error (RE values were less than ± 30%, wh ereas most were approximately ± 20%. Applying the Bland-Altman plot, only two of 47 values remained outside the limits of agreement (LA. In addition, agreement of potency determination between INCQS and the manufacturer coefficient of variation of reproducibility (% CVR was considered satisfactory. Taken together, our results demonstrate (i. the potency assay of rhEPO performed at INCQS, is standardized and controlled, (ii. the comparison of our results with those of the manufacturer, revealed an adequate inter-laboratory variation, and (iii. the critical appraisal proposed here appears to be a feasible tool to assess the reproducibility of biological activity, providing additional information regarding monitoring and production consistency to manufacturers and NCLs.

  9. Acute Vhl gene inactivation induces cardiac HIF-dependent erythropoietin gene expression.

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    Marta Miró-Murillo

    Full Text Available Von Hippel Lindau (Vhl gene inactivation results in embryonic lethality. The consequences of its inactivation in adult mice, and of the ensuing activation of the hypoxia-inducible factors (HIFs, have been explored mainly in a tissue-specific manner. This mid-gestation lethality can be also circumvented by using a floxed Vhl allele in combination with an ubiquitous tamoxifen-inducible recombinase Cre-ER(T2. Here, we characterize a widespread reduction in Vhl gene expression in Vhl(floxed-UBC-Cre-ER(T2 adult mice after dietary tamoxifen administration, a convenient route of administration that has yet to be fully characterized for global gene inactivation. Vhl gene inactivation rapidly resulted in a marked splenomegaly and skin erythema, accompanied by renal and hepatic induction of the erythropoietin (Epo gene, indicative of the in vivo activation of the oxygen sensing HIF pathway. We show that acute Vhl gene inactivation also induced Epo gene expression in the heart, revealing cardiac tissue to be an extra-renal source of EPO. Indeed, primary cardiomyocytes and HL-1 cardiac cells both induce Epo gene expression when exposed to low O(2 tension in a HIF-dependent manner. Thus, as well as demonstrating the potential of dietary tamoxifen administration for gene inactivation studies in UBC-Cre-ER(T2 mouse lines, this data provides evidence of a cardiac oxygen-sensing VHL/HIF/EPO pathway in adult mice.

  10. Long-term cadmium exposure induces anemia in rats through hypoinduction of erythropoietin in the kidneys

    Energy Technology Data Exchange (ETDEWEB)

    Horiguchi, Hyogo [Department of Public Health, Fukushima Medical College, Fukushima (Japan); Sato, Masao [Department of Biomolecular Sciences, Institute of Biomedical Sciences, Fukushima Medical College, Fukushima (Japan); Konno, Nobuhiro [Department of Public Health, Fukushima Medical College, Fukushima (Japan); Fukushima, Masaaki [Department of Public Health, Fukushima Medical College, Fukushima (Japan)

    1996-11-01

    Cadmium (Cd), a highly toxic heavy metal, is distributed widely in the general environment of today. The characteristic clinical manifestations of chronic Cd intoxication include renal proximal tubular dysfunction, general osteomalacia with severe pains, and anemia. We have recently reported that the serum level of erythropoietin (EPO) remained low despite the severe anemia in patients with Itai-itai disease, the most severe form of chronic Cd intoxication. In order to prove that the anemia observed in chronic Cd intoxication arises from low production of EPO in the kidneys following the renal injury, we administered Cd to rats for a long period and performed the analysis of EPO mRNA inducibility in the kidneys. The rats administered Cd for 6 and 9 months showed anemia with low levels of plasma EPO as well as biochemical and histological renal tubular damage, and also hypoinduction of EPO mRNA in the kidneys. The results indicate that chronic Cd intoxication causes anemia by disturbing the EPO-production capacity of renal cells. (orig.). With 4 figs., 4 tabs.

  11. Huh-7 cell line as an alternative cultural model for the production of human like erythropoietin (EPO

    Directory of Open Access Journals (Sweden)

    Kausar Humera

    2011-11-01

    Full Text Available Abstract Background and Aims Erythropoietin (EPO is a glycoprotein hormone which is required to regulate the production of red blood cells. Deficiency of EPO is known to cause anemia in chronically infected renal patients and they require regular blood transfusion. Availability of recombinant EPO has eliminated the need for blood transfusion and now it is extensively used for the treatment of anemia. Glycosylation of erythropoietin is essential for its secretion, stability, protein conformation and biological activity. However, maintenance of human like glycosylation pattern during manufacturing of EPO is a major challenge in biotechnology. Currently, Chinese hamster ovary (CHO cell line is used for the commercial production of erythropoietin but this cell line does not maintain glycosylation resembling human system. With the trend to eliminate non-human constituent from biopharmaceutical products, as a preliminary approach, we have investigated the potential of human hepatoma cell line (Huh-7 to produce recombinant EPO. Materials and methods Initially, the secretory signal and Kozak sequences was added before the EPO mature protein sequence using overlap extension PCR technique. PCR-amplified cDNA fragments of EPO was inserted into mammalian expression vector under the control of the cytomegalovirus (CMV promoter and transiently expressed in CHO and Huh-7 cell lines. After RT-PCR analysis, ELISA and Western blotting was performed to verify the immunochemical properties of secreted EPO. Results Addition of secretory signal and Kozak sequence facilitated the extra-cellular secretion and enhanced the expression of EPO protein. Significant expression (P Conclusion Huh-7 cell line has a great potential to produce glycosylated EPO, suggesting the use of this cell line to produce glycoproteins of the therapeutic importance resembling to the natural human system.

  12. An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Rodríguez Cruz, Yamila; Strehaiano, Manon; Rodríguez Obaya, Teresita; García Rodríguez, Julío César; Maurice, Tangui

    2017-01-01

    Erythropoietin (EPO) is a cytokine known to have effective cytoprotective action in the brain, particularly in ischemic, traumatic, inflammatory, and neurodegenerative conditions. We previously reported the neuroprotective effect of a low sialic form of EPO, Neuro-EPO, applied intranasally in rodent models of stroke or cerebellar ataxia and in a non-transgenic mouse model of Alzheimer's disease (AD). Here we analyzed the protective effect of Neuro-EPO in APPSwe mice, a reference transgenic mouse model of AD. Mice were administered 3 times a day, 3 days in the week with Neuro-EPO (125, 250 μg/kg) intranasally, between 12 and 14 months of age. Motor responses, general activity, and memory responses were analyzed during and after treatment. The deficits in spontaneous alternation, place learning in the water-maze, and novel object recognition observed in APPSwe mice were alleviated by the low dose of Neuro-EPO. Oxidative stress, neuroinflammation, trophic factor levels, and a synaptic marker were analyzed in the hippocampus or cortex of the animals. The increases in lipid peroxidation or in GFAP and Iba-1 contents in APPSwe mice were significantly reduced after Neuro-EPO. Activation of intrinsic and extrinsic apoptotic pathways was analyzed. The increases in Bax/Bcl-2 ratio, TNFα, or Fas ligand levels observed in APPSwe mice were reduced by Neuro-EPO. Finally, immunohistochemical and ELISA analyses of Aβ1-42 levels in the APPSwe mouse cortex and hippocampus showed a marked reduction in Aβ deposits and in soluble and insoluble Aβ1-42 forms. This study therefore confirmed the neuroprotective activity of EPO, particularly for an intranasally deliverable formulation, devoid of erythropoietic side effects, in a transgenic mouse model of AD. Neuro-EPO alleviated memory alterations, oxidative stress, neuroinflammation, apoptosis induction, and amyloid load in 14-month-old APPSwe mice.

  13. Simultaneous Expression from Both the Sense and Antisense Strand of the Erythropoietin Receptor Gene Mitigates Acute Lung Injury

    Science.gov (United States)

    2017-09-01

    concept efficacy that increasing EpoR or RopE expression by cDNA delivery to lung cells in vitro enhances cytoprotection against hyperoxia-induced injury...oxidative damage, cell culture, rodent model, inhalation cDNA delivery, sense and antisense erythropoietin receptor transcripts 16. SECURITY...prevention of acute lung injury. 1-6 50% Subtask 1: Prepare plasmid cDNA of EpoR and RopE in nanoparticle formulation. 1 Completed 06.2017 Subtask 2

  14. Pharmacodynamically optimized erythropoietin treatment combined with phlebotomy reduction predicted to eliminate blood transfusions in selected preterm infants.

    Science.gov (United States)

    Rosebraugh, Matthew R; Widness, John A; Nalbant, Demet; Cress, Gretchen; Veng-Pedersen, Peter

    2014-02-01

    Preterm very-low-birth-weight (VLBW) infants weighing eliminated by reducing laboratory blood loss in combination with pharmacodynamically optimized erythropoietin (Epo) treatment. Twenty-six VLBW ventilated infants receiving RBCTx were studied during the first month of life. RBCTx simulations were based on previously published RBCTx criteria and data-driven Epo pharmacodynamic optimization of literature-derived RBC life span and blood volume data corrected for phlebotomy loss. Simulated pharmacodynamic optimization of Epo administration and reduction in phlebotomy by ≥ 55% predicted a complete elimination of RBCTx in 1.0-1.5 kg infants. In infants 1.0 kg.

  15. Brain and skin do not contribute to the systemic rise in erythropoietin during acute hypoxia in humans

    DEFF Research Database (Denmark)

    Rasmussen, Peter; Nordsborg, Nikolai; Taudorf, Sarah

    2012-01-01

    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......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...

  16. Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.

    Science.gov (United States)

    Aachmann-Andersen, Niels J; Christensen, Soren J; Lisbjerg, Kristian; Oturai, Peter; Johansson, Pär I; Holstein-Rathlou, Niels-Henrik; Olsen, Niels V

    2018-03-01

    The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  17. Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder

    Directory of Open Access Journals (Sweden)

    Paulson Olaf B

    2010-10-01

    Full Text Available Abstract Background Depression and bipolar disorder are associated with reduced neural plasticity and deficits in memory, attention and executive function. Drug treatments for these affective disorders have insufficient clinical effects in a large group and fail to reverse cognitive deficits. There is thus a need for more effective treatments which aid cognitive function. Erythropoietin (Epo is involved in neuroplasticity and is a candidate for future treatment of affective disorders. The investigators have demonstrated that a single dose of Epo improves cognitive function and reduces neurocognitive processing of negative emotional information in healthy and depressed individuals similar to effects seen with conventional antidepressants. The current study adds to the previous findings by investigating whether repeated Epo administration has antidepressant effects in patients with treatment resistant depression and reverses cognitive impairments in these patients and in patients with bipolar disorder in remission. Methods/design The trial has a double-blind, placebo-controlled, parallel-group design. 40 patients with treatment-resistant major depression and 40 patients with bipolar disorder in remission are recruited and randomised to receive weekly infusions of Epo (Eprex; 40,000 IU or saline (NaCl 0.9% for 8 weeks. Randomisation is stratified for age and gender. The primary outcome parameters for the two studies are: depression severity measured with the Hamilton Depression Rating Scale 17 items (HDRS-17 1 in study 1 and, in study 2, verbal memory measured with the Rey Auditory Verbal Learning Test (RAVLT 23. With inclusion of 40 patients in each study we obtain 86% power to detect clinically relevant differences between intervention and placebo groups on these primary outcomes. Trial registration The trial is approved by the Local Ethics Committee: H-C-2008-092, Danish Medicines Agency: 2612-4020, EudraCT: 2008-04857-14, Danish Data Agency

  18. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo.

    Science.gov (United States)

    Ohls, Robin K; Kamath-Rayne, Beena D; Christensen, Robert D; Wiedmeier, Susan E; Rosenberg, Adam; Fuller, Janell; Lacy, Conra Backstrom; Roohi, Mahshid; Lambert, Diane K; Burnett, Jill J; Pruckler, Barbara; Peceny, Hannah; Cannon, Daniel C; Lowe, Jean R

    2014-06-01

    We previously reported decreased transfusions and donor exposures in preterm infants randomized to Darbepoetin (Darbe) or erythropoietin (Epo) compared with placebo. As these erythropoiesis-stimulating agents (ESAs) have shown promise as neuroprotective agents, we hypothesized improved neurodevelopmental outcomes at 18 to 22 months among infants randomized to receive ESAs. We performed a randomized, masked, multicenter study comparing Darbe (10 μg/kg, 1×/week subcutaneously), Epo (400 U/kg, 3×/week subcutaneously), and placebo (sham dosing 3×/week) given through 35 weeks' postconceptual age, with transfusions administered according to a standardized protocol. Surviving infants were evaluated at 18 to 22 months' corrected age using the Bayley Scales of Infant Development III. The primary outcome was composite cognitive score. Assessments of object permanence, anthropometrics, cerebral palsy, vision, and hearing were performed. Of the original 102 infants (946 ± 196 g, 27.7 ± 1.8 weeks' gestation), 80 (29 Epo, 27 Darbe, 24 placebo) returned for follow-up. The 3 groups were comparable for age at testing, birth weight, and gestational age. After adjustment for gender, analysis of covariance revealed significantly higher cognitive scores among Darbe (96.2 ± 7.3; mean ± SD) and Epo recipients (97.9 ± 14.3) compared with placebo recipients (88.7 ± 13.5; P = .01 vs ESA recipients) as was object permanence (P = .05). No ESA recipients had cerebral palsy, compared with 5 in the placebo group (P < .001). No differences among groups were found in visual or hearing impairment. Infants randomized to receive ESAs had better cognitive outcomes, compared with placebo recipients, at 18 to 22 months. Darbe and Epo may prove beneficial in improving long-term cognitive outcomes of preterm infants. Copyright © 2014 by the American Academy of Pediatrics.

  19. Expression of hypoxia-inducible factor-1α and erythropoietin at corneal neovascularization in rats

    Directory of Open Access Journals (Sweden)

    Ji-Min Wang

    2014-12-01

    Full Text Available AIM: To describe the expression of hypoxia-inducible factor-1α(HIF-1αand erythropoietin(EPOin rats' corneal and evaluate its potential effect on corneal neovascularization(CNVgrowth. METHODS: The young SD rats(3mowas chosen and randomly divided into 2 groups, which were experimental group and normal control group. CNV model was established by alkali burn, and the length and area of CNV was observed everyday after operation by slit lamp. After that, the expression of HIF-1α and EPO was measured by SABC and RT-PCR methods at 1, 3, 5, 7, and 14d after alkali burn. The data was analyzed by SPSS 20.0. RESULTS: The area of CNV was increasing at 1, 3, 5, 7, and 14d after alkali burn, and the peak point appear at 7d. The growth speed was decreased after 14d. SABC method told us that no HIF-1α and very tiny amount EPO was detected at normal rats' corneal. The expression of the two factors increased at 1d after alkali burn in corneal epithelium and endoderm. The results of RT-PCR showed that a few amounts of HIF-1α and EPO mRNA were detected at normal group. The expression of the two factors was increased at 3d after alkali burn, and the peak value was found at 7d, however, it was decreased at 14d. Statistical difference was found at different time(PCONCLUSION: HIF-1α and EPO is closely related to CNV.

  20. Improvement of in vivo efficacy of recombinant human erythropoietin by encapsulation in PEG–PLA micelle

    Directory of Open Access Journals (Sweden)

    Shi YN

    2012-12-01

    Full Text Available Yanan Shi,1,2,* Wan Huang,1,* Rongcai Liang,1–3 Kaoxiang Sun,2,3 Fangxi Zhang,2,3 Wanhui Liu,2,3 Youxin Li1–31College of Life Science, Jilin University, Changchun, China; 2State Key Laboratory of Long-acting and Targeting Drug Delivery System, Luye Pharmaceutical Co, Ltd, Yantai, China; 3School of Pharmacy, Yantai University, Yantai, China*These authors contributed equally to this workAbstract: To improve the pharmacokinetics and stability of recombinant human erythropoietin (rhEPO, rhEPO was successfully formulated into poly(ethylene glycol–poly(d,l-lactide (PEG–PLA di-block copolymeric micelles at diameters ranging from 60 to 200 nm with narrow polydispersity indices (PDIs; PDI < 0.3 and trace amount of protein aggregation. The zeta potential of the spherical micelles was in the range of −3.78 to 4.65 mV and the highest encapsulation efficiency of rhEPO in the PEG–PLA micelles was about 80%. In vitro release profiles indicated that the stability of rhEPO in the micelles was improved significantly and only a trace amount of aggregate was found. Pharmacokinetic studies in rats showed highly enhanced plasma retention time of the rhEPO-loaded PEG-PLA micelles in comparison with the native rhEPO group. Increased hemoglobin concentrations were also found in the rat study. Native polyacrylamide gel electrophoresis results demonstrated that rhEPO was successfully encapsulated into the micelles, which was stable in phosphate buffered saline with different pHs and concentrations of NaCl. Therefore, PEG–PLA micelles can be a potential protein drug delivery system.Keywords: rhEPO, PEG–PLA micelle, in vitro, pharmacokinetics, pharmacodynamics

  1. Oral Zinc Supplementation Reduces the Erythropoietin Responsiveness Index in Patients on Hemodialysis

    Directory of Open Access Journals (Sweden)

    Hiroki Kobayashi

    2015-05-01

    Full Text Available Background: In hemodialysis (HD patients, zinc depletion caused by inadequate intake, malabsorption, and removal by HD treatment leads to erythropoiesis-stimulating agent (ESA hyporesponsiveness. This study investigated the effects of zinc supplementation in HD patients with zinc deficiency on changes in the erythropoietin responsiveness index (ERI. Methods: Patients on HD with low serum zinc levels (<65 μg/dL were randomly assigned to two groups: The polaprezinc group (who received daily polaprezinc, containing 34 mg/day of zinc (n = 35 and the control group (no supplementation (n = 35 for 12 months. All the 70 patients had been taking epoetin alpha as treatment for renal anemia. ERI was measured with the following equation: Weekly ESA dose (units/dry weight (kg/hemoglobin (g/dL. Results: There were no significant changes in hemoglobin levels within groups or between the control and polaprezinc groups during the study period. Although reticulocyte counts were increased immediately after zinc supplementation, this change was transient. Serum zinc levels were significantly increased and serum copper levels were significantly decreased in the polaprezinc group after three months; this persisted throughout the study period. Although there was no significant change in the serum iron or transferrin saturation levels in the polaprezinc group during the study period, serum ferritin levels significantly decreased following polaprezinc treatment. Further, in the polaprezinc group, ESA dosage and ERI were significantly decreased at 10 months and nine months, respectively, as compared with the baseline value. Multiple stepwise regression analysis revealed that the change in the serum zinc level was an independent predictor of lowered ERI. Conclusions: Zinc supplementation reduces ERI in patients undergoing HD and may be a novel therapeutic strategy for patients with renal anemia and low serum zinc levels.

  2. Association of Neutrophil-to-Lymphocyte Ratio With Inflammation and Erythropoietin Resistance in Chronic Dialysis Patients

    Directory of Open Access Journals (Sweden)

    Jérôme Pineault

    2017-11-01

    Full Text Available Background: Neutrophil-to-lymphocyte ratio (NLR was widely studied as a prognostic marker in various medical and surgical specialties, but its significance in nephrology is not yet established. Objective: We evaluated its accuracy as an inflammation biomarker in a dialysis population. Design setting: Single-center retrospective study. Patients: The records of all 550 patients who were treated with hemodialysis (HD or peritoneal dialysis (PD from September 2008 to March 2011 were included. Measurements: NLR was calculated from the monthly complete blood count. Methods: Association between NLR and markers of inflammation (C-reactive protein [CRP], serum albumin, and erythropoietin resistance index [ERI] was measured using Spearman coefficient. Results: In total, 120 patients were eligible for the correlation analyses. We found a positive correlation between NLR and CRP (all patients: r = 0.45, P < .001; HD: r = 0.47, P < .001; PD: r = 0.48, P = .13. NLR and albumin were inversely correlated ( r = −0.51, P < .001. Finally, high NLR was associated with a nonsignificant increased ERI, but we have not demonstrated a direct correlation. Limitations: CRP and albumin are not measured routinely and were ordered for a specific clinical reason leading to an indication bias. Also, no relationship with clinical outcome was established. Conclusions: NLR seems to be a good inflammatory biomarker in dialysis in addition to being easily available. However, controlled studies should be conducted to properly assess and validate NLR levels that would be clinically significant and relevant, as well as its prognostic significance and utility in a clinical setting.

  3. Effects of recombinant human erythropoietin injections on physical self in endurance athletes.

    Science.gov (United States)

    Ninot, Grégory; Connes, Philippe; Caillaud, Corrine

    2006-04-01

    This study examined the time course of mean self-esteem and physical self scores in three groups: male endurance athletes treated with recombinant human erythropoietin (rHuEPO group, n = 6), a placebo group (n = 5) injected with a sodium chloride solution and a control group who did not receive any injection (n = 6). Each participant completed the Physical Self Inventory twice a day (between 07.00 and 09.00 h and between 19.00 and 21.00 h). Using a 10 cm visual analog scale, the participants assessed global self-esteem, physical self-worth and the sub-domains of physical condition, sport competence, attractive body and physical strength (Fox & Corbin, 1989). This was conducted over three consecutive periods: in the 2 weeks before the course of injections, during the 6 weeks of injections and for 4 weeks after the injections. Aerobic capacity was assessed before and after 4 weeks of treatment. The results showed a significant increase in aerobic physical fitness in the rHuEPO group and a significant increase in perceived physical condition and physical strength scores at the end of treatment. The main psychological result was that endurance athletes were highly sensitive to the effects of rHuEPO on physical fitness. The perception of increased physical condition may lead to a stronger commitment to training. The rHuEPO injections presented a dangerous hedonic effect linked to endurance training. These results confirm the need to tackle rHuEPO abuse at any time during the training season.

  4. Erythropoietin doping in cycling: lack of evidence for efficacy and a negative risk-benefit.

    Science.gov (United States)

    Heuberger, Jules A A C; Cohen Tervaert, Joost M; Schepers, Femke M L; Vliegenthart, Adriaan D B; Rotmans, Joris I; Daniels, Johannes M A; Burggraaf, Jacobus; Cohen, Adam F

    2013-06-01

    Imagine a medicine that is expected to have very limited effects based upon knowledge of its pharmacology and (patho)physiology and that is studied in the wrong population, with low-quality studies that use a surrogate end-point that relates to the clinical end-point in a partial manner at most. Such a medicine would surely not be recommended. The use of recombinant human erythropoietin (rHuEPO) to enhance performance in cycling is very common. A qualitative systematic review of the available literature was performed to examine the evidence for the ergogenic properties of this drug, which is normally used to treat anaemia in chronic renal failure patients. The results of this literature search show that there is no scientific basis from which to conclude that rHuEPO has performance-enhancing properties in elite cyclists. The reported studies have many shortcomings regarding translation of the results to professional cycling endurance performance. Additionally, the possibly harmful side-effects have not been adequately researched for this population but appear to be worrying, at least. The use of rHuEPO in cycling is rife but scientifically unsupported by evidence, and its use in sports is medical malpractice. What its use would have been, if the involved team physicians had been trained in clinical pharmacology and had investigated this properly, remains a matter of speculation. A single well-controlled trial in athletes in real-life circumstances would give a better indication of the real advantages and risk factors of rHuEPO use, but it would be an oversimplification to suggest that this would eradicate its use. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  5. Nonclinical evaluation of the potential for mast cell activation by an erythropoietin analog

    Energy Technology Data Exchange (ETDEWEB)

    Weaver, James L., E-mail: James.Weaver@fda.hhs.gov [Division of Applied Regulatory Science, OCP/OTS/CDER/FDA, Silver Spring, MD (United States); Boyne, Michael, E-mail: mboyne@biotechlogic.com [Division of Pharmaceutical Analysis, OTR/OPQ/CDER/FDA, Silver Spring, MD (United States); Pang, Eric, E-mail: Eric.Pang@fda.hhs.gov [Division of Applied Regulatory Science, OCP/OTS/CDER/FDA, Silver Spring, MD (United States); Chimalakonda, Krishna, E-mail: Krishna.Chimalakonda@fda.hhs.gov [Division of Applied Regulatory Science, OCP/OTS/CDER/FDA, Silver Spring, MD (United States); Howard, Kristina E., E-mail: Kristina.Howard@fda.hhs.gov [Division of Applied Regulatory Science, OCP/OTS/CDER/FDA, Silver Spring, MD (United States)

    2015-09-15

    The erythropoietin analog peginesatide was withdrawn from marketing due to unexpected severe anaphylactic reactions associated with administration of the multi-use formulation. The adverse events occurred rapidly following the first ever administration of the drug with most affected patients becoming symptomatic in less than 30 min. This is most consistent with an anaphylactoid reaction due to direct activation of mast cells. Laboratory evaluation was undertaken using rat peritoneal mast cells as the model system. Initial studies showed that high concentrations of the formulated drug as well as formulated vehicle alone could cause mast cell degranulation as measured by histamine release. The purified active drug was not able to cause histamine release whereas the vehicle filtrate and lab created drug vehicle were equally potent at causing histamine release. Individual formulations of vehicle leaving one component out showed that histamine release was due to phenol. Dose response studies with phenol showed a very sharp dose response curve that was similar in three buffer systems. Cellular analysis by flow cytometry showed that the histamine release was not due to cell death, and that changes in light scatter parameters consistent with degranulation were rapidly observed. Limited testing with primary human mast cells showed a similar dose response of histamine release with exposure to phenol. To provide in vivo confirmation, rats were injected with vehicle formulated with various concentrations of phenol via a jugular vein cannula. Significant release of histamine was detected in blood samples taken 2 min after dosing at the highest concentrations tested. - Highlights: • Peginesatide caused severe anaphylactoid reactions in 0.2% of patients. • Both formulated drug and vehicle cause degranulation of rat mast cells. • Phenol was identified as the vehicle component causing degranulation. • Human mast cells show similar dose response to phenol as rat mast cells

  6. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors.

    Science.gov (United States)

    McGraw, Kathy L; Basiorka, Ashley A; Johnson, Joseph O; Clark, Justine; Caceres, Gisela; Padron, Eric; Heaton, Ruth; Ozawa, Yukiyasu; Wei, Sheng; Sokol, Lubomir; List, Alan F

    2014-01-01

    Anemia remains the principal management challenge for patients with lower risk Myelodysplastic Syndromes (MDS). Despite appropriate cytokine production and cellular receptor display, erythropoietin receptor (EpoR) signaling is impaired. We reported that EpoR signaling is dependent upon receptor localization within lipid raft microdomains, and that disruption of raft integrity abolishes signaling capacity. Here, we show that MDS erythroid progenitors display markedly diminished raft assembly and smaller raft aggregates compared to normal controls (p = 0.005, raft number; p = 0.023, raft size). Because lenalidomide triggers raft coalescence in T-lymphocytes promoting immune synapse formation, we assessed effects of lenalidomide on raft assembly in MDS erythroid precursors and UT7 cells. Lenalidomide treatment rapidly induced lipid raft formation accompanied by EpoR recruitment into raft fractions together with STAT5, JAK2, and Lyn kinase. The JAK2 phosphatase, CD45, a key negative regulator of EpoR signaling, was displaced from raft fractions. Lenalidomide treatment prior to Epo stimulation enhanced both JAK2 and STAT5 phosphorylation in UT7 and primary MDS erythroid progenitors, accompanied by increased STAT5 DNA binding in UT7 cells, and increased erythroid colony forming capacity in both UT7 and primary cells. Raft induction was associated with F-actin polymerization, which was blocked by Rho kinase inhibition. These data indicate that deficient raft integrity impairs EpoR signaling, and provides a novel strategy to enhance EpoR signal fidelity in non-del(5q) MDS.

  7. Erythropoietin promotes network formation of transplanted adipose tissue-derived microvascular fragments

    Directory of Open Access Journals (Sweden)

    P Karschnia

    2018-05-01

    Full Text Available The seeding of tissue constructs with adipose tissue-derived microvascular fragments (ad-MVF is an emerging pre-vascularisation strategy. Ad-MVF rapidly reassemble into new microvascular networks after in vivo implantation. Herein it was analysed whether this process was improved by erythropoietin (EPO. Ad-MVF were isolated from green fluorescent protein (GFP+ as well as wild-type C57BL/6 mice and cultivated for 24 h in medium supplemented with EPO (20 IU/mL or vehicle. Freshly isolated, non-cultivated ad-MVF served as controls. Protein expression, cell viability and proliferation of ad-MVF were assessed by proteome profiler array and fluorescence microscopy. GFP+ ad-MVF were seeded on collagen-glycosaminoglycan matrices, which were implanted into dorsal skinfold chambers of C57BL/6 mice, to analyse their vascularisation over 14 d by intravital fluorescence microscopy, histology and immunohistochemistry. Cultivation up-regulated the expression of pro- and anti-angiogenic factors within both vehicle- and EPO-treated ad-MVF when compared with non-cultivated controls. Moreover, EPO treatment suppressed cultivation-associated apoptosis and significantly increased the number of proliferating endothelial cells in ad-MVF when compared with vehicle-treated and non-cultivated ad-MVF. Accordingly, implanted matrices seeded with EPO-treated ad-MVF exhibited an improved vascularisation, as indicated by a significantly higher functional microvessel density. The matrices of the three groups contained a comparably large fraction of GFP+ microvessels originating from the ad-MVF, whereas the tissue surrounding the matrices seeded with EPO-treated ad-MVF exhibited a significantly increased microvessel density when compared with the other two groups. These findings indicated that EPO represents a promising cytokine to further boost the excellent vascularisation properties of ad-MVF in tissue-engineering applications.

  8. Erythropoietin does not reduce plasma lactate, H⁺, and K⁺ during intense exercise.

    Science.gov (United States)

    Nordsborg, N B; Robach, P; Boushel, R; Calbet, J A L; Lundby, C

    2015-12-01

    It is investigated if recombinant human erythropoietin (rHuEPO) treatment for 15 weeks (n = 8) reduces extracellular accumulation of metabolic stress markers such as lactate, H(+) , and K(+) during incremental exhaustive exercise. After rHuEPO treatment, normalization of blood volume and composition by hemodilution preceded an additional incremental test. Group averages were calculated for an exercise intensity ∼80% of pre-rHuEPO peak power output. After rHuEPO treatment, leg lactate release to the plasma compartment was similar to before (4.3 ± 1.6 vs 3.9 ± 2.5 mmol/min) and remained similar after hemodilution. Venous lactate concentration was higher (P release to the plasma compartment after rHuEPO was similar to before (19.6 ± 5.4 vs 17.6 ± 6.0 mmol/min) and remained similar after hemodilution. Nevertheless, venous pH was lower (P release to the plasma compartment after rHuEPO treatment was similar to before (0.8 ± 0.5 vs 0.7 ± 0.7 mmol/min) and remained similar after hemodilution. Additionally, venous K(+) concentrations were similar after vs before rHuEPO (5.3 ± 0.3 vs 5.1 ± 0.4 mM). In conclusion, rHuEPO does not reduce plasma accumulation of lactate, H(+) , and K(+) at work rates corresponding to ∼80% of peak power output. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. THE COMBINATION OF α-LIPOIC ACID INTAKE WITH ECCENTRIC EXERCISE MODULATES ERYTHROPOIETIN RELEASE.

    Science.gov (United States)

    Morawin, B; Turowski, D; Naczk, M; Siatkowski, I; Zembron-Lacny, A

    2014-08-01

    The generation of reactive nitrogen/oxygen species (RN/OS) represents an important mechanism in erythropoietin (EPO) expression and skeletal muscle adaptation to physical and metabolic stress. RN/OS generation can be modulated by intense exercise and nutrition supplements such as α-lipoic acid, which demonstrates both anti- and pro-oxidative action. The study was designed to show the changes in the haematological response through the combination of α-lipoic acid intake with running eccentric exercise. Sixteen healthy young males participated in the randomised and placebo-controlled study. The exercise trial involved a 90-min run followed by a 15-min eccentric phase at 65% VO2max (-10% gradient). It significantly increased serum concentrations of nitric oxide (NO), hydrogen peroxide (H2O2) and pro-oxidative products such as 8-isoprostanes (8-iso), lipid peroxides (LPO) and protein carbonyls (PC). α-Lipoic acid intake (Thiogamma: 1200 mg daily for 10 days prior to exercise) resulted in a 2-fold elevation of serum H2O2 concentration before exercise, but it prevented the generation of NO, 8-iso, LPO and PC at 20 min, 24 h, and 48 h after exercise. α-Lipoic acid also elevated serum EPO level, which highly correlated with NO/H2O2 ratio (r = 0.718, P exercise (placebo 732 ± 207 IU · L(-1), α-lipoic acid 481 ± 103 IU · L(-1)), and correlated with EPO (r = 0.478, P release and reduces muscle damage after running eccentric exercise.

  10. THE COMBINATION OF α-LIPOIC ACID INTAKE WITH ECCENTRIC EXERCISE MODULATES ERYTHROPOIETIN RELEASE

    Directory of Open Access Journals (Sweden)

    B. Morawin

    2014-08-01

    Full Text Available The generation of reactive nitrogen/oxygen species (RN/OS represents an important mechanism in erythropoietin (EPO expression and skeletal muscle adaptation to physical and metabolic stress. RN/OS generation can be modulated by intense exercise and nutrition supplements such as α-lipoic acid, which demonstrates both anti- and pro-oxidative action. The study was designed to show the changes in the haematological response through the combination of α-lipoic acid intake with running eccentric exercise. Sixteen healthy young males participated in the randomised and placebo-controlled study. The exercise trial involved a 90-min run followed by a 15-min eccentric phase at 65% VO2max (-10% gradient. It significantly increased serum concentrations of nitric oxide (NO, hydrogen peroxide (H2O2 and pro-oxidative products such as 8-isoprostanes (8-iso, lipid peroxides (LPO and protein carbonyls (PC. α-Lipoic acid intake (Thiogamma: 1200 mg daily for 10 days prior to exercise resulted in a 2-fold elevation of serum H2O2 concentration before exercise, but it prevented the generation of NO, 8-iso, LPO and PC at 20 min, 24 h, and 48 h after exercise. α-Lipoic acid also elevated serum EPO level, which highly correlated with NO/H2O2 ratio (r=0.718, P<0.01. Serum total creatine kinase (CK activity, as a marker of muscle damage, reached a peak at 24 h after exercise (placebo 732 ± 207 IU · L-1, α-lipoic acid 481 ± 103 IU · L-1, and correlated with EPO (r = 0.478, P<0.01 in the α-lipoic acid group. In conclusion, the intake of high α-lipoic acid modulates RN/OS generation, enhances EPO release and reduces muscle damage after running eccentric exercise.

  11. Erythropoietin Pretreatment Attenuates Seawater Aspiration-Induced Acute Lung Injury in Rats.

    Science.gov (United States)

    Ji, Mu-Huo; Tong, Jian-Hua; Tan, Yuan-Hui; Cao, Zhen-Yu; Ou, Cong-Yang; Li, Wei-Yan; Yang, Jian-Jun; Peng, Y G; Zhu, Si-Hai

    2016-02-01

    Seawater drowning-induced acute lung injury (ALI) is a serious clinical condition characterized by increased alveolar-capillary permeability, excessive inflammatory responses, and refractory hypoxemia. However, current therapeutic options are largely supportive; thus, it is of great interest to search for alternative agents to treat seawater aspiration-induced ALI. Erythropoietin (EPO) is a multifunctional agent with antiinflammatory, antioxidative, and antiapoptotic properties. However, the effects of EPO on seawater aspiration-induced ALI remain unclear. In the present study, male rats were randomly assigned to the naive group, normal saline group, seawater group, or seawater + EPO group. EPO was administered intraperitoneally at 48 and 24 h before seawater aspiration. Arterial blood gas analysis was performed with a gas analyzer at baseline, 30 min, 1 h, 4 h, and 24 h after seawater aspiration, respectively. Histological scores, computed tomography scan, nuclear factor kappa B p65, inducible nitric oxide synthase, caspase-3, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-10, wet-to-dry weight ratio, myeloperoxidase activity, malondialdehyde, and superoxide dismutase in the lung were determined 30 min after seawater aspiration. Our results showed that EPO pretreatment alleviated seawater aspiration-induced ALI, as indicated by increased arterial partial oxygen tension and decreased lung histological scores. Furthermore, EPO pretreatment attenuated seawater aspiration-induced increase in the expressions of pulmonary nuclear factor kappa B p65, inducible nitric oxide synthase, caspase-3, tumor necrosis factor-alpha, IL-1β, myeloperoxidase activity, and malondialdehyde when compared with the seawater group. Collectively, our study suggested that EPO pretreatment attenuates seawater aspiration-induced ALI by down-regulation of pulmonary pro-inflammatory cytokines, oxidative stress, and apoptosis.

  12. Pharmacological strategies for blood conservation in cardiac surgery: erythropoietin and antifibrinolytics.

    Science.gov (United States)

    Hardy, J F

    2001-04-01

    We review the clinically important benefits of the two principal pharmacological strategies, erythropoietin (EPO) and antifibrinolytics (aprotinin and lysine analogues), to decrease transfusion of allogeneic blood products (ABP) during and after cardiac surgery. Articles were selected from an ongoing review of the literature, with special attention to meta-analyses dealing with EPO and/or antifibrinolytics and cardiac surgery. The few studies available include a number of patients insufficient to allow definitive conclusions on the benefits of EPO in cardiac surgery. Further studies are required to determine the optimal dose of EPO and to compare its cost-effectiveness with other blood sparing strategies in this context. Both aprotinin and lysine analogues effectively decrease ABP transfusions and the incidence of re-thoracotomy. In addition, high-dose aprotinin reduces cerebrovascular morbidity and mortality after cardiopulmonary bypass. Several mechanisms have been put forward to explain these beneficial effects, some of which could well be common to all antifibrinolytics. The clinical benefits of aprotinin's unique anti-inflammatory effect are not entirely clear but the finding that it reduces the incidence of stroke and death is certainly a major argument in favor of its utilization. Yet, we have to ensure that aprotinin's benefits are not offset by side-effects such as allergy. We still need large scale studies to definitely confirm the benefits and exclude the deleterious effects of these drugs on outcomes other than ABP requirements. At present, aprotinin is the only agent that has been shown to reduce the risk of cerebrovascular accident and mortality after cardiac surgery in adults.

  13. Combined aprotinin and erythropoietin use for blood conservation: results with Jehovah's Witnesses.

    Science.gov (United States)

    Rosengart, T K; Helm, R E; Klemperer, J; Krieger, K H; Isom, O W

    1994-11-01

    Despite recent advances in blood conservation techniques, major risks persist for excessive bleeding and blood transfusion after open heart operations. We reviewed the records of 100 consecutive patients undergoing first-time coronary artery bypass grafting at our institution to define these risks and develop a multimodality blood conservation program based on the results. This program was subsequently applied on a prospective basis to a select group of patients who refuse blood transfusion on religious grounds (Jehovah's Witnesses [JW]) (n = 15). Encouraging initial results with coronary artery bypass grafting in this group (n = 8) led to the application of the program to more complex operations (n = 7), including repeat bypass grafting with use of the internal mammary artery, repeat mitral valve replacement, aortic and mitral valve replacement with coronary artery bypass grafting, mitral valve replacement with bypass grafting, chronic type 1 dissection repair, aortic valve replacement, and atrial septal defect repair in 1 patient each. The blood conservation program employed in these patients included the use of (1) aprotinin (full Hammersmith regimen), (2) high-dose erythropoietin, (3) "maximal"-volume intraoperative autologous blood donation, (4) low-prime cardiopulmonary bypass, (5) exclusive use of intraoperative cell salvage, and (6) continuous reinfusion of shed mediastinal blood. There were no deaths in the JW group. Thromboembolic complications consisted of a transient posterior circulation stroke in only 1 patient (dissection repair). No blood or blood products were transfused compared with the transfusion of 5.1 +/- 7.8 units (mean +/- standard deviation) in the 100 primary coronary bypass patients in whom the blood conservation program was not employed.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Capillary/myocyte mismatch in the heart in renal failure--a role for erythropoietin?

    Science.gov (United States)

    Amann, K; Buzello, M; Simonaviciene, A; Miltenberger-Miltenyi, G; Koch, A; Nabokov, A; Gross, M L; Gless, B; Mall, G; Ritz, E

    2000-07-01

    Chronic renal failure is characterized by remodeling of the heart with left ventricular hypertrophy (increasing oxygen demand) and capillary deficit leading to capillary/myocyte mismatch (decreasing oxygen supply). Erythropoietin (Epo) has known angiogenic properties causing endothelial cell activation, migration and sprouting, mediated at least in part via the JAK/STAT (Janus kinase/signal transducers and activators of transcription) pathway. In uraemic cardiac hypertrophy the presence of diminished capillary supply implies that capillary growth does not keep pace with development of hypertrophy. To investigate whether this was due to a deficit of the angiogenic hormone Epo we examined whether Epo levels are altered and whether an increase in haematocrit by administration of rhEpo influences capillary supply, i.e. capillary/myocyte mismatch in experimental renal failure. Male Spraque-Dawley rats were either subjected to partial renal ablation or sham operation. Only modest amounts of renal tissue were removed so that the rats were not anemic. Subgroups of rats received either human (rh)Epo alone or in combination with unspecific antihypertensive treatment (dihydralazine plus furosemide) in order to control the Epo induced rise in blood pressure. Capillary supply was measured stereologically as capillary length per volume myocardium using the orientator method. Capillary length density was reduced by approximately 25% after partial renal ablation (3237+/-601 vs 4293+/-501 mm/mm(3) in controls). It was not statistically different in animals with partial renal ablation+rhEpo+antihypertensive treatment (3620+/-828 mm/mm(3)) compared to partial ablation alone. The study shows that lack of Epo does not cause, or contribute to, the deficit of capillary growth in the hypertrophied left ventricle of rats with renal failure. In addition, a rise in haematocrit is not accompanied by beneficial effects on alterations of cardiovascular structure in experimental renal failure.

  15. Poly(norepinephrine)-coated open tubular column for the separation of proteins and recombination human erythropoietin by capillary electrochromatography.

    Science.gov (United States)

    Xiao, Xue; Zhang, Yamin; Wu, Jia; Jia, Li

    2017-12-01

    Recombinant human erythropoietin is an important therapeutic protein with high economic interest due to the benefits provided by its clinical use for the treatment of anemias associated with chronic renal failure and chemotherapy. In this work, a poly(norepinephrine)-coated open tubular column was successfully prepared based on the self-polymerization of norepinephrine under mild alkaline condition, the favorable film forming and easy adhesive properties of poly(norepinephrine). The poly(norepinephrine) coating was characterized by scanning electron microscopy and measurement of the electro-osmotic flow. The thickness of the coating was about 431 nm. The electrochromatographic performance of the poly(norepinephrine)-coated open tubular column was evaluated by separation of proteins. Some basic and acidic proteins including two variants of bovine serum albumin and two variants of β-lactoglobulin achieved separation in the poly(norepinephrine)-coated open tubular column. More importantly, the column demonstrated separation ability for the glycoforms of recombinant human erythropoietin. In addition, the column demonstrated good repeatability with the run-to-run, day-to-day, and column-to-column relative standard deviations of migration times of proteins less than 3.40%. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. High-level expression of human stem cell factor fused with erythropoietin mimetic peptide in Escherichia coli.

    Science.gov (United States)

    Su, Lin; Chen, Song-Sen; Yang, Ke-Gong; Liu, Chang-Zheng; Zhang, Yan-Li; Liang, Zhi-Quan

    2006-06-01

    Stem cell factor (SCF) and erythropoietin are essential for normal erythropoiesis and induce proliferation and differentiation synergistically for erythroid progenitor cells. Here, we report our work on construction of SCF/erythropoietin mimetic peptide (EMP) fusion protein gene, in which human SCF cDNA (1-165aa) and EMP sequence (20aa) were connected using a short (GGGGS) or long (GGGGSGGGGGS) linker sequence. The SCF/EMP gene was cloned into the pBV220 vector and expressed in the Escherichia coli DH5alpha strain. The expression level of the fusion protein was about 30% of total cell protein. The resulting inclusion bodies were solubilized with 8 M urea, followed by dilution refolding. The renatured protein was subsequently purified by Q-Sepharose FF column. The final product was >95% pure by SDS-PAGE and the yield of fusion protein was about 40 mg/L of culture. UT-7 cell proliferation and human cord blood cell colony-forming assays showed that the fusion proteins exhibited more potent activity than recombinant human SCF, suggesting a new strategy to enhance biological activities of growth factors.

  17. Erythropoietin Receptor Positive Circulating Progenitor Cells and Endothelial Progenitor Cells in Patients with Different Stages of Diabetic Retinopathy

    Institute of Scientific and Technical Information of China (English)

    Liu-mei Hu; Guo-xu Xu; Guo-tong XU; Wei-ye Li; Xia Lei; Bo Ma; Yu Zhang; Yan Yan; Ya-lan Wu; Ge-zhi Xu; Wen Ye; Ling Wang

    2011-01-01

    Objective To investigate the possible involvement of erythropoietin (EPO)/erythropoietin receptor(EPOR) system in neovascularization and vascular regeneration in diabetic retinopathy (DR).Methods EPOR positive circulating progenitor cells (CPCs: CD34+) and endothelial progenitor cells (EPCs: CD34+KDR+) were assessed by flow cytometry in type 2 diabetic patients with different stages of DR. The cohort consisted of age- and sex-matched control patients without diabetes (n=7), non-prolif-erative DR (NPDR, n=7), proliferative DR (PDR, n=8), and PDR complicated with diabetic nephropathy (PDR-DN, n=7). Results The numbers of EPOR+ CPCs and EPOR+ EPCs were reduced remarkably in NPDR compared with the control group (both P<0.01), whereas rebounded in PDR and PDR-DN groups in varying degrees. Similar changes were observed in respect of the proportion of EPOR+ CPCs in CPCs (NPDR vs.control, P< 0.01) and that of EPOR+ EPCs in EPCs (NPDR vs. control, P< 0.05). Conclusion Exogenous EPO, mediated via the EPO/EPOR system of EPCs, may alleviate the im-paired vascular regeneration in NPDR, whereas it might aggravate retinal neovascularization in PDR due to a rebound of EPOR+ EPCs associated with ischemia.

  18. EPOR-Based Purification and Analysis of Erythropoietin Mimetic Peptides from Human Urine by Cys-Specific Cleavage and LC/MS/MS

    Science.gov (United States)

    Vogel, Matthias; Thomas, Andreas; Schänzer, Wilhelm; Thevis, Mario

    2015-09-01

    The development of a new class of erythropoietin mimetic agents (EMA) for treating anemic conditions has been initiated with the discovery of oligopeptides capable of dimerizing the erythropoietin (EPO) receptor and thus stimulating erythropoiesis. The most promising amino acid sequences have been mounted on various different polymeric structures or carrier molecules to obtain highly active EPO-like drugs exhibiting beneficial and desirable pharmacokinetic profiles. Concomitant with creating new therapeutic options, erythropoietin mimetic peptide (EMP)-based drug candidates represent means to artificially enhance endurance performance and necessitate coverage by sports drug testing methods. Therefore, the aim of the present study was to develop a strategy for the comprehensive detection of EMPs in doping controls, which can be used complementary to existing protocols. Three model EMPs were used to provide proof-of-concept data. Following EPO receptor-facilitated purification of target analytes from human urine, the common presence of the cysteine-flanked core structure of EMPs was exploited to generate diagnostic peptides with the aid of a nonenzymatic cleavage procedure. Sensitive detection was accomplished by targeted-SIM/data-dependent MS2 analysis. Method characterization was conducted for the EMP-based drug peginesatide concerning specificity, linearity, precision, recovery, stability, ion suppression/enhancement, and limit of detection (LOD, 0.25 ng/mL). Additionally, first data for the identification of the erythropoietin mimetic peptides EMP1 and BB68 were generated, demonstrating the multi-analyte testing capability of the presented approach.

  19. RECOMBINANT HUMAN MAST-CELL GROWTH-FACTOR SUPPORTS ERYTHROID COLONY FORMATION IN POLYCYTHEMIA-VERA IN THE PRESENCE AND ABSENCE OF ERYTHROPOIETIN AND SERUM

    NARCIS (Netherlands)

    MULLER, EW; DEWOLF, JTM; HENDRIKS, DW; ESSELINK, MT; HALIE, MR; VELLENGA, E

    The effect of mast cell growth factor (MGF) was studied on erythropoietin (Epo)-dependent and Epo-independent (''spontaneous'') erythroid colony formation in patients with polycythemia vera (PV). MGF stimulated both Epo-dependent and Epo-independent erythroid colony formation from PV peripheral

  20. Magnetic resonance imaging of the bone marrow following treatment with recombinant human erythropoietin in patients with end-stage renal disease

    DEFF Research Database (Denmark)

    Jensen, K E; Stenver, D; Jensen, M

    1990-01-01

    We used magnetic resonance imaging (MRI) to study vertebral bone marrow in hemodialysis patients during treatment with recombinant human erythropoietin (rHuEPO). We found changes in T1 relaxation times and image contrast within 14 days after starting treatment, before any response was seen in the...

  1. Erythropoietin Restores Long-Term Neurocognitive Function Involving Mechanisms of Neuronal Plasticity in a Model of Hyperoxia-Induced Preterm Brain Injury

    Directory of Open Access Journals (Sweden)

    Daniela Hoeber

    2016-01-01

    Full Text Available Cerebral white and grey matter injury is the leading cause of an adverse neurodevelopmental outcome in prematurely born infants. High oxygen concentrations have been shown to contribute to the pathogenesis of neonatal brain damage. Here, we focused on motor-cognitive outcome up to the adolescent and adult age in an experimental model of preterm brain injury. In search of the putative mechanisms of action we evaluated oligodendrocyte degeneration, myelination, and modulation of synaptic plasticity-related molecules. A single dose of erythropoietin (20,000 IU/kg at the onset of hyperoxia (24 hours, 80% oxygen in 6-day-old Wistar rats improved long-lasting neurocognitive development up to the adolescent and adult stage. Analysis of white matter structures revealed a reduction of acute oligodendrocyte degeneration. However, erythropoietin did not influence hypomyelination occurring a few days after injury or long-term microstructural white matter abnormalities detected in adult animals. Erythropoietin administration reverted hyperoxia-induced reduction of neuronal plasticity-related mRNA expression up to four months after injury. Thus, our findings highlight the importance of erythropoietin as a neuroregenerative treatment option in neonatal brain injury, leading to improved memory function in adolescent and adult rats which may be linked to increased neuronal network connectivity.

  2. Erythropoietin receptor is not a surrogate marker for tumor hypoxia and does not correlate with survival in head and neck squamous cell carcinomas.

    NARCIS (Netherlands)

    Hoogsteen, I.J.; Peeters, W.J.M.; Marres, H.A.M.; Rijken, P.F.J.W.; Hoogen, F.J.A. van den; Kogel, A.J. van der; Kaanders, J.H.A.M.

    2005-01-01

    BACKGROUND AND PURPOSE: To evaluate erythropoietin receptor (EPOR) expression in human head and neck squamous cell carcinomas and correlate this to the presence of tumor hypoxia and treatment outcome. PATIENTS AND METHODS: Eighty-five patients with locally advanced tumors of the head and neck were

  3. Hyperfractionated chemoradiation with carbogen breathing, with or without erythropoietin: A stepwise developed treatment schedule for advanced head-and-neck cancer

    International Nuclear Information System (INIS)

    Martinez, Jose Carlos; Villar, Alfonso; Cabezon, Maria Auxiliadora; Serdio, Jose Luis de; Fuentes, Claudio; Espineira, Manuel; Perez, Maria Dolores; Gil, Jose; Artazkoz, Juan Jose; Borque, Carlos; Suner, Marcos; Saavedra, Juan Antonio

    2001-01-01

    Purpose: To investigate the influence of carbogen breathing on chemoradiation and the effects of erythropoietin on transfusions. Methods and Materials: From March 1996 to April 2000, 42 (4 Stage III and 38 Stage IV) patients with head and neck cancer were treated with a twice-a-day hyperfractionated schedule. Each fraction consisted of 5 mg/m 2 of carboplatin plus 115 cGy with carbogen breathing. Treatment was given 5 days per week up to total doses of 350 mg/m 2 of carboplatin plus 8050 cGy in 7 weeks. Anemia was treated either by transfusion or by erythropoietin. Results: Forty-one patients tolerated the treatment as scheduled. All patients tolerated the planned radiation dose. Five transfusions were given in the first group, but no transfusion was needed in the erythropoietin group. Local toxicities remained at the level expected with irradiation alone. Chemotherapy toxicity was moderate. Forty-two complete responses were achieved. At two years actuarial local control, cause-specific survival and overall survival are respectively 85%, 69%, and 68%. At four years estimated probabilities of local control, cause-specific survival and overall survival are also 85%, 69%, and 68%. Conclusions: These results compare favorably with those of most reported studies. The addition of carbogen breathing appears to improve the results of chemoradiation alone. Erythropoietin therapy avoided transfusions

  4. Age-related pattern and monocyte-acquired haemozoin associated production of erythropoietin in children with severe malarial anaemia in Ghana.

    Science.gov (United States)

    Abugri, James; Tetteh, John Kweku Amissah; Oseni, Lateef Adebayo; Mensah-Brown, Henrietta Esi; Delimini, Rupert Kantunye; Obuobi, David Osei; Akanmori, Bartholomew Dicky

    2014-08-20

    Malaria continues to be a global health challenge, affecting more than half the world's population and causing approximately 660,000 deaths annually. The majority of malaria cases are caused by Plasmodium falciparum and occur in sub-Saharan Africa. One of the major complications asscociated with malaria is severe anaemia, caused by a cycle of haemoglobin digestion by the parasite. Anaemia due to falciparum malaria in children has multifactorial pathogenesis, which includes suppression of bone marrow activity. Recent studies have shown that haemozoin, which is a by-product of parasite haemoglobin digestion, may play an important role in suppression of haemoglobin production, leading to anaemia. In this study we correlated the levels of erythropoietin (EPO), as an indicator of stimulation of haemoglobin production, to the levels of monocyte acquired haemozoin in children with both severe and uncomplicated malaria. There was a significantly negative correlation between levels of haemozoin-containing monocytes and EPO, which may suggest that haemozoin suppresses erythropoiesis in severe malaria. A multiple linear regression analysis and simple bar was used to investigate associations between various haematological parameters. To examine the levels of erythropoietin in the age categories, the levels of erythropoietin was measured using a commercial Enyme-Linked Immunosorbent Assay (ELISA). Giemsa-stained blood smears were used to determine percentage pigment containing monocytes. The haemozoin containing monocytes was expressed as a percentage of the total number of monocytes. To obtain the number of haemozoin containing monocytes/μL the percentage of haemozoin containing monocytes was multiplied by the absolute number of monocytes/μL from the automated haematology analyzer. The levels of erythropoietin in younger children (<3 years) was significantly higher than in older children with a similar degree of malaria anaemia (Hb levels) (p < 0.005). Haemozoin

  5. Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth.

    Science.gov (United States)

    Asano, Ryoko; Asai-Sato, Mikiko; Miyagi, Yohei; Mizushima, Taichi; Koyama-Sato, Makiko; Nagashima, Yoji; Taguri, Masataka; Sakakibara, Hideya; Hirahara, Fumiki; Miyagi, Etsuko

    2015-08-01

    Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth. Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry. EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 ± 4122 vs 1455 ± 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (ρ = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test). This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which

  6. The feed-back regulation of erythropoietin production in healthy humans

    International Nuclear Information System (INIS)

    Klausen, T.

    1998-01-01

    The proposed oxygen-dependent feed-back loop regulation of EPO (erythropoietin) production is mainly supported by data from studies in animals and cell cultures. The feed-back loop and its dependence on oxygen was therefore challenged by studies in healthy humans: Exposure of humans to different levels of acute and continued altitude hypobaria provided evidence for an oxygen dependence of the EPO response. This response is consistent with the proposed feed-back loop regulation of EPO production; Exposure to continued altitude hypobaria demonstrated that the decline in human EPO production is initiated before an EPO-induced erythopoiesis is detectable, and that this decline is related to a concomitant decrease in the haemoglobin-oxygen affinity. Contrary to the feed-back loop, this time-relation indicate that the feed-back regulation of EPO production during continued hypobaric hypoxia is exerted primarily through a decrease in the haemoglobin-oxygen affinity, rather than by the effects of an EPO-stimulated erythropoiesis; Increased circulating levels of the proinflammatory cytokine IL-6 was found in healthy humans during four days of altitude exposure as compared with sea level. The other proinflammatory cytokines IL-1 beta, and TNF alpha remained unchanged, and the increased serum IL-6 did not induce production of c-reactive protein; Comparable circadian variations in human EPO production were shown in sedentary subjects, athletes, and healthy but hypoxaemic subjects. Human EPO production could not be triggered by one hour of high-intensity exercise, whereas longitudinal changes in exercise showed a trend of relation between human EPO production, serum concentration of free testosterone, and indices of body composition. These results have demonstrated and endogenous, probably hormonal, and oxygen-independent regulation of human EPO production, which is at variance with the oxygen dependent feed-back loop regulation of EPO production. Conclusively, the present

  7. Oral vitamin C supplementation reduces erythropoietin requirement in hemodialysis patients with functional iron deficiency.

    Science.gov (United States)

    Sultana, Tanjim; DeVita, Maria V; Michelis, Michael F

    2016-09-01

    Functional iron deficiency (FID) is a major cause of persistent anemia in dialysis patients and also contributes to a suboptimal response to erythropoietin (Epo) administration. Vitamin C acts as an enzyme cofactor and enhances mobilization of the ferrous form of iron to transferrin thus increasing its bioavailability. High-dose intravenous vitamin C has been shown to decrease the Epo requirement and improve hemoglobin levels in previous studies. This study assessed the effect of low-dose oral vitamin C on possible reduction in Epo dose requirements in stable hemodialysis patients with FID. This prospective study included 22 stable hemodialysis patients with FID defined as transferrin saturation (T sat) 100 mcg/L with Epo requirement of ≥4000 U/HD session. Patients received oral vitamin C 250 mg daily for 3 months. Hemoglobin, iron and T sat levels were recorded monthly. No one received iron supplementation during the study period. There was a significant reduction in median Epo dose requirement in the 15 patients who completed the study, from 203.1 U/kg/week (95 % CI 188.4-270.6) to 172.8 U/kg/week (95 % CI 160.2-214.8), (P = 0.01). In the seven responders, there was 33 % reduction in Epo dose from their baseline. Despite adjustment of Epo dose, the mean hemoglobin level was significantly increased from 10.1 ± 0.6 to 10.7 ± 0.6 mg/dL (P = 0.03). No adverse effects of oral vitamin C were observed. Daily low-dose oral vitamin C supplementation reduced Epo dose requirements in hemodialysis patients with FID. Limitations of this study include a small sample size and the lack of measurements of vitamin C and oxalate levels. Despite concerns regarding oral vitamin C absorption in dialysis patients, this study indicates vitamin C was well tolerated by all participants without reported adverse effect.

  8. Mechanisms and mediators of hypertension induced by erythropoietin and related molecules.

    Science.gov (United States)

    Agarwal, Rajiv

    2017-12-08

    Hypertension is a common but frequently overlooked adverse effect of erythropoietin (EPO) therapy. Underreporting of hypertension with EPO is likely due to either more aggressively managing hypertension through the prescription of antihypertensive drugs or closer attention to dry weight. The purpose and focus of this review is to critically evaluate the mechanisms of EPO-induced hypertension. Preclinical data are considered first, followed by clinical data where available. Mediated by a variety of molecules, there is an imbalance in the vascular tone favoring net vasoconstriction that mediates EPO-induced hypertension. Animal studies show the primary importance of chronic kidney disease in the genesis of EPO-induced hypertension. Preclinical studies show deranged regulation of the nitric oxide, endothelins and porstanoids and the sympathoadrenal and renin-angiotensin pathways as causes of EPO-induced hypertension. Human studies suggest that EPO administration is also associated with increased responsiveness to catecholamines and angiotensin II on vascular tissue; in addition, hypoxia-induced vasodilation may be impaired in those with EPO-induced hypertension. There is little evidence for EPO as a direct vasoconstrictor or its effect on blood viscosity as a mechanism of EPO-induced hypertension. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in blood pressure (BP) by simply treating the animals with EPO-binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP. However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in patients with chronic kidney disease, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that hypoxia-inducible factor stablizers may induce

  9. Damage of tracer erythropoietin results in erroneous estimation of concentration in mouse submaxillary gland.

    Science.gov (United States)

    Vidal, A; Carcagno, M; Criscuolo, M; Barcelò, A C; Alippi, R M; Leal, T; Bozzini, C E

    1993-02-01

    It has been previously reported that 1) plasma erythropoietin (Epo) titer during exposure to hypobaria is lower in nephrectomized rats and mice whose submaxillary glands (SMG) were either ablated or atrophied than in nephrectomized controls whose SMG were intact and 2) that the gland shows one of the highest levels of immunoreactive Epo (iEpo) in the body. The latter observation, however, was questioned recently when it was observed that SMG extracts degrade labeled Epo used as tracer antigen in the radioimmunoassay (RIA), thus giving invalid estimates of Epo. Since this interpretation was in turn questioned, the present study was conducted to obtain more information on the subject and make these conflicting points clear. Investigation of the reported/possible degradation of Epo by SMG homogenates was conducted via polyacrylamide gel electrophoresis followed by radioautography or by a RIA in solid phase in which there was no simultaneous incubation of the tracer antigen with the SMG homogenates. It was observed that 125I-labeled rhEpo was degraded when incubated with SMG homogenates. Degradation was rapid, being evident when incubation lasted 30 minutes, and occurred in the presence of a protease inhibitor. It showed a high degree of specificity since it did not occur when Epo was incubated with kidney homogenate or normal mouse serum. SMG homogenate did not degrade labeled thyrotrophic hormone and degraded alpha interferon (IFN-alpha) only partially. When estimates of iEpo in SMG homogenate were performed in conditions of simultaneous (SI-RIA) or nonsimultaneous (NSI-RIA) incubation of the homogenate with tracer Epo, it was observed that while estimates of Epo in plasma were similar in both types of RIA and somewhat higher in kidney homogenate in the SI-RIA than in the NSI-RIA, estimates of Epo in SMG were about 60 times higher in the former than in the latter. Therefore, it could be concluded that most of the Epo detected by standard RIA in SMG homogenate does

  10. Analysis of human reticulocyte genes reveals altered erythropoiesis: potential use to detect recombinant human erythropoietin doping.

    Science.gov (United States)

    Varlet-Marie, Emmanuelle; Audran, Michel; Lejeune, Mireille; Bonafoux, Béatrice; Sicart, Marie-Therese; Marti, Jacques; Piquemal, David; Commes, Thérèse

    2004-08-01

    Enhancement of oxygen delivery to tissues is associated with improved sporting performance. One way of enhancing oxygen delivery is to take recombinant human erythropoietin (rHuEpo), which is an unethical and potentially dangerous practice. However, detection of the use of rHuEpo remains difficult in situations such as: i) several days after the end of treatment ii) when a treatment with low doses is conducted iii) if the rHuEpo effect is increased by other substances. In an attempt to detect rHuEpo abuse, we selected erythroid gene markers from a SAGE library and analyzed the effects of rHuEpo administration on expression of the HBB, FTL and OAZ genes. Ten athletes were assigned to the rHuEpo or placebo group. The rHuEpo group received subcutaneous injections of rHuEpo (50 UI/kg three times a week, 4 weeks; 20 UI/kg three times a week, 2 weeks). HBB, FTL and OAZ gene profiles were monitored by real time-polymerase chain reaction (PCR) quantification during and for 3 weeks after drug administration. The global analysis of these targeted genes detected in whole blood samples showed a characteristic profile of subjects misusing rHuEpo with a increase above the threshold levels. The individual analysis of OAZ mRNA seemed indicative of rHuEpo treatment. The performance-enhancing effect of rHuEpo treatment is greater than the duration of hematologic changes associated with rHuEpo misuse. Although direct electrophoretic methods to detect rHuEpo have been developed, recombinant isoforms of rHuEpo are not detectable some days after the last subcutaneous injection. To overcome these limitations indirect OFF models have been developed. Our data suggest that, in the near future, it will be possible to consolidate results achievable with the OFF models by analyzing selected erythroid gene markers as a supplement to indirect methods.

  11. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin.

    Science.gov (United States)

    Jolling, Koen; Perez Ruixo, Juan Jose; Hemeryck, Alex; Vermeulen, An; Greway, Tony

    2005-04-01

    humans suggest a less frequent dosing regimen relative to erythropoietin and darbepoetin, potentially leading to a simplification of anemia management.

  12. Use of erythropoietin and its effects on blood lactate and 2, 3-diphosphoglycerate in premature neonates.

    Science.gov (United States)

    Soubasi, V; Kremenopoulos, G; Tsantali, C; Savopoulou, P; Mussafiris, C; Dimitriou, M

    2000-11-01

    The aim of this study was to investigate the effect of recombinant human erythropoietin (rHu-EPO) on oxygen affinity and adequate oxygen delivery to the tissues of stable premature infants. 36 very-low-birth-weight infants were randomly assigned to either receive rHu-EPO (200 units/kg every other day) or not, and both groups were supplemented with iron, folic acid and vitamin E. Arterial blood gases, oxygen saturation, complete blood counts, fetal haemoglobin, 2,3-diphosphoglycerate (2,3-DPG) and blood lactate were analysed weekly, from the 1st week till discharge. Patients in the two groups were comparable. There was a trend in increasing lactate values towards the 4th to 5th weeks of life, which did not reach statistical significance. There was no correlation between lactate values and the studied variables (pH, BE, oxygen saturation). In 35 transfusions, pre- and 24 h post-transfusion blood lactate status was studied. In 23 of them, a decrease in post-transfusion lactate was noticed, whilst an increased post-transfusion level was shown in 10 cases and no change in 2 cases. The mean pre-transfusion lactate value was significantly higher than the post-transfusion one (24.04 +/- 11.9 mg/dl before and 16.27 +/- 8.5 mg/dl after transfusion; p = 0.0025). In both groups there was a steady rise in 2,3-DPG concentration over the period of study, and the 2,3-DPG values at the end of our study were significantly increased in the rHu-EPO group (rHu-EPO 5.98 +/- 0.9, control 4.84 +/- 0.7; p = 0.04). In conclusion, the use of rHu-EPO did not affect blood lactate levels compared to the control group. Regarding oxygen affinity, it seems that rHu-EPO causes a shift of the oxy-haemoglobin dissociation curve to the right. This is a previously unreported effect of rHu-EPO and its clinical use may, thus, confer to preterm babies an added advantage.

  13. Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study.

    Science.gov (United States)

    Lauria, Giuseppe; Dalla Bella, Eleonora; Antonini, Giovanni; Borghero, Giuseppe; Capasso, Margherita; Caponnetto, Claudia; Chiò, Adriano; Corbo, Massimo; Eleopra, Roberto; Fazio, Raffaella; Filosto, Massimiliano; Giannini, Fabio; Granieri, Enrico; La Bella, Vincenzo; Logroscino, Giancarlo; Mandrioli, Jessica; Mazzini, Letizia; Monsurrò, Maria Rosaria; Mora, Gabriele; Pietrini, Vladimiro; Quatrale, Rocco; Rizzi, Romana; Salvi, Fabrizio; Siciliano, Gabriele; Sorarù, Gianni; Volanti, Paolo; Tramacere, Irene; Filippini, Graziella

    2015-08-01

    To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91. We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes. RhEPO 40,000 IU fortnightly did not change the course of ALS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  14. Design, modeling, expression, and chemoselective PEGylation of a new nanosize cysteine analog of erythropoietin

    Directory of Open Access Journals (Sweden)

    Ahangari Cohan R

    2011-06-01

    Full Text Available Reza Ahangari Cohan1, Armin Madadkar-Sobhani2,3, Hossein Khanahmad1, Farzin Roohvand4, Mohammad Reza Aghasadeghi4, Mohammad Hossein Hedayati5, Zahra Barghi5, Mehdi Shafiee Ardestani4, Davoud Nouri Inanlou1, Dariush Norouzian11Research and Development Department, Production and Research Complex, Pasteur Institute of Iran, Tehran, Iran; 2Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; 3Department of Life Sciences, Barcelona Supercomputing Center, Barcelona, Spain; 4Hepatitis and AIDS Department, Pasteur Institute of Iran, Tehran, Iran; 5Quality Control Department, Production and Research Complex, Pasteur Institute of Iran, Tehran, IranBackground: Recombinant human erythropoietin (rhEPO is considered to be one of the most pivotal pharmaceutical drugs in the market because of its clinical application in the treatment of anemia-associated disorders worldwide. However, like other therapeutic proteins, it does not have suitable pharmacokinetic properties for it to be administrated at least two to three times per week. Chemoselective cysteine PEGylation, employing molecular dynamics and graphics in in silico studies, can be considered to overcome such a problem.Methods: A special kind of EPO analog was elicited based on a literature review, homology modeling, molecular dynamic simulation, and factors affecting the PEGylation reaction. Then, cDNA of the selected analog was generated by site-directed mutagenesis and subsequently cloned into the expression vector. The construct was transfected to Chinese hamster ovary/dhfr- cells, and highly expressed clones were selected via methotrexate amplification. Ion-immobilized affinity and size exclusion (SE chromatography techniques were used to purify the expressed analog. Thereafter, chemoselective PEGylation was performed and a nanosize PEGylated EPO was obtained through dialysis. The in vitro biologic assay and in vivo pharmacokinetic parameters were

  15. A radioimmunoassay for erythropoietin: serum levels in normal human subjects and patients with hemopoietic disorders

    International Nuclear Information System (INIS)

    Rege, A.B.; Brookins, J.; Fisher, J.W.

    1982-01-01

    An RIA for Ep has been developed that is highly sensitive and specific. A homogeneous Ep preparation was labeled with 125 I by the chloramine-T method to a specific activity of 90 to 136 micro Ci/microgram and immunoreactivity of 80%. Ep antiserum, which was produced to a human urinary Ep preparation (80 U/mg of protein), was adsorbed with normal human urinary and serum proteins without any loss in sensitivity of the RIA to increase the specificity of the assay. A good correlation was seen between the RIA and the exhypoxic polycythemic mouse assay (corr. coef. 0.967; slope 1.05 and y intercept 0.75). Ep titers in sera from 175 hematologically normal human subjects exhibited a normal frequency distribution and ranged between 5.8 and 36.6 mU/ml with a mean of 14.9 +/- 4.7 (S.D.) and median of 14.3 Serum Ep titers were markedly elevated in seven patients with aplastic anemia and one patient with pure red cell aplasia (1350 to 20,640 mU/ml) and were lower than normal in two patients with polycythemia vera (8.1 and 9.4 mU/ml). The serum Ep titers in a prenephrectomy patient with chronic glomerulonephritis (32.1 mU/ml) decreased to below normal levels (9.04 mU/ml) after nephrectomy. The cord serum erythropoietin titers in 10 IDM [90.82 +/- 134.1 (S.D.) mu/ml] returned to values within the normal range (13.86 +/- 5.55) on day 3 after birth, suggesting the utility of the RIA in elucidating the role of hypoxia and/or insulin in increased erythropoiesis in IDM. The serum Ep titers in patients with anemias and polycythemias were compared to those of normal human subjects and agreed well with pathophysiologic mechanisms of these hemopoietic disorders, confirming the validity of the RIA

  16. A radioimmunoassay for erythropoietin: serum levels in normal human subjects and patients with hemopoietic disorders

    International Nuclear Information System (INIS)

    Rege, A.B.; Brookins, J.; Fisher, J.W.

    1982-01-01

    An RIA for Ep has been developed that is highly sensitive and specific. A homogeneous Ep preparation was labeled with 125 I by the chloramine-T method to a specific activity of 90 to 136 μCi/μg and immunoreactivity of 80%. Ep antiserum, which was produced to a human urinary Ep preparation (80 U/mg of protein), was adsorbed with normal human urinary and serum proteins without any loss in sensitivity of the RIA to increase the specificity of the assay. A good correlation was seen between the RIA and the exhypoxic polycythemic mouse assay (corr. coef. 0.967; slope 1.05 and ''y'' intercept 0.75). Ep titers in sera from 175 hematologically normal human subjects exhibited a normal frequency distribution and ranged between 5.8 and 36.6 mU/ml with a mean of 14.9 +/- 4.7 (S.D.) and median of 14.3. Serum Ep titers were markedly elevated in seven patients with aplastic anemia and one patient with pure red cell aplasia (1350 to 20,640 mU/ml) and were lower than normal in two patients with polycythemia vera (8.1 and 9.4 mU/ml). The serum Ep titers in a prenephrectomy patient with chronic glomerulonephritis (31.1 mU/ml) decreased to below normal levels (9.04 mU/ml) after nephrectomy. The cord serum erythropoietin titers in 10 IDM [90.82 +/- 134.1 (S.D.) mu/ml] returned to values within the normal range (13.86 +/- 5.55) on day 3 after birth, suggesting the utility of the RIA in elucidating the role of hypoxia and/or insulin in increased erythropoiesis in IDM. The serum Ep titers in patients with anemias and polycythemias were compared to those of normal human subjects and agreed well with pathophysiologic mechanisms of these hemopoietic disorders, confirming the validity of the RIA

  17. Biosimilar versus patented erythropoietins: learning from 5 years of European and Japanese experience.

    Science.gov (United States)

    Bocquet, François; Paubel, Pascal; Fusier, Isabelle; Cordonnier, Anne-Laure; Sinègre, Martine; Le Pen, Claude

    2015-02-01

    Patent expiries on leading biologics are creating new momentum in the market for biosimilars (copies of off-patent biologics), paving the way for their development. However, little is known about the factors influencing the competition between biosimilars and their reference products (REF). The aim of this study was to analyse key global erythropoietin (EPO) markets and factors affecting biosimilar EPO (BIOSIM-EPO) uptakes, and to identify countries where BIOSIM-EPOs have gained significant market shares. Inclusion criteria for countries in the study were a biosimilar regulatory framework similar to the EU framework, and biological market value higher than US$2.5 billion. Factors evaluated included EPO market size, EPO retail/hospital distribution mix, national incentives to use biosimilars and BIOSIM-EPO/REF price differences. IMS Health provided EPO consumption in volumes, values, and EPO ex-manufacturer prices from 2007 to 2012. Japan: large-sized market, mixed retail/hospital distribution, no incentives, low BIOSIM-EPO uptake (6.8 % in 2012). France: large-sized market, dominant retail distribution, no incentives, low BIOSIM-EPO uptake (5.8 %). Spain and Italy: medium-sized market, dominant hospital distribution, no incentives, moderate BIOSIM-EPO uptakes (11.5 and 8.6 %). Germany: small-sized market, dominant retail distribution, presence of incentives, high BIOSIM-EPO uptake (30.4 %). UK: small-sized market, mixed retail/hospital distribution, no incentives, low BIOSIM-EPO uptake (2.0 %). BIOSIM-EPO/REF price differences play no role at a global level (-10.8 % in Germany and -26.9 % in Japan). EPO markets have proven to be highly country-specific. EPO market sizes, EPO retail/hospital distribution mixes and BIOSIM-EPO/REF price differences may not be determining factors of BIOSIM-EPO uptakes. Prescription and substitution incentives to use BIOSIM-EPO appear to be determining factors in Germany. The heterogeneity of national EPO markets makes it

  18. Serum erythropoietin level in anemic and non-anemic nephrotic children with normal kidney functions

    International Nuclear Information System (INIS)

    Moustafa, A.M.E.; Moawad, A.T.; Gad, A.A.; Ahmed, S.M.

    2005-01-01

    Nephrotic syndrome (NS) is associated with a significant alteration in protein metabolism. While lowering the concentration of certain proteins, the disease often raises the level of certain other proteins. The current study aimed to investigate the serum erythropoietin (EPO) levels in children with NS either anemic or non-anemic and to compare them to children with iron deficiency anemia (IDA) and healthy controls with normal hemoglobin level (NHB). Sixteen nephrotic children with anemia (NS-A) and 15 nephrotic children with normal hemoglobin level (NS-NHB) were examined and compared with 10 children with iron deficiency anemia (IDA) and 10 healthy controls (NHB). Circulating serum EPO levels, blood indices and iron status were measured in nephrotic patients with anemia (NS-A) and compared to those nephrotic patients with normal HE (NS-NHB). Most NS-A children were steroid resistant. The NS-A children showed greater EPO levels than those without anemia (21.01 ±4.02 mlU/ml versus 9.18 ± 0.79 mlU/ml; P < 0.001) but their response to treatment of anemia was inappropriately low when compared to IDA (EPO 96.9 ±4.9 mlU/ml) despite similar HB concentration. A significant positive correlation was observed between serum EPO and serum albumin in NS-A (r = 0.84, P < 0.001) and in NS-NHB group (r = 0.89, P < 0.001). Moreover, a significant positive correlation was observed between serum EPO and HB in the nephrotic groups indicating a blunted EPO response to anemia in NS-A (r 0.63, P < 0.05) and in NS-NHB group (r = 0.80, P < 0.001). In conclusion, anemia is a common feature of NS and is present even before the worsening of kidney function. Depletion of the iron stores due to loss of iron and transferrin in urine due to massive proteinurea may contribute to the development of anemia, but it was found that iron replacement was ineffective alone

  19. Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates.

    Directory of Open Access Journals (Sweden)

    Steven J Korzeniewski

    Full Text Available We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI.Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age.Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55 Mental (OR 2.3; 95% CI 1.5-3.5 and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7 Development Indices (MDI, PDI, and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8. Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3, but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI.hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.

  20. [Effects of intermittent hypoxic exposure on the parameter of erythrocyte and serum hypoxia inducible factor-1 alpha and erythropoietin levels].

    Science.gov (United States)

    Zhang, Cheng-yan; Zhang, Ji-xin; Lü, Xiao-tao; Li, Bao-yu

    2009-10-01

    To investigate the effects of intermittent hypoxic exposure and normoxic convalescence on the parameter of erythrocyte and serum hypoxia inducible factor-1 alpha (HIF-1alpha) and erythropoietin (EPO) levels. Rat models of intermittent hypoxic exposure were established, combined with the clinical research on volunteers experiencing the intermittent plateau work. Blood samples for red blood cell (RBC) counts, hemoglobin (Hb) and hematocrit (HCT) were collected, serum HIF-1alpha and EPO levels were measured using enzyme linked immunosorbent assay. RBC counts, Hb concentration and HCT were significantly higher than the normoxic group (P hypoxic exposure can enhance serum hypoxia inducible factor-1 alpha and erythropointin levels and the generation of red blood cells, which leads to an increase in hemoglobin concentration and hematocrit. The results have changed with the hypoxic exposure period prolonged. Normoxic convalescence after intermittent hypoxic exposure can make the related indexes reduced, and contribute to the organism recovery.

  1. Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Favaron, Elisa; Hafizi, Sepehr

    2010-01-01

    . The current study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients. METHOD: Nineteen acutely depressed patients were randomized to receive Epo (40,000 IU) or saline intravenously in a double-blind, parallel-group design. On day 3, we......OBJECTIVE: Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers...... assessed neuronal responses to fearful and happy faces using functional magnetic resonance imaging and measured facial expression recognition after the scan. RESULTS: Epo reduced neural response to fearful vs. happy faces in the amygdala and hippocampus, and to fearful faces vs. baseline in superior...

  2. Specific binding of 125I-rErythropoietin to Friend polycythemia virus-transformed erythroleukemia cells purified by centrifugal elutriation

    International Nuclear Information System (INIS)

    Correa, P.N.; Bard, V.; Axelrad, A.A.

    1990-01-01

    We have used countercurrent centrifugal elutriation (CCE) to determine the distribution of cells with respect to cell volume and buoyant density for an erythroleukemia cell line (JG6) transformed by the polycythemia strain of Friend virus (FV-P), and to determine the effect of inducing the cells to differentiate with dimethylsulfoxide (DMSO) on this distribution. CCE made it possible to obtain suspensions of modal JG6 populations virtually free of dead cells and uniform with respect to volume and buoyant density. These modal populations were assayed for specific binding of erythropoietin (Epo). Between 500 and 550 Epo receptors per cell were detected. These belonged to a single class having a dissociation constant of 0.36 nM. DMSO induction of differentiation of the JG6 cells had no effect on the number of Epo receptors expressed

  3. Factors Affecting Successful use of Erythropoietin in the Treatment of Anemia in Patients on Hemodialysis: Experience in Hajjah Region, Yemen

    Directory of Open Access Journals (Sweden)

    AL-Rohani Muhamed

    2001-01-01

    Full Text Available The use of recombinant human erythropoietin (rHuEpo became an essential part of the treatment of anemia in patients with end stage renal failure (ESRF. Our experience at the Hajjah region, Yemen, confirms that the use of rHuEpo significantly increases the level of hemoglobin (HB and hematocrit (Hct, improves work tolerance and overall quality of life of patients on hemodialysis. The observable improvement occurred in 87.5% of patients. The most prominent factors that caused deterioration in the increment of HB and Hct were infection with malaria and chronic infection. Failure of patients′ compliance, largely due to lack of education, was another important factor effecting the results. Many of our patients did not understand the importance of diet and drug regime. It is very important to spend more time on educating such patients.

  4. Beyond anaemia management: evolving role of erythropoietin therapy in neurological disorders, multiple myeloma and tumour hypoxia models.

    Science.gov (United States)

    Boogaerts, Marc; Mittelman, Moshe; Vaupel, Peter

    2005-01-01

    Recombinant human erythropoietin (epoetin) has become the standard of care in the treatment of anaemia resulting from cancer and its treatment, and chronic kidney disease. The discovery that erythropoietin and its receptor are located in regions outside the erythropoietic system has led to interest in the potential role of epoetin in other tissues, such as the central nervous system. Animal studies have shown that systemically applied epoetin can cross the blood-brain barrier, where it reduces tissue injury associated with stroke, blunt trauma and experimental autoimmune encephalomyelitis. Pilot studies in humans have shown that epoetin treatment given within 8 h of stroke reduces infarct size and results in a significantly better outcome when compared with placebo treatment. Studies also suggest that epoetin has the potential to improve cognitive impairment associated with adjuvant chemotherapy in patients with cancer. Anaemia is a major factor causing tumour hypoxia, a condition that can promote changes within neoplastic cells that further tumour survival and malignant progression and also reduces the effectiveness of several anticancer therapies including radiotherapy and oxygen-dependent cytotoxic agents. Use of epoetin to prevent or correct anaemia has the potential to reduce tumour hypoxia and improve treatment outcome. Several therapeutic studies in anaemic animals with experimental tumours have shown a beneficial effect of epoetin on delaying tumour growth. Furthermore, clinical observations in patients with multiple myeloma and animal studies have suggested that epoetin has an antimyeloma effect, mediated via the immune system through activation of CD8+ T cells. Therefore, the role of epoetin may go well beyond that of increasing haemoglobin levels in anaemic patients, although additional studies are required to confirm these promising results. Copyright 2005 S. Karger AG, Basel.

  5. Recombinant human erythropoietin alpha improves the efficacy of radiotherapy of a human tumor xenograft, affecting tumor cells and microvessels

    International Nuclear Information System (INIS)

    Loevey, J.; Bereczky, B.; Gilly, R.; Kenessey, I.; Raso, E.; Simon, E.; Timar, J.; Dobos, J.; Vago, A.; Kasler, M.; Doeme, B.; Tovari, J.

    2008-01-01

    Background and purpose: tumor-induced anemia often occurs in cancer patients, and is corrected by recombinant human erythropoietins (rHuEPOs). Recent studies indicated that, besides erythroid progenitor cells, tumor and endothelial cells express erythropoietin receptor (EPOR) as well; therefore, rHuEPO may affect their functions. Here, the effect of rHuEPOα on irradiation in EPOR-positive human squamous cell carcinoma xenograft was tested. Material and methods: A431 tumor-bearing SCID mice were treated from the tumor implantation with rHuEPOα at human-equivalent dose. Xenografts were irradiated (5 Gy) on day 14, and the final tumor mass was measured on day 22. The systemic effects of rHuEPOα on the hemoglobin level, on tumor-associated blood vessels and on hypoxia-inducible factor-(HIF-)1α expression of the tumor xenografts were monitored. The proliferation, apoptosis and clonogenic capacity of A431 cancer cells treated with rHuEPOα and irradiation were also tested in vitro. Results: in vitro, rHuEPOα treatment alone did not modify the proliferation of EPOR-positive A431 tumor cells but enhanced the effect of irradiation on proliferation, apoptosis and clonogenic capacity. In vivo, rHuEPOα administration compensated the tumor-induced anemia in SCID mice and decreased tumoral HIF-1α expression but had no effect on tumor growth. At the same time rHuEPOα treatment significantly increased the efficacy of radiotherapy in vivo (tumor weight of 23.9 ± 4.7 mg and 34.9 ± 4.6 mg, respectively), mediated by increased tumoral blood vessel destruction. Conclusion: rHuEPOα treatment may modulate the efficacy of cancer radiotherapy not only by reducing systemic hypoxia and tumoral HIF-1α expression, but also by destroying tumoral vessels. (orig.)

  6. Use of erythropoietin is associated with threshold retinopathy of prematurity (ROP) in preterm ELBW neonates: a retrospective, cohort study from two large tertiary NICUs in Italy.

    Science.gov (United States)

    Manzoni, Paolo; Memo, Luigi; Mostert, Michael; Gallo, Elena; Guardione, Roberta; Maestri, Andrea; Saia, Onofrio Sergio; Opramolla, Anna; Calabrese, Sara; Tavella, Elena; Luparia, Martina; Farina, Daniele

    2014-09-01

    Retinopathy of prematurity (ROP) is a multifactorial disease with evidence of many associated risk factors. Erythropoietin has been reported to be associated with this disorder in a murine model, as well as in humans in some single-center reports. We reviewed the data from two large tertiary NICUs in Italy to test the hypothesis that the use of erythropoietin may be associated with the development of the most severe stages of ROP in extremely low birth weight (ELBW) neonates. Retrospective study by review of patient charts and eye examination index cards on infants with birth weight large tertiary NICUs in Northern Italy (Sant'Anna Hospital NICU in Torino, and Ca' Foncello Hospital Neonatology in Treviso) in the years 2005 to 2007. Standard protocol of administration of EPO in the two NICUs consisted of 250 UI/kg three times a week for 6-week courses (4-week in 1001-1500g infants). Univariate analysis was performed to assess whether the use of EPO was associated with severe (threshold) ROP. A control, multivariate statistical analysis was performed by entering into a logistic regression model a number of neonatal and perinatal variables that - in univariate analysis - had been associated with threshold ROP. During the study period, 211 ELBW infants were born at the two facilities and survived till discharge. Complete data were obtained for 197 of them. Threshold retinopathy of prematurity occurred in 26.9% (29 of 108) of ELBW infants who received erythropoietin therapy, as compared with 13.5% (12 of 89) of those who did not receive erythropoietin (OR 2.35; 95% CI 1.121-4.949; p=0.02 in univariate analysis, and p=0.04 at multivariate logistic regression after controlling for the following variables: birth weight, gestational age, days on supplemental oxygen, systemic fungal infection, vaginal delivery). Use of erythropoietin was not significantly associated with other major sequelae of prematurity (intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing

  7. Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men.

    Directory of Open Access Journals (Sweden)

    Jérôme Durussel

    Full Text Available UNLABELLED: Recombinant human erythropoietin (rHuEpo increases haemoglobin mass (Hb(mass and maximal oxygen uptake (v O(2 max. PURPOSE: This study defined the time course of changes in Hb(mass, v O(2 max as well as running time trial performance following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual improvements in running performance in the field. METHODS: 19 trained men received rHuEpo injections of 50 IU•kg(-1 body mass every two days for 4 weeks. Hb(mass was determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. v O(2 max and 3,000 m time trial performance were measured pre, post administration and at the end of the study. RESULTS: Relative to baseline, running performance significantly improved by ∼6% after administration (10:30±1:07 min:sec vs. 11:08±1:15 min:sec, p<0.001 and remained significantly enhanced by ∼3% 4 weeks after administration (10:46±1:13 min:sec, p<0.001, while v O(2 max was also significantly increased post administration (60.7±5.8 mL•min(-1•kg(-1 vs. 56.0±6.2 mL•min(-1•kg(-1, p<0.001 and remained significantly increased 4 weeks after rHuEpo (58.0±5.6 mL•min(-1•kg(-1, p = 0.021. Hb(mass was significantly increased at the end of administration compared to baseline (15.2±1.5 g•kg(-1 vs. 12.7±1.2 g•kg(-1, p<0.001. The rate of decrease in Hb(mass toward baseline values post rHuEpo was similar to that of the increase during administration (-0.53 g•kg(-1•wk(-1, 95% confidence interval (CI (-0.68, -0.38 vs. 0.54 g•kg(-1•wk(-1, CI (0.46, 0.63 but Hb(mass was still significantly elevated 4 weeks after administration compared to baseline (13.7±1.1 g•kg(-1, p<0.001. CONCLUSION: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after administration compared to baseline. These field performance effects coincided with r

  8. Erythropoietin as an add-on treatment for cognitive side effects of electroconvulsive therapy: a study protocol for a randomized controlled trial.

    Science.gov (United States)

    Schmidt, Lejla Sjanic; Petersen, Jeff Zarp; Vinberg, Maj; Hageman, Ida; Olsen, Niels Vidiendal; Kessing, Lars Vedel; Jørgensen, Martin Balslev; Miskowiak, Kamilla Woznica

    2018-04-19

    Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but its use is impeded by its cognitive side effects. Novel treatments that can counteract these side effects may therefore improve current treatment strategies for depression. The present randomized trial investigates (1) whether short-term add-on treatment with erythropoietin (EPO) can reduce the cognitive side -effects of ECT and (2) whether such effects are long-lasting. Further, structural and functional magnetic resonance imaging (MRI) will be used to explore the neural underpinnings of such beneficial effects of EPO. Finally, the trial examines whether potential protective effects of EPO on cognition are accompanied by changes in markers of oxidative stress, inflammation, and neuroplasticity. The trial has a double-blind, randomized, placebo-controlled, parallel group design. Patients with unipolar or bipolar disorder with current moderate to severe depression referred to ECT (N = 52) are randomized to receive four high-dose infusions of EPO (40,000 IU/ml) or placebo (saline). The first EPO/saline infusion is administered within 24 h before the first ECT. The following three infusions are administered at weekly intervals immediately after ECT sessions 1, 4, and 7. Cognition assessments are conducted at baseline, after the final EPO/saline infusion (3 days after eight ECT sessions), and at a 3 months follow-up after ECT treatment completion. The neuronal substrates for potential cognitive benefits of EPO are investigated with structural and functional MRI after the final EPO/saline infusion. The primary outcome is change from baseline to after EPO treatment (3 days after eight ECT sessions) in a cognitive composite score spanning attention, psychomotor speed, and executive functions. With a sample size of N = 52 (n = 26 per group), we have ≥ 80% power to detect a clinically relevant between-group difference in the primary outcome measure at an alpha

  9. Wound Healing and ndash; A Proteomic Analysis of the Effect of Erythropoietin on Granulation Tissue Isolated from ePTFE Implants

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    Bekka Christensen

    2014-02-01

    Conclusion: Daily injection of recombinant human erythropoietin of 1000 IU/kg alters the protein expression of GAPDH, ENOA and TPIS in granulation tissue from wounds on postoperative day 9. The successful combination of proteomic analysis of wound tissue and the ePTFE wound model could advance our knowledge of the complex healing process. [Arch Clin Exp Surg 2014; 3(1.000: 26-33

  10. Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells.

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    Ruth Merkle

    2016-08-01

    Full Text Available Lung cancer, with its most prevalent form non-small-cell lung carcinoma (NSCLC, is one of the leading causes of cancer-related deaths worldwide, and is commonly treated with chemotherapeutic drugs such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO. However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells. Here, we verified that the NSCLC cell line H838 expresses functional erythropoietin receptors (EPOR and that treatment with EPO reduces cisplatin-induced apoptosis. To pinpoint differences in EPO-induced survival signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid and H838 cells, we combined mathematical modeling with a method for feature selection, the L1 regularization. Utilizing an example model and simulated data, we demonstrated that this approach enables the accurate identification and quantification of cell type-specific parameters. We applied our strategy to quantitative time-resolved data of EPO-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative real-time PCR (qRT-PCR in CFU-E and H838 cells as well as H838 cells overexpressing human EPOR (H838-HA-hEPOR. The established parsimonious mathematical model was able to simultaneously describe the data sets of CFU-E, H838 and H838-HA-hEPOR cells. Seven cell type-specific parameters were identified that included for example parameters for nuclear translocation of STAT5 and target gene induction. Cell type-specific differences in target gene induction were experimentally validated by qRT-PCR experiments. The systematic identification of pathway differences and sensitivities of EPOR signaling in CFU-E and H838 cells revealed potential targets for intervention to selectively inhibit EPO-induced signaling in the tumor cells but leave the responses in

  11. Leukemic blast cell colony formation in semisolid culture with erythropoietin: a case report of acute poorly differentiated erythroid leukemia.

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    Tomonaga, M; Jinnai, I; Tagawa, M; Amenomori, T; Nishino, K; Yao, E; Nonaka, H; Kuriyama, K; Yoshida, Y; Matsuo, T

    1987-02-01

    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.

  12. Epobis is a Nonerythropoietic and Neuroprotective Agonist of the Erythropoietin Receptor with Anti-Inflammatory and Memory Enhancing Effects

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    Oksana Dmytriyeva

    2016-01-01

    Full Text Available The cytokine erythropoietin (EPO stimulates proliferation and differentiation of erythroid progenitor cells. Moreover, EPO has neuroprotective, anti-inflammatory, and antioxidative effects, but the use of EPO as a neuroprotective agent is hampered by its erythropoietic activity. We have recently designed the synthetic, dendrimeric peptide, Epobis, derived from the sequence of human EPO. This peptide binds the EPO receptor and promotes neuritogenesis and neuronal cell survival. Here we demonstrate that Epobis in vitro promotes neuritogenesis in primary motoneurons and has anti-inflammatory effects as demonstrated by its ability to decrease TNF release from activated AMJ2-C8 macrophages and rat primary microglia. When administered systemically Epobis is detectable in both plasma and cerebrospinal fluid, demonstrating that the peptide crosses the blood-brain barrier. Importantly, Epobis is not erythropoietic, but systemic administration of Epobis in rats delays the clinical signs of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, and the peptide has long-term, but not short-term, effects on working memory, detected as an improved social memory 3 days after administration. These data reveal Epobis to be a nonerythropoietic and neuroprotective EPO receptor agonist with anti-inflammatory and memory enhancing properties.

  13. Antibody-based enzyme-linked lectin assay (ABELLA) for the sialylated recombinant human erythropoietin present in culture supernatant.

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    Kim, Hyoung Jin; Lee, Seung Jae; Kim, Hong-Jin

    2008-11-04

    The terminal sialic acid of human erythropoietin (hEPO) is essential for in vivo activity. The current resorcinol and HPLC methods for analyzing alpha2,3-linked sialic acid require more than a microgram of purified rhEPO, and purification takes a great deal of time and labor. In this study, we assessed the use of an antibody-based enzyme-linked lectin assay (ABELLA) for analyzing non-purified recombinant hEPO (rhEPO). The major problem of this method was the high background due to terminal sialylation of components of the assay (antibody and bovine serum albumin) other than rhEPO. To solve this problem, we used a monoclonal antibody (Mab 287) to capture the rhEPO, and oxidized the bovine serum albumin used for blocking with meta-periodate. The sialic acid content of non-purified rhEPO measured by ABELLA was similar to that obtained by the resorcinol method on purified rhEPO. ABELLA has advantages such as adaptability and need for minimal amounts of rhEPO (40 ng/ml). Our observations suggest that ABELLA should reduce the time and labor needed to improve culture conditions so as to increase protein sialylation, and also facilitate the study of sialylation mechanisms.

  14. Gene doping detection: evaluation of approach for direct detection of gene transfer using erythropoietin as a model system.

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    Baoutina, A; Coldham, T; Bains, G S; Emslie, K R

    2010-08-01

    As clinical gene therapy has progressed toward realizing its potential, concern over misuse of the technology to enhance performance in athletes is growing. Although 'gene doping' is banned by the World Anti-Doping Agency, its detection remains a major challenge. In this study, we developed a methodology for direct detection of the transferred genetic material and evaluated its feasibility for gene doping detection in blood samples from athletes. Using erythropoietin (EPO) as a model gene and a simple in vitro system, we developed real-time PCR assays that target sequences within the transgene complementary DNA corresponding to exon/exon junctions. As these junctions are absent in the endogenous gene due to their interruption by introns, the approach allows detection of trace amounts of a transgene in a large background of the endogenous gene. Two developed assays and one commercial gene expression assay for EPO were validated. On the basis of ability of these assays to selectively amplify transgenic DNA and analysis of literature on testing of gene transfer in preclinical and clinical gene therapy, it is concluded that the developed approach would potentially be suitable to detect gene doping through gene transfer by analysis of small volumes of blood using regular out-of-competition testing.

  15. Influence of hypothermia combined with erythropoietin on serum neurological function indexes in newborns with severe hypoxic ischemic encephalopathy

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    Hua Tian

    2017-05-01

    Full Text Available Objective: To study the influence of hypothermia combined with erythropoietin (EPO on serum neurological function indexes in newborns with severe hypoxic ischemic encephalopathy (HIE. Methods: A total of 48 cases of newborns with severe hypoxic ischemic encephalopathy in our hospital were enrolled and divided into control group and observation group according to random number table, 24 cases in each group. On the basis of conventional treatment, patients in control group were treated with mild hypothermia, and those in observation group were treated with mild hypothermia combined with EPO. Serum nerve injury indexes, neurological function indexes and nerve apoptosis indexes were compared between two groups before and after treatment. Results: Before treatment, differences in the levels of nerve injury indexes, neurological function indexes and nerve apoptosis indexes were not statistically significant between two groups. After treatment, serum nerve injury indexes NSE and S-100B levels of observation group were lower than those of control group, neurolocial function indexes BDNF, NGF, IGF-1 and GH levels of observation group were higher than those of control group, and nerve apoptosis indexes sFas and sFasL levels of observation group were lower than those of control group. Conclusion: Mild hypothermia combined with EPO can reduce the neurological damage and inhibit neuronal apoptosis in children with severe HIE.

  16. Topical Erythropoietin Treatment Accelerates the Healing of Cutaneous Burn Wounds in Diabetic Pigs Through an Aquaporin-3-Dependent Mechanism.

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    Hamed, Saher; Ullmann, Yehuda; Egozi, Dana; Keren, Aviad; Daod, Essam; Anis, Omer; Kabha, Hoda; Belokopytov, Mark; Ashkar, Manal; Shofti, Rona; Zaretsky, Asaph; Schlesinger, Michal; Teot, Luc; Liu, Paul Y

    2017-08-01

    We have previously reported that the topical application of erythropoietin (EPO) to cutaneous wounds in rats and mice with experimentally induced diabetes accelerates their healing by stimulating angiogenesis, reepithelialization, and collagen deposition, and by suppressing the inflammatory response and apoptosis. Aquaporins (AQPs) are integral membrane proteins whose function is to regulate intracellular fluid hemostasis by enabling the transport of water and glycerol. AQP3 is the AQP that is expressed in the skin where it facilitates cell migration and proliferation and re-epithelialization during wound healing. In this report, we provide the results of an investigation that examined the contribution of AQP3 to the mechanism of EPO action on the healing of burn wounds in the skin of pigs with experimentally induced type 1 diabetes. We found that topical EPO treatment of the burns accelerated their healing through an AQP3-dependent mechanism that activates angiogenesis, triggers collagen and hyaluronic acid synthesis and the formation of the extracellular matrix (ECM), and stimulates reepithelialization by keratinocytes. We also found that incorporating fibronectin, a crucial constituent of the ECM, into the topical EPO-containing gel, can potentiate the accelerating action of EPO on the healing of the burn injury. © 2017 by the American Diabetes Association.

  17. Combination Anti-Apoptotic Effect of Erythropoietin and Melatonin on Ischemia Reperfusion-Induced Renal Injury in Rats

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    Shokofeh Banaei

    2016-11-01

    Full Text Available Renal ischemia-reperfusion (IR contributes to the development of acute renal failure (ARF. Oxygen free radicals are considered to be principal components involved in the pathophysiological tissue alterations observed during renal IR. The purpose of this study was to investigate the combination effect of melatonin (MEL and erythropoietin (EPO, which are a potent antioxidant and anti-apoptotic agents, in IR-induced renal injury in rats. Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. MEL (10 mg/kg, i.p and EPO (5000 U/kg, i.p were administered prior to ischemia. After 24 h reperfusion, following decapitation, blood samples were collected for the determination of superoxide dismutase (SOD, glutathione peroxidase (GPx, and malondialdehyde (MDA levels. Also, renal samples were taken for histological evaluation and apoptosis assay. Ischemia-reperfusion increased SOD, GPx, MDA levels, and TUNEL positive cells. Histopathological findings of the IR group confirmed that there was renal impairment in the tubular epithelium. Treatment with EPO and MEL decreased SOD, GPx, and MDA levels, histopathological changes, and TUNEL positive cells. These results indicated that the combination of MEL and EPO could not exert more nephroprotective and anti-apoptotic effects than MEL treatment in renal ischemia-reperfusion injury.

  18. Erythropoietin-enhanced endothelial progenitor cell recruitment in peripheral blood and renal vessels during experimental acute kidney injury in rats.

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    Cakiroglu, Figen; Enders-Comberg, Sora Maria; Pagel, Horst; Rohwedel, Jürgen; Lehnert, Hendrik; Kramer, Jan

    2016-03-01

    Beneficial effects of erythropoietin (EPO) have been reported in acute kidney injury (AKI) when administered prior to induction of AKI. We studied the effects of EPO administration on renal function shortly after ischemic AKI. For this purpose, rats were subjected to renal ischemia for 30 min and EPO was administered at a concentration of 500 U/kg either i.v. as a single shot directly after ischemia or with an additional i.p. dose until 3 days after surgery. The results were compared with AKI rats without EPO application and a sham-operated group. Renal function was assessed by measurement of serum biochemical markers, histological grading, and using an isolated perfused kidney (IPK) model. Furthermore, we performed flow cytometry to analyze the concentration of endothelial progenitor cells (EPCs) in the peripheral blood and renal vessels. Following EPO application, there was only a statistically non-significant tendency of serum creatinine and urea to improve, particularly after daily EPO application. Renal vascular resistance and the renal perfusion rate were not significantly altered. In the histological analysis, acute tubular necrosis was only marginally ameliorated following EPO administration. In summary, we could not demonstrate a significant improvement in renal function when EPO was applied after AKI. Interestingly, however, EPO treatment resulted in a highly significant increase in CD133- and CD34-positive EPC both in the peripheral blood and renal vessels. © 2015 International Federation for Cell Biology.

  19. Effects of a Single Dose of Erythropoietin on Motor Function and Cognition after Focal Brain Ischemia in Adult Rats

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    Michaela Hralová

    2014-01-01

    Full Text Available We tested the influence of erythropoietin (EPO, a basic cytokine in erythropoiesis regulation, on the process of motor function and cognition after focal brain ischemia induced by a local application of endothelin. Endothelin-1 (ET-1 induced short lasting strong vasoconstriction, with described impact on the structure and on the function of neuronal cells. Neurological description of motor function and Morris water maze test (the swimming test is one of most widely used methods for studying cognitive functions in rodents were used to study the process of learning and memory in three-month-old male albino Wistar rats (n=52. Both tests were performed one week before, and three weeks after ischemia induction (endothelin application on the cortex in the area of a. cerebri media dx.. Experimental group received i.p. injection of EPO (5,000 IU/kg body weight, 10 min before endothelin application. Control group of animals received one i.p. injection of saline at the dose of 1 ml/kg body weight at the same time. Only sham surgery was performed in the third group of animals. Rats with EPO pretreatment before the experimental lesion exhibited significantly better motor and cognitive function then those with saline injection. No significant changes in the motor and cognitive function were found in the third group of rats (sham operated controls.

  20. Fundamentos del uso clínico de la eritropoyetina como neuroprotector Foundations of the clinical use of erythropoietin as a neuroprotective agent

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    Alain Valdivia Acosta

    2008-08-01

    Full Text Available Hace aproximadamente una década, se reportaron por primera vez, las propiedades neuroprotectoras de la eritropoyetina en estudios preclínicos. Todavía no se ha podido esclarecer con firmeza el posible mecanismo de acción neuroprotector de esta hormona, pero existen varias hipótesis. La eritropoyetina ha mostrado buenos resultados en preclínica como agente neuroprotector y todavía queda mucho camino por recorrer para lograr una adecuada efectividad y seguridad en la clínica en este sentido. Se investiga para lograr una eritropoyetina con actividad neuroprotectora que carezca, o al menos tenga disminuida su actividad hematopoyética. Disminuir sus efectos adversos, lograr una significativa biodisponibilidad al sistema nervioso central, alargar el tiempo de vida media y con ello evitar una alta frecuencia de administración al paciente, es lo que principalmente se está buscando. En este trabajo se realizó una búsqueda sobre los mecanismos de acción neuroprotectora hasta ahora propuestos para la eritropoyetina y se detallaron importantes consideraciones a tomar en cuenta, que pudieran influir sobre su utilización en la clínica.The neuroprotective properties of erythropoietin were reported for the first time in preclinical studies approximately a decade ago. The possible mechanism of neuroprotective action of this hormone has not been cleared yet, but here are diverse hypotheses. Erythropoietin has showed good results in preclinic as a neuroprotective agent and there is still a long way to go to attain an adequate effectivity and safety in the clinic in this sense. Research is being carried out to obtain an erythropoietin with neuroprotective activity that lacks or at least has a diminished hematopoietic activity. To reduce its adverse effects, to achieve a significant bioavailability to the central nervous system, to prolong its mean life and to avoid this way a high frequency of administration to the patient, is our main objective. In

  1. Whistleblower Protection

    Science.gov (United States)

    The Whistleblower Protection Enhancement Act of 2012 (WPA) and the Whistleblower Protection Act of 1989 Enhanced by the Act of 2012 provides protection rights for Federal employees against retaliation for whistleblowing activities.

  2. Therapeutic effect of erythropoietin in patients with traumatic brain injury: a meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Liu, Wen-Chao; Wen, Liang; Xie, Tao; Wang, Hao; Gong, Jiang-Biao; Yang, Xiao-Feng

    2017-07-01

    OBJECTIVE Erythropoietin (EPO) exerts a neuroprotective effect in animal models of traumatic brain injury (TBI). However, its effectiveness in human patients with TBI is unclear. In this study, the authors conducted the first meta-analysis to assess the effectiveness and safety of EPO in patients with TBI. METHODS In December 2015, a systematic search was performed of PubMed, Web of Science, MEDLINE, Embase, the Cochrane Library databases, and Google Scholar. Only English-language publications of randomized controlled trials (RCTs) using EPO in patients with TBI were selected for analysis. The assessed outcomes included mortality, favorable neurological outcome, hospital stay, and associated adverse effects. Continuous variables were presented as mean difference (MD) with a 95% confidence interval (CI). Dichotomous variables were presented as risk ratio (RR) or risk difference (RD) with a 95% CI. Statistical heterogeneity was examined using both I 2 and chi-square tests. RESULTS Of the 346 studies identified in the search, 5 RCTs involving 915 patients met the inclusion criteria. The overall results demonstrated that EPO significantly reduced mortality (RR 0.69, 95% CI 0.49-0.96, p = 0.03) and shortened the hospitalization time (MD -7.59, 95% CI -9.71 to -5.46, p deep vein thrombosis (DVT; RD 0.00, 95% CI -0.05 to 0.05, p = 1.00) did not show a significant difference. CONCLUSIONS The authors suggested that EPO is beneficial for patients with TBI in terms of reducing mortality and shortening hospitalization time without increasing the risk of DVT. However, its effect on improving favorable neurological outcomes did not reach statistical significance. Therefore, more well-designed RCTs are necessary to ascertain the optimum dosage and time window of EPO treatment for patients with TBI.

  3. Therapeutic superiority and safety of combined hydroxyurea with recombinant human erythropoietin over hydroxyurea in young β-thalassemia intermedia patients.

    Science.gov (United States)

    Elalfy, Mohsen S; Adly, Amira A M; Ismail, Eman A; Elhenawy, Yasmine I; Elghamry, Islam R

    2013-12-01

    To assess the efficacy and safety of combined hydroxyurea (HU) and recombinant human erythropoietin (rHuEPO) in β-thalassemia intermedia (TI) patients compared with single HU therapy. An interventional prospective randomized study registered in the ClinicalTrials.gov (NCT01624038) was performed on 80 TI patients (≤ 18 yr) divided into group A (40 patients received combined HU and rHuEPO) and group B (40 patients received single HU therapy). Baseline serum EPO levels were measured, and both groups were followed up for a mean period of 1 yr with regular assessment of transfusion requirements, blood pressure, ferritin, liver and renal functions, hemoglobin, and HbF. Quality of life (QoL) was assessed at the start and end of the study. Transfusion frequency and index were significantly decreased, while QoL was increased in group A compared with group B where 85% of patients showed improvement on combined therapy compared with 50% of patients on HU. Hemoglobin and HbF were significantly increased in both TI groups; however, this was more evident in group A than in group B. Also, 37.5% of patients in group A became transfusion-independent compared with 15% in group B. EPO levels were negatively related to increments of hemoglobin and HbF. Splenectomized patients and those with initial HbF% >40% had the best response to combined therapy. No serious adverse events necessitating discontinuation of therapy in both groups. HU was effective in management of TI; however, combination with rHuEPO gave a superior therapeutic effect resulting in the best clinical and hematological responses without adverse events. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. A sequential erythropoietin and GM-CSF schedule offers clinical benefits in the treatment of anaemia in myelodysplastic syndromes.

    Science.gov (United States)

    Bernell, P; Stenke, L; Wallvik, J; Hippe, E; Hast, R

    1996-08-01

    In order to reduce anaemia in patients with myelodysplastic syndromes (MDS) a stepwise treatment protocol including erythropoietin (EP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was designed. Thirty-seven MDS patients (stages I-III) with symptomatic anaemia were first given EPO 10,000 U s.c. 3 times weekly for 6 weeks. Those not responding, i.e. increased their haemoglobin levels > 15 g/l, proceeded into the second phase of the study where GM-CSF (200 micrograms/d. s.c. on weeks 1-6) was combined with EPO (10,000 U s.c. 3 times weekly on weeks 5-14). Following the initial EPO treatment phase, 14 of the 37 patients (38%) responded with increased haemoglobin levels. Responders were significantly different from non-responders in that their pre-treatment values of s-EPO, s-LDH and bone marrow blast cell counts were lower, their baseline haemoglobin levels higher and their transfusion dependency less pronounced. Eighteen of the 23 non-responders proceeded into the second phase, 13 of those were evaluable having completed the entire schedule. Three of the 13 initially EPO resistant patients (23%) responded to the GM-CSF/EPO combination with increased haemoglobin levels, suggesting a positive synergy between the two cytokines. Thus, the overall response rate to the present protocol was 46% (17 of 37 cases), but only a limited subset of the patients did clearly benefit from the combined GM-CSF/EPO administration. Therefore, we believe this step-wise approach to multiple growth factor treatment in MDS, starting with EPO alone and reserving the combination for refractory cases, has considerable advantages, taking into account both medical and socio-economical aspects.

  5. Impact of anemia prevention by recombinant human erythropoietin on the sensitivity of xenografted glioblastomas to fractionated irradiation

    International Nuclear Information System (INIS)

    Stueben, G.; Poettgen, C.; Knuehmann, K.; Sack, H.; Stuschke, M.; Thews, O.; Vaupel, P.

    2003-01-01

    Background: Pronounced oxygen deficiency in tumors which might be caused by a diminished oxygen transport capacity of the blood (e.g., in anemia) reduces the efficacy of ionizing radiation. The aim of this study was to analyze whether anemia prevention by recombinant human erythropoietin (rHuEPO) affects the radiosensitivity of human glioblastoma xenografts during fractionated irradiation. Material and Methods: Anemia was induced by total body irradiation (TBI, 2 x 4 Gy) of mice prior to tumor implantation into the subcutis of the hind leg. In one experimental group, the development of anemia was prevented by rHuEPO (750 U/kg s.c.) given three times weekly starting 10 days prior to TBI. 13 days after tumor implantation (tumor volume approx. 40 mm 3 ), fractionated irradiation (4 x 7 Gy, one daily fraction) of the glioblastomas was performed resulting in a growth delay with subsequent regrowth of the tumors. Results: Compared to nonanemic control animals (hemoglobin concentration cHb = 14.7 g/dl), the growth delay in anemic mice (cHb = 9.9 g/dl) was significantly shorter (49 ± 5 days vs. 79 ± 4 days to reach four times the initial tumor volume) upon fractionated radiation. The prevention of anemia by rHuEPO treatment (cHb = 13.3 g/dl) resulted in a significantly prolonged growth delay (61 ± 5 days) compared to the anemia group, even though the growth inhibition found in control animals was not completely achieved. Conclusions: These data indicate that moderate anemia significantly reduces the efficacy of radiotherapy. Prevention of anemia with rHuEPO partially restores the radiosensitivity of xenografted glioblastomas to fractionated irradiation. (orig.)

  6. Serum proteomic changes after randomized prolonged erythropoietin treatment and/or endurance training: detection of novel biomarkers.

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    Britt Christensen

    Full Text Available Despite implementation of the biological passport to detect erythropoietin abuse, a need for additional biomarkers remains. We used a proteomic approach to identify novel serum biomarkers of prolonged erythropoiesis-stimulating agent (ESA exposure (Darbepoietin-α and/or aerobic training.Thirty-six healthy young males were randomly assigned to the following groups: Sedentary-placebo (n = 9, Sedentary-ESA (n = 9, Training-placebo (n = 10, or Training-ESA (n = 8. They were treated with placebo/Darbepoietin-α subcutaneously once/week for 10 weeks followed by a 3-week washout period. Training consisted of supervised biking 3/week for 13 weeks at the highest possible intensity. Serum was collected at baseline, week 3 (high dose Darbepoietin-α, week 10 (reduced dose Darbepoietin-α, and after a 3-week washout period.Serum proteins were separated according to charge and molecular mass (2D-gel electrophoresis. The identity of proteins from spots exhibiting altered intensity was determined by mass spectrometry.Six protein spots changed in response to Darbepoietin-α treatment. Comparing all 4 experimental groups, two protein spots (serotransferrin and haptoglobin/haptoglobin related protein showed a significant response to Darbepoietin-α treatment. The haptoglobin/haptoglobin related protein spot showed a significantly lower intensity in all subjects in the training-ESA group during the treatment period and increased during the washout period.An isoform of haptoglobin/haptoglobin related protein could be a new anti-doping marker and merits further research.ClinicalTrials.gov NCT01320449.

  7. Enhancement of gene expression under hypoxic conditions using fragments of the human vascular endothelial growth factor and the erythropoietin genes

    International Nuclear Information System (INIS)

    Shibata, Toru; Akiyama, Nobutake; Noda, Makoto; Sasai, Keisuke; Hiraoka, Masahiro

    1998-01-01

    Purpose: Selective gene expression in response to tumor hypoxia may provide new avenues, not only for radiotherapy and chemotherapy, but also for gene therapy. In this study, we have assessed the extent of hypoxia responsiveness of various DNA constructs by the luciferase assay to help design vectors suitable for cancer therapy. Materials and Methods: Reporter plasmids were constructed with fragments of the human vascular endothelial growth factor (VEGF) and the erythropoietin (Epo) genes encompassing the putative hypoxia-responsive elements (HRE) and the pGL3 promoter vector. Test plasmids and the control pRL-CMV plasmid were cotransfected into tumor cells by the calcium phosphate method. After 6 h hypoxic treatment, the reporter assay was performed. Results: The construct pGL3/VEGF containing the 385 bp fragment of the 5' flanking region in human VEGF gene showed significant increases in luciferase activity in response to hypoxia. The hypoxic/aerobic ratios were about 3-4, and 8-12 for murine and human tumor cells, respectively. Despite the very high degree of conservation among the HREs of mammalian VEGF genes, murine cells showed lower responsiveness than human cells. We next tested the construct pGL3/Epo containing the 150 bp fragment of the 3' flanking region in the Epo gene. Luciferase activity of pGL3/Epo was increased with hypoxia only in human cell lines. The insertion of 5 copies of the 35-bp fragments derived from the VEGF HREs and 32 bp of the E1b minimal promoter resulted in maximal enhancement of hypoxia responsiveness. Conclusions: The constructs with VEGF or Epo fragments containing HRE may be useful for inducing specific gene expression in hypoxic cells. Especially, the application of multiple copies of the HREs and an E1b minimal promoter appears to have the advantage of great improvement in hypoxia responsiveness

  8. The combined effect of erythropoietin and granulocyte macrophage colony stimulating factor on liver regeneration after major hepatectomy in rats

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    Frangou Matrona

    2010-07-01

    Full Text Available Abstract Background The liver presents a remarkable capacity for regeneration after hepatectomy but the exact mechanisms and mediators involved are not yet fully clarified. Erythropoietin (EPO and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF have been shown to promote liver regeneration after major hepatectomy. Aim of this experimental study is to compare the impact of exogenous administration of EPO, GM-CSF, as well as their combination on the promotion of liver regeneration after major hepatectomy. Methods Wistar rats were submitted to 70% major hepatectomy. The animals were assigned to 4 experimental groups: a control group (n = 21 that received normal saline, an EPO group (n = 21, that received EPO 500 IU/kg, a GM-CSF group (n = 21 that received 20 mcg/kg of GM-CSF and a EPO+GMCSF group (n = 21 which received a combination of the above. Seven animals of each group were killed on the 1st, 3rd and 7th postoperative day and their remnant liver was removed to evaluate liver regeneration by immunochemistry for PCNA and Ki 67. Results Our data suggest that EPO and GM-CSF increases liver regeneration following major hepatectomy when administered perioperatively. EPO has a more significant effect than GM-CSF (p Conclusion EPO, GM-CSF and their combination enhance liver regeneration after hepatectomy in rats when administered perioperatively. However their combination has a weaker effect on liver regeneration compared to EPO alone. Further investigation is needed to assess the exact mechanisms that mediate this finding.

  9. Progenitor cells of erythroblasts: an in vitro investigation of erythropoietin-responsive cells of guinea pig bone marrow

    International Nuclear Information System (INIS)

    Rosse, C.; Beaufait, D.W.

    1978-01-01

    The experiments were designed to therst whether erythroblast progenitor cell function could be demonstrated in a morphological cell type designated as transitional cells. Two cell fractions were obtained from the bone marrow of normal and polycythemic guinea pigs. One fraction (F1) was enriched in transitional cells and contained few other cell types which could be considered as candidates for erythropoietin responsive cells (ERC). The other fraction (F2) contained undifferentiated blast cells as well as transitional cells. The effect of human urinary erythropoiesis stimulating factors (ESF) on heme synthesis was compared in these two fractions by measuring 59 Fe incorporation into heme. ESF was more effective in stimulating heme synthesis in guinea pig bone marrow cells than homologous sera obtained from anemic or hypoxic animals. The majority of ERC sedimented in F2, but the stimulation index was comparable in the two fractions. It was confirmed by radioautography that the ESF response in F1 was due to the generation of proerythroblasts and basophilic erythroblasts that incorporated 55 Fe. The generation of these cells in F1 was dependent on the addition of ESF to the cultures, whereas 55 Fe-labeled erythroblasts were recovered from cultures of F2 not supplemented with ESF. ESF induced a proportion of transitional cells to incorporate 55 Fe in both F1 and F2. Transitional cells were the only cell type in which heme synthesis was dependent on ESF. Radioautography with 55 Fe identified a proportion of these cells as ERC in both F1 and F2 fractions of bone marrow obtained from normal and polycythemic guinea pigs. The present studies show that some transitional cells function as progenitors of erythroblasts because they respond to ESF by initiation of heme synthesis and by transformation into the earliest recognizable erythroid cells

  10. Plasma erythropoietin by high-detectability immunoradiometric assay in untreated and treated patients with polycythaemia vera and essential thrombocythaemia

    Energy Technology Data Exchange (ETDEWEB)

    Carneskog, J.; Kutti, J.; Wadenvik, H. [Univ. of Goeteborg, Sahlgrenska Univ. Hospital, Dept. of Medicine, Haematology Section (Sweden); Lundberg, P.A.; Lindstedt, G. [Univ. of Goeteborg, Sahlgrenska Univ. Hospital, Dept. of Clinical Chemistry and Transfusion Medicine (Sweden)

    1998-12-31

    By using an immunoradiometric method with a stated detection limit of {<=}1 IU/l (stated normal reference limit in adults 3.7-16 IU/l) we determined EDTA-plasma erythropoietin (EPO) in 58 patients with polycythaemia vera (PV) and 49 patients with essential thrombocythaemia (ET). At the time of blood sampling, 20 of the PV patients were newly diagnosed and untreated, 23 were treated by phlebotomy only, and 30 also received myelosuppressive treatment (with 32P, hydroxyurea of alpha-interferon). Of the ET patients 24 were untreated and 28 received myelosuppressive therapy. For comparison plasma EPO was also determined in 10 patients with pseudopolycythaemia (PP). In this latter group the results for plasma EPO agreed well with the cited normal reference limits. The majority of untreated PV patients (12/20) had undetectable plasma EPO concentration, and the remainder all had values below the lower normal reference limit. Plasma EPO in PV was not significantly influenced by phlebotomy therapy. Twelve of the 24 untreated ET patients (50%) had plasma EPO values below the reference interval (undetectable in 2 patients). The mean EPO concentration was significantly lower in PV patients receiving phlebotomy therapy than in patients with untreated ET. In the total material of PV and ET treated with myelosuppressive agents the PV patients showed significantly lower values for EPO concentration than did patients with ET. The present results support the view that EPO measurements by high-detectability methods are diagnostically useful and should be included in the panel of new criteria for the diagnosis of PV. (au) 20 refs.

  11. Polycythemia and high levels of erythropoietin in blood and brain blunt the hypercapnic ventilatory response in adult mice.

    Science.gov (United States)

    Menuet, Clément; Khemiri, Hanan; de la Poëze d'Harambure, Théodora; Gestreau, Christian

    2016-05-15

    Changes in arterial Po2, Pco2, and pH are the strongest stimuli sensed by peripheral and central chemoreceptors to adjust ventilation to the metabolic demand. Erythropoietin (Epo), the main regulator of red blood cell production, increases the hypoxic ventilatory response, an effect attributed to the presence of Epo receptors in both carotid bodies and key brainstem structures involved in integration of peripheral inputs and control of breathing. However, it is not known whether Epo also has an effect on the hypercapnic chemoreflex. In a first attempt to answer this question, we tested the hypothesis that Epo alters the ventilatory response to increased CO2 levels. Basal ventilation and hypercapnic ventilatory response (HCVR) were recorded from control mice and from two transgenic mouse lines constitutively expressing high levels of human Epo in brain only (Tg21) or in brain and plasma (Tg6), the latter leading to polycythemia. To tease apart the potential effects of polycythemia and levels of plasma Epo in the HCVR, control animals were injected with an Epo analog (Aranesp), and Tg6 mice were treated with the hemolytic agent phenylhydrazine after splenectomy. Ventilatory parameters measured by plethysmography in conscious mice were consistent with data from electrophysiological recordings in anesthetized animals and revealed a blunted HCVR in Tg6 mice. Polycythemia alone and increased levels of plasma Epo blunt the HCVR. In addition, Tg21 mice with an augmented level of cerebral Epo also had a decreased HCVR. We discuss the potential implications of these findings in several physiopathological conditions. Copyright © 2016 the American Physiological Society.

  12. Chronic restraint stress after injury and shock is associated with persistent anemia despite prolonged elevation in erythropoietin levels.

    Science.gov (United States)

    Bible, Letitia E; Pasupuleti, Latha V; Gore, Amy V; Sifri, Ziad C; Kannan, Kolenkode B; Mohr, Alicia M

    2015-07-01

    Following severe traumatic injury, critically ill patients have a prolonged hypercatacholamine state that is associated with bone marrow (BM) dysfunction and persistent anemia. However, current animal models of injury and shock result in a transient anemia. Daily restraint stress (chronic stress [CS]) has been shown to increase catecholamines. We hypothesize that adding CS following injury or injury and shock in rats will prolong the hypercatecholaminemia and prolong the initial anemia, despite elevated erythropoietin (EPO) levels. Male Sprague-Dawley rats (n = 6-8 per group) underwent lung contusion (LC) or combined LC/hemorrhagic shock (LCHS) followed by 6 days of CS. CS consisted of a 2-hour restraint period interrupted with repositioning and alarms every 30 minutes. At 7 days, urine was assessed for norepinephrine (NE) levels, blood for EPO and hemoglobin (Hgb), and BM for erythroid progenitor growth. Animals undergoing LC or combined LCHS predictably recovered by Day 7; urine NE, EPO, and Hgb levels were normal. The addition of CS to LC and LCHS models was associated with a significant elevation in NE on Day 6. The addition of CS to LC led to a persistent 20% to 25% decrease in the growth of BM hematopoietic progenitor cells. These findings were further exaggerated when CS was added following LCHS, resulting in a 20%q to 40% reduction in BM erythroid progenitor colony growth and a 20% decrease in Hgb when compared with LCHS alone. Exposing injured animals to CS results in prolonged elevation of NE and EPO, which is associated with worsening BM erythroid function and persistent anemia. Chronic restraint stress following injury and shock provides a clinically relevant model to further evaluate persistent injury-associated anemia seen in critically ill trauma patients. Furthermore, alleviating CS after severe injury is a potential therapeutic target to improve BM dysfunction and anemia.

  13. Repetitive Neonatal Erythropoietin and Melatonin Combinatorial Treatment Provides Sustained Repair of Functional Deficits in a Rat Model of Cerebral Palsy

    Directory of Open Access Journals (Sweden)

    Lauren L. Jantzie

    2018-04-01

    Full Text Available Cerebral palsy (CP is the leading cause of motor impairment for children worldwide and results from perinatal brain injury (PBI. To test novel therapeutics to mitigate deficits from PBI, we developed a rat model of extreme preterm birth (<28 weeks of gestation that mimics dual intrauterine injury from placental underperfusion and chorioamnionitis. We hypothesized that a sustained postnatal treatment regimen that combines the endogenous neuroreparative agents erythropoietin (EPO and melatonin (MLT would mitigate molecular, sensorimotor, and cognitive abnormalities in adults rats following prenatal injury. On embryonic day 18 (E18, a laparotomy was performed in pregnant Sprague–Dawley rats. Uterine artery occlusion was performed for 60 min to induce placental insufficiency via transient systemic hypoxia-ischemia, followed by intra-amniotic injections of lipopolysaccharide, and laparotomy closure. On postnatal day 1 (P1, approximately equivalent to 30 weeks of gestation, injured rats were randomized to an extended EPO + MLT treatment regimen, or vehicle (sterile saline from P1 to P10. Behavioral assays were performed along an extended developmental time course (n = 6–29. Open field testing shows injured rats exhibit hypermobility and disinhibition and that combined neonatal EPO + MLT treatment repairs disinhibition in injured rats, while EPO alone does not. Furthermore, EPO + MLT normalizes hindlimb deficits, including reduced paw area and paw pressure at peak stance, and elevated percent shared stance after prenatal injury. Injured rats had fewer social interactions than shams, and EPO + MLT normalized social drive. Touchscreen operant chamber testing of visual discrimination and reversal shows that EPO + MLT at least partially normalizes theses complex cognitive tasks. Together, these data indicate EPO + MLT can potentially repair multiple sensorimotor, cognitive, and behavioral realms following PBI, using

  14. Extended Erythropoietin Treatment Prevents Chronic Executive Functional and Microstructural Deficits Following Early Severe Traumatic Brain Injury in Rats

    Directory of Open Access Journals (Sweden)

    Shenandoah Robinson

    2018-06-01

    Full Text Available Survivors of infant traumatic brain injury (TBI are prone to chronic neurological deficits that impose lifelong individual and societal burdens. Translation of novel interventions to clinical trials is hampered in part by the lack of truly representative preclinical tests of cognition and corresponding biomarkers of functional outcomes. To address this gap, the ability of a high-dose, extended, post-injury regimen of erythropoietin (EPO, 3000U/kg/dose × 6d to prevent chronic cognitive and imaging deficits was tested in a postnatal day 12 (P12 controlled-cortical impact (CCI model in rats, using touchscreen operant chambers and regional analysis of diffusion tensor imaging (DTI. Results indicate that EPO prevents functional injury and MRI injury after infant TBI. Specifically, subacute DTI at P30 revealed widespread microstructural damage that is prevented by EPO. Assessment of visual discrimination on a touchscreen operant chamber platform demonstrated that all groups can perform visual discrimination. However, CCI rats treated with vehicle failed to pass reversal learning, and perseverated, in contrast to sham and CCI-EPO rats. Chronic DTI at P90 showed EPO treatment prevented contralateral white matter and ipsilateral lateral prefrontal cortex damage. This DTI improvement correlated with cognitive performance. Taken together, extended EPO treatment restores executive function and prevents microstructural brain abnormalities in adult rats with cognitive deficits in a translational preclinical model of infant TBI. Sophisticated testing with touchscreen operant chambers and regional DTI analyses may expedite translation and effective yield of interventions from preclinical studies to clinical trials. Collectively, these data support the use of EPO in clinical trials for human infants with TBI.

  15. Radiation protection

    International Nuclear Information System (INIS)

    Koelzer, W.

    1975-01-01

    Physical and radiological terms, quantities, and units. Basic principles of radiation protection (ICRP, IAEA, EURATOM, FRG). Biological effects of ionizing radiation. Objectives of practical radiation protection. (HP) [de

  16. Optimizing Combinations of Flavonoids Deriving from Astragali Radix in Activating the Regulatory Element of Erythropoietin by a Feedback System Control Scheme

    Directory of Open Access Journals (Sweden)

    Hui Yu

    2013-01-01

    Full Text Available Identifying potent drug combination from a herbal mixture is usually quite challenging, due to a large number of possible trials. Using an engineering approach of the feedback system control (FSC scheme, we identified the potential best combinations of four flavonoids, including formononetin, ononin, calycosin, and calycosin-7-O-β-D-glucoside deriving from Astragali Radix (AR; Huangqi, which provided the best biological action at minimal doses. Out of more than one thousand possible combinations, only tens of trials were required to optimize the flavonoid combinations that stimulated a maximal transcriptional activity of hypoxia response element (HRE, a critical regulator for erythropoietin (EPO transcription, in cultured human embryonic kidney fibroblast (HEK293T. By using FSC scheme, 90% of the work and time can be saved, and the optimized flavonoid combinations increased the HRE mediated transcriptional activity by ~3-fold as compared with individual flavonoid, while the amount of flavonoids was reduced by ~10-fold. Our study suggests that the optimized combination of flavonoids may have strong effect in activating the regulatory element of erythropoietin at very low dosage, which may be used as new source of natural hematopoietic agent. The present work also indicates that the FSC scheme is able to serve as an efficient and model-free approach to optimize the drug combination of different ingredients within a herbal decoction.

  17. Physical protection

    International Nuclear Information System (INIS)

    Myers, D.A.

    1989-01-01

    Physical protection is defined and its function in relation to other functions of a State System of Accounting for and Control of Nuclear Materials is described. The need for a uniform minimum international standard for physical protection as well as the need for international cooperation in physical protection is emphasized. The IAEA's INFCIRC/225/Rev. 1 (Annex 1) is reviewed. The Convention on the Physical Protection of Nuclear Material (Annex 2) is discussed. Photographs show examples of typical physical protection technology (Annex 3)

  18. Diplomatic Protection

    OpenAIRE

    Režná, Jana

    2006-01-01

    Final thesis Topic: Diplomatic protection Thesis supervisor: JUDr. Vladimír Balaš, CSc. Student: Marek Čermák Thesis on the topic of diplomatic protection deals with the granting of exercise of diplomatic protection by the states and is divided into seven chapters which follow each other. The first chapter describes the diplomatic protection and its historical foundations. The second chapter focuses on the possibility of exercise of diplomatic protection in respect of natural persons and the ...

  19. Enhanced metabolic effect of erythropoietin and keto acids in CRF patients on low-protein diet: Czech multicenter study.

    Science.gov (United States)

    Teplan, Vladimír; Schück, Otto; Knotek, Antonín; Hajný, Jan; Horácková, Miroslava; Kvapil, Milan

    2003-03-01

    Our study is designed to establish whether supplementation with erythropoietin (EPO) exerts additional beneficial metabolic effects in patients with chronic renal failure (CRF) treated with keto acids (KAs) on a low-protein diet (LPD). A long-term, prospective, randomized study was designed to use three therapeutic protocols: (A) EPO plus KAs plus LPD (group I), (B) EPO plus LPD (group II), and (C) LPD (group III). One hundred eighty-six randomly selected patients (90 men, 96 women; age, 22 to 78 years) with a creatinine clearance of 22 to 36 mL/min were monitored at the beginning and at every 6 months for 3 years. During the study period, glomerular filtration rate measured as inulin clearance decreased slightly (from 26.2 +/- 3.4 to 23.4 +/- 4.1 mL/min in group I), 27.4 +/- 4.8 to 20.2 +/- 4.4 mL/min in group II, and 26.8 +/- 3.6 to 17.4 +/- 4.1 mL/min in group III; P < 0.01). Serum urea levels also declined (P < 0.01), more pronouncedly in group I (P < 0.025). In group I, there was a significant increase in levels of leucine (P < 0.01) and albumin (P < 0.01) and a decrease in proteinuria (P < 0.01). Analysis of the lipid spectrum showed a mild, yet significant, decrease in total cholesterol and low-density lipoprotein cholesterol levels (P < 0.025), more pronounced in group I. In group I, there was a decrease in plasma triglyceride levels (from 362.85 +/- 115.05 mg/dL [4.1 +/- 1.3 mmol/L] to values as low as 203.55 +/- 70.80 mg/dL [2.3 +/- 0.8 mmol/L]; P < 0.01), whereas high-density lipoprotein cholesterol levels increased (from 34.75 +/- 7.72 mg/dL [0.9 +/- 0.2 mmol/L] to 46.33 +/- 7.72 mg/dL [1.2 +/- 0.2 mmol/L]; P < 0.025). Mean arterial blood pressure was stable. EPO supplementation in patients with CRF administered KAs potentiates the beneficial effects on metabolism of proteins, amino acids, and lipids. Long-term coadministration of EPO, KA, and LPD was associated with a delay in progression of renal failure and reduction in proteinuria.

  20. Validation of whole-blood transcriptome signature during microdose recombinant human erythropoietin (rHuEpo) administration.

    Science.gov (United States)

    Wang, Guan; Durussel, Jérôme; Shurlock, Jonathan; Mooses, Martin; Fuku, Noriyuki; Bruinvels, Georgie; Pedlar, Charles; Burden, Richard; Murray, Andrew; Yee, Brendan; Keenan, Anne; McClure, John D; Sottas, Pierre-Edouard; Pitsiladis, Yannis P

    2017-11-14

    Recombinant human erythropoietin (rHuEpo) can improve human performance and is therefore frequently abused by athletes. As a result, the World Anti-Doping Agency (WADA) introduced the Athlete Biological Passport (ABP) as an indirect method to detect blood doping. Despite this progress, challenges remain to detect blood manipulations such as the use of microdoses of rHuEpo. Forty-five whole-blood transcriptional markers of rHuEpo previously derived from a high-dose rHuEpo administration trial were used to assess whether microdoses of rHuEpo could be detected in 14 trained subjects and whether these markers may be confounded by exercise (n = 14 trained subjects) and altitude training (n = 21 elite runners and n = 4 elite rowers, respectively). Differential gene expression analysis was carried out following normalisation and significance declared following application of a 5% false discovery rate (FDR) and a 1.5 fold-change. Adaptive model analysis was also applied to incorporate these markers for the detection of rHuEpo. ALAS2, BCL2L1, DCAF12, EPB42, GMPR, SELENBP1, SLC4A1, TMOD1 and TRIM58 were differentially expressed during and throughout the post phase of microdose rHuEpo administration. The CD247 and TRIM58 genes were significantly up- and down-regulated, respectively, immediately following exercise when compared with the baseline both before and after rHuEpo/placebo. No significant gene expression changes were found 30 min after exercise in either rHuEpo or placebo groups. ALAS2, BCL2L1, DCAF12, SLC4A1, TMOD1 and TRIM58 tended to be significantly expressed in the elite runners ten days after arriving at altitude and one week after returning from altitude (FDR > 0.059, fold-change varying from 1.39 to 1.63). Following application of the adaptive model, 15 genes showed a high sensitivity (≥ 93%) and specificity (≥ 71%), with BCL2L1 and CSDA having the highest sensitivity (93%) and specificity (93%). Current results provide further evidence that

  1. Neonatal erythropoietin mitigates impaired gait, social interaction and diffusion tensor imaging abnormalities in a rat model of prenatal brain injury.

    Science.gov (United States)

    Robinson, Shenandoah; Corbett, Christopher J; Winer, Jesse L; Chan, Lindsay A S; Maxwell, Jessie R; Anstine, Christopher V; Yellowhair, Tracylyn R; Andrews, Nicholas A; Yang, Yirong; Sillerud, Laurel O; Jantzie, Lauren L

    2018-04-01

    Children who are born preterm are at risk for encephalopathy of prematurity, a leading cause of cerebral palsy, cognitive delay and behavioral disorders. Current interventions are limited and none have been shown to reverse cognitive and behavioral impairments, a primary determinant of poor quality of life for these children. Moreover, the mechanisms of perinatal brain injury that result in functional deficits and imaging abnormalities in the mature brain are poorly defined, limiting the potential to target interventions to those who may benefit most. To determine whether impairments are reversible after a prenatal insult, we investigated a spectrum of functional deficits and diffusion tensor imaging (DTI) abnormalities in young adult animals. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) would induce multiple functional deficits concomitant with reduced microstructural white and gray matter integrity, and tested whether these abnormalities could be ameliorated using postnatal erythropoietin (EPO), an emerging neurorestorative intervention. On embryonic day 18 uterine arteries were transiently occluded for 60min via laparotomy. Shams underwent anesthesia and laparotomy for 60min. Pups were born and TSHI pups were randomized to receive EPO or vehicle via intraperitoneal injection on postnatal days 1 to 5. Gait, social interaction, olfaction and open field testing was performed from postnatal day 25-35 before brains underwent ex vivo DTI to measure fractional anisotropy, axial diffusivity and radial diffusivity. Prenatal TSHI injury causes hyperactivity, impaired gait and poor social interaction in young adult rats that mimic the spectrum of deficits observed in children born preterm. Collectively, these data show for the first time in a model of encephalopathy of prematurity that postnatal EPO treatment mitigates impairments in social interaction, in addition to gait deficits. EPO also normalizes TSHI-induced microstructural abnormalities

  2. Effects of cadmium on hypoxia-induced expression of hemoglobin and erythropoietin in larval sheepshead minnow, Cyprinodon variegatus

    Energy Technology Data Exchange (ETDEWEB)

    Dangre, A.J.; Manning, S. [Department of Coastal Sciences, University of Southern Mississippi, 703 East Beach Drive, Ocean Springs, MS 39564 (United States); Brouwer, M., E-mail: marius.brouwer@usm.edu [Department of Coastal Sciences, University of Southern Mississippi, 703 East Beach Drive, Ocean Springs, MS 39564 (United States)

    2010-08-15

    Hypoxia and toxic metals are two common stressors found in the estuarine environment. To date little information is available on the combined effects of these stressors on early larval development in fish. We investigated the effect of cadmium and hypoxia exposure alone as well in combination on larval Cyprinodon variegatus. The LC{sub 10} for cadmium was determined to be 0.3 ppm in a 96 h acute exposure. This concentration was used in all studies. Cadmium in larvae increased significantly with exposure time (1, 3, 5 and 7 days post-hatch). The increase was proportional to body weight and not affected by hypoxia. Cadmium responsive genes were identified by suppression subtractive hybridization (SSH) in Cyprinodonvariegatus larvae after exposure to cadmium for 1, 3, 5 and 7 days. We obtained over 700 sequences from the cadmium cDNA library. Blast search of ESTs suggested that cadmium modulates multiple physiological processes. Pertinent to this study, cadmium was found to down-regulate both embryonic {alpha} and {beta} globin, which are expressed in erythrocytes generated during the first, or primitive, wave of erythropoiesis in teleosts. Hemoglobin (Hb) and erythropoietin (Epo) (the hormone that promotes red blood cell production) are known hypoxia-inducible genes. To explore the possibility that cadmium might offset the hypoxia-induced expression of Hb and Epo, we investigated the expression of both genes following hypoxia, cadmium and combined exposures for 1, 3, 5 and 7 days post-hatch. Since Epo had not yet been identified in C. variegatus we first successfully cloned a partial coding sequence of the C. variegatus hormone. Subsequent studies revealed that expression levels of Hb and Epo remained unchanged in the normoxic controls during the time course of the study. Hypoxia increased Epo expression relative to normoxic controls, on days 3, 5 and 7, while cadmium in hypoxia inhibited the increase. Only the changes on days 5 and 7 were statistically significant

  3. Natural form of noncytolytic flexible human Fc as a long-acting carrier of agonistic ligand, erythropoietin.

    Directory of Open Access Journals (Sweden)

    Se Jin Im

    Full Text Available Human IgG1 Fc has been widely used as a bioconjugate, but exhibits shortcomings, such as antibody- and complement-mediated cytotoxicity as well as decreased bioactivity, when applied to agonistic proteins. Here, we constructed a nonimmunogenic, noncytolytic and flexible hybrid Fc (hyFc consisting of IgD and IgG4, and tested its function using erythropoietin (EPO conjugate, EPO-hyFc. Despite low amino acid homology (20.5% between IgD Fc and IgG4 Fc, EPO-hyFc retained "Y-shaped" structure and repeated intravenous administrations of EPO-hyFc into monkeys did not generate EPO-hyFc-specific antibody responses. Furthermore, EPO-hyFc could not bind to FcγR I and C1q in contrast to EPO-IgG1 Fc. In addition, EPO-hyFc exhibited better in vitro bioactivity and in vivo bioactivity in rats than EPO-IgG1 Fc, presumably due to the high flexibility of IgD. Moreover, the mean serum half-life of EPO-hyFc(H, a high sialic acid content form of EPO-hyFc, was approximately 2-fold longer than that of the heavily glycosylated EPO, darbepoetin alfa, in rats. More importantly, subcutaneous injection of EPO-hyFc(H not only induced a significantly greater elevation of serum hemoglobin levels than darbepoetin alfa in both normal rats and cisplatin-induced anemic rats, but also displayed a delayed time to maximal serum level and twice final area-under-the-curve (AUC(last. Taken together, hyFc might be a more attractive Fc conjugate for agonistic proteins/peptides than IgG1 Fc due to its capability to elongate their half-lives without inducing host effector functions and hindering bioactivity of fused molecules. Additionally, a head-to-head comparison demonstrated that hyFc-fusion strategy more effectively improved the in vivo bioactivity of EPO than the hyperglycosylation approach.

  4. Natural form of noncytolytic flexible human Fc as a long-acting carrier of agonistic ligand, erythropoietin.

    Science.gov (United States)

    Im, Se Jin; Yang, Sang In; Yang, Se Hwan; Choi, Dong Hoon; Choi, So Young; Kim, Hea Sook; Jang, Do Soo; Jin, Kyeong Sik; Chung, Yo-Kyung; Kim, Seung-Hee; Paik, Sang Hoon; Park, Yoo Chang; Chung, Moon Koo; Kim, Yong Bum; Han, Kang-Hyun; Choi, Kwan Yong; Sung, Young Chul

    2011-01-01

    Human IgG1 Fc has been widely used as a bioconjugate, but exhibits shortcomings, such as antibody- and complement-mediated cytotoxicity as well as decreased bioactivity, when applied to agonistic proteins. Here, we constructed a nonimmunogenic, noncytolytic and flexible hybrid Fc (hyFc) consisting of IgD and IgG4, and tested its function using erythropoietin (EPO) conjugate, EPO-hyFc. Despite low amino acid homology (20.5%) between IgD Fc and IgG4 Fc, EPO-hyFc retained "Y-shaped" structure and repeated intravenous administrations of EPO-hyFc into monkeys did not generate EPO-hyFc-specific antibody responses. Furthermore, EPO-hyFc could not bind to FcγR I and C1q in contrast to EPO-IgG1 Fc. In addition, EPO-hyFc exhibited better in vitro bioactivity and in vivo bioactivity in rats than EPO-IgG1 Fc, presumably due to the high flexibility of IgD. Moreover, the mean serum half-life of EPO-hyFc(H), a high sialic acid content form of EPO-hyFc, was approximately 2-fold longer than that of the heavily glycosylated EPO, darbepoetin alfa, in rats. More importantly, subcutaneous injection of EPO-hyFc(H) not only induced a significantly greater elevation of serum hemoglobin levels than darbepoetin alfa in both normal rats and cisplatin-induced anemic rats, but also displayed a delayed time to maximal serum level and twice final area-under-the-curve (AUC(last)). Taken together, hyFc might be a more attractive Fc conjugate for agonistic proteins/peptides than IgG1 Fc due to its capability to elongate their half-lives without inducing host effector functions and hindering bioactivity of fused molecules. Additionally, a head-to-head comparison demonstrated that hyFc-fusion strategy more effectively improved the in vivo bioactivity of EPO than the hyperglycosylation approach.

  5. CIRCULATING ANTIBODIES TO ERYTHROPOIETIN ARE ASSOCIATED WITH LOWER EFFICACY OF RECOMBINANT EPOETIN TREATMENT IN PATIENTS UNDERGOING HAEMODIALYSIS

    Directory of Open Access Journals (Sweden)

    V. D. Nazarov

    2018-01-01

    Full Text Available Biological preparations (BP obtained by gene engineering possess a special characteristic called immunogenicity, i.e. propensity of biological drugs to induce an undesired immune response associated with arising anti-drug antibodies. These antibodies can change BP pharmacokinetics and pharmacodynamics, and therapeutical efficacy. A significant proportion of hemodialysis patients with end-stage renal disease treated by recombinant erythropoietin (rEPO have clinical features of resistance to such therapy. The aim of the study was to investigate whether anti-rEPO antibodies are associated with hemoglobin concentrations (Hb and red blood cells counts (RBC in hemodialysis patients, receiving long-term rEPO therapy. This research was performed at the Research Institute of Nephrology at the First St. Petersburg I.Pavlov State Medical University. Thirty-seven hemodialysis patients (pts with end-stage renal disease and anemia treated with different rEPO formulations were included into the study. The patients were further divided into two groups: those with diminished and normal clinical response to rEPO therapy (DCR, n = 21 vs NCR group, n = 16, respectively. To determine threshold levels of antibodies to rEPO-beta (Roche, Switzerland we tested blood serum samples of 35 healthy blood donors who never received rEPO in the past. Concentration of antibodies was measured by means of dot-blot method. The threshold antibody concentrations were defined by measurement of anti-rEPO concentrations in 2-fold stepwise dilutions (1:10 to 1:200 of blood sera from 35 healthy donors .The threshold value for rEPO-binding antibodies was 20.27 µg/ml (95 CI%±0.43. Antibodies to rEPO were found in 54 % of serum samples in the patients. Anti-rEPO antibodies concentrations correlated with mean values of hemoglobin and erythrocyte counts over a period of 12-months for the entire group of hemodialysis patients (r = -0.368, p = 0.025 and r = -0.336, p = 0.042 respectively

  6. Environmental protection

    International Nuclear Information System (INIS)

    Klinda, J.; Lieskovska, Z.

    1998-01-01

    In this chapter environmental protection in the Slovak Republic in 1997 are reviewed. The economics of environmental protection, state budget, Slovak state environmental fund, economic instruments, environmental laws, environmental impact assessment, environmental management systems, and environmental education are presented

  7. Protective relay

    International Nuclear Information System (INIS)

    Lim, Mu Ji; Jung, Hae Sang

    1974-10-01

    This book is divided into two chapters, which deals with protective relay. The first chapter deals with the basic knowledge of relay on development of relay, classification of protective relay, rating of protective relay general structure of protective relay, detecting of ground protection, about point of contact, operating relay and trip relaying. The second chapter is about structure and explanation of relay on classification by structure such as motor type and moving-coil type, explanation of other relays over current relay, over voltage relay, short voltage relay, relay for power, relay for direction, test of over voltage relay, test of short voltage relay and test of directional circuit relay.

  8. Protecting knowledge

    DEFF Research Database (Denmark)

    Sofka, Wolfgang; de Faria, Pedro; Shehu, Edlira

    2018-01-01

    Most firms use secrecy to protect their knowledge from potential imitators. However, the theoretical foundations for secrecy have not been well explored. We extend knowledge protection literature and propose theoretical mechanisms explaining how information visibility influences the importance...... of secrecy as a knowledge protection instrument. Building on mechanisms from information economics and signaling theory, we postulate that secrecy is more important for protecting knowledge for firms that have legal requirements to reveal information to shareholders. Furthermore, we argue that this effect...... and a firm's investment in fixed assets. Our findings inform both academics and managers on how firms balance information disclosure requirements with the use of secrecy as a knowledge protection instrument....

  9. Transfection of primary brain capillary endothelial cells for protein synthesis and secretion of recombinant erythropoietin: a strategy to enable protein delivery to the brain

    DEFF Research Database (Denmark)

    Burkhart, Annette; Andresen, Thomas Lars; Aigner, Achim

    2017-01-01

    , as turning BCECs into recombinant protein factories by transfection could result in protein secretion further into the brain. The present study aims to investigate the possibility of transfecting primary rat brain endothelial cells (RBECs) for recombinant protein synthesis and secretion...... of the neuroprotective protein erythropoietin (EPO). We previously showed that 4% of RBECs with BBB properties can be transfected without disrupting the BBB integrity in vitro, but it can be questioned whether this is sufficient to enable protein secretion at therapeutic levels. The present study examined various......-derived neurotropic factor (BDNF). In conclusion, non-viral gene therapy to RBECs leads to protein secretion and signifies a method for therapeutic proteins to target cells inside the CNS otherwise omitted due to the BBB....

  10. The homozygous VHL(D126N) missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension.

    Science.gov (United States)

    Sarangi, Susmita; Lanikova, Lucie; Kapralova, Katarina; Acharya, Suchitra; Swierczek, Sabina; Lipton, Jeffrey M; Wolfe, Lawrence; Prchal, Josef T

    2014-11-01

    von Hippel-Lindau (VHL) protein is the principal negative regulator of hypoxia sensing mediated by transcription factors. Mutations in exon 3 of the VHL gene lead to Chuvash (VHL(R200W)) and Croatian (VHL(H191D)) polycythemias. Here, we describe an infant of Bangladesh ethnicity with a novel homozygous VHL(D126N) mutation with congenital polycythemia and dramatically elevated erythropoietin (EPO) levels, who developed severe fatal pulmonary hypertension. In contrast to Chuvash polycythemia, erythroid progenitors (BFU-Es) did not reveal a marked EPO hypersensitivity. Further, NF-E2 and RUNX1 transcripts that correlate with BFU-Es EPO hypersensitivity in polycythemic mutations were not elevated. © 2014 Wiley Periodicals, Inc.

  11. Stabilization of bacterially expressed erythropoietin by single site-specific introduction of short branched PEG chains at naturally occurring glycosylation sites.

    Science.gov (United States)

    Hoffmann, E; Streichert, K; Nischan, N; Seitz, C; Brunner, T; Schwagerus, S; Hackenberger, C P R; Rubini, M

    2016-05-24

    The covalent attachment of polyethylene glycol (PEG) to therapeutic proteins can improve their physicochemical properties. In this work we utilized the non-natural amino acid p-azidophenylalanine (pAzF) in combination with the chemoselective Staudinger-phosphite reaction to install branched PEG chains to recombinant unglycosylated erythropoietin (EPO) at each single naturally occurring glycosylation site. PEGylation with two short 750 or 2000 Da PEG units at positions 24, 38, or 83 significantly decreased unspecific aggregation and proteolytic degradation while biological activity in vitro was preserved or even increased in comparison to full-glycosylated EPO. This site-specific bioconjugation approach permits to analyse the impact of PEGylation at single positions. These results represent an important step towards the engineering of site-specifically modified EPO variants from bacterial expression with increased therapeutic efficacy.

  12. Radiation Protection

    International Nuclear Information System (INIS)

    Loos, M.

    2002-01-01

    Major achievements of SCK-CEN's Radiation Protection Department in 2001 are described. The main areas for R and D of the department are enviromnental remediation, emergency planning, radiation protection research, low-level radioactvity measurements, safeguards and physics measurements, decision strategy research and policy support and social sciences in nuclear research. Main achievements for 2001 in these areas are reported

  13. Sun protection

    Science.gov (United States)

    ... sun exposure. The start of summer is when UV rays can cause the most skin damage. Use sun protection, even on cloudy days. Clouds and haze don't protect you from the sun. Avoid surfaces that reflect light, such as water, sand, concrete, snow, and areas ...

  14. Radiation protection

    International Nuclear Information System (INIS)

    1989-01-01

    A NRPB leaflet in the 'At-a-Glance' series explains in a simple but scientifically accurate way what radiation is, the biological effects and the relative sensitivity of different parts of the human body. The leaflet then discusses radiation protection principles, radiation protection in the UK and finally the effectiveness of this radiation protection as judged by a breakdown of the total dose received by an average person in the UK, a heavy consumer of Cumbrian seafood, an average nuclear industry worker and an average person in Cornwall. (UK)

  15. Protected Areas

    Data.gov (United States)

    Kansas Data Access and Support Center — This dataset shows the boundaries of properties in Kansas in public or institutional ownership that contain ecological resources that merit some level of protection....

  16. Protective clothing

    International Nuclear Information System (INIS)

    Malet, J.C.; Regnier, J.

    1979-01-01

    The present operational and intervention suits are described. Research work is currently in progress to improve the performance of the existing suits and to develop more resistant protective clothing. (author)

  17. Radiation protection

    International Nuclear Information System (INIS)

    Ures Pantazi, M.

    1994-01-01

    This work define procedures and controls about ionizing radiations. Between some definitions it found the following topics: radiation dose, risk, biological effects, international radioprotection bodies, workers exposure, accidental exposure, emergencies and radiation protection

  18. Employment protection

    OpenAIRE

    Stefano Scarpetta

    2014-01-01

    Laws on hiring and firing are intended to protect workers from unfair behavior by employers, to counter imperfections in financial markets that limit workers’ ability to insure themselves against job loss, and to preserve firm-specific human capital. But by imposing costs on firms’ adaptation to changes in demand and technology, employment protection legislation may reduce not only job destruction but also job creation, hindering the efficient allocation of labor and productivity growth....

  19. Environmental protection

    International Nuclear Information System (INIS)

    Martinez, A.S.

    1987-01-01

    The question of environment protection related to the use of nuclear energy aiming to power generation, based on the harmonic concept of economic and industrial development, preserving the environment, is discussed. A brief study of environmental impacts for some energy sources, including nuclear energy, to present the systems of a nuclear power plant which aim at environmental protection, is done. (M.C.K.) [pt

  20. Radiation protection

    International Nuclear Information System (INIS)

    Koelzer, W.

    1976-01-01

    The lecture is divided into five sections. The introduction deals with the physical and radiological terms, quantities and units. Then the basic principles of radiological protection are discussed. In the third section attention is paid to the biological effects of ionizing radiation. The fourth section deals with the objectives of practical radiological protection. Finally the emergency measures are discussed to be taken in radiation accidents. (HP) [de

  1. Copyright protection

    OpenAIRE

    Plchotová, Gabriela

    2011-01-01

    The aim of this thesis is to offer a straightforward manual to anyone who authors their own original work or who utilises the original work of other creators. As such, it is necessary to briefly and clearly explain the historical development and essential terms of authorship as a concept and the origin of the need for copyright protection. Furthermore, this thesis includes chapters on copyright protection development specifically in the Czech Republic and the current definition of related law...

  2. Protective effect of total flavonoids of seabuckthorn (Hippophae rhamnoides) in simulated high-altitude polycythemia in rats.

    Science.gov (United States)

    Zhou, Ji-Yin; Zhou, Shi-Wen; Du, Xiao-Huang; Zeng, Sheng-Ya

    2012-09-28

    Seabuckthorn (Hippophae rhamnoides L.) has been used to treat high altitude diseases. The effects of five-week treatment with total flavonoids of seabuckthorn (35, 70, 140 mg/kg, ig) on cobalt chloride (5.5 mg/kg, ip)- and hypobaric chamber (simulating 5,000 m)-induced high-altitude polycythemia in rats were measured. Total flavonoids decreased red blood cell number, hemoglobin, hematocrit, mean corpuscular hemoglobin levels, span of red blood cell electrophoretic mobility, aggregation index of red blood cell, plasma viscosity, whole blood viscosity, and increased deformation index of red blood cell, erythropoietin level in serum. Total flavonoids increased pH, pO₂, Sp(O₂), pCO₂ levels in arterial blood, and increased Na⁺, HCO₃⁻, Cl⁻, but decreased K⁺ concentrations. Total flavonoids increased mean arterial pressure, left ventricular systolic pressure, end-diastolic pressure, maximal rate of rise and decrease, decreased heart rate and protected right ventricle morphology. Changes in hemodynamic, hematologic parameters, and erythropoietin content suggest that administration of total flavonoids from seabuckthorn may be useful in the prevention of high altitude polycythaemia in rats.

  3. Radiological protection

    International Nuclear Information System (INIS)

    Azorin N, J.; Azorin V, J. C.

    2010-01-01

    This work is directed to all those people related with the exercise of the radiological protection and has the purpose of providing them a base of knowledge in this discipline so that they can make decisions documented on technical and scientist factors for the protection of the personnel occupationally exposed, the people in general and the environment during the work with ionizing radiations. Before de lack of a text on this matter, this work seeks to cover the specific necessities of our country, providing a solid presentation of the radiological protection, included the bases of the radiations physics, the detection and radiation dosimetry, the radiobiology, the normative and operational procedures associates, the radioactive wastes, the emergencies and the transport of the radioactive material through the medical and industrial applications of the radiations, making emphasis in the relative particular aspects to the radiological protection in Mexico. The book have 16 chapters and with the purpose of supplementing the given information, are included at the end four appendixes: 1) the radioactive waste management in Mexico, 2-3) the Mexican official standards related with the radiological protection, 4) a terms glossary used in radiological protection. We hope this book will be of utility for those people that work in the investigation and the applications of the ionizing radiations. (Author)

  4. Comparison of Dosage Requirement of Erythropoietin Stimulating Agent (ESA in Maintenance of Hemoglobin Concentration in patients undergoing twice weekly versus thrice weekly Hemodialysis in Pakistani Population

    Directory of Open Access Journals (Sweden)

    Osama Kunwer Naveed

    2018-03-01

    Full Text Available Anemia is one of the major complications of patients with chronic kidney disease (CKD undergoing hemodialysis (HD and is associated with left ventricular hypertrophy and also increases morbidity and mortality. Anemia in patients with CKD can be due to two major reasons; iron deficiency or erythropoietin insufficiency. Erythropoietin Stimulating Agent (ESAs administration is the mainstay in treating anemia if the patient is iron sufficient. However, higher doses of ESAs have been associated with increased cerebrovascular and cardiovascular events. We conducted this study to see how much erythropoietin is required in our setting in iron sufficient patients to maintain hemoglobin(Hb  level and the effect of dialysis frequency on ESA doses.  Methods and Findings: A cross-sectional study was conducted at the Department of Nephrology at Ziauddin University Hospital. Patients’ charts were reviewed for Hb levels and doses of ESA to maintain Hb between 10-12 mg/dl. Patients were excluded if they had iron deficiency, malignancy, were on immunosuppressive agents, had renal transplant, and with Hb >12 mg/dl or <10 mg/dl and their ferritin levels, transferrin saturation, hemoglobin concentration, frequency of hemodialysis and ESA dosage were monitored. We also compared these variables between patients undergoing hemodialysis thrice weekly with those undergoing hemodialysis twice a week. A total of 105 patients were analyzed. 24 were excluded as they did not match the inclusion criteria. 81 patients were included in the study. 36 (44.4% were males and 45 (55.6% were females. Mean age of the patient was 56.47 ± 11.72 years. The average dose of ESA was 106.91 ± 61.47 for patients undergoing hemodialysis thrice weekly and 183.94 ± 116.71 for patients undergoing hemodialysis twice a week. Significant difference was found to exist between dosage of patients undergoing thrice weekly dialysis versus twice weekly dialysis(p=<0.001.  Our study has limitations

  5. Hmb(off/on) as a switchable thiol protecting group for native chemical ligation.

    Science.gov (United States)

    Qi, Yun-Kun; Tang, Shan; Huang, Yi-Chao; Pan, Man; Zheng, Ji-Shen; Liu, Lei

    2016-05-04

    A new thiol protecting group Hmb(off/on) is described, which has a switchable activity that may be useful in the chemical synthesis of proteins. When placed on the side chain of Cys, Cys(Hmb(off)) is stable to trifluoroacetic acid (TFA) in the process of solid-phase peptide synthesis. When Cys(Hmb(off)) is treated with neutral aqueous buffers, it is cleanly converted to acid-labile Cys(Hmb(on)), which can later be fully deprotected by TFA to generate free Cys. The utility of Cys(Hmb(off/on)) is demonstrated by the chemical synthesis of an erythropoietin segment, EPO[Cys(98)-Arg(166)]-OH through native chemical ligation.

  6. Radiation protection

    International Nuclear Information System (INIS)

    Jain, Aman; Sharma, Shivam; Parasher, Abhishek

    2014-01-01

    Radiation dose measurement, field of radiobiology, is considered to be critical factor for optimizing radiation protection to the health care practitioners, patients and the public. This lead to equipment that has dose - area product meters permanently installed. In many countries and even institution, the range of equipment is vast and with the opportunity for radiation protection and dose recording varies considerably. Practitioners must move with the changed demands of radiation protection but in many cases without assistance of modern advancements in technology Keeping the three basic safety measures Time, Dose and Shielding we can say 'Optimum dose is safe dose' instead of 'No dose is safe dose'. The purpose enclosed within the title 'Radiation Protection'. The use of radiation is expanding widely everyday around the world and crossing boundaries of medical imaging, diagnostic and. The way to get the ''As low as reasonably achievable' is only achievable by using methodology of radiation protection and to bring the concern of general public and practitioners over the hazards of un-necessary radiation dose. Three basic principles of radiation protection are time, distance and shielding. By minimizing the exposure time increasing the distance and including the shielding we can reduce the optimum range of dose. The ability of shielding material to attenuate radiation is generally given as half value layer. This is the thickness of the material which will reduce the amount of radiation by 50%. Lab coat and gloves must be worn when handling radioactive material or when working in a labeled radiation work area. Safety glasses or other appropriate splash shields should be used when handling radioactive material. 1. Reached to low dose level to occupational workers, public as per prescribed dose limit. 2. By mean of ALARA principle we achieved the protection from radiation besides us using the radiation for our benefit

  7. Machine Protection

    International Nuclear Information System (INIS)

    Schmidt, R

    2014-01-01

    The protection of accelerator equipment is as old as accelerator technology and was for many years related to high-power equipment. Examples are the protection of powering equipment from overheating (magnets, power converters, high-current cables), of superconducting magnets from damage after a quench and of klystrons. The protection of equipment from beam accidents is more recent. It is related to the increasing beam power of high-power proton accelerators such as ISIS, SNS, ESS and the PSI cyclotron, to the emission of synchrotron light by electron–positron accelerators and FELs, and to the increase of energy stored in the beam (in particular for hadron colliders such as LHC). Designing a machine protection system requires an excellent understanding of accelerator physics and operation to anticipate possible failures that could lead to damage. Machine protection includes beam and equipment monitoring, a system to safely stop beam operation (e.g. dumping the beam or stopping the beam at low energy) and an interlock system providing the glue between these systems. The most recent accelerator, the LHC, will operate with about 3 × 10 14 protons per beam, corresponding to an energy stored in each beam of 360 MJ. This energy can cause massive damage to accelerator equipment in case of uncontrolled beam loss, and a single accident damaging vital parts of the accelerator could interrupt operation for years. This article provides an overview of the requirements for protection of accelerator equipment and introduces the various protection systems. Examples are mainly from LHC, SNS and ESS

  8. Serum level of vascular endothelial growth factor is influenced by erythropoietin treatment in peritoneal dialysis patients. (Grupo de Estudios Peritoneales de Madrid).

    Science.gov (United States)

    del Peso, G; Selgas, R; Bajo, M A; Fernández de Castro, M; Aguilera, A; Cirugeda, A; Jiménez, C

    2000-01-01

    Some patients on long-term peritoneal dialysis (PD) develop a hyperpermeability state, owing to peritoneal neoangiogenesis. Vascular endothelial growth factor (VEGF), a potent mitogen for endothelial cells, has been implicated in most diseases characterized by microvascular neoformation. Erythropoietin (EPO) is able to induce endothelial proliferation in vitro. Our aim was to elucidate whether VEGF serum levels are influenced by EPO treatment, and whether VEGF serum level maintains a relationship with peritoneal transport data. We analyzed serum levels of VEGF in 35 PD patients (18 males, 17 females). Mean age was 58 years, with a mean time on PD of 98 +/- 75 months. Of the 35 patients, 19 were on automated peritoneal dialysis, and 16 were on continuous ambulatory peritoneal dialysis. Seven patients had diabetes. Peritoneal transport parameters were: urea mass transfer coefficient (MTC), 19.5 +/- 6.6 mL/min; creatinine MTC, 9.9 +/- 4.7 mL/min; net ultrafiltration, 491 +/- 166 mL per 4-hour dwell. Twenty seven patients were under therapy with recombinant human erythropoietin (rHuEPO). Mean serum VEGF levels were 347 +/- 203 pg/mL (range 66-857 pg/mL), with most patients in the normal range (60-700 pg/mL). VEGF levels did not correlate with age, sex, primary renal disease, diabetes, type of PD, time on PD, peritonitis, and cumulative glucose load. We found no correlation with urea MTC, creatinine MTC, ultrafiltration rate, or protein effluent levels. However, a significant negative correlation with residual renal function was seen (r = -0.39, p < 0.05). Patients treated with rHuEPO showed significantly higher serum levels of VEGF than non treated patients (375 +/- 220 pg/mL vs 251 +/- 75 pg/mL, p < 0.05), although they had similar residual renal function. We conclude that increased serum VEGF levels are associated with EPO treatment. Consequently, VEGF might have a role in the EPO effects found in PD patients. Whether both agents are related to peritoneal

  9. Machine Protection

    CERN Document Server

    Schmidt, R

    2014-01-01

    The protection of accelerator equipment is as old as accelerator technology and was for many years related to high-power equipment. Examples are the protection of powering equipment from overheating (magnets, power converters, high-current cables), of superconducting magnets from damage after a quench and of klystrons. The protection of equipment from beam accidents is more recent. It is related to the increasing beam power of high-power proton accelerators such as ISIS, SNS, ESS and the PSI cyclotron, to the emission of synchrotron light by electron–positron accelerators and FELs, and to the increase of energy stored in the beam (in particular for hadron colliders such as LHC). Designing a machine protection system requires an excellent understanding of accelerator physics and operation to anticipate possible failures that could lead to damage. Machine protection includes beam and equipment monitoring, a system to safely stop beam operation (e.g. dumping the beam or stopping the beam at low energy) and an ...

  10. Machine Protection

    International Nuclear Information System (INIS)

    Zerlauth, Markus; Schmidt, Rüdiger; Wenninger, Jörg

    2012-01-01

    The present architecture of the machine protection system is being recalled and the performance of the associated systems during the 2011 run will be briefly summarized. An analysis of the causes of beam dumps as well as an assessment of the dependability of the machine protection systems (MPS) itself is being presented. Emphasis will be given to events that risked exposing parts of the machine to damage. Further improvements and mitigations of potential holes in the protection systems will be evaluated along with their impact on the 2012 run. The role of rMPP during the various operational phases (commissioning, intensity ramp up, MDs...) will be discussed along with a proposal for the intensity ramp up for the start of beam operation in 2012

  11. Machine Protection

    CERN Document Server

    Zerlauth, Markus; Wenninger, Jörg

    2012-01-01

    The present architecture of the machine protection system is being recalled and the performance of the associated systems during the 2011 run will be briefly summarized. An analysis of the causes of beam dumps as well as an assessment of the dependability of the machine protection systems (MPS) itself is being presented. Emphasis will be given to events that risked exposing parts of the machine to damage. Further improvements and mitigations of potential holes in the protection systems will be evaluated along with their impact on the 2012 run. The role of rMPP during the various operational phases (commissioning, intensity ramp up, MDs...) will be discussed along with a proposal for the intensity ramp up for the start of beam operation in 2012.

  12. Machine Protection

    Energy Technology Data Exchange (ETDEWEB)

    Zerlauth, Markus; Schmidt, Rüdiger; Wenninger, Jörg [European Organization for Nuclear Research, Geneva (Switzerland)

    2012-07-01

    The present architecture of the machine protection system is being recalled and the performance of the associated systems during the 2011 run will be briefly summarized. An analysis of the causes of beam dumps as well as an assessment of the dependability of the machine protection systems (MPS) itself is being presented. Emphasis will be given to events that risked exposing parts of the machine to damage. Further improvements and mitigations of potential holes in the protection systems will be evaluated along with their impact on the 2012 run. The role of rMPP during the various operational phases (commissioning, intensity ramp up, MDs...) will be discussed along with a proposal for the intensity ramp up for the start of beam operation in 2012.

  13. Physical protection

    International Nuclear Information System (INIS)

    Myre, W.C.; DeMontmollin, J.M.

    1989-01-01

    Serious concern about physical protection of nuclear facilities began around 1972. R and D was initiated at Sandia National Laboratories which had developed techniques to protect weapons for many years. Special vehicles, convoy procedures, and a communications system previously developed for weapons shipments were improved and extended for shipments of other sensitive materials. Barriers, perimeter alarms, portal and internal control systems were developed, tested, and published in handbooks and presented at symposia. Training programs were initiated for U.S. and foreign personnel. Containment and surveillance techniques were developed for the IAEA. Presently emphasis is on computer security, active barriers, and techniques to prevent theft or sabotage by ''insiders''

  14. Shift working in the Chilean Andes (> 3,600 m) and its influence on erythropoietin and the low-pressure system.

    Science.gov (United States)

    Gunga, H C; Röcker, L; Behn, C; Hildebrandt, W; Koralewski, E; Rich, I; Schobersberger, W; Kirsch, K

    1996-08-01

    It was hypothesized that, in shift workers with a history of intermittent hypoxic stress (working 10 days at > 3,600 m, then resting for 4 days at sea level) for > 5 yr, the initial erythropoietin (EPO) response and the changes in central venous pressure (CVP) are different from those in Caucasian lowlanders. We studied the kitchen personnel (n = 11) of a mine (3,600 m) and a group of Caucasian lowlanders (n = 5). Blood samples were taken, and CVP was determined several times before, during, and after a typical shift. At baseline data collection (BDC) before transition, the shift workers had EPO concentrations of 5.2 +/- 2.4 mU/ml, which increased at altitude (P < 0.01) and returned to BDC values on the recovery (day 16). The Caucasians showed the same time course. Serum transferrin receptor concentrations did not change in either group. CVP values were generally higher in the shift workers than in the Caucasians. In conclusion, the hypothesis that the initial EPO response to a hypoxic stimulus is altered in these shift workers has to be refuted. Higher hemoglobin concentrations and/or CVP values in shift workers might be responsible for the rather low EPO concentrations in shift workers at BDC.

  15. Superimposition of carbon dioxide on acute isobaric hypoxia: plasma erythropoietin, acid-base status, and P/sub 50/ in the unanesthetized rabbit

    Energy Technology Data Exchange (ETDEWEB)

    Wolf-Priessnitz, J.

    1978-06-01

    Major factors affecting changes of the arterial Hb--O/sub 2/ affinity (P/sub 50/) were examined in relation to the initiation of erythropoietin (ESF) production in unanesthetized New Zealand white male rabbits. They were exposed to an isobaric hypoxic environment (8.8 percent O/sub 2/) with and without CO/sub 2/ (5.6 percent or 10 percent). During 5 hrs exposure, samples of arterial blood were collected for measurements of plasma ESF titers; whole-blood pH, P/sub CO2/, S/sub O2/, lactate, pyruvate, and P/sub 50/; and intraerythrocytic 2,3-DPG, ATP and ADP. Exposure to 8.8 percent oxygen alone stimulated ESF production and caused a leftward shift in the in vivo P/sub 50/; the addition of CO/sub 2/ significantly inhibited ESF production and blocked the shift in P/sub 50//sub (i.v.)/. The data suggest that increased oxygenation of the whole-body tissues occurs with exposure to 8.8 percent O/sub 2/ + CO/sub 2/ as reflected by lower whole-blood excess lactate accumulation. In keeping with the prevailing theory, the suppression of ESF production is probably a result of this increased oxygenation.

  16. The use of laser-induced fluorescence or ultraviolet detectors for sensitive and selective analysis of tobramycin or erythropoietin in complex samples

    Science.gov (United States)

    Ahmed, Hytham M.; Ebeid, Wael B.

    2015-05-01

    Complex samples analysis is a challenge in pharmaceutical and biopharmaceutical analysis. In this work, tobramycin (TOB) analysis in human urine samples and recombinant human erythropoietin (rhEPO) analysis in the presence of similar protein were selected as representative examples of such samples analysis. Assays of TOB in urine samples are difficult because of poor detectability. Therefore laser induced fluorescence detector (LIF) was combined with a separation technique, micellar electrokinetic chromatography (MEKC), to determine TOB through derivatization with fluorescein isothiocyanate (FITC). Borate was used as background electrolyte (BGE) with negative-charged mixed micelles as additive. The method was successively applied to urine samples. The LOD and LOQ for Tobramycin in urine were 90 and 200 ng/ml respectively and recovery was >98% (n = 5). All urine samples were analyzed by direct injection without sample pre-treatment. Another use of hyphenated analytical technique, capillary zone electrophoresis (CZE) connected to ultraviolet (UV) detector was also used for sensitive analysis of rhEPO at low levels (2000 IU) in the presence of large amount of human serum albumin (HSA). Analysis of rhEPO was achieved by the use of the electrokinetic injection (EI) with discontinuous buffers. Phosphate buffer was used as BGE with metal ions as additive. The proposed method can be used for the estimation of large number of quality control rhEPO samples in a short period.

  17. Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification of a subgroup of responders. The Spanish Erythropathology Group.

    Science.gov (United States)

    Remacha, A F; Arrizabalaga, B; Villegas, A; Manteiga, R; Calvo, T; Julià, A; Fernández Fuertes, I; González, F A; Font, L; Juncà, J; del Arco, A; Malcorra, J J; Equiza, E P; de Mendiguren, B P; Romero, M

    1999-12-01

    Anemia leading to transfusion is probably the most important problem in patients with myelodysplastic syndromes (MDS). Human recombinant erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G-CSF) have been used to treat patients with anemia of MDS, but fewer than 50% respond. The aim of this work was to evaluate the benefit of rHuEpo +/- G-CSF treatment and to isolate the response predictive variables in a group of selected patients with MDS. A non-randomized multicenter trial was carried out in 32 patients with MDS. The inclusion criteria were age >= 18 years, refractory anemia (RA) or refractory anemia with ringed sideroblasts, Hb +1 (77% of cases responded). In contrast, when this score was <= 1 only 15 % of the cases responded. Use of the Scandinavian-American response score is to be recommended in a patient-oriented approach to treating MDS cases with the Epo and G-CSF. Treatment with rHuEpo and G-CSF is safe, its main drawback being its cost. However, a long-term study evaluating the regimen's cost-benefit ratio is warranted.

  18. Single nucleotide polymorphisms at erythropoietin, superoxide dismutase 1, splicing factor, arginine/serin-rich 15 and plasmacytoma variant translocation genes association with diabetic nephropathy

    Directory of Open Access Journals (Sweden)

    Maisaa Alwohhaib

    2014-01-01

    Full Text Available A number of genes have been identified in diabetic nephropathy. Association between diabetes-associated nephropathy and polymorphisms in the erythropoietin (EPO gene, variants in the superoxide dismutase 1 (SOD1 gene and plasmacytoma variant translocation 1 (PVT1 gene have been identified. The EPO, SOD1:SFRS15 and PVT1 genes were genotyped using the single nucleotide polymorphism (SNP technique in 38 diabetic nephropathy patients (Group 1 compared with 64 diabetic type 2 subjects without nephropathy (Group 2 at the Mubarak Alkabeer Hospital, Kuwait. The frequency of the risk allele T of the EPO (rs1617640 gene was high in both groups (0.96 in Group 1 and 0.92 in Group 2. Similarly, SNPs of the PVT1 (rs2720709 gene showed a higher frequency of the risk allele G in both groups (0.70 in the Group 1 and 0.68 in Group 2. Although the frequency of the risk allele A was higher than the frequency of the non-risk allele C of the SOD1:SFRS15 gene in both groups, the lowest probability value was observed in those gene SNPs (P = 0.05. We observed that the A allele of the SOD1:SFRS15 gene (rs17880135 was more frequently present in Group 1 (0.75 compared with Group 2 (0.62. Susceptibility to diabetes-associated nephropathy is partially mediated by genetic predisposition, and screening tests may open the gate for new therapeutic approaches.

  19. Influence of erythropoietin on cognitive performance during experimental hypoglycemia in patients with type 1 diabetes mellitus: a randomized cross-over trial.

    Directory of Open Access Journals (Sweden)

    Peter Lommer Kristensen

    Full Text Available The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone erythropoietin (EPO enhances cognitive function during hypoglycemia.Eleven patients with type 1 diabetes, hypoglycemia unawareness and recurrent severe hypoglycemia completed the study. In a double-blind, randomized, balanced, cross-over study using clamped hypoglycemia they were treated with 40,000 IU of EPO or placebo administered intravenously six days before the two experiments. Cognitive function (primary endpoint, hypoglycemic symptoms, and counter-regulatory hormonal response were recorded.Compared with placebo, EPO treatment was associated with a significant reduction in errors in the most complex reaction time task (-4.7 (-8.1 to -1.3, p = 0.01 and a less reaction time prolongation (-66 (-117 to -16 msec, p = 0.02. EPO treatment did not change performance in other measures of cognition. Hypoglycemic symptoms, EEG-changes, and counter-regulatory hormone concentrations did not differ between EPO and placebo treatment.In patients with type 1 diabetes and hypoglycemia unawareness, treatment with EPO is associated with a beneficial effect on cognitive function in a complex reaction time task assessing sustained attention/working memory. Hypoglycemic symptoms and hormonal responses were not changed by EPO treatment.ClinicalTrials.gov NCT00615368.

  20. Bioenergetics of the calf muscle in Friedreich ataxia patients measured by 31P-MRS before and after treatment with recombinant human erythropoietin.

    Directory of Open Access Journals (Sweden)

    Wolfgang Nachbauer

    Full Text Available Friedreich ataxia (FRDA is caused by a GAA repeat expansion in the FXN gene leading to reduced expression of the mitochondrial protein frataxin. Recombinant human erythropoietin (rhuEPO is suggested to increase frataxin levels, alter mitochondrial function and improve clinical scores in FRDA patients. Aim of the present pilot study was to investigate mitochondrial metabolism of skeletal muscle tissue in FRDA patients and examine effects of rhuEPO administration by phosphorus 31 magnetic resonance spectroscopy (31P MRS. Seven genetically confirmed FRDA patients underwent 31P MRS of the calf muscles using a rest-exercise-recovery protocol before and after receiving 3000 IU of rhuEPO for eight weeks. FRDA patients showed more rapid phosphocreatine (PCr depletion and increased accumulation of inorganic phosphate (Pi during incremental exercise as compared to controls. After maximal exhaustive exercise prolonged regeneration of PCR and slowed decline in Pi can be seen in FRDA. PCr regeneration as hallmark of mitochondrial ATP production revealed correlation to activity of complex II/III of the respiratory chain and to demographic values. PCr and Pi kinetics were not influenced by rhuEPO administration. Our results confirm mitochondrial dysfunction and exercise intolerance due to impaired oxidative phosphorylation in skeletal muscle tissue of FRDA patients. MRS did not show improved mitochondrial bioenergetics after eight weeks of rhuEPO exposition in skeletal muscle tissue of FRDA patients.EU Clinical Trials Register2008-000040-13.

  1. Further evidence of the in vivo role of erythropoietin or companion molecules induced by hypoxia on proliferation and continuing differentiation of BFU-e in PCDC

    International Nuclear Information System (INIS)

    Harigaya, K.; Cronkite, E.P.; Miller, M.E.; Moccia, G.

    1981-01-01

    Normal and plethoric bone marrow cells were grown in plasma clot diffusion chambers (PCDC) implanted into the peritoneum of normal mice or mice submitted to 7 h of hypoxia (23,000 ft) daily, on a single day or on 2 consecutive days at different times after implantation of the PCDC's. Daily discontinuous hypoxia (DDH) produced more 6-day bursts than other treatments. Hypoxia on days 1 and 2 after implantation was nearly as effective as DDH on day-6 bursts. Erythropoietin (Ep) levels were measured by bioassay on both diffusion chamber (DC) contents and serum. Serum Ep levels peaked after a 7-hr hypoxic exposure while the DC content Ep levels were in the nondetectable range. The data implies that either higher than normal Ep levels or a companion molecule(s) produced by hypoxia are required for 1 to 2 days early in the culture period to force an increasing number of BFU-d-e down the erythrocytic pathway and thus increase red cell production at times of need in vivo

  2. Once-Monthly Continuous Erythropoietin Receptor Activator (C.E.R.A.) in Patients with Hemodialysis-Dependent Chronic Kidney Disease: Pooled Data from Phase III Trials.

    Science.gov (United States)

    Locatelli, Francesco; Choukroun, Gabriel; Truman, Matt; Wiggenhauser, Alfons; Fliser, Danilo

    2016-04-01

    Erythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups. Data from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0-12.0 g/dL)/upper (10.5-13.0 g/dL)], gender (female/male), age (Basel, Switzerland.

  3. Use of Erythropoietin-Stimulating Agents (ESA) in Patients With End-Stage Renal Failure Decided to Forego Dialysis: Palliative Perspective.

    Science.gov (United States)

    Cheng, Hon Wai Benjamin; Chan, Kwok Ying; Lau, Hoi To; Man, Ching Wah; Cheng, Suk Ching; Lam, Carman

    2017-05-01

    Normochromic normocytic anemia is a common complication in chronic kidney disease (CKD) and is associated with many adverse clinical consequences. Erythropoiesis-stimulating agents (ESAs) act to replace endogenous erythropoietin for patients with end-stage renal disease having anemia. Today, ESAs remain the main tool for treating anemia associated with CKD. In current practice, the use of ESA is not limited to the patients on renal replacement therapy but has extended to nondialysis patients under palliative care (PC). Current evidence on ESA usage in patients with CKD decided to forego dialysis often have to take reference from studies conducted in other groups of patients with CKD, including pre-dialysis patients and those on renal replacement therapy. There is paucity of studies targeting use of ESAs in renal PC patients. Small-scale retrospective study in renal PC patients had suggested clinical advantage of ESAs in terms of hemoglobin improvement, reduction in fatigue, and hospitalization rate. With the expected growth in elderly patients with CKD decided to forego dialysis and manage conservatively, there remains an urgent need to call for large-scale prospective trial in exploring efficacy of ESAs in this population, targeting on quality of life and symptoms improvement outcome. This article also reviews the mechanism of action, pharmacology, adverse effects, and clinical trial evidence for ESA in patients with CKD under renal PC.

  4. Negotiating Protection

    DEFF Research Database (Denmark)

    Bille, Mikkel

    efficacy. Some informants, for example, adopt an orthodox scriptural Islamic approach to protection and denounce certain material registers as un-Islamic and materialistic leftovers from an ignorant past, and rather prescribe Qur'anic remembrance. For other informants the very physicality of such contested...

  5. Protection Myopia

    DEFF Research Database (Denmark)

    Laursen, Keld; Salter, Ammon; Li, Cher

    from having an orientation towards legal appropriability, we conjecture that protection myopia may lead some firms to allocate too much attention to legal appropriability, in particular when the behavioral and structural contingencies are unfavorable. Examining a panel of three successive waves...

  6. Protective articles

    International Nuclear Information System (INIS)

    Wardley, R.B.

    1983-01-01

    This patent specification describes an article affording protection against radiation, and especially against X-rays comprising at least one flexible layer of lead filled material in an envelope of, or sandwiched between two layers of a knitted, woven or non-woven fabric preferably of synthetic fibrous material, carrying on its outer surface a coating of flexible polyurethane. The outer fabric provides a resilient, extremely tough and cut resistant covering for the relatively soft lead filled material. (author)

  7. Eye Protection

    OpenAIRE

    Pashby, Tom

    1986-01-01

    Eye injuries frequently occur in the home, at work and at play. Many result in legally blind eyes, and most are preventable. Awareness of potential hazards is essential to preventing eye injuries, particularly in children. In addition, protective devices must be used appropriately. We have developed eye protectors that have proved effective in reducing both the overall incidence and the severity of sports eye injuries.

  8. [Cerebral protection].

    Science.gov (United States)

    Cattaneo, A D

    1993-09-01

    Cerebral protection means prevention of cerebral neuronal damage. Severe brain damage extinguishes the very "human" functions such as speech, consciousness, intellectual capacity, and emotional integrity. Many pathologic conditions may inflict injuries to the brain, therefore the protection and salvage of cerebral neuronal function must be the top priorities in the care of critically ill patients. Brain tissue has unusually high energy requirements, its stores of energy metabolites are small and, as a result, the brain is totally dependent on a continuous supply of substrates and oxygen, via the circulation. In complete global ischemia (cardiac arrest) reperfusion is characterized by an immediate reactive hyperemia followed within 20-30 min by a delayed hypoperfusion state. It has been postulated that the latter contributes to the ultimate neurologic outcome. In focal ischemia (stroke) the primary focus of necrosis is encircled by an area (ischemic penumbra) that is underperfused and contains neurotoxic substances such as free radicals, prostaglandins, calcium, and excitatory neurotransmitters. The variety of therapeutic effort that have addressed the question of protecting the brain reflects their limited success. 1) Barbiturates. After an initial enthusiastic endorsement by many clinicians and years of vigorous controversy, it can now be unequivocally stated that there is no place for barbiturate therapy following resuscitation from cardiac arrest. One presumed explanation for this negative statement is that cerebral metabolic suppression by barbiturates (and other anesthetics) is impossible in the absence of an active EEG. Conversely, in the event of incomplete ischemia EEG activity in usually present (albeit altered) and metabolic suppression and hence possibly protection can be induced with barbiturates. Indeed, most of the animal studies led to a number of recommendations for barbiturate therapy in man for incomplete ischemia. 2) Isoflurane. From a cerebral

  9. Pretransplant HbA1c Is a Useful Predictor for the Development of New-Onset Diabetes in Renal Transplant Recipients Receiving No or Low-Dose Erythropoietin

    Directory of Open Access Journals (Sweden)

    Kazuaki Tokodai

    2014-01-01

    Full Text Available Aims. To evaluate the predictive power of pretransplant HbA1c for new-onset diabetes after transplantation (NODAT in kidney transplant candidates, who had several predispositions for fluctuated HbA1c levels. Methods. We performed a retrospective study of 119 patients without diabetes who received kidney transplantation between March 2000 and January 2012. Univariate and multivariate logistic regression analyses were used to investigate the association of several parameters with NODAT. Predictive discrimination of HbA1c was assessed using a receiver-operating characteristic curve. Results. Seventeen patients (14.3% developed NODAT within 1 year of transplantation. Univariate logistic regression analysis revealed that recipient age, gender, and HbA1c were predictors of NODAT. In the multivariate analysis, the association between pretransplant HbA1c and NODAT development did not reach statistical significance (P=0.07. To avoid the strong influence of high-dose erythropoietin on HbA1c levels, we performed subgroup analyses on 85 patients receiving no or low-dose (≤6000 IU/week erythropoietin. HbA1c was again an independent predictor for NODAT. Receiver-operating characteristic analysis revealed a cut-off value of 5.2% with an optimal sensitivity of 64% and specificity of 78% for predicting NODAT. Conclusions. Our results reveal that the pretransplant HbA1c level is a useful predictor for NODAT in patients receiving no or low-dose erythropoietin.

  10. Concepts of radiation protection

    International Nuclear Information System (INIS)

    2013-01-01

    This seventh chapter presents the concepts and principles of safety and radiation protection, emergency situations; NORM and TENORM; radiation protection care; radiation protection plan; activities of the radiation protection service; practical rules of radiation protection and the radiation symbol

  11. Environmental protection

    International Nuclear Information System (INIS)

    Hull, A.P.

    1979-01-01

    Environmental Studies and Internal Dosimetry projects include: Environmental Protection; 1977 Environmental Monitoring Report; Sewage Sludge Disposal on the Sanitary Landfill; Radiological Analyses of Marshall Islands Environmental Samples, 1974 to 1976; External Radiation Survey and Dose Predictions for Rongelap, Utirik, Rongerik, Ailuk, and Wotje Atolls; Marshall Islands - Diet and Life Style Study; Dose Reassessment for Populations on Rongelap and Utirik Following Exposure to Fallout from BRAVO Incident (March 1, 1954); Whole Body Counting Results from 1974 to 1979 for Bikini Island Residents; Dietary Radioactivity Intake from Bioassay Data, a Model Applied to 137 Cs Intake by Bikini Island Residents; and External Exposure Measurements at Bikini Atoll

  12. Radiation protection

    International Nuclear Information System (INIS)

    Kamalaksh Shenoy, K.

    2013-01-01

    Three main pillars underpin the IAEA's mission: Safety and Security - The IAEA helps countries to upgrade their infrastructure for nuclear and radiation safety and security, and to prepare for and respond to emergencies. Work is keyed to international conventions, the development of international standards and the application of these standards. The aim is to protect people and the environment from the harmful effects of exposure to ionizing radiation. Science and Technology - The IAEA is the world's focal point for mobilizing peaceful applications of nuclear science and technology for critical needs in developing countries. The work contributes to alleviating poverty, combating disease and pollution of the environment and to other goals of sustainable development. Safeguards and Verification - The IAEA is the nuclear inspectorate, with more than four decades of verification experience. Inspectors work to verify that nuclear material and activities are not diverted towards military purposes. Quantities and Units: Dose equivalent is the product of absorbed dose of radiation and quality factor (Q). For absorbed dose in rads, dose equivalent is in rems. If absorbed dose is in gray, the dose equivalent is in sievert. Quality factor is defined without reference to any particular biological end point. Quality factors are recommended by committees such as the International Commission on Radiological Protection (ICRP) or the National Council on Radiation Protection and Measurements (NCRP), based on experimental RBE values but with some judgment exercised. Effective Dose Equivalent: It is the sum of the weighted dose equivalents for all irradiated tissues, in which the weighting factors represent the different risks of each tissue to mortality from cancer and hereditary effects. Committed dose equivalent: It is the integral over 50 years of dose equivalent following the intake of a radionuclide. Collective effective dose equivalent: It is a quantity for a population and is

  13. Protecting Antarctica

    Science.gov (United States)

    Carlowicz, Michael

    House Science Committee Chairman Robert Walker (R-Pa.) has introduced a bill into Congress to give the United States the legislative authority to implement the 1991 Environmental Protocol to the Antarctic Treaty. That protocol established rules and principles to shield the Antarctic environment from human spoilage—placing limits on the discharge of pollutants, protecting plant and animal life, and requiring environmental impact assessments before new activities and programs are launched. The protocol also forbids prospecting or developing of mineral resources except for scientific research.

  14. Food protection

    International Nuclear Information System (INIS)

    Gummer, Selwyn; Campbell-Savours, D.N.; Maxwell-Hyslop, R.

    1987-01-01

    The motion is to consolidate the Food Protection (Emergency Prohibitions) (England) (No 2) Order 1987 and seven subsequent amendment orders, into one order. The orders are those under which restrictions on the movement of sheep as a result of the Chernobyl accident are carried out. A debate lasting more than two hours followed and this is reported verbatim. Much of the early part of the debate concerns a telex message allegedly from the chief scientist of the radiochemical institute saying that meat contaminated by radiation after Chernobyl was sold in Britain. Both the source and the content of the telex were found not to be as alleged. In particular, the allegation that 10kg lambs had gone to market. The minister pointed out that these lambs were not big enough to be sold. The debate broadened into a more general discussion as to levels of contamination in sheep and the government diligence or otherwise in protecting the public. The motion was agreed to. (U.K.)

  15. Expression patterns of the hypoxia-related genes osteopontin, CA9, erythropoietin, VEGF and HIF-1α in human glioma in vitro and in vivo

    International Nuclear Information System (INIS)

    Said, Harun M.; Hagemann, Carsten; Staab, Adrian; Stojic, Jelena; Kuehnel, Siglinde; Vince, Giles H.; Flentje, Michael; Roosen, Klaus; Vordermark, Dirk

    2007-01-01

    Background and purpose: To identify molecular markers of tumor hypoxia and potential therapeutic targets in glioblastoma (GBM), we investigated the hypoxia-related expression of osteopontin (OPN), carbonic anhydrase 9 (CA9), erythropoietin (EPO), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) in vitro in human GBM cell lines and in vivo in human tumor samples of GBM, compared to low-grade astrocytoma (LGA). Materials and methods: Expression of the hypoxia-induced genes OPN, CA9, EPO, VEGF and HIF-1α was analyzed in three GBM cell lines, GaMG, U373 and U251, under in vitro hypoxia (1, 6 or 24 h at 5%, 1% or 0.1% O 2 ) and in tumor samples from two patient groups with LGA and GBM (n = 15 each), at the mRNA level (semiquantitative RT-PCR). Selected conditions and representative tumor samples were also evaluated at the protein level by Western blot. Results: OPN and CA9 mRNA was most consistently upregulated in relation to severity and duration of in vitro hypoxia. In tumor samples, mean expression levels (LGA vs. GBM, normalized to mean expression in normal brain) were 1.71 vs. 4.57 (p < 0.001) for OPN, 1.11 vs. 3.35 (p < 0.001) for CA9, 2.79 vs. 5.28 (not significant, n.s.) for Epo, 1.13 vs. 2.0 (p = 0.007) for VEGF and 0.97 vs. 0.97 (n.s.) for HIF-1α. In tumor samples, GBM showed a particularly strong protein expression of OPN. Conclusions: Among a panel of known hypoxia-inducible genes, OPN and CA9 emerge as most consistently induced by in vitro hypoxia in human GBM cell lines and most specifically expressed in patient GBM tumor tissue, rendering these two genes attractive targets for hypoxia-directed treatment approaches

  16. Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines

    International Nuclear Information System (INIS)

    Chen, Chien-Liang; Chou, Kang-Ju; Lee, Po-Tsang; Chen, Ying-Shou; Chang, Tsu-Yuan; Hsu, Chih-Yang; Huang, Wei-Chieh; Chung, Hsiao-Min; Fang, Hua-Chang

    2010-01-01

    Purpose: Tumor growth factor-β1 (TGF-β1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-β1-mediated EMT and fibrosis in kidney injury. Methods: We examined apoptosis and EMT in TGF-β1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-β1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-β1 signal pathway proteins and EMT markers. Results: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-β1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-β1-mediated apoptosis and also partially inhibited TGF-β1-mediated EMT. We showed that EPO treatment suppressed TGF-β1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-β1-treated cells. Conclusions: EPO inhibited apoptosis and EMT in TGF-β1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.

  17. A multi-center study on the regenerative effects of erythropoietin in burn and scalding injuries: study protocol for a randomized controlled trial.

    Science.gov (United States)

    Günter, Christina Irene; Bader, Augustinus; Dornseifer, Ulf; Egert, Silvia; Dunda, Sebastian; Grieb, Gerrit; Wolter, Thomas; Pallua, Norbert; von Wild, Tobias; Siemers, Frank; Mailänder, Peter; Thamm, Oliver; Ernert, Carsten; Steen, Michael; Sievers, Reiner; Reichert, Bert; Rahmanian-Schwarz, Afshin; Schaller, Hans; Hartmann, Bernd; Otte, Max; Kehl, Victoria; Ohmann, Christian; Jelkmann, Wolfgang; Machens, Hans-Günther

    2013-05-03

    Although it was initially assumed that erythropoietin (EPO) was a hormone that only affected erythropoiesis, it has now been proposed that EPO plays an additional key role in the regulation of acute and chronic tissue damage. This is a large, prospective, randomized, double-blind, multi-center study, funded by the German Federal Ministry of Education and Research, and fully approved by the designated ethics committee. The trial, which is to investigate the effects of EPO in severely burned patients, is in its recruitment phase and is being carried out in 13 German burn care centers. A total of 150 patients are to be enrolled to receive study medication every other day for 21 days (EPO 150 IU/kg body weight or placebo). A follow-up of one year is planned. The primary endpoint of this study is the time until complete re-epithelialization of a defined skin graft donor site is reached. Furthermore, clinical parameters such as wound healing, scar formation (using the Vancouver scar scale), laboratory values, quality of life (SF-36), angiogenic effects, and gene- and protein-expression patterns are to be determined. The results will be carefully evaluated for gender differences. We are seeking new insights into the mechanisms of wound healing in thermally injured patients and more detailed information about the role EPO plays, specifically in these complex interactions. We additionally expect that the biomimetic effects of EPO will be useful in the treatment of acute thermal dermal injuries. EudraCT Number: 2006-002886-38, Protocol Number: 0506, ISRCT Number: http://controlled-trials.com/ISRCTN95777824/ISRCTN95777824.

  18. Use of UV-vis-NIR spectroscopy to monitor label-free interaction between molecular recognition elements and erythropoietin on a gold-coated polycarbonate platform.

    Science.gov (United States)

    Citartan, Marimuthu; Gopinath, Subash C B; Tominaga, Junji; Chen, Yeng; Tang, Thean-Hock

    2014-08-01

    Label-free-based detection is pivotal for real-time monitoring of biomolecular interactions and to eliminate the need for labeling with tags that can occupy important binding sites of biomolecules. One simplest form of label-free-based detection is ultraviolet-visible-near-infrared (UV-vis-NIR) spectroscopy, which measure changes in reflectivity as a means to monitor immobilization and interaction of biomolecules with their corresponding partners. In biosensor development, the platform used for the biomolecular interaction should be suitable for different molecular recognition elements. In this study, gold (Au)-coated polycarbonate was used as a platform and as a proof-of-concept, erythropoietin (EPO), a doping substance widely abused by the athletes was used as the target. The interaction of EPO with its corresponding molecular recognition elements (anti-EPO monoclonal antibody and anti-EPO DNA aptamer) is monitored by UV-vis-NIR spectroscopy. Prior to this, to show that UV-vis-NIR spectroscopy is a suitable method for measuring biomolecular interaction, the interaction between biotin and streptavidin was demonstrated via this strategy and reflectivity of this interaction decreased by 25%. Subsequent to this, interaction of the EPO with anti-EPO monoclonal antibody and anti-EPO DNA aptamer resulted in the decrease of reflectivity by 5% and 10%, respectively. The results indicated that Au-coated polycarbonate could be an ideal biosensor platform for monitoring biomolecular interactions using UV-vis-NIR spectroscopy. A smaller version of the Au-coated polycarbonate substrates can be derived from the recent set-up, to be applied towards detecting EPO abuse among atheletes. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Serial blood donations for intrauterine transfusions of severe hemolytic disease of the newborn with the use of recombinant erythropoietin in a pregnant woman alloimmunized with anti-Ku.

    Science.gov (United States)

    Lydaki, Evaggelia; Nikoloudi, Irene; Kaminopetros, Petros; Bolonaki, Irene; Sifakis, Stavros; Kikidi, Katerina; Koumantakis, Evgenios; Foundouli, Kaliopi

    2005-11-01

    The management of a pregnant woman with the rare Ko phenotype and anti-Ku is a special challenge, because matched blood is extremely rare and the possibility of severe hemolytic disease of the newborn is high. A 30-year-old woman with rare Ko (Knull) phenotype presented at 18 weeks of gestation with positive indirect agglutination test results. She had anti-Ku due to previous blood transfusion, one pregnancy, and two abortions. During this pregnancy, anti-Ku titers ranged from 1024 to 4096. At the 26th week of gestation ultrasound showed a hydropic fetus and urgent intrauterine exchange transfusion was performed with the maternal red blood cells (RBCs). Recombinant human erythropoietin (rHu-EPO) and intravenous (IV) iron were administered to the mother to ensure an adequate supply of matched RBCs for intrauterine transfusions and possible perinatal hemorrhage. Intrauterine transfusions were repeated every 1 to 3 weeks. By 35 weeks 2 days of gestation, the mother had donated 4 units of blood, and four intrauterine transfusions had been performed. Cesarean section was then decided and a healthy male newborn was born. He was treated with phototherapy but without exchange transfusions. By the 15th day of life rHu-EPO was administrated to the newborn because of anemia. The maternal RBCs completely disappeared from the child's blood by Day 100. As shown in this case, treatment with rHu-EPO and IV Fe has effectively increased the mother's capacity to donate RBCs for autologous use and intrauterine transfusions, with no adverse effects to the mother or the child.

  20. Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in-vitro model of hypoxia ischemia

    Science.gov (United States)

    Souvenir, Rhonda; Flores, Jerry J.; Ostrowski, Robert P.; Manaenko, Anatol; Duris, Kamil; Tang, Jiping

    2014-01-01

    Hypoxia inducible factor (HIF)-1α is the central transcriptional factor for the regulation of oxygen-associated genes in response to hypoxia. Erythropoietin (EPO), a hematopoietic growth factor, increases oxygen availability during hypoxia/ischemia and is associated with neuroprotection following hypoxia ischemia in laboratory models of stroke. However, EPO has failed to translate in a clinical setting. Thus it is critical to elucidate the key players in EPO-induced neuroprotection. Our preliminary studies have shown that EPO, as a downstream gene of hypoxia inducible factor (HIF), inhibits HIF-1α in a dose-dependent manner in an in-vitro model of hypoxia ischemia. This study is designed to elucidate the primary mediator of EPO-induced HIF-1α inhibition and subsequent cell survival/neuroprotection. Oxygen and glucose deprivation (OGD) of nerve growth factor (NGF) differentiated rat pheochromocytoma (PC-12) cells were used to model hypoxia ischemia in an in vitro environment. The profile of HIF-1α, HIF-2α and PHD-2 expression, HIF-1α and prolyl hydroxylase (PHD-2) mRNA levels, MMP-9 and cell death was evaluated in the presence and absence of either EPO or PHD-2 inhibitor during OGD. Our findings showed that EPO treatment resulted in an increase in PHD-2 transcription and translation, inhibition of HIF-1α expression, reactive oxygen species (ROS) formation and matrix metalloproteinase (MMP)-9 activity, resulting in increased cell survival after OGD. We also observed that EPO-induced cell survival/neuroprotection was reversed by siRNA silencing of PHD-2. This led to the conclusion that PHD-2 is a key mediator of EPO-induced HIF-1α inhibition and subsequent neuroprotection in an in vitro model of hypoxia ischemia. PMID:24323731

  1. Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in vitro model of hypoxia-ischemia.

    Science.gov (United States)

    Souvenir, Rhonda; Flores, Jerry J; Ostrowski, Robert P; Manaenko, Anatol; Duris, Kamil; Tang, Jiping

    2014-02-01

    Hypoxia inducible factor (HIF)-1α is the central transcriptional factor for the regulation of oxygen-associated genes in response to hypoxia. Erythropoietin (EPO), a hematopoietic growth factor, increases oxygen availability during hypoxia/ischemia and is associated with neuroprotection following hypoxia-ischemia in laboratory models of stroke. However, EPO has failed to translate in a clinical setting. Thus, it is critical to elucidate the key players in EPO-induced neuroprotection. Our preliminary studies have shown that EPO, as a downstream gene of HIF, inhibits HIF-1α in a dose-dependent manner in an in vitro model of hypoxia-ischemia. This study is designed to elucidate the primary mediator of EPO-induced HIF-1α inhibition and subsequent cell survival/neuroprotection. Oxygen and glucose deprivation (OGD) of nerve growth factor-differentiated rat pheochromocytoma (PC-12) cells were used to model hypoxia-ischemia in an in vitro environment. The profile of HIF-1α, HIF-2α and prolyl hydroxylase domain 2 (PHD-2) expression; HIF-1α and prolyl hydroxylase (PHD-2) mRNA levels; matrix metalloproteinase (MMP)-9; and cell death was evaluated in the presence and absence of either EPO or PHD-2 inhibitor during OGD. Our findings showed that EPO treatment resulted in an increase in PHD-2 transcription and translation, inhibition of HIF-1α expression, reactive oxygen species formation, and MMP-9 activity, resulting in increased cell survival after OGD. We also observed that EPO-induced cell survival/neuroprotection was reversed by siRNA silencing of PHD-2. This led to the conclusion that PHD-2 is a key mediator of EPO-induced HIF-1α inhibition and subsequent neuroprotection in an in vitro model of hypoxia-ischemia.

  2. A single dose of erythropoietin reduces perioperative transfusions in cardiac surgery: results of a prospective single-blind randomized controlled trial.

    Science.gov (United States)

    Weltert, Luca; Rondinelli, Beatrice; Bello, Ricardo; Falco, Mauro; Bellisario, Alessandro; Maselli, Daniele; Turani, Franco; De Paulis, Ruggero; Pierelli, Luca

    2015-07-01

    We conducted a prospective single-blind randomized study to assess whether a single 80,000 IU dose of human recombinant erythropoietin (HRE), given just 2 days before cardiac surgery, could be effective in reducing perioperative allogeneic red blood cell transfusion (aRBCt). Six-hundred patients presenting with preoperative hemoglobin (Hb) level of not more than 14.5 g/dL were randomly assigned to either HRE or control. The primary endpoint was the incidence of perioperative aRBCt. The secondary endpoints were mortality and the incidence of adverse events in the first 45 days after surgery, Hb level on Postoperative Day 4, and number of units of RBC transfusions in the first 4 days after surgery. A total of 17% (HRE) versus 39% (control) required transfusion (relative risk, 0.436; pHRE (0%) and control (3.5%) among the patients with baseline Hb of 13.0 g/dL or more, which included the nonanemic fraction of the study population. The mean (range) Hb level on Postoperative Day 4 was 10.2 (9.9-10.6) g/dL (HRE) versus 8.7 (8.5-9.2) g/dL (control; pHRE (pHRE) versus 3.33% (control). The 45-day adverse event rate was 4.33% (HRE) versus 5.67% (control; both p=NS). In anemic patients (HbHRE administered 2 days before cardiac surgery is effective in reducing the incidence of aRBCt without increasing adverse events. © 2015 AABB.

  3. Transfection of primary brain capillary endothelial cells for protein synthesis and secretion of recombinant erythropoietin: a strategy to enable protein delivery to the brain.

    Science.gov (United States)

    Burkhart, Annette; Andresen, Thomas Lars; Aigner, Achim; Thomsen, Louiza Bohn; Moos, Torben

    2017-07-01

    Treatment of chronic disorders affecting the central nervous system (CNS) is complicated by the inability of drugs to cross the blood-brain barrier (BBB). Non-viral gene therapy applied to brain capillary endothelial cells (BCECs) denotes a novel approach to overcome the restraints in this passage, as turning BCECs into recombinant protein factories by transfection could result in protein secretion further into the brain. The present study aims to investigate the possibility of transfecting primary rat brain endothelial cells (RBECs) for recombinant protein synthesis and secretion of the neuroprotective protein erythropoietin (EPO). We previously showed that 4% of RBECs with BBB properties can be transfected without disrupting the BBB integrity in vitro, but it can be questioned whether this is sufficient to enable protein secretion at therapeutic levels. The present study examined various transfection vectors, with regard to increasing the transfection efficiency without disrupting the BBB integrity. Lipofectamine 3000™ was the most potent vector compared to polyethylenimine (PEI) and Turbofect. When co-cultured with astrocytes, the genetically modified RBECs secreted recombinant EPO into the cell culture medium both luminally and abluminally, and despite lower levels of EPO reaching the abluminal chamber, the amount of recombinant EPO was sufficient to evolve a biological effect on astrocytes cultured at the abluminal side in terms of upregulated gene expression of brain-derived neurotropic factor (BDNF). In conclusion, non-viral gene therapy to RBECs leads to protein secretion and signifies a method for therapeutic proteins to target cells inside the CNS otherwise omitted due to the BBB.

  4. Sciatic nerve regeneration by transplantation of Schwann cells via erythropoietin controlled-releasing polylactic acid/multiwalled carbon nanotubes/gelatin nanofibrils neural guidance conduit.

    Science.gov (United States)

    Salehi, Majid; Naseri-Nosar, Mahdi; Ebrahimi-Barough, Somayeh; Nourani, Mohammdreza; Khojasteh, Arash; Hamidieh, Amir-Ali; Amani, Amir; Farzamfar, Saeed; Ai, Jafar

    2018-05-01

    The current study aimed to enhance the efficacy of peripheral nerve regeneration using an electrically conductive biodegradable porous neural guidance conduit for transplantation of allogeneic Schwann cells (SCs). The conduit was produced from polylactic acid (PLA), multiwalled carbon nanotubes (MWCNTs), and gelatin nanofibrils (GNFs) coated with the recombinant human erythropoietin-loaded chitosan nanoparticles (rhEpo-CNPs). The PLA/MWCNTs/GNFs/rhEpo-CNPs conduit had the porosity of 85.78 ± 0.70%, the contact angle of 77.65 ± 1.91° and the ultimate tensile strength and compressive modulus of 5.51 ± 0.13 MPa and 2.66 ± 0.34 MPa, respectively. The conduit showed the electrical conductivity of 0.32 S cm -1 and lost about 11% of its weight after 60 days in normal saline. The produced conduit was able to release the rhEpo for at least 2 weeks and exhibited favorable cytocompatibility towards SCs. For functional analysis, the conduit was seeded with 1.5 × 10 4 SCs and implanted into a 10 mm sciatic nerve defect of Wistar rat. After 14 weeks, the results of sciatic functional index, hot plate latency, compound muscle action potential amplitude, weight-loss percentage of wet gastrocnemius muscle and Histopathological examination using hematoxylin-eosin and Luxol fast blue staining demonstrated that the produced conduit had comparable nerve regeneration to the autograft, as the gold standard to bridge the nerve gaps. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1463-1476, 2018. © 2017 Wiley Periodicals, Inc.

  5. Immuno-magnetic beads-based extraction-capillary zone electrophoresis-deep UV laser-induced fluorescence analysis of erythropoietin.

    Science.gov (United States)

    Wang, Heye; Dou, Peng; Lü, Chenchen; Liu, Zhen

    2012-07-13

    Erythropoietin (EPO) is an important glycoprotein hormone. Recombinant human EPO (rhEPO) is an important therapeutic drug and can be also used as doping reagent in sports. The analysis of EPO glycoforms in pharmaceutical and sports areas greatly challenges analytical scientists from several aspects, among which sensitive detection and effective and facile sample preparation are two essential issues. Herein, we investigated new possibilities for these two aspects. Deep UV laser-induced fluorescence detection (deep UV-LIF) was established to detect the intrinsic fluorescence of EPO while an immuno-magnetic beads-based extraction (IMBE) was developed to specifically extract EPO glycoforms. Combined with capillary zone electrophoresis (CZE), CZE-deep UV-LIF allows high resolution glycoform profiling with improved sensitivity. The detection sensitivity was improved by one order of magnitude as compared with UV absorbance detection. An additional advantage is that the original glycoform distribution can be completely preserved because no fluorescent labeling is needed. By combining IMBE with CZE-deep UV-LIF, the overall detection sensitivity was 1.5 × 10⁻⁸ mol/L, which was enhanced by two orders of magnitude relative to conventional CZE with UV absorbance detection. It is applicable to the analysis of pharmaceutical preparations of EPO, but the sensitivity is insufficient for the anti-doping analysis of EPO in blood and urine. IMBE can be straightforward and effective approach for sample preparation. However, antibodies with high specificity were the key for application to urine samples because some urinary proteins can severely interfere the immuno-extraction. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Radiation protection and environmental protection

    International Nuclear Information System (INIS)

    Xie Zi; Dong Liucan; Zhang Yongxing

    1994-01-01

    A collection of short papers is presented which review aspects of research in radiation and environmental protection carried out by the Chinese Institute of Atomic Energy in 1991. The topics covered are: the analysis of Po 210 in the gaseous effluent of coal-fired boilers; the determination of natural radionuclide levels in various industrial waste slags and management countermeasures; assessment of the collective radiation dose from natural sources for the Chinese population travelling by water; the preliminary environmental impact report for the multipurpose heavy water research reactor constructed by China for the Islamic Republic of Algeria. (UK)

  7. Protective clothing

    International Nuclear Information System (INIS)

    Winnett, G.F.

    1979-01-01

    A protective suit used for isolating its wearer from radioactively contaminated areas is described in three parts. The first part includes the covering for the wearer's head, arms and upper body and at the waist is releasably fitted around an opening into the contaminated area. The second part includes the legs of the suit and is releasably connectible to the first part of the suit to enclose the wearer who is then supplied with air through an umbilical pipe. A further part surrounds the second part and is releasably connectible to it, enclosing a space between the parts. This further part is also releasably connectible to the opening at the waist to prevent egress from the contaminated area. The releasable connections between the parts may be bayonet type fittings or may be rotating T-shaped projections which engage in T-shaped grooves. (author)

  8. Fire protection

    International Nuclear Information System (INIS)

    Janetzky, E.

    1980-01-01

    Safety and fire prevention measurements have to be treated like the activities developing, planning, construction and erection. Therefore it is necessary that these measurements have to be integrated into the activities mentioned above at an early stage in order to guarantee their effectiveness. With regard to fire accidents the statistics of the insurance companies concerned show that the damage caused increased in the last years mainly due to high concentration of material. Organization of fire prevention and fire fighting, reasons of fire break out, characteristics and behaviour of fire, smoke and fire detection, smoke and heat venting, fire extinguishers (portable and stationary), construction material in presence of fire, respiratory protection etc. will be discussed. (orig./RW)

  9. Protecting Democracy

    DEFF Research Database (Denmark)

    Galster, Kjeld

    2007-01-01

    of a democratic state as defence per se is to its government. Democratic governance rests on the mutual dependence and influence of leadership and led, and the practical function subsumes professional bureaucracies. Thus, defence debate is the exchange of views on matters important to national security amongst...... the democratically elected leadership, the public, and the defence bureaucracy’s professional experts. Defence debate is a decisive contributor to defence policy and it normally includes quantitative issues like the size of military forces and the proportion of the state’s resources devoted to the armed forces......ABSTRACT Galster, Kjeld Hald. Doctoral Student (History). Saxo Institute. May 2007. Protecting Democracy: Danish Defence Debate in Times of Change. Supervisor: Professor, Dr. Gunner Lind. Democratic debate on defence and democratic organisation of the forces are as central to the life...

  10. Protective Coatings

    Science.gov (United States)

    1980-01-01

    General Magnaplate Corporation's pharmaceutical machine is used in the industry for high speed pressing of pills and capsules. Machine is automatic system for molding glycerine suppositories. These machines are typical of many types of drug production and packaging equipment whose metal parts are treated with space spinoff coatings that promote general machine efficiency and contribute to compliance with stringent federal sanitation codes for pharmaceutical manufacture. Collectively known as "synergistic" coatings, these dry lubricants are bonded to a variety of metals to form an extremely hard slippery surface with long lasting self lubrication. The coatings offer multiple advantages; they cannot chip, peel or be rubbed off. They protect machine parts from corrosion and wear longer, lowering maintenance cost and reduce undesired heat caused by power-robbing friction.

  11. Offspring Protection

    Directory of Open Access Journals (Sweden)

    Eric T. Steiner

    2016-08-01

    Full Text Available Parental aggression, that is, offspring protection aggression, can be viewed as a type of parental investment. Most mammalian males do not exhibit parental investment and therefore exhibit little, if any, parental aggression. Men demonstrate parental investment, and are typically more physically aggressive than women, but parental physical aggression in humans has been largely unexplored. The current study examined potential sex differences in estimates of parental physical aggression involving hypothetical situations, while controlling for general physical aggression. A self-report measure was administered to 217 students from a western U.S. university (55 male nonparents, 50 female nonparents, 54 fathers, and 58 mothers. Male nonparents reported higher parental physical aggression than female nonparents, but there was no difference between mothers and fathers. The results are interpreted in light of ancestral effects of sexual selection and proximal effects of sex differences in testosterone, risk taking, and fear aversion.

  12. Metabolic effects of keto acid--amino acid supplementation in patients with chronic renal insufficiency receiving a low-protein diet and recombinant human erythropoietin--a randomized controlled trial.

    Science.gov (United States)

    Teplan, V; Schück, O; Votruba, M; Poledne, R; Kazdová, L; Skibová, J; Malý, J

    2001-09-17

    Supplement with keto acids/amino acids (KA) and erythropoietin can independently improve the metabolic sequels of chronic renal insufficiency. Our study was designed to establish whether a supplementation with keto acids/amino acids (KA) exerts additional beneficial metabolic effects in patients with chronic renal insufficiency (CRF) treated with a low-protein diet (LPD) and recombinant human erythropoietin (EPO). In a prospective randomized controlled trial over a period of 12 months, we evaluated a total of 38 patients (20 M/18 F) aged 32-68 years with a creatinine clearance (CCr) of 20-36 ml/min. All patients were receiving EPO (40 U/kg twice a week s.c.) and a low-protein diet (0.6 g protein/kg/day and 145 kJ/kg/day). The diet of 20 patients (Group I) was supplemented with KA at a dosage of 100 mg/kg/day while 18 patients (Group II) received no supplementation. During the study period, the glomerular filtration rate slightly decreased (CCr from 28.2 +/- 3.4 to 26.4 +/- 4.1 ml/min and 29.6 +/- 4.8 to 23.4 +/- 4.4 ml/min in groups I and II, respectively and Cin); this however was more marked in Group II (Group I vs. Group II, p diet presents an effective treatment modality in the conservative management of CRF.

  13. Nonalcoholic fatty liver disease (NAFLD)--is it a new marker of hyporesponsiveness to recombinant human erythropoietin in patients that are on chronic hemodialysis?

    Science.gov (United States)

    Orlic, L; Mikolasevic, I; Lukenda, V; Racki, S; Stimac, D; Milic, S

    2014-12-01

    Anemia is a major consequence of chronic kidney disease (CKD) that develops early in the course of illness and affects most patients who exhibit some degree of reduced renal function. Erythropoietin (EPO) deficiency is considered the most important cause of anemia in CKD. Renal anemia has serious clinical consequence. In addition to reducing patient physical capacity and quality of life, anemia induces adaptive cardiovascular mechanisms that increase the risk of cardiovascular disease and death. Thus, treatment of anemia in CKD is very important. While EPO is effective in correcting anemia in most cases, up to 10% of patients however, have an inadequate response to therapy. The two most common and important reasons why patients become relatively unresponsive to EPO therapy are the development of true iron deficiency and the onset of an inflammatory state that impairs the response to EPO. Indeed, the role of inflammation and pro-inflammatory cytokines in resistance to EPO therapy is gaining increasing recognition. On the other hand, the main organ for C-reactive protein (CRP) synthesis is the liver and it is well known that the synthesis of an acute-phase proteins by the liver is up regulated by inflammation. The main consequence of nonalcoholic fatty liver disease (NAFLD) is sub-chronic liver inflammation that leads and contributes to dyslipidemia, inflammation, enhanced oxidative stress and endothelial dysfunction. Considering the recent data about high prevalence of NAFLD in CKD patients, probably due to shared metabolic risk factors, we hypothesized that end-stage renal disease (ESRD) patients with NAFLD will need a much higher dose of EPO to achieve the target hemoglobin levels in comparison with ESRD patients without NAFLD. The possible underlying mechanism is sub-chronic liver inflammation in NAFLD patients that leads and contributes to poor response to EPO. Therefore, we believe that NAFLD could be a new clinical marker of poor response to EPO therapy in

  14. Sustained trilineage recovery and disappearance of abnormal chromosome clone in a patient with myelodysplastic syndrome following combination therapy with cytokines (granulocyte colony-stimulating factor and erythropoietin) and high-dose methylprednisolone.

    Science.gov (United States)

    Imai, Y; Fukuoka, T; Nakatani, A; Ohsaka, A; Takahashi, A

    1996-04-01

    We report a case of hypoplastic myelodyplastic syndrome (MDS) (refractory anemia (RA)) in which sustained trilineage haematological response and persistent disappearance of an abnormal chromosome clone were achieved after treatment with combination therapy of cytokines (granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Epo)) and methylprednisolone (mPSL) pulse dose. The patient's haematological recovery was rapid and maintained even after cessation of the therapy. In addition, the predominant chromosome clone 13q- in bone marrow cells disappeared in the fourth week. The patient's improved bone marrow haemopoiesis and disappearance of the abnormal chromosome has continued to the present, 13 months after treatment. The occurrence of both trilineage response and abnormal chromosome disappearance in MDS patients treated with cytokine(s) or steroids is rare. Combination therapy might therefore be advantageous in MDS.

  15. Radiation protection principles

    International Nuclear Information System (INIS)

    Ismail Bahari

    2007-01-01

    The presentation outlines the aspects of radiation protection principles. It discussed the following subjects; radiation hazards and risk, the objectives of radiation protection, three principles of the system - justification of practice, optimization of protection and safety, dose limit

  16. [Light protection: principles of UV protection].

    Science.gov (United States)

    Stege, H; Mang, R

    2006-05-01

    UV radiation is responsible for the induction of epithelial and melanocytic skin cancer, photoaging, and photodermatoses. UV protection is necessary to prevent damage caused by non-physiologic exposure. UV protection includes not only reduction of sun exposure but also use of sun protective filters, UV protective clothes, DNA repair enzymes, and antioxidant supplementation. Consumers are uncertain about the possibilities and limitations of commercial sun protection measures. Dermatologists must explain protective measures to the general public which continues to believe that UV-tanned skin is healthy. The sunscreen market is a highly competitive but lucrative market. The range of products with different designations and promises makes difficult for both consumers and dermatologists to determine what is sensible UV protection.

  17. Skin regeneration in deep second-degree scald injuries either by infusion pumping or topical application of recombinant human erythropoietin gel

    Directory of Open Access Journals (Sweden)

    Giri P

    2015-05-01

    Full Text Available Priya Giri,1 Sabine Ebert,1 Ulf-Dietrich Braumann,2 Mathias Kremer,3 Shibashish Giri,1 Hans-Günther Machens,4 Augustinus Bader1 1Department of Cell Techniques and Applied Stem Cell Biology, Center for Biotechnology and Biomedicine (BBZ, Faculty of Medicine, University of Leipzig, Leipzig, Germany; 2Interdisciplinary Center for Bioinformatics (IZBI, University of Leipzig, Leipzig, Germany; 3Department of Plastic and Hand Surgery, University of Lübeck, Lübeck, Germany; 4Department of Plastic and Hand Surgery, Technical University of Munich, Munich, Germany Abstract: Large doses of recombinant growth factors formulated in solution form directly injected into the body is usual clinical practice in treating second-degree scald injuries, with promising results, but this approach creates side effects; furthermore, it may not allow appropriate levels of the factor to be sensed by the target injured tissue/organ in the specific time frame, owing to complications arising from regeneration. In this research, two delivery methods (infusion pumping and local topical application were applied to deliver recombinant human erythropoietin (rHuEPO for skin regeneration. First, rHuEPO was given in deep second-degree scald injury sites in mice by infusion pump. Vascularization was remarkably higher in the rHuEPO pumping group than in controls. Second, local topical application of rHuEPO gel was given in deep second-degree scald injury sites in rats. Histological analysis showed that epithelialization rate was significantly higher in the rHuEPO gel-treated group than in controls. Immunohistochemical studies showed that the rHuEPO gel-treated group showed remarkably higher expression of skin regeneration makers than the control group. An accurate method for visualization and quantification of blood vessel networks in target areas has still not been developed up to this point, because of technical difficulties in detecting such thin blood vessels. A method which

  18. Laser Protection TIL

    Data.gov (United States)

    Federal Laboratory Consortium — The Laser Protection TIL conducts research and analysis of laser protection materials along with integration schemes. The lab's objectives are to limit energy coming...

  19. Environmental protection economically viable

    International Nuclear Information System (INIS)

    Dartsch, B.; Hildebrandt, T.

    1994-01-01

    The Environmental Technology Forum for Industry and Research (Utech) was held for the fifth time this year at the International Congress Centre in Berlin. The main themes of this year's Utech were additive environmental protection, production-integrated environmental protection, management and economic aspects of environmental protection, research and development in environmental protection as well as environmental information legislation. (orig.) [de

  20. Nature and landscape protection

    International Nuclear Information System (INIS)

    Klinda, J.; Lieskovska, Z.

    1998-01-01

    In accordance with National Council of the Slovak Republic Act N. 287/1994 Coll. on Nature and Landscape Protection, the system of complex nature landscape protection has been designed based on five levels of protection. Categories of protected areas as well as cultural monuments in the Slovak Republic are reviewed.Slovak contribution to the world heritage is included

  1. Operational radiation protection and radiation protection training

    International Nuclear Information System (INIS)

    Kraus, W.

    1989-01-01

    The radiation protection system in the German Democratic Republic (GDR) is reviewed. The competent authority (the SAAS) and its systems of licensing and supervision are described. Discussion covers the role of the Radiation Protection Officer, the types of radiation monitoring, medical surveillance programs and the classification of workers and work areas. Unusual occurrences in the GDR, 1963-1976, are presented and the occupational radiation protection problems at some specific types of workplaces are discussed. The GDR's system of training in radiation protection and nuclear safety is described. 5 figs., 18 tabs

  2. Focus radiation protection

    International Nuclear Information System (INIS)

    Ebermann, Lutz

    2016-01-01

    The publication of the Bundesamt fuer Strahlenschutz on radiation protection covers the following issues: (i) exposure from natural sources: health hazard due to radon, radiation protection in residential homes, radon in Germany, natural raw materials in industrial processes; (ii) clearance of radioactive wastes: clearance in the frame of nuclear power plant dismantling, the situation in Germany and Europe; (iii) emergency management: principles of radiation protection, fictive sequence of accident events; (iiii) other actual radiation protection topics: more limits - more protection? radiation protection in medicine, occupational radiation protection.

  3. Radiation. Protection. Health. Proceedings

    International Nuclear Information System (INIS)

    Hajek, Michael; Maringer, Franz Josef; Steurer, Andreas; Schwaiger, Martina; Timal, Guenter

    2015-01-01

    The topics of the meeting are the diagnostic and therapeutic application of ionizing radiations, the application of radiation in research, industry and engineering and radiation protection. The volume includes the following chapters: Radiation protection and society, radiation protection infrastructure, population and environment, metrology and measuring techniques, 1. Workshop on population and environment, NORM and radon, 2. Update: dose - extent of damage - limiting value definition, radiation protection for personnel (except medicine), radiation protection in medicine.

  4. Loft fire protection

    International Nuclear Information System (INIS)

    White, E.R.; Jensen, J.D.

    1980-01-01

    Quantified criteria that was developed and applied to provide in-depth fire protection for the Loss of Fluid Test (LOFT) Facility are presented. The presentation describes the evolution process that elevated the facility's fire protection from minimal to that required for a highly protected risk or improved risk. Explored are some infrequently used fire protection measures that are poorly understood outside the fire protection profession

  5. Treatment of renal anemia: Erythropoiesis stimulating agents and beyond

    Directory of Open Access Journals (Sweden)

    Patrick Biggar

    2017-09-01

    Full Text Available Anemia, complicating the course of chronic kidney disease, is a significant parameter, whether interpreted as subjective impairment or an objective prognostic marker. Renal anemia is predominantly due to relative erythropoietin (EPO deficiency. EPO inhibits apoptosis of erythrocyte precursors. Studies using EPO substitution have shown that increasing hemoglobin (Hb levels up to 10-11 g/dL is associated with clinical improvement. However, it has not been unequivocally proven that further intensification of erythropoiesis stimulating agent (ESA therapy actually leads to a comprehensive benefit for the patient, especially as ESAs are potentially associated with increased cerebro-cardiovascular events. Recently, new developments offer interesting options not only via stimulating erythropoeisis but also by employing additional mechanisms. The inhibition of activin, a member of the transforming growth factor superfamily, has the potential to correct anemia by stimulating liberation of mature erythrocyte forms and also to mitigate disturbed mineral and bone metabolism as well. Hypoxia-inducible factor prolyl hydroxylase inhibitors also show pleiotropic effects, which are at the focus of present research and have the potential of reducing mortality. However, conventional ESAs offer an extensive body of safety evidence, against which the newer substances should be measured. Carbamylated EPO is devoid of Hb augmenting effects whilst exerting promising tissue protective properties. Additionally, the role of hepcidin antagonists is discussed. An innovative new hemodialysis blood tube system, reducing blood contact with air, conveys a totally different and innocuous option to improve renal anemia by reducing mechanical hemolysis.

  6. rhEPO Enhances Cellular Anti-oxidant Capacity to Protect Long-Term Cultured Aging Primary Nerve Cells.

    Science.gov (United States)

    Wang, Huqing; Fan, Jiaxin; Chen, Mengyi; Yao, Qingling; Gao, Zhen; Zhang, Guilian; Wu, Haiqin; Yu, Xiaorui

    2017-08-01

    Erythropoietin (EPO) may protect the nervous system of animals against aging damage, making it a potential anti-aging drug for the nervous system. However, experimental evidence from natural aging nerve cell models is lacking, and the efficacy of EPO and underlying mechanism of this effect warrant further study. Thus, the present study used long-term cultured primary nerve cells to successfully mimic the natural aging process of nerve cells. Starting on the 11th day of culture, cells were treated with different concentrations of recombinant human erythropoietin (rhEPO). Using double immunofluorescence labeling, we found that rhEPO significantly improved the morphology of long-term cultured primary nerve cells and increased the total number of long-term cultured primary cells. However, rhEPO did not improve the ratio of nerve cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure nerve cell activity and showed that rhEPO significantly improved the activity of long-term cultured primary nerve cells. Moreover, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double immunofluorescence labeling flow cytometry revealed that rhEPO reduced the apoptotic rate of long-term cultured primary nerve cells. Senescence-associated β-galactosidase (SA-β-gal) immunohistochemistry staining showed that rhEPO significantly reduced the aging rate of long-term cultured primary nerve cells. Immunochemistry revealed that rhEPO enhanced intracellular superoxide dismutase (SOD) activity and glutathione (GSH) abundance and reduced the intracellular malondialdehyde (MDA) level. In addition, this effect depended on the dose, was maximized at a dose of 100 U/ml and was more pronounced than that of vitamin E. In summary, this study finds that rhEPO protects long-term cultured primary nerve cells from aging in a dose-dependent manner. The mechanism of this effect may be associated with the enhancement of the intracellular anti

  7. Aircraft Fire Protection Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — The Navy Aircraft Protection Laboratory provides complete test support for all Navy air vehicle fire protection systems.The facility allows for the simulation of a...

  8. Noise and Hearing Protection

    Science.gov (United States)

    ... ENTCareers Marketplace Find an ENT Doctor Near You Noise and Hearing Protection Noise and Hearing Protection Patient ... it is. How can I tell if a noise is dangerous? People differ in their sensitivity to ...

  9. Radiation protection standards

    International Nuclear Information System (INIS)

    Koelzer, W.

    1980-01-01

    The present paper deals with: Objectives and basic concepts of radiation protection, basic radiobiological considerations, the ICRP system of dose limitation and with operational radiation protection (limits, reference levels, occupational exposure). (RW)

  10. Cathodic protection -- Rectifier 46

    International Nuclear Information System (INIS)

    Lane, W.M.

    1995-01-01

    This Acceptance Test Procedure (ATP) has been prepared to demonstrate that the cathodic protection system functions as required by project criteria. The cathodic protection system is for the tank farms on the Hanford Reservation. The tank farms store radioactive waste

  11. Healthy Watersheds Protection

    Science.gov (United States)

    ... for restoring areas with degraded water quality, as well as protecting healthy waters from emerging problems before expensive damages occur. ... exclusively on restoring impaired waters, EPA created the Healthy ... more emphasis to proactively protecting high quality waters, following the ...

  12. Cathodic protection -- Rectifier 47

    International Nuclear Information System (INIS)

    Lane, W.M.

    1995-01-01

    This Acceptance Test Procedure (ATP) has been prepared to demonstrate that the cathodic protection system functions as required by project criteria. The cathodic protection system is for the tank farms at the Hanford Reservation. The tank farms store radioactive waste

  13. Endangered Species Protection Bulletins

    Science.gov (United States)

    Endangered Species Protection Bulletins set forth geographically specific pesticide use limitations for the protection of threatened and endangered (listed) species and their designated critical habitat. Find out how to get and use Bulletins.

  14. Information protection playbook

    CERN Document Server

    Kane, Greg

    2013-01-01

    The primary goal of the Information Protection Playbook is to serve as a comprehensive resource for information protection (IP) professionals who must provide adequate information security at a reasonable cost. It emphasizes a holistic view of IP: one that protects the applications, systems, and networks that deliver business information from failures of confidentiality, integrity, availability, trust and accountability, and privacy. Using the guidelines provided in the Information Protection Playbook, security and information technology (IT) managers will learn how to

  15. Machine protection systems

    CERN Document Server

    Macpherson, A L

    2010-01-01

    A summary of the Machine Protection System of the LHC is given, with particular attention given to the outstanding issues to be addressed, rather than the successes of the machine protection system from the 2009 run. In particular, the issues of Safe Machine Parameter system, collimation and beam cleaning, the beam dump system and abort gap cleaning, injection and dump protection, and the overall machine protection program for the upcoming run are summarised.

  16. Environmental Protection Agency, Protecting Children's Environmental Health

    Science.gov (United States)

    ... and Research Centers Contact Us Share Protecting Children's Environmental Health Children are often more vulnerable to pollutants ... during development. Learn more about children's health, the environment, and what you can do. Basic Information Children ...

  17. Protective Behavior in Games

    OpenAIRE

    Fiestras-Janeiro, G.; Borm, P.E.M.; van Megen, F.J.C.

    1996-01-01

    This paper introduces the notion of protective equilibrium in the context of fin ite games in strategic form.It shows that for matrix games the set of protective equilibria equals the set of proper equilibria.Moreover, in the context of bima trix games, the notion of protective behaviour is used as a refinement tool.

  18. Protective Behavior in Games

    NARCIS (Netherlands)

    Fiestras-Janeiro, G.; Borm, P.E.M.; van Megen, F.J.C.

    1996-01-01

    This paper introduces the notion of protective equilibrium in the context of fin ite games in strategic form.It shows that for matrix games the set of protective equilibria equals the set of proper equilibria.Moreover, in the context of bima trix games, the notion of protective behaviour is used as

  19. Radiation protection seminar

    International Nuclear Information System (INIS)

    2012-01-01

    The Radiation Protection Seminar, was organized by the Argentina Association of Biology and Nuclear Medicine, and Bacon Laboratory, the 20 june 2012, in the Buenos Aires city of Argentina. In this event were presented some papers on the following topics: methods of decontamination, radiation protection of patients; concepts of radiation protection and dosimetry.

  20. Ozone Layer Protection

    Science.gov (United States)

    ... and Research Centers Contact Us Share Ozone Layer Protection The stratospheric ozone layer is Earth’s “sunscreen” – protecting ... GreenChill Partnership Responsible Appliance Disposal (RAD) Program Ozone Protection vs. Ozone Pollution This website addresses stratospheric ozone ...

  1. Recommendations for the clinical practice: Standards, options and recommendations 2003 for the use of recombinant erythropoietin (alpha and beta epoetine, alpha darbepoetine, EPO) in the taking charge of anemia in oncology for the patients treated by radiotherapy, update

    International Nuclear Information System (INIS)

    Marchal, Ch.; Spaeth, C.; Casadevall, N.; Daouphars, M.; Marec-Berard, P.; Fabre, N.; Haugh, M.

    2004-01-01

    Standards, Options and Recommendations for the use of recombinant erythropoietin (epoietin alpha and beta darbepoietin alpha, EPO) in the management of anaemia in oncology for patient undergoing radiotherapy - UPDATE 2003. Context. - 'The Standards, Options and Recommendations' (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the twenty French cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. Objectives. - To update the Standards, Options and Recommendations clinical practice guidelines for the use of recombinant erythropoietin (epoietin alpha and beta darbepoietin-alpha, EPO) in the management of anaemia in oncology for patient undergoing radiotherapy. Methods. - The working group identified the questions requiring up-dating from the previous guideline. Medline and Embase were searched using specific search strategies from January 1999 to October 2002. Literature monitoring was performed to identify randomized clinical trials published between October 2002 to November 2003. In addition several Internet sites were searched in October 2002. Results. - There is no standard attitude for use of rHuEPO in patients undergoing radiotherapy. There is no evidence to support use of rHuEPO in patients with ENT cancer receiving radiotherapy alone. In patients undergoing curative radiotherapy, it is recommended to correct anaemia under 10 g/dL using transfusion rather than rHuEPO. When the haemoglobin concentration is between 12 g/dL and 14 g/dL initial use of rHuEPO can be an option under certain conditions for radio-chemotherapy if the risk of anaemia is

  2. Designing physical protection technology for insider protection

    International Nuclear Information System (INIS)

    Trujillo, A.A.; Waddoups, I.G.

    1986-01-01

    Since its inception, the nuclear industry has been engaged in providing protection against an insider threat. Although insider protection activities have been fairly successful in the past, present societal conditions require increased protection to further minimize the existence of an insider or the consequences of an insider-perpetrated incident. Integration of insider protection techniques into existing administrative and operational procedures has resulted in economic and operational impacts. Future increases in insider protection may result in even greater impacts, so we must proceed wisely as new approaches are developed. Increased emphasis on background investigations, security clearances, human reliability programs, security awareness activities, and the development of technology to address the insider threat are evidence of continuing concern in this area. Experience ranging from operational test and evaluation of developmental equipment to conceptual designs for new facilities has led to the development of general principles and conclusions for mitigating the insider threat while minimizing adverse impacts on site operations. Important principles include real-time monitoring of personnel and material and requiring that the physical protection and material control and accounting systems to be much more coordinated and integrated than in the past

  3. Priming dose of phenylhydrazine protects against hemolytic and lethal effects of 2-butoxyethanol

    International Nuclear Information System (INIS)

    Palkar, Prajakta S.; Philip, Binu K.; Reddy, Ramesh N.; Mehendale, Harihara M.

    2007-01-01

    Protection against a high dose of a toxicant by prior exposure to another toxicant is called heteroprotection. Our objective was to establish a heteroprotection model in RBCs. Female Sprague Dawley rats treated with an LD90 dose of 2-butoxyethanol (BE, 1500 mg/kg in water, 5 ml/kg po) 14 days after priming with 0.9% NaCl suffered 90% mortality by 15 days, whereas all rats receiving the LD90 dose of BE 14 days after priming with phenylhydrazine (PHZ, 125 mg/kg in 0.9% NaCl, 3 ml/kg po) survived. Hematocrit decreased from normal 45% to 24% by day 3 after PHZ priming and improved thereafter. Increasing the time interval between the priming and LD90 dose to 21 days abolished the heteroprotection. RBCs obtained on days 7 and 14 after PHZ priming unlike those on day 21 were resilient to the hemotoxic metabolite of BE, butoxyacetic acid (BAA). Unaltered hepatic alcohol and aldehyde dehydrogenase activities upon PHZ priming suggested that bioactivation of BE to BAA was unaffected. Lower renal (6 and 12 h) and hepatic (12 h) BAA levels and 3 fold higher excretion of BAA in PHZ-primed rat urine suggested a protective role of toxicokinetics. Higher erythropoietin, reticulocytes, and resiliency of PHZ-primed rat RBCs indicated that newly formed RBCs are resilient to hemolytic BAA. The antioxidant levels in the PHZ-primed rat RBCs did not indicate a protective role in heteroprotection. In conclusion, the resistance of PHZ-primed rats against BE-induced hemotoxicity and lethality is mediated by a combination of altered toxicokinetics, robust erythropoiesis, and resiliency of new RBCs

  4. Numerical distance protection

    CERN Document Server

    Ziegler, Gerhard

    2011-01-01

    Distance protection provides the basis for network protection in transmission systems and meshed distribution systems. This book covers the fundamentals of distance protection and the special features of numerical technology. The emphasis is placed on the application of numerical distance relays in distribution and transmission systems.This book is aimed at students and engineers who wish to familiarise themselves with the subject of power system protection, as well as the experienced user, entering the area of numerical distance protection. Furthermore it serves as a reference guide for s

  5. Radiation protection in Sudan

    International Nuclear Information System (INIS)

    Elamin, O.I.; Hajmusa, E.A.; Shaddad, I.A.

    2001-01-01

    The regulatory framework as established by the Sudan Atomic Energy Commission (SAEC) Act, promulgated in 1996, is described in the report. Three levels of responsibility in meeting radiation protection requirements are established: the Board, the Radiation Protection Technical Committee as the competent authority in the field of radiation protection, and the SAEC Department of Radiation Protection and Environmental Monitoring as the implementing technical body. The report also refers to environmental activities, patient doses in diagnostic radiology, the management of disused sources, emergency preparedness and orphan sources, and the national training activities in the radiation protection field. (author)

  6. Fire Protection Program Manual

    Energy Technology Data Exchange (ETDEWEB)

    Sharry, J A

    2012-05-18

    This manual documents the Lawrence Livermore National Laboratory (LLNL) Fire Protection Program. Department of Energy (DOE) Orders 420.1B, Facility Safety, requires LLNL to have a comprehensive and effective fire protection program that protects LLNL personnel and property, the public and the environment. The manual provides LLNL and its facilities with general information and guidance for meeting DOE 420.1B requirements. The recommended readers for this manual are: fire protection officers, fire protection engineers, fire fighters, facility managers, directorage assurance managers, facility coordinators, and ES and H team members.

  7. Numerical differential protection

    CERN Document Server

    Ziegler, Gerhard

    2012-01-01

    Differential protection is a fast and selective method of protection against short-circuits. It is applied in many variants for electrical machines, trans?formers, busbars, and electric lines.Initially this book covers the theory and fundamentals of analog and numerical differential protection. Current transformers are treated in detail including transient behaviour, impact on protection performance, and practical dimensioning. An extended chapter is dedicated to signal transmission for line protection, in particular, modern digital communication and GPS timing.The emphasis is then pla

  8. Glutamine domain of the chimeric protein, CAD, that initiates pyrimidine biosynthesis in mammalian cells

    International Nuclear Information System (INIS)

    Kelly, R.E.; Kim, H.; Evans, D.R.

    1986-01-01

    Glutamine dependent carbamyl phosphate synthesis, the first step in mammalian de novo pyrimidine biosynthesis, is catalyzed by a 240 kDa chimeric protein, CAD, that also has the aspartate transcarbamylase and dihydroorotase activities. The complex was found to have a separate glutaminase activity of 0.04 μmol/min/mg, that increased five fold in the presence of bicarbonate and ATP. To determine whether the glutaminase activity, which provides ammonia for carbamyl phosphate synthesis, is associated with a separate structural domain (GLN), CAD was subjected to controlled proteolysis with elastase. The glutaminase, glutamine and ammonia dependent carbamyl phosphate synthetase activities, as well as the partial reactions; carbamyl phosphate dependent ATP synthesis and bicarbonate dependent ATPase, were correlated with the concentration of the various proteolytic fragments that accumulated in the digest. While the glutamine dependent carbamyl phosphate synthetase was rapidly inactivated, the glutaminase activity was found to be very resistant to proteolysis. The glutamine binding site of CAD was also specifically modified with 6-diazo-5-oxo-L-norleucine (DON). The modification was accompanied by a loss of both glutaminase and glutamine dependent carbamyl phosphate synthetase activities. Bicarbonate and ATP increased the rate of reaction of CAD with DON, while glutamine protected against inactivation. The stoichiometry of the reaction and the identity of the modified proteolytic fragments was determined using 14 C labelled DON

  9. Personal protective equipment

    International Nuclear Information System (INIS)

    2004-01-01

    This Practical Radiation Technical Manual is one of a series that has been designed to provide guidance on radiological protection for employers, radiation protection officers, managers and other technically competent persons who have responsibility for ensuring the safety of employees working with ionizing radiation. The Manual may be used with the appropriate IAEA Practical Radiation Safety Manuals to provide training, instruction and information for all employees engaged in work with ionizing radiation. Personal protective equipment (PPE) includes clothing or other special equipment that is issued to individual workers to provide protection against actual or potential exposure to ionizing radiations. It is used to protect each worker against the prevailing risk of external or internal exposure in circumstances in which it is not reasonably practicable to provide complete protection by means of engineering controls or administrative methods. Adequate personal protection depends on PPE being correctly selected, fitted and maintained. Appropriate training for the users and arrangements to monitor usage are also necessary to ensure that PPE provides the intended degree of protection effectively. This Manual explains the principal types of PPE, including protective clothing and respiratory protective equipment (RPE). Examples of working procedures are also described to indicate how PPE should be used within a safe system of work. The Manual will be of most benefit if it forms part of a more comprehensive training programme or is supplemented by the advice of a qualified expert in radiation protection. Some of the RPE described in this Manual should be used under the guidance of a qualified expert

  10. Adaptive protection scheme

    Directory of Open Access Journals (Sweden)

    R. Sitharthan

    2016-09-01

    Full Text Available This paper aims at modelling an electronically coupled distributed energy resource with an adaptive protection scheme. The electronically coupled distributed energy resource is a microgrid framework formed by coupling the renewable energy source electronically. Further, the proposed adaptive protection scheme provides a suitable protection to the microgrid for various fault conditions irrespective of the operating mode of the microgrid: namely, grid connected mode and islanded mode. The outstanding aspect of the developed adaptive protection scheme is that it monitors the microgrid and instantly updates relay fault current according to the variations that occur in the system. The proposed adaptive protection scheme also employs auto reclosures, through which the proposed adaptive protection scheme recovers faster from the fault and thereby increases the consistency of the microgrid. The effectiveness of the proposed adaptive protection is studied through the time domain simulations carried out in the PSCAD⧹EMTDC software environment.

  11. Theory of vibration protection

    CERN Document Server

    Karnovsky, Igor A

    2016-01-01

    This text is an advancement of the theory of vibration protection of mechanical systems with lumped and distributed parameters. The book offers various concepts and methods of solving vibration protection problems, discusses the advantages and disadvantages of different methods, and the fields of their effective applications. Fundamental approaches of vibration protection, which are considered in this book, are the passive, parametric and optimal active vibration protection. The passive vibration protection is based on vibration isolation, vibration damping and dynamic absorbers. Parametric vibration protection theory is based on the Shchipanov-Luzin invariance principle. Optimal active vibration protection theory is based on the Pontryagin principle and the Krein moment method. The book also contains special topics such as suppression of vibrations at the source of their occurrence and the harmful influence of vibrations on humans. Numerous examples, which illustrate the theoretical ideas of each chapter, ar...

  12. The absence of protective effect of candesartan and angiotensin IV in the moderate brain injury in rats

    International Nuclear Information System (INIS)

    Nasser, M.; Botelle, L.; Javellaud, J.; Oudart, N.; Achard, J-M

    2012-01-01

    Background: angiotensin receptor blockers (ARB) are protective in various models of experimental ischemic stroke. This protective effect is mediated by the stimulation of non-AT1 receptors by angiotensin II and angiotensin IV. Since traumatic brain injury shares with ischemic cerebral injury several common mechanisms, we examined if a pretreatment with the ARB candesartan, or a post-treatment with angiotensin IV are also protective in a rat model of blunt traumatic brain injury (TBI). Methods :adults Sprague Dawley rats were treated for five days with candesartan (0.5 mg/kg/day) or saline by gavage prior to the induction of diffuse moderate TBI using the impact-acceleration model. Two others groups of rats were treated by a daily intraperitoneal injection of angiotensin IV (1.5 mg/kg/day) or saline for five days following TBI. Overall neurological insult were assessed daily by measuring the neurological score. Sensitive deficits (scotch test) and sensorimotor deficits (beam-walking test) were evaluated daily from day 1 to 7 and at day 15; cognitive impairment (object recognition test) was evaluated at day 15. Results : TBI induced significant sensitive and sensorimotor deficits that were maximal at day 1 and spontaneously improved with time. At day 15, traumatised animals had a marked alteration of the working memory. Neither treatment with candesartan, angiotensin IV or with erythropoietin decreased the severity of the initial sensorimotor deficits, nor accelerate the recovery rate. Candesartan, angiotensin IV had likewise no protective effect on the cognitive deficit evaluated to day 15. Conclusion: pretreatment with candesartan and post-treatment with angiotensin IV are both ineffective to protect against sensorimotor and c ognitive impairment in a rat model of impact-acceleration TBI. (author)

  13. Resilience from coastal protection.

    Science.gov (United States)

    Ewing, Lesley C

    2015-10-28

    Coastal areas are important residential, commercial and industrial areas; but coastal hazards can pose significant threats to these areas. Shoreline/coastal protection elements, both built structures such as breakwaters, seawalls and revetments, as well as natural features such as beaches, reefs and wetlands, are regular features of a coastal community and are important for community safety and development. These protection structures provide a range of resilience to coastal communities. During and after disasters, they help to minimize damages and support recovery; during non-disaster times, the values from shoreline elements shift from the narrow focus on protection. Most coastal communities have limited land and resources and few can dedicate scarce resources solely for protection. Values from shore protection can and should expand to include environmental, economic and social/cultural values. This paper discusses the key aspects of shoreline protection that influence effective community resilience and protection from disasters. This paper also presents ways that the economic, environmental and social/cultural values of shore protection can be evaluated and quantified. It presents the Coastal Community Hazard Protection Resilience (CCHPR) Index for evaluating the resilience capacity to coastal communities from various protection schemes and demonstrates the use of this Index for an urban beach in San Francisco, CA, USA. © 2015 The Author(s).

  14. Training in radiation protection

    International Nuclear Information System (INIS)

    Schreiber, F.

    1998-01-01

    Persons who are exposed to ionizing radiation at their workplace have to be trained in radiation protection. According to the Radiation Protection Ordinance the person with responsibility in radiation protection has to guarantee that the training is performed twice a year. Our training material was created especially for the persons defined in the Radiation Protection Ordinance and the X-ray Ordinance. It enables persons who teach (generally the radiation protection officer) to perform the training without tedious study and preparation of the documents. Our material is not just another textbook for radiation protection but rather a folder with colour transparencies and explanatory texts which make a difference in volume and price in comparison to other existing materials. (orig.) [de

  15. Protecting plutonium: physical safeguards

    International Nuclear Information System (INIS)

    Ney, J.F.

    1975-10-01

    In the development of physical protection systems, objectives for improving overall performance include the following: (1) Increase the time required for the malefactor to achieve his goal; (2) decrease the time required for detection of malevolent activities; (3) reduce the time for adequate response force arrival; (4) increase the capability to neutralize the malefactor; (5) reduce the total protection system costs, while increasing the level of protection; (6) improve acceptance levels (social, environmental, legal, and institutional); and (7) increase nuclear fuel cycle safety. Fortunately, there is sufficient lead time and technical base to explore and develop new protection system concepts so that a completely integrated and tested protection system capable of providing unprecedented levels of security can be available when needed. Although it will be impossible to completely eliminate all risks, it should be both possible and economically feasible to install protection systems which will deter or prevent a malefactor from using the nuclear fuel cycle to disrupt society

  16. Emergency Protection from Aerosols

    Energy Technology Data Exchange (ETDEWEB)

    Cristy, G.A.

    2001-11-13

    Expedient methods were developed that could be used by an average person, using only materials readily available, to protect himself and his family from injury by toxic (e.g., radioactive) aerosols. The most effective means of protection was the use of a household vacuum cleaner to maintain a small positive pressure on a closed house during passage of the aerosol cloud. Protection factors of 800 and above were achieved.

  17. Emergency protection from aerosols

    International Nuclear Information System (INIS)

    Cristy, G.A.; Chester, C.V.

    1981-07-01

    Expedient methods were developed that could be used by an average person, using only materials readily available, to protect himself and his family from injury by toxic (e.g., radioactive) aerosols. The most effective means of protection was the use of a household vacuum cleaner to maintain a small positive pressure on a closed house during passage of the aerosol cloud. Protection factors of 800 and above were achieved

  18. Protecting genetic privacy.

    Science.gov (United States)

    Roche, P A; Annas, G J

    2001-05-01

    This article outlines the arguments for and against new rules to protect genetic privacy. We explain why genetic information is different to other sensitive medical information, why researchers and biotechnology companies have opposed new rules to protect genetic privacy (and favour anti-discrimination laws instead), and discuss what can be done to protect privacy in relation to genetic-sequence information and to DNA samples themselves.

  19. Radiological protection act, 1991

    International Nuclear Information System (INIS)

    1991-01-01

    This Act provides for the establishment of the Radiological Protection Institute of Ireland and dissolves An Bord Fuinnimh Nuicleigh (the Board), transferring its assets and liabilities to the Institute. It sets out a range of radiation protection measures to be taken by various Ministers in the event of a radiological emergency and gives effect at national level to the Assistance Convention, the Early Notification Convention and the Physical Protection Convention. The Institute is the competent Irish authority for the three Conventions. (NEA) [fr

  20. Protection using telecommunications

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-07-01

    Deregulation in both the telecommunication and electric power industry, together with new telecommunication network technologies and advances in numerical protection, has resulted in the need to reconsider traditional methods of delivering tele-protection schemes and their associated bearer services. Fibre-optic technology is commonly deployed in new telecommunication networks for inter-station communication and utility-owned and public telecommunication networks from third parties are available for protection purposes. (author)