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Sample records for human erythropoietin therapy

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. 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 ...

  8. 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.

  9. 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...

  10. 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

  11. 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  

  12. Recombinant human erythropoietin in sports: a review

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    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.

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

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    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.

  14. 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...

  15. 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....

  16. 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

  17. Biological evaluation of recombinant human erythropoietin in pharmaceutical products

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    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.

  18. 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...

  19. 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.

  20. Aberrant phenotypes of transgenic mice expressing dimeric human erythropoietin

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    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

  1. 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...

  2. 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)

  3. 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

  4. Rational hemochromatosis therapy with erythrocytapheresis under low doses of erythropoietin

    OpenAIRE

    Brückl, Dorothea

    2016-01-01

    Summary: Hereditary hemochromatosis with an incidence of 1:200 – 1:400 is the most common hereditary disease. It is characterized by increased iron absorption and deposition in various organs, leading to organ damage and even death. To date, phlebotomy (bloodletting) is the standard therapy of iron-overload in hemochromatosis. However, this treatment is long lasting, frequently intolerable and/or remains limited due the development of significant anemia. All these difficulties might be ov...

  5. 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...

  6. 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.

  7. 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

  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. 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.

  10. 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...

  11. 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...

  12. 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...

  13. 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.

  14. Erythropoietin treatment enhances muscle mitochondrial capacity in humans

    DEFF Research Database (Denmark)

    Plenge, Ulla; Belhage, Bo; Guadalupe-Grau, Amelia

    2012-01-01

    in humans. In six healthy volunteers rhEpo was administered by sub-cutaneous injection over 8 weeks with oral iron (100 mg) supplementation taken daily. Mitochondrial OXPHOS was quantified by high-resolution respirometry in saponin-permeabilized muscle fibers obtained from biopsies of the vastus lateralis...

  15. 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.

  16. 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...

  17. 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)

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. 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.)

  12. 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....

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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...

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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...

  5. 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...

  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. 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 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. 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.

  10. 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...

  11. 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...

  12. Antibody-based enzyme-linked lectin assay (ABELLA) for the sialylated recombinant human erythropoietin present in culture supernatant.

    Science.gov (United States)

    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.

  13. 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.)

  14. 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

  15. 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...

  16. 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)

  17. 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

  18. 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

  19. Radioimmunoassay of erythropoietin: circulating levels in normal and polycythemic human beings

    International Nuclear Information System (INIS)

    Garcia, J.F.; Ebbe, S.N.; Hollander, L.; Cutting, H.O.; Miller, M.E.; Cronkite, E.P.

    1982-01-01

    Techniques are described in detail for the RIA of human Ep in unextracted plasma or serum. With 100 μl of sample, the assay is sensitive at an Ep concentration of approximately 4 mU/ml, and when required, the sensitivity can be increased to 0.4 mU/ml, a range considerably less than the concentration observed in normal human beings. This is approximately 100 times more sensitive than existing in vivo bioassays for this hormone. Studies concerned with the validation of the Ep RIA show a high degree of correlation with the polycythemic mouse bioassay. Dilutions of a variety of human serum samples show a parallel relationship with the standard reference preparation for Ep. Validation of the RIA is further confirmed by observations of appropriate increases or decreases of circulating Ep levels in physiological and clinical conditions known to be associated with stimulation or suppression of Ep secretion. Significantly different mean serum concentrations of 17.2 mU/ml for normal male subjects and 18.8 mU/ml for normal female subjects were observed. Mean plasma Ep concentrations in patients with polycythemia vera are significantly decreased, and those of patients with secondary polycythemia are significantly increased as compared to plasma levels in normal subjects. These results demonstrate an initial practical value of the Ep RA in the hematology clinic, which will most certainly be expanded with its more extensive use

  20. [Recombinant human erythropoietin in neonates: guidelines for clinical practice from the French Society of Neonatology].

    Science.gov (United States)

    Lopez, E; Beuchée, A; Truffert, P; Pouvreau, N; Patkai, J; Baud, O; Boubred, F; Flamant, C; Jarreau, P-H

    2015-10-01

    1/To assess the effectiveness and safety of EPO in reducing red blood cell (RBC) transfusions in preterm infants. 2/To provide guidelines for clinical practice in France. 1/This systematic evidence review is based on PubMed search, Cochrane library. 2/Using French National Authority for Health methods concerning guidelines for clinical practice. Early EPO reduced the risk of RBC transfusions, donor exposure, and the number of transfusions in very preterm infants (LE2). Late EPO reduced the risk of RBC transfusions and the number of transfusions in very preterm infants (LE2). There is no difference between the effectiveness of early and late EPO (LE2). There is no difference between high-dose and low-dose EPO (LE2). The level of evidence is too low to recommend the intravenous route. EPO has no impact on the rate of bronchopulmonary dysplasia, necrotizing enterocolitis (LE3), and retinopathy of prematurity (LE2). The level of evidence is too low to recommend EPO for neuroprotection in very preterm or term infants. EPO to reduce RBC transfusion in very preterm infants is recommended (Level A). The optimal time to start therapy is unknown (Level B). The recommended dose is 750IU/kg/week via three subcutaneous injections for 6weeks (Level B). Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  1. 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.

  2. 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.

  3. 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.

  4. Erythropoietin augments the cytokine response to acute endotoxin-induced inflammation in humans

    DEFF Research Database (Denmark)

    Hojman, Pernille; Taudorf, Sarah; Lundby, Carsten

    2009-01-01

    in a human in vivo model of acute systemic low-grade inflammation, we measured circulating inflammatory mediators after intravenous administration of Escherichia coli endotoxin (LPS) bolus injection (0.1 ng/kg of body weight) in young healthy male subjects. The subjects were divided into three groups...... receiving either (1) LPS alone, (2) EPO alone (15,000 IE of rHuEPO) or (3) EPO and LPS. Endotoxin administration alone induced a 3-, 12- and 5-fold increase in plasma concentrations of TNF-alpha, IL-6 and IL-10, respectively, 3h after LPS challenge. When EPO was given prior to a bolus injection...... with endotoxin, the levels of TNF-alpha and IL-6 were enhanced by 5- and 40-fold, respectively, whereas the endotoxin-induced increase in IL-10 response was not influenced by EPO. In contrast to our hypothesis, we find that EPO augments the acute inflammatory effect....

  5. 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.

  6. 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...

  7. 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.

  8. 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...

  9. 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...

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. 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?

  16. 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

  17. 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

  18. [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.

  19. 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.

  20. 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...

  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. 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

  4. 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.

  5. Serum zinc and hormonal profile in male dialysis patients receiving human recombinant erythropoietin Zinco sérico e perfil hormonal de pacientes do sexo masculino submetidos à hemodiálise em uso de eritropoetina humana recombinante

    Directory of Open Access Journals (Sweden)

    Maria Mouranilda Schleicher

    2005-08-01

    Full Text Available INTRODUCTION: Treatment with recombinant human erythropoietin (rHuEpo is associated with an improvement in well-being and quality of life in patients submitted to maintenance hemodialysis (HD. OBJECTIVES: The goal of this work was to evaluate the levels of sex hormones, hematocrit, albumin and zinc in HD patients with rHuEpo therapy and compare them with those observed in patients without rHuEpo treatment. MATERIAL AND METHODS: Two groups of twelve male HD patients each were selected for a transversal study; one did not receive rHuEpo (group 1 whereas the other one did (group 2. Levels of hematocrit, albumin, zinc, luteinizing hormone (LH, follicle-stimulating hormone (FSH, prolactin, and testosterone were determined. RESULTS: Group 2 patients showed significantly higher medians (p INTRODUÇÃO: Em pacientes submetidos à hemodiálise crônica (HD, o tratamento com eritropoetina humana recombinante (rHuEpo está associado a melhora no bem-estar geral e na qualidade de vida. OBJETIVOS: O objetivo do presente trabalho foi avaliar os níveis dos hormônios sexuais e do zinco em pacientes sob HD e em uso de rHuEpo em comparação com pacientes sem tratamento com essa droga. MATERIAL E MÉTODOS: Dois grupos de doze pacientes do sexo masculino cada um, submetidos à HD, sendo um deles sem uso de rHuEpo (grupo 1 e o outro utilizando a droga (grupo 2, foram selecionados para um estudo transversal, comparando-se os níveis séricos do zinco, da albumina, dos hormônios FSH, LH, prolactina, testosterona e do hematócrito. RESULTADOS: No grupo 2, os valores de testosterona (4,65 vs. 3,5ng/ml, hematócrito (30,5 vs. 22%, albumina (3,9 vs. 3,7g/dl e zinco (62,5 vs. 50,5microg/dl foram significativamente maiores do que no grupo 1 (p < 0,05. DISCUSSÃO: Sugere-se que, em pacientes recipientes da rHuEpo, os níveis mais altos de hematócrito, zinco, albumina e testosterona possam ser fatores que contribuam para melhorar a disfunção sexual e a qualidade de

  6. 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.

  7. 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

  8. 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

  9. Human Gene Therapy: Genes without Frontiers?

    Science.gov (United States)

    Simon, Eric J.

    2002-01-01

    Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

  10. 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 ...

  11. 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.

  12. 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)

  13. 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.

  14. 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

  15. 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...

  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. 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

  18. Rational Emotive Behavior Therapy: Humanism in Action.

    Science.gov (United States)

    Hill, Larry K.

    1996-01-01

    Claims that humanism, in both concept and philosophy, is encased in a literature that is predominantly abstract, making humanism difficult to translate into tangible day-to-day action. Argues that rational emotive behavior therapy (REBT), however, provides a detailed method for translating humanist concepts into humanist behavior. (RJM)

  19. 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...

  20. A case of recurrent autoimmune hemolytic anemia during remission associated with acute pure red cell aplasia and hemophagocytic syndrome due to human parvovirus B19 infection successfully treated by steroid pulse therapy with a review of the literature.

    Science.gov (United States)

    Sekiguchi, Yasunobu; Shimada, Asami; Imai, Hidenori; Wakabayashi, Mutsumi; Sugimoto, Keiji; Nakamura, Noriko; Sawada, Tomohiro; Komatsu, Norio; Noguchi, Masaaki

    2014-01-01

    The patient was a 47-year-old man diagnosed as having autoimmune hemolytic anemia (AIHA) in April 2011. He also had a congenital chromosomal abnormality, a balanced translocation. Treatment with prednisolone (PSL) 60 mg/day resulted in resolution of the AIHA, and the treatment was completed in November 2011. While the patient no longer had anemia, the direct and indirect Coombs tests remained positive. In May 2013, he developed recurrent AIHA associated with acute pure red cell aplasia (PRCA) and hemophagocytic syndrome (HPS) caused by human parvovirus B19 (HPV B19) infection. Tests for anti-erythropoietin and anti-erythropoietin receptor antibodies were positive. Steroid pulse therapy resulted in resolution of the AIHA, PRCA, as well as HPS. The serum test for anti-erythropoietin antibodies also became negative after the treatment. However, although the serum was positive for anti-HPV B19 IgG antibodies, the patient continued to have a low CD4 lymphocyte count (CD4, B19 infection (HPV B19 DNA remained positive), suggesting the risk of recurrence and bone marrow failure.

  1. 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...

  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. Role of Erythropoietin in Renal Anemia Therapy

    African Journals Online (AJOL)

    Department of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, Henan 453003, PR China ... on; that the use of EPO can reduce transfusion- .... accumulation of metabolites affects carnitine ... spinal cord ischemic injury.

  4. Ethical issues of perinatal human gene therapy.

    Science.gov (United States)

    Fletcher, J C; Richter, G

    1996-01-01

    This paper examines some key ethical issues raised by trials of human gene therapy in the perinatal period--i.e., in infants, young children, and the human fetus. It describes five resources in ethics for researchers' considerations prior to such trials: (1) the history of ethical debate about gene therapy, (2) a literature on the relevance of major ethical principles for clinical research, (3) a body of widely accepted norms and practices, (4) knowledge of paradigm cases, and (5) researchers' own professional integrity. The paper also examines ethical concerns that must be met prior to any trial: benefits to and safety of subjects, informed assent of children and informed parental permission, informed consent of pregnant women in fetal gene therapy, protection of privacy, and concerns about fairness in the selection of subjects. The paper criticizes the position that cases of fetal gene therapy should be restricted only to those where the pregnant woman has explicitly refused abortion. Additional topics include concerns about genetic enhancement and germ-line gene therapy.

  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. 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...

  7. Human gene therapy and imaging: cardiology

    International Nuclear Information System (INIS)

    Wu, Joseph C.; Yla-Herttuala, Seppo

    2005-01-01

    This review discusses the basics of cardiovascular gene therapy, the results of recent human clinical trials, and the rapid progress in imaging techniques in cardiology. Improved understanding of the molecular and genetic basis of coronary heart disease has made gene therapy a potential new alternative for the treatment of cardiovascular diseases. Experimental studies have established the proof-of-principle that gene transfer to the cardiovascular system can achieve therapeutic effects. First human clinical trials provided initial evidence of feasibility and safety of cardiovascular gene therapy. However, phase II/III clinical trials have so far been rather disappointing and one of the major problems in cardiovascular gene therapy has been the inability to verify gene expression in the target tissue. New imaging techniques could significantly contribute to the development of better gene therapeutic approaches. Although the exact choice of imaging modality will depend on the biological question asked, further improvement in image resolution and detection sensitivity will be needed for all modalities as we move from imaging of organs and tissues to imaging of cells and genes. (orig.)

  8. Magneto-therapy of human joint cartilage.

    Science.gov (United States)

    Wierzcholski, Krzysztof; Miszczak, Andrzej

    2017-01-01

    The topic of the present paper concerns the human joint cartilage therapy performed by the magnetic induction field. There is proved the thesis that the applied magnetic field for concrete cartilage illness should depend on the proper relative and concrete values of applied magnetic induction, intensity as well the time of treatment duration. Additionally, very important are frequencies and amplitudes of magnetic field as well as magnetic permeability of the synovial fluid. The research methods used in this paper include: magnetic induction field produced by a new Polish and German magneto electronic devices for the therapy of human joint cartilage diseases, stationary and movable magnetic applicators, magnetic bandage, ferrofluid injections, author's experience gained in Germany research institutes and practical results after measurements and information from patients. The results of this paper concern concrete parameters of time dependent electro-magnetic field administration during the joint cartilage therapy duration and additionally concern the corollaries which are implied from reading values gained on the magnetic induction devices. The main conclusions obtained in this paper are as follows: Time dependent magnetic induction field increases the dynamic viscosity of movable synovial fluid and decreases symptoms of cartilage illness for concrete intensity of magnetic field and concrete field line architecture. The ferrofluid therapy and phospholipids bilayer simultaneously with the administrated external electromagnetic field, increases the dynamic viscosity of movable synovial fluid.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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

  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. 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.

  17. 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

  18. 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.

  19. 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

  20. Long-Term Results of Radiation Therapy Oncology Group 9903: A Randomized Phase 3 Trial to Assess the Effect of Erythropoietin on Local-Regional Control in Anemic Patients Treated With Radiation Therapy for Squamous Cell Carcinoma of the Head and Neck

    Energy Technology Data Exchange (ETDEWEB)

    Shenouda, George, E-mail: George.shenouda@muhc.mcgill.ca [McGill University, Montreal, Quebec (Canada); Zhang, Qiang [NRG Oncology Statistics and Data Management Center (United States); Ang, K. Kian [University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Machtay, Mitchell [University Hospitals of Cleveland, Cleveland, Ohio (United States); Parliament, Matthew B. [Cross Cancer Institute, Edmonton, Alberta (Canada); Hershock, Diane [University of Pennsylvania Medical Center, Philadelphia, Pennsylvania (United States); Suntharalingam, Mohan [University of Maryland Medical System, Baltimore, Maryland (United States); Lin, Alexander [University of Pennsylvania Medical Center, Philadelphia, Pennsylvania (United States); Rotman, Marvin [Brooklyn Minority-based Community Clinical Oncology Program, State University of New York Downstate Medical Center, Brooklyn, New York (United States); Nabid, Abdenour [Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke (Québec), Québec (Canada); Hong, Susan [Akron City Hospital, Akron, Ohio (United States); Shehata, Sarwat [Northeastern Ontario Regional Cancer Centre, Sudbury, Ontario (Canada); Cmelak, Anthony J. [Vanderbilt University Medical Center, Nashville, Tennessee (United States); Sultanem, Khalil [McGill University, Montreal, Quebec (Canada); Le, Quynh-Thu [Stanford University Medical Center, Stanford, California (United States)

    2015-04-01

    Purpose: This paper reports long-term results of RTOG 9903, to determine whether the addition of erythropoietin (EPO) would improve the outcomes of radiation therapy (RT) in mildly to moderately anemic patients with head and neck squamous cell carcinoma (HNSCCa). Methods and Materials: The trial included HNSCCa patients treated with definitive RT. Patients with stage III or IV disease received concomitant chemoradiation therapy or accelerated fractionation. Pretreatment hemoglobin levels were required to be between 9.0 and 13.5 g/dL (12.5 g/dL for females). EPO, 40,000 U, was administered weekly starting 7 to 10 days before RT was initiated in the RT + EPO arm. Results: A total of 141 of 148 enrolled patients were evaluable. The baseline median hemoglobin level was 12.1 g/dL. In the RT + EPO arm, the mean hemoglobin level at 4 weeks increased by 1.66 g/dL, whereas it decreased by 0.24 g/dL in the RT arm. With a median follow-up of 7.95 years (range: 1.66-10.08 years) for surviving patients and 3.33 years for all patients (range: 0.03-10.08 years), the 5-year estimate of local-regional failure was 46.2% versus 39.4% (P=.42), local-regional progression-free survival was 31.5% versus 37.6% (P=.20), and overall survival was 36.9% versus 38.2% (P=.54) for the RT + EPO and RT arms, respectively. Late toxicity was not different between the 2 arms. Conclusions: This long-term analysis confirmed that despite the ability of EPO to raise hemoglobin levels in anemic patients with HNSCCa, it did not improve outcomes when added to RT. The possibility of a detrimental effect of EPO could not be ruled out.

  1. 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.

  2. 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.

  3. 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.)

  4. 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)

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. Role of Occupational Therapy in Combating Human Trafficking.

    Science.gov (United States)

    Gorman, Kathleen W; Hatkevich, Beth Ann

    Human trafficking is a modern-day form of slavery that includes sex trafficking, labor trafficking, and trafficking of children. It is estimated that 35.8 million people are enslaved around the world. Because of the traumatic experiences that victims of human trafficking encounter, the needs of victims are extensive and require the services of several providers, including health care providers, for victims to transform into survivors and thrivers. Currently, the role of occupational therapy is minimal and unexplored. The profession of occupational therapy has the capacity of having a profound role in both providing client-centered care services to victims and survivors of human trafficking and partaking in preventive advocacy efforts to combat human trafficking. Further advocacy efforts are required to promote the profession of occupational therapy in combating human trafficking. Copyright © 2016 by the American Occupational Therapy Association, Inc.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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.

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

    Directory of Open Access Journals (Sweden)

    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

  16. Gene therapy, human nature and the churches.

    Science.gov (United States)

    Dunstan, G R

    1991-12-01

    Moral analysis must begin with respect for the empirical features, the "facts of the case". Major advances in genetic knowledge and technology -- as in other sciences -- inevitably change mental attitudes. But they could not change human nature, a product of the distinctively human cerebral cortex. Human capacities like compassion and justice are our own and for us to guard. To ask (as some do) about a "right" to inherit a non-manipulated genome is to ask an unanswerable question: the language of rights is inappropriate in this context. Parents have a duty to safeguard and to serve the interests of their potential child. The medical duty is to help in that task in ways which they have limited freedom to choose. The role of churches is to be faithful to their deposit of faith and their theological principles, including that of freedom of conscience. Churches are too easily led in practice to over-rule conscience on grounds of authority, ecclesiastical or biblical, not sustained by convincing reason. This is most evident in some declarations concerning human reproduction. Better were it for them to help their faithful in moral reasoning, the ethics of choice; to keep consciences tender.

  17. Autophagy Therapeutic Potential of Garlic in Human Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Yung-Lin Chu

    2013-07-01

    Full Text Available Cancer is one of the deadliest diseases against humans. To tackle this menace, humans have developed several high-technology therapies, such as chemotherapy, tomotherapy, targeted therapy, and antibody therapy. However, all these therapies have their own adverse side effects. Therefore, recent years have seen increased attention being given to the natural food for complementary therapy, which have less side effects. Garlic 大 蒜 Dà Suàn; Allium sativum, is one of most powerful food used in many of the civilizations for both culinary and medicinal purpose. In general, these foods induce cancer cell death by apoptosis, autophagy, or necrosis. Studies have discussed how natural food factors regulate cell survival or death by autophagy in cancer cells. From many literature reviews, garlic could not only induce apoptosis but also autophagy in cancer cells. Autophagy, which is called type-II programmed cell death, provides new strategy in cancer therapy. In conclusion, we wish that garlic could be the pioneer food of complementary therapy in clinical cancer treatment and increase the life quality of cancer patients.

  18. 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.

  19. Erythropoietin enhances hippocampal long-term potentiation and memory

    Directory of Open Access Journals (Sweden)

    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. 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

  1. 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....

  2. Animal-Assisted Therapy for Improving Human Health

    Directory of Open Access Journals (Sweden)

    Sibel Cevizci

    2009-06-01

    Full Text Available ABSTRACT Animal Assisted Therapy (AAT or Pet Therapy is an adjunctive therapy by taking advantage of human and animal interaction, activate the physiological and psychological mechanisms, initiate positive changes improving health in metabolism. In recent years, this interaction are in use to treat psychological and psychiatric disorders such as stress, depression, loneliness, pervasive developmental disorders affect negatively to human health. Furthermore, AAT has been increasingly used to improve quality of life, hypertension, cardiovascular diseases, chronic illnesses such as cancer and AIDS. The aim of this paper is to identify AAT by reviewing human and animal interaction, evaluate how AAT has a scientific background from past to now. Also, we aim to give some information about the risks, institutional applications, some factors referring AAT’s mechanism of action and chronic diseases, psychological and physical improvements provided with animal assisted therapies. The therapy results will be evaluated more advisable providing AAT is being applied with public health specialist, veterinarian, physician, psychologist, psychiatrist and veterinary public health experts who are monitor applications. Especially, the psychosomatic effects result from physical, emotional and play mechanism of action of HDT can be used for improving quality of life in individuals with chronic diseases. In Turkey, there is no any investigation which have been performed in this scientific field. It is quitely important to evaluate the benefits of this therapy accurately and to select various methods proper to diseases. Consequently, it is obvious that AAT will be considered by the healthcare services as a supportive therapy process for improving human health in Turkey and needs further studies. [TAF Prev Med Bull 2009; 8(3.000: 263-272

  3. 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...

  4. 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.)

  5. 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 ...

  6. 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

  7. 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.

  8. Gene therapy in nonhuman primate models of human autoimmune disease

    NARCIS (Netherlands)

    t'Hart, B. A.; Vervoordeldonk, M.; Heeney, J. L.; Tak, P. P.

    2003-01-01

    Before autoimmune diseases in humans can be treated with gene therapy, the safety and efficacy of the used vectors must be tested in valid experimental models. Monkeys, such as the rhesus macaque or the common marmoset, provide such models. This publication reviews the state of the art in monkey

  9. Counseling Children and Adolescents: Rational Emotive Behavior Therapy and Humanism.

    Science.gov (United States)

    Vernon, Ann

    1996-01-01

    Describes specific parallels between rational emotive behavior therapy and humanism. Places specific emphasis on the application of these principles with children and adolescents. Concepts are illustrated with case studies and a description of the similarities between rational emotive and humanistic, or affective, education. Highlights emotional…

  10. 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

  11. Contemporary Animal Models For Human Gene Therapy Applications.

    Science.gov (United States)

    Gopinath, Chitra; Nathar, Trupti Job; Ghosh, Arkasubhra; Hickstein, Dennis Durand; Nelson, Everette Jacob Remington

    2015-01-01

    Over the past three decades, gene therapy has been making considerable progress as an alternative strategy in the treatment of many diseases. Since 2009, several studies have been reported in humans on the successful treatment of various diseases. Animal models mimicking human disease conditions are very essential at the preclinical stage before embarking on a clinical trial. In gene therapy, for instance, they are useful in the assessment of variables related to the use of viral vectors such as safety, efficacy, dosage and localization of transgene expression. However, choosing a suitable disease-specific model is of paramount importance for successful clinical translation. This review focuses on the animal models that are most commonly used in gene therapy studies, such as murine, canine, non-human primates, rabbits, porcine, and a more recently developed humanized mice. Though small and large animals both have their own pros and cons as disease-specific models, the choice is made largely based on the type and length of study performed. While small animals with a shorter life span could be well-suited for degenerative/aging studies, large animals with longer life span could suit longitudinal studies and also help with dosage adjustments to maximize therapeutic benefit. Recently, humanized mice or mouse-human chimaeras have gained interest in the study of human tissues or cells, thereby providing a more reliable understanding of therapeutic interventions. Thus, animal models are of great importance with regard to testing new vector technologies in vivo for assessing safety and efficacy prior to a gene therapy clinical trial.

  12. 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...

  13. The Humanism of Rational Emotive Behavior Therapy and Other Cognitive Behavior Therapies.

    Science.gov (United States)

    Ellis, Albert

    1996-01-01

    Describes aspects of rational emotive behavior therapy (REBT). REBT shows how people can both create and uncreate many of their emotional disturbances. It is a theory of personality which avoids devotion to any kind of magic and supernaturalism and emphasizes unconditional self-acceptance, antiabsolutism, uncertainty, and human fallibility. (RJM)

  14. The detection, diagnosis and therapy of human lung cancer

    International Nuclear Information System (INIS)

    1978-01-01

    The Cancergram covers clinical aspects of cancers of the lung and tracheo-bronchial tree, i.e., the lower respiratory tract. This includes primary lung cancer in both early and advanced disease status. The topic includes clinically relevant aspects of the prevention, detection, diagnosis, evaluation, and therapy of lung cancer. Certain aspects of metastatic lung disease treatment or therapy which involve aspects of interest to primary lung cancer are included. With certain exceptions, general pre-clinical or animal studies not directly related to the primary human disease are excluded

  15. 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

  16. 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.

  17. 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.

  18. 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...

  19. 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

  20. Human Placenta Extract Therapy for Feline Hepatic Lipidosis

    OpenAIRE

    2018-01-01

    Feline hepatic lipidosis (HL), the most common hepatobiliary disease in cats, is characterized by the accumulation of excessive triglycerides (TGs) in more than 80% of hepatocytes. Forced oral feeding is recommended as the only therapy for this disease but the prognosis is often poor. As human placenta extract (Laennec) has been used to improve hepatic metabolism, we investigated the efficacy of this drug for the treatment of cats with HL. Ten cats diagnosed with HL in this study were treated...

  1. Limits to human enhancement: nature, disease, therapy or betterment?

    Science.gov (United States)

    Hofmann, Bjørn

    2017-10-10

    New technologies facilitate the enhancement of a wide range of human dispositions, capacities, or abilities. While it is argued that we need to set limits to human enhancement, it is unclear where we should find resources to set such limits. Traditional routes for setting limits, such as referring to nature, the therapy-enhancement distinction, and the health-disease distinction, turn out to have some shortcomings. However, upon closer scrutiny the concept of enhancement is based on vague conceptions of what is to be enhanced. Explaining why it is better to become older, stronger, and more intelligent presupposes a clear conception of goodness, which is seldom provided. In particular, the qualitative better is frequently confused with the quantitative more. We may therefore not need "external" measures for setting its limits - they are available in the concept of enhancement itself. While there may be shortcomings in traditional sources of limit setting to human enhancement, such as nature, therapy, and disease, such approaches may not be necessary. The specification-of-betterment problem inherent in the conception of human enhancement itself provides means to restrict its unwarranted proliferation. We only need to demand clear, sustainable, obtainable goals for enhancement that are based on evidence, and not on lofty speculations, hypes, analogies, or weak associations. Human enhancements that specify what will become better, and provide adequate evidence, are good and should be pursued. Others should not be accepted.

  2. Glucosamine-Based Supramolecular Nanotubes for Human Mesenchymal Cell Therapy.

    Science.gov (United States)

    Talloj, Satish Kumar; Cheng, Bill; Weng, Jen-Po; Lin, Hsin-Chieh

    2018-04-23

    Herein, we demonstrate an example of glucosamine-based supramolecular hydrogels that can be used for human mesenchymal cell therapy. We designed and synthesized a series of amino acid derivatives based on a strategy of capping d-glucosamine moiety at the C-terminus and fluorinated benzyl group at the N-terminus. From a systematic study on chemical structures, we discovered that the glucosamine-based supramolecular hydrogel [pentafluorobenzyl (PFB)-F-Glu] self-assembled with one-dimensional nanotubular structures at physiological pH. The self-assembly of a newly discovered PFB-F-Glu motif is attributed to the synergistic effect of π-π stacking and extensive intermolecular hydrogen bonding network in aqueous medium. Notably, PFB-F-Glu nanotubes are proven to be nontoxic to human mesenchymal stem cells (hMSCs) and have been shown to enhance hMSC proliferation while maintaining their pluripotency. Retaining of pluripotency capabilities provides potentially unlimited source of undifferentiated cells for the treatment of future cell therapies. Furthermore, hMSCs cultured on PFB-F-Glu are able to secrete paracrine factors that downregulate profibrotic gene expression in lipopolysaccharide-treated human skin fibroblasts, which demonstrates that PFB-F-Glu nanotubes have the potential to be used for wound healing applications. Overall, this article addresses the importance of chemical design to generate supramolecular biomaterials for stem cell therapy.

  3. 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 ...

  4. 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.

  5. 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...

  6. 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

  7. 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

  8. Human gene therapy and imaging in neurological diseases

    International Nuclear Information System (INIS)

    Jacobs, Andreas H.; Winkler, Alexandra; Castro, Maria G.; Lowenstein, Pedro

    2005-01-01

    Molecular imaging aims to assess non-invasively disease-specific biological and molecular processes in animal models and humans in vivo. Apart from precise anatomical localisation and quantification, the most intriguing advantage of such imaging is the opportunity it provides to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Further, molecular imaging can be used to address basic scientific questions, e.g. transcriptional regulation, signal transduction or protein/protein interaction, and will be essential in developing treatment strategies based on gene therapy. Most importantly, molecular imaging is a key technology in translational research, helping to develop experimental protocols which may later be applied to human patients. Over the past 20 years, imaging based on positron emission tomography (PET) and magnetic resonance imaging (MRI) has been employed for the assessment and ''phenotyping'' of various neurological diseases, including cerebral ischaemia, neurodegeneration and brain gliomas. While in the past neuro-anatomical studies had to be performed post mortem, molecular imaging has ushered in the era of in vivo functional neuro-anatomy by allowing neuroscience to image structure, function, metabolism and molecular processes of the central nervous system in vivo in both health and disease. Recently, PET and MRI have been successfully utilised together in the non-invasive assessment of gene transfer and gene therapy in humans. To assess the efficiency of gene transfer, the same markers are being used in animals and humans, and have been applied for phenotyping human disease. Here, we review the imaging hallmarks of focal and disseminated neurological diseases, such as cerebral ischaemia, neurodegeneration and glioblastoma multiforme, as well as the attempts to translate gene therapy's experimental knowledge into clinical applications and the way in which this process is being promoted through the use of

  9. 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

  10. 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.

  11. 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.

  12. 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

  13. 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)

  14. 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.

  15. 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.

  16. 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

  17. 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....

  18. 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...

  19. 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....

  20. 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...

  1. Microwave therapy for cutaneous human papilloma virus infection.

    Science.gov (United States)

    Bristow, Ivan; Lim, Wen Chean; Lee, Alvin; Holbrook, Daniel; Savelyeva, Natalia; Thomson, Peter; Webb, Christopher; Polak, Marta; Ardern-Jones, Michael R

    2017-10-01

    Human papilloma virus (HPV) infects keratinocytes of the skin and mucous membranes, and is associated with the induction of cutaneous warts and malignancy. Warts can induce significant morbidity and disability but most therapies, including cryotherapy, laser, and radiofrequency devices show low efficacy and induce discomfort through tissue destruction. Microwaves are readily capable of passing through highly keratinised skin to deliver energy and induce heating of the tissue in a highly controllable, uniform manner. To determine the effects of microwave on cutaneous HPV infection. We undertook a pilot study of microwave therapy to the skin in 32 consecutive individuals with 52 recalcitrant long-lived viral cutaneous warts. Additionally, we undertook a molecular characterisation of the effects of microwaves on the skin. Tissue inflammation was minimal, but 75.9% of lesions cleared which compares favourably with previous studies showing a clearance rate of 23-33% for cryotherapy or salicylic acid. We show that microwaves specifically induce dendritic cell cross-presentation of HPV antigen to CD8+ T cells and suggest that IL-6 may be important for DC IRF1 and IRF4 modulation to enhance this process. Keratinocyte-skin dendritic cell cross-talk is integral to host defence against HPV infections, and this pilot study supports the concept of microwave induction of anti-HPV immunity which offers a promising approach for treatment of HPV-induced viral warts and potentially HPV-related cancers.

  2. Bacteriophage therapy for safeguarding animal and human health: a review.

    Science.gov (United States)

    Tiwari, Ruchi; Dhama, Kuldeep; Kumar, Amit; Rahal, Anu; Kapoor, Sanjay

    2014-02-01

    Since the discovery of bacteriophages at the beginning of the 19th century their contribution to bacterial evolution and ecology and use in a variety of applications in biotechnology and medicine has been recognized and understood. Bacteriophages are natural bacterial killers, proven as best biocontrol agents due to their ability to lyse host bacterial cells specifically thereby helping in disease prevention and control. The requirement of such therapeutic approach is straight away required in view of the global emergence of Multidrug Resistant (MDR) strains of bacteria and rapidly developing resistance to antibiotics in both animals and humans along with increasing food safety concerns including of residual antibiotic toxicities. Phage typing is a popular tool to differentiate bacterial isolates and to identify and characterize outbreak-associated strains of Salmonella, Campylobacter, Escherichia and Listeria. Numerous methods viz. plaque morphology, ultracentrifugation in the density gradient of CsCl2, and random amplified polymorphic DNA (RAPD) have been found to be effective in detection of various phages. Bacteriophages have been isolated and recovered from samples of animal waste products of different livestock farms. High titer cocktails of broad spectrum lytic bacteriophages are usually used for clinical trial for assessing their therapeutic efficacy against antibiotic unresponsive infections in different animals. Bacteriophage therapy also helps to fight various bacterial infections of poultry viz. colibacillosis, salmonellosis and listeriosis. Moreover, the utility of phages concerning biosafety has raised the importance to explore and popularize the therapeutic dimension of this promising novel therapy which forms the topic of discussion of the present review.

  3. 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

  4. Wound Healing and ndash; A Proteomic Analysis of the Effect of Erythropoietin on Granulation Tissue Isolated from ePTFE Implants

    Directory of Open Access Journals (Sweden)

    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

  5. Designing a Long Acting Erythropoietin by Fusing Three Carboxyl-Terminal Peptides of Human Chorionic Gonadotropin β Subunit to the N-Terminal and C-Terminal Coding Sequence

    Directory of Open Access Journals (Sweden)

    Fuad Fares

    2011-01-01

    Full Text Available A new analog of EPO was designed by fusing one and two CTPs to the N-terminal and C-terminal ends of EPO (EPO-(CTP3, respectively. This analog was expressed and secreted efficiently in CHO cells. The in vitro test shows that the activity of EPO-(CTP3 in TFI-1 cell proliferation assay is similar to that of EPO-WT and commercial rHEPO. However, in vivo studies indicated that treatment once a week with EPO-(CTP3 (15 μg/kg dramatically increased (~8 folds haematocrit as it was compared to rHuEPO. Moreover, it was found that EPO-(CTP3 is more effective than rHuEPO and Aranesp in increasing reticulocyte number in mice blood. The detected circulatory half-lives of rHuEPO, Aranesp, and EPO-(CTP3 following IV injection of 20 IU were 4.4, 10.8, and 13.1 h, respectively. These data established the rational for using this chimera as a long-acting EPO analog in clinics. The therapeutic efficacy of EPO-CTP analog needs to be established in higher animals and in human clinical trials.

  6. 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)

  7. 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

  8. Experimental research of radiogenic therapy on human melanoma

    International Nuclear Information System (INIS)

    Min Fengling; Chinese Academy of Sciences, Beijing; Zhang Hong; Li Wenjiang; Liu Bing; Zhou Qingming; Duan Xin; Zhou Guangming; Gao Qingxiang

    2006-01-01

    To investigate the effect of low dose irradiation on gene transfer efficiency and the effect of adenoviral-mediated exogenous P53 overexpression on radiosensitivity of radioresistant human melanoma cell line A375 with wild type p53, control vector, a replication deficient recombinant adenoviral vector containing a CMV promoter and green fluorescent protein (AdCMV-GFP), was used to transfect the A375 cells preirradiated with or without 1 Gy X-ray radiation. The transduction efficiency of GFP gene was determined with fluorescence microscope directly. A375 cells radiated by 1 Gy X-ray were transfected with a replication deficient recombinant adenoviral vector carrying human wild p53 were detected using flow cytometry (FCM) at different time after transfection. The radiosensitivity of A375 cells after p53 transduction was assayed by clonoy formation. The authors found that 1 Gy exposure increased the gene transfer efficiency of A375 cells. The expression of exogenous P53 was found to be 60% to 80% of transfected cells during the first three days after transduction and then declined continuously down to the control level on the day 10. The G1 cell cycle arrest was also observed after p53 gene transfer. A375 cells that were transfected with p53 showed higher sensitivity of X-ray-induced cell killing than those cells that either were transfected with the viral vector carrying a green fluorescent protein gene or were not transfected at all. Low dose ionizing radiation can improve gene transfer efficiency of A375 cells mediated by adenovirus vector. Althrough the overexpresion of exogenous P53 may not inhibit cell growth and induce apoptosis of melanoma cell line A375 in vitro, it made the tumor cells much sensitive to death by irradiation. the data suggested that p53 gene might be a potential gene for melanoma therapy and provide the experimental evidences to clinically using the combination of radiation with gene therapy on melanoma. Namely, there may be a reduction of

  9. Nonadherence with pediatric human immunodeficiency virus therapy as medical neglect.

    Science.gov (United States)

    Roberts, Gretchen M; Wheeler, J Gary; Tucker, Nancy C; Hackler, Chris; Young, Karen; Maples, Holly D; Darville, Toni

    2004-09-01

    To examine the results of an interventionist approach applied to human immunodeficiency virus (HIV)-infected children for whom caregiver nonadherence was suspected as the cause of treatment failure. The medical records of a cohort of 16 perinatally HIV-infected children whose care was managed at the Arkansas Children's Hospital Pediatric HIV Clinic for an uninterrupted period of >or=3 years were reviewed through July 2003. Data collected included date of birth, dates of and explanations for clinic visits and hospitalizations, dates of laboratory evaluations, CD4(+) T cell percentages, plasma HIV-1 RNA levels, antiretroviral medications, viral resistance tests (eg, phenotype and genotype), and physician-initiated interventions to enhance adherence to the medication regimen. A stepwise interventionist approach was undertaken when patients continued to demonstrate high viral loads, despite documented viral sensitivity to the medication regimen and caregivers' insistence that medications were being administered regularly. Step 1 was prescribing a home health nurse referral, step 2 was administering directly observed therapy (DOT) while the patient was hospitalized for 4 days, and step 3 was submitting a physician-initiated medical neglect report to the Arkansas Department of Human Services. The results for 6 patients for whom this stepwise approach was initiated are reported. Home health nurse referrals failed to result in sustained improvements in adherence in all 6 cases. Viral load assays performed before and after DOT provided an objective measure of the effect of adherence, with 12 hospitalizations resulting in a mean +/- SD decrease in HIV RNA levels of 1.09 +/- 0.5 log(10) copies per mL, with a range of 0.6 to 2.1 log(10) copies per mL. Four families responded to DOT hospitalization, and sustained decreases in the respective patients' viral loads were noted. In 2 cases, medical neglect reports were submitted when DOT did not result in improved adherence. These

  10. Effect of recombinant human erythropoietin expressions of apoptosis ...

    African Journals Online (AJOL)

    apoptosis genes in rats following traumatic brain injury. Xuesong Yuan1* ... ĸB)-, c-myc-, and Fas/Fasl-positive cells were identified in brain tissues by ... stem cells present in the bone marrow. ... neuronal regeneration [12], lowering toxicity of.

  11. Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla Woznica; Ehrenreich, Hannelore; Christensen, Ellen M

    2014-01-01

    was randomized in September 2009 and last assessment was completed in October 2012. Patients were assessed at baseline and at weeks 9 and 14. The primary outcome was change in verbal memory indexed by the total words recalled across Rey Auditory Verbal Learning Test learning trials (I-V) from baseline to week 9...

  12. Recombinant Human Erythropoietin for Treating Treatment-Resistant Depression

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Vinberg, Maj; Christensen, Ellen M

    2014-01-01

    improves mood and memory in treatment-resistant depression. Forty treatment-resistant depressed unipolar patients with Hamilton Depression Rating Scale-17 (HDRS-17) score ≥ 17 were randomized to eight weekly EPO (Eprex; 40,000 IU) or saline infusions in a double-blind, placebo-controlled, parallel...

  13. Human Embryonic Stem Cell Therapy in Crohn’s Disease: A Case Report

    Science.gov (United States)

    Shroff, Geeta

    2016-01-01

    Patient: Male, 21 Final Diagnosis: Crohn’s disease Symptoms: Intolerance to specific foods • abdominal pain and diarrhea Medication: Human embryonic stem cell therapy Clinical Procedure: Human embryonic stem cell transplantation Specialty: Gastroenterology Objective: Unusual or unexpected effect of treatment Background: Crohn’s disease is a chronic inflammatory disease of the intestines, mainly the colon and ileum, related with ulcers and fistulae. It is estimated to affect 565 000 people in the United States. Currently available therapies, such as antibiotics, thiopurines, and anti-tumor necrosis factor-alpha agents, are only observed to reduce the complications associated with Crohn’s disease and to improve quality of life, but cannot cure the disease. Stem cell therapy appears to have certain advantages over conventional therapies. Our study aimed to evaluate the efficacy of human embryonic stem cell therapy in a patient with Crohn’s disease. Case Report: A 21-year-old male with chief complaints of intolerance to specific foods, abdominal pain, and diarrhea underwent human embryonic stem cell therapy for two months. After undergoing human embryonic stem cell therapy, the patient showed symptomatic relief. He had no complaints of back pain, abdominal pain, or diarrhea and had improved digestion. The patient had no signs and symptoms of skin infection, and had improved limb stamina, strength, and endurance. The condition of patient was stable after the therapy. Conclusions: Human embryonic stem cell therapy might serve as a new optimistic treatment approach for Crohn’s disease. PMID:26923312

  14. 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.

  15. 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)

  16. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement

    OpenAIRE

    Cideciyan, Artur V.; Jacobson, Samuel G.; Beltran, William A.; Sumaroka, Alexander; Swider, Malgorzata; Iwabe, Simone; Roman, Alejandro J.; Olivares, Melani B.; Schwartz, Sharon B.; Komáromy, András M.; Hauswirth, William W.; Aguirre, Gustavo D.

    2013-01-01

    The first retinal gene therapy in human blindness from RPE65 mutations has focused on safety and efficacy, as defined by improved vision. The disease component not studied, however, has been the fate of photoreceptors in this progressive retinal degeneration. We show that gene therapy improves vision for at least 3 y, but photoreceptor degeneration progresses unabated in humans. In the canine model, the same result occurs when treatment is at the disease stage equivalent to humans. The study ...

  17. [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.

  18. 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.

  19. 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.

  20. 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

  1. Human rights in occupational therapy education: A step towards a more occupationally just global society.

    Science.gov (United States)

    Crawford, Emma; Aplin, Tammy; Rodger, Sylvia

    2017-04-01

    Education on human rights will place occupational therapists in a strong position to address societal inequities that limit occupational engagement for many client groups. The imminent changes to the Minimum Standard for the Education of Occupational Therapists engender efforts towards social change and will require university-level human rights education. This education might enhance the profession's influence on disadvantaging social structures in order to effect social change. To contribute to the evidence base for social change education in occupational therapy, this research aims to understand the knowledge, skills, confidence and learning experiences of occupational therapy students who completed a human rights course. Final year occupational therapy students responded to questionnaires which included listing human rights, a human rights scale measuring knowledge and confidence for working towards human rights, and open questions. Numbers of rights listed, knowledge scores and confidence scores were calculated. Responses to the open questions were thematically analysed. After completing a human rights course, students had good knowledge and moderate confidence to work with human rights. Three themes were identified including 'learning about human rights', 'learning about structural, societal and global perspectives on occupational engagement' and 'learning how occupational therapists can work with groups, communities and populations: becoming articulate and empowered'. Human rights education fosters the development of occupational therapists who are skilled, knowledgeable, confident and empowered to address occupational injustices, according to these research findings. To develop a more occupationally just global society, education that considers iniquitous social structures and human rights is necessary. © 2016 Occupational Therapy Australia.

  2. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. 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.

  5. [Diagnosis and therapy of anemia in chronic diseases].

    Science.gov (United States)

    Scudla, V; Adam, Z; Scudlová, M

    2001-06-01

    The article deals with contemporary views on anaemia associated with chronic diseases. The authors present the definition of this nosological unit, draw attention to its high incidence in clinical practice and fact that it is frequently mistaken for iron deficiency anaemia. The authors submit a review of the most frequent diseases which cause the development of this type of anaemia and analyze the role of activation of the system of cellular immunity, the monocyte-macrophage system, agents of the cytokine network in inhibition of proliferation and differentiation of erythroid precursors, reduced production of endogenous erythropoietin with a reduced sensitivity of erythroid progenitor cells to its action and impaired iron homeostasis and inhibition of its reutilization. Special attention is devoted to diagnostic and differential diagnostic criteria in relation to other types of anaemia caused by impaired haeme synthesis and some secondary multifactorially conditioned types of anaemia. More detailed attention is paid to the diagnostic value of evaluating serum levels of soluble transferrin receptors and explanation of the asset of calculation of the transferrin receptor/ferririn index as a sensitive indicator of latent sideropenia as well as the Fe-absorption test using low oral iron doses. Part of the paper is also an account of contemporary possibilities of treatment including the use of the recombinant form of human erythropoietin, and attention is drawn to the unsuitability and pitfalls of iron therapy in this type of anaemia.

  6. 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....

  7. 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.

  8. Human Embryonic Stem Cell Therapy in Crohn's Disease: A Case Report.

    Science.gov (United States)

    Shroff, Geeta

    2016-02-29

    Crohn's disease is a chronic inflammatory disease of the intestines, mainly the colon and ileum, related with ulcers and fistulae. It is estimated to affect 565,000 people in the United States. Currently available therapies, such as antibiotics, thiopurines, and anti-tumor necrosis factor-alpha agents, are only observed to reduce the complications associated with Crohn's disease and to improve quality of life, but cannot cure the disease. Stem cell therapy appears to have certain advantages over conventional therapies. Our study aimed to evaluate the efficacy of human embryonic stem cell therapy in a patient with Crohn's disease. A 21-year-old male with chief complaints of intolerance to specific foods, abdominal pain, and diarrhea underwent human embryonic stem cell therapy for two months. After undergoing human embryonic stem cell therapy, the patient showed symptomatic relief. He had no complaints of back pain, abdominal pain, or diarrhea and had improved digestion. The patient had no signs and symptoms of skin infection, and had improved limb stamina, strength, and endurance. The condition of patient was stable after the therapy. Human embryonic stem cell therapy might serve as a new optimistic treatment approach for Crohn's disease.

  9. 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.

  10. An electroconvulsive therapy procedure impairs reconsolidation of episodic memories in humans

    NARCIS (Netherlands)

    Kroes, Marijn C. W.; Tendolkar, Indira; van Wingen, Guido A.; van Waarde, Jeroen A.; Strange, Bryan A.; Fernández, Guillén

    2014-01-01

    Despite accumulating evidence for a reconsolidation process in animals, support in humans, especially for episodic memory, is limited. Using a within-subjects manipulation, we found that a single application of electroconvulsive therapy following memory reactivation in patients with unipolar

  11. 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.

  12. 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.

  13. Treatment facilities, human resource development, and future prospect of particle beam therapy

    International Nuclear Information System (INIS)

    Tamaki, Tomoaki; Nakano, Takashi

    2015-01-01

    The number of particle beam therapy facilities is increasing globally. Among the countries practicing particle beam therapy, Japan is one of the leading countries in the field with four operating carbon-ion therapy facilities and ten operating proton therapy facilities. With the increasing number of particle beam therapy facilities, the human resource development is becoming extremely important, and there has been many such efforts including the Gunma University Program for Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering, which aimed to educate and train the radiation oncologists, medical physicists, accelerator engineers, and radiation biologists to become global leaders in the field of particle beam therapy. In the future, the benefit and effectiveness of particle beam therapy should be discussed and elucidated objectively in a framework of comprehensive cancer care. (author)

  14. [The physical therapy undergraduate students' responses to the gross human anatomy subjects].

    Science.gov (United States)

    Anahara, Reiko; Kawashiro, Yukiko; Matsuno, Yoshiharu; Mori, Chisato; Kohno, Toshihiko

    2008-09-01

    Instruction in gross human anatomy is one of the important items in the subject for co-medical students of the physical therapist course. The physical therapy undergraduate students are required to have a solid understanding of the structure and formation of the human body. Therefore, their good-understanding of the course on the gross human anatomy and their experience of the gross human anatomy laboratory (observation practice) are acquired to improve their knowledge of the human body. To clarify the student responses to the gross human anatomy course including the gross human anatomy laboratory, several questionnaires were administered to the freshman physical therapy undergraduate student for two years. We found that more than 80% of the students, who felt a negative attitude for gross human anatomy before the course started, had a positive attitude about the gross human anatomy after going through the course. The experience of the gross human anatomy laboratory increased the students' activity of learning and they thought more about the dignity of being human after the course than before viewing. In addition, the results suggested that the multiple experiences of the gross human anatomy course are useful for the physical therapy undergraduate students to improve the quality of their understanding of the human body.

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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...

  20. 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.

  1. Endocrine therapy of human breast cancer grown in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Osborne, C K; Spang-Thomsen, M

    1987-01-01

    mice bearing transplanted human breast tumors have been proposed as such a model. This review therefore discusses the use of the athymic nude mouse model of the study of human breast cancer biology, and focuses on four subjects: 1. biological characteristics of heterotransplanted breast tumors; 2...

  2. "Voice Forum" The Human Voice as Primary Instrument in Music Therapy

    DEFF Research Database (Denmark)

    Pedersen, Inge Nygaard; Storm, Sanne

    2009-01-01

    Aspects will be drawn on the human voice as tool for embodying our psychological and physiological state, and attempting integration of feelings. Presentations and dialogues on different methods and techniques in "Therapy related body-and voice work.", as well as the human voice as a tool for non...

  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. 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.

  5. 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.

  6. 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.

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. 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.

  10. 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...

  11. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. A review on stem cell therapy for multiple sclerosis: special focus on human embryonic stem cells.

    Science.gov (United States)

    Shroff, Geeta

    2018-01-01

    Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury. Human embryonic stem cell (hESC) transplantation is one of the promising cell therapies; hESCs play an important role in remyelination and help in preventing demylenation of the axons. In this study, an overview of the current knowledge about the unique properties of hESC and their comparison with other cell therapies has been presented for the treatment of patients with MS.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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...

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. Human gene therapy: novel approaches to improve the current gene delivery systems.

    Science.gov (United States)

    Cucchiarini, Magali

    2016-06-01

    Even though gene therapy made its way through the clinics to treat a number of human pathologies since the early years of experimental research and despite the recent approval of the first gene-based product (Glybera) in Europe, the safe and effective use of gene transfer vectors remains a challenge in human gene therapy due to the existence of barriers in the host organism. While work is under active investigation to improve the gene transfer systems themselves, the use of controlled release approaches may offer alternative, convenient tools of vector delivery to achieve a performant gene transfer in vivo while overcoming the various physiological barriers that preclude its wide use in patients. This article provides an overview of the most significant contributions showing how the principles of controlled release strategies may be adapted for human gene therapy.

  5. Cyclotron Produced Radionuclides for Diagnosis and Therapy of Human Neoplasms

    Energy Technology Data Exchange (ETDEWEB)

    Steven Larson MD

    2009-09-21

    This project funded since 1986 serves as a core project for cancer research throughout MSKCC, producing key radiotracers as well as basic knowledge about thel physics of radiation decay and imaging, for nuclear medicine applications to cancer diagnosis and therapy. In recent years this research application has broadened to include experiments intended to lead to an improved understanding of cancer biology and into the discovery and testing of new cancer drugs. Advances in immune based radiotargeting form the basis for this project. Both antibody and cellular based immune targeting methods have been explored. The multi-step targeting methodologies (MST) developed by NeoRex (Seattle,Washington), have been adapted for use with positron emitting isotopes and PET allowing the quantification and optimization of targeted delivery. In addition, novel methods for radiolabeling immune T-cells with PET tracers have advanced our ability to track these cells of prolonged period of time.

  6. The Role of Therapy Education of Islamic Meaning to Overcome Today’s Global Human Crisis

    Directory of Open Access Journals (Sweden)

    Nina Aminah

    2016-02-01

    Full Text Available Modern community are exposed to current issues related to the very complex personality. Islam offers a therapeutic meaning to overcome the global human crisis through the holy Qu’ran. This study aims to provide a qualitative analysis of logotherapy alternative to global human who experience critical conditions such as the door of death (sakaratul maut, acute illnesses, HIV Aids, kidney illness, stroke, coma, depression / stress, due to the hazards, and other refractory disease. The study showed that the therapy of Islamic meaning based on the holy Qur’an is broader and more comprehensive than the meaning therapy by Viktor E. Frankl.

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

    Science.gov (United States)

    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.

  8. 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

  9. Application of the Human Activity Assistive Technology model for occupational therapy research.

    Science.gov (United States)

    Giesbrecht, Ed

    2013-08-01

    Theoretical models provide a framework for describing practice and integrating evidence into systematic research. There are few models that relate specifically to the provision of assistive technology in occupational therapy practice. The Human Activity Assistive Technology model is an enduring example that has continued to develop by integrating a social model of disability, concepts from occupational therapy theory and principles of assistive technology adoption and abandonment. This study first describes the core concepts of the Human Activity Assistive Technology model and reviews its development over three successive published versions. A review of the research literature reflects application of the model to clinical practice, study design, outcome measure selection and interpretation of results, particularly among occupational therapists. An evaluative framework is used to critique the adequacy of the Human Activity Assistive Technology model for practice and research, exploring attributes of clarity, simplicity, generality, accessibility and importance. Finally, recommendations are proposed for continued development of the model and research applications. Most of the existing research literature employs the Human Activity Assistive Technology model for background and study design; there is emerging evidence to support the core concepts as predictive factors. Although the concepts are generally simple, clear and applicable to occupational therapy practice and research, evolving terminology and outcomes become more complex with the conflation of integrated theories. The development of the Human Activity Assistive Technology model offers enhanced access and application for occupational therapists, but poses challenges to clarity among concepts. Suggestions are made for further development and applications of the model. © 2013 Occupational Therapy Australia.

  10. 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

  11. 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...

  12. Bench to Bedside: Future Therapies For Treatment Of Anemia In Patients With Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    KM Murali

    2017-10-01

    Full Text Available The link between chronic kidney disease (CKD and anemia has been known for over 180 years ever since it was highlighted by the legendary Richard Bright. The key etiological factors responsible for anemia due to renal disease were identified in the 1950s as relative deficiency of erythropoietin and reduced red cell survival as well as abnormalities in iron metabolism. This knowledge was not translated to therapeutics for the next three decades and red cell transfusions were the main-stay of treatment of renal anemia till recombinant human erythropoietin (rHuEPO was introduced in the 1980s. Recurrent transfusions, in addition to causing HLA sensitization, frequently resulted in iron overload with subsequent parenchymal iron deposition and organ dysfunction - a well-known scenario in the pre-erythropoetin era and use of iron chelation therapy was a feasible therapeutic option in long-term dialysis patients. This situation changed dramatically with the widespread clinical use of erythropoiesis stimulating agents (ESA, and polar opposite to the iron overload problems, most patient on erythropoietin therapy required oral or parenteral iron supplements to replenish iron stores for optimal erythropoiesis. Over the last three decades developments in molecular engineering lead to the modification of the original rHuEPO to longer acting analogues such as darbepoetin (Aranesp ® and methoxy polyethylene glycol-epoetin beta (Mircera ® and a raft of EPO biosimilars. In India, where the cost of medications constrains the universal access to ESA therapy, biosimilar erythropoetins offer a relative advantage in that they cost less than half the price of the premium brands. Nevertheless, the progress in clinically prescribed ESA therapy since the discovery of rHuEPO has resulted from modest modification of existing knowledge rather than a revolutionary break from convention. Over the last few years newer molecules capable of revolutionizing the therapy of renal

  13. 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.

  14. 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.

  15. 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.

  16. Progressing a human embryonic stem-cell-based regenerative medicine therapy towards the clinic.

    Science.gov (United States)

    Whiting, Paul; Kerby, Julie; Coffey, Peter; da Cruz, Lyndon; McKernan, Ruth

    2015-10-19

    Since the first publication of the derivation of human embryonic stem cells in 1998, there has been hope and expectation that this technology will lead to a wave of regenerative medicine therapies with the potential to revolutionize our approach to managing certain diseases. Despite significant resources in this direction, the path to the clinic for an embryonic stem-cell-based regenerative medicine therapy has not proven straightforward, though in the past few years progress has been made. Here, with a focus upon retinal disease, we discuss the current status of the development of such therapies. We also highlight some of our own experiences of progressing a retinal pigment epithelium cell replacement therapy towards the clinic. © 2015 The Author(s).

  17. Further development of thermal neutron capture therapy for metastatic and deeply-invasive human malignant melanoma

    International Nuclear Information System (INIS)

    Mishima, Yutaka

    1995-03-01

    This issue is the collection of the papers presented thermal neutron capture therapy for metastatic and deeply-invasive human malignant melanoma. Separate abstracts were prepared for 2 of the papers in this report. The remaining 32 papers were considered outside the subject scope of INIS. (J.P.N.)

  18. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)--associated tuberculous meningitis

    NARCIS (Netherlands)

    Török, M. Estee; Yen, Nguyen Thi Bich; Chau, Tran Thi Hong; Mai, Nguyen Thi Hoang; Phu, Nguyen Hoan; Mai, Pham Phuong; Dung, Nguyen Thi; Chau, Nguyen Van Vinh; Bang, Nguyen Duc; Tien, Nguyen Anh; Minh, N. H.; Hien, Nguyen Quang; Thai, Phan Vuong Khac; Dong, Doan The; Anh, Do Thi Tuong; Thoa, Nguyen Thi Cam; Hai, Nguyen Ngoc; Lan, Nguyen Ngoc; Lan, Nguyen Thi Ngoc; Quy, Hoang Thi; Dung, Nguyen Huy; Hien, Tran Tinh; Chinh, Nguyen Tran; Simmons, Cameron Paul; de Jong, Menno; Wolbers, Marcel; Farrar, Jeremy James

    2011-01-01

    The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-associated tuberculous meningitis is unknown. We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to

  19. In vitro assessment of the efficacy of thermal therapy in human benign prostatic hyperplasia

    NARCIS (Netherlands)

    Bhowmick, P.; Coad, J. E.; Bhowmick, S.; Pryor, J. L.; Larson, T.; de la Rosette, J.; Bischof, J. C.

    2004-01-01

    The successful management of BPH with minimally invasive thermal therapies requires a firm understanding of the temperature-time relationship for tissue destruction. In order to accomplish this objective, the present in vitro study assesses the cellular viability of human BPH tissue subjected to an

  20. Efficient and Fast Differentiation of Human Neural Stem Cells from Human Embryonic Stem Cells for Cell Therapy

    Directory of Open Access Journals (Sweden)

    Xinxin Han

    2017-01-01

    Full Text Available Stem cell-based therapies have been used for repairing damaged brain tissue and helping functional recovery after brain injury. Aberrance neurogenesis is related with brain injury, and multipotential neural stem cells from human embryonic stem (hES cells provide a great promise for cell replacement therapies. Optimized protocols for neural differentiation are necessary to produce functional human neural stem cells (hNSCs for cell therapy. However, the qualified procedure is scarce and detailed features of hNSCs originated from hES cells are still unclear. In this study, we developed a method to obtain hNSCs from hES cells, by which we could harvest abundant hNSCs in a relatively short time. Then, we examined the expression of pluripotent and multipotent marker genes through immunostaining and confirmed differentiation potential of the differentiated hNSCs. Furthermore, we analyzed the mitotic activity of these hNSCs. In this report, we provided comprehensive features of hNSCs and delivered the knowledge about how to obtain more high-quality hNSCs from hES cells which may help to accelerate the NSC-based therapies in brain injury treatment.

  1. Effect of recombinant adenovirus encoding human p53 tumor suppressor gene combined with radiation therapy on human lymphoma cells lines

    International Nuclear Information System (INIS)

    Yu Zeyang; Fan Wo; Li Dongqing; Zhu Ran; Wan Jianmei; Wang Yongqing; Wu Jinchang

    2008-01-01

    This paper analyzes the inhibitory effect and radiation sensitization of recombinant adenovirus encoding human p53 tumor suppressor gene (rAd-p53) on human lymphoma cell lines. Human lymphoma cell lines were treated with rAd-p53, radiation therapy and combined treatment, respectively. The cell growth inhibition was assessed by MTF. The cell cycle and apoptosis were detected by flow cytometry, and the p53 protein expression was detected by Western blotting. The results showed that extrinsic p53 gene have expressed to some degree, but not at high level. The role of inhibition and radiation sensitivity of rAd-p53 was not significant to human lymphoma cell lines. (authors)

  2. Gene doping detection: evaluation of approach for direct detection of gene transfer using erythropoietin as a model system.

    Science.gov (United States)

    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.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. Electrical signature analysis to quantify human and animal performance on fitness and therapy equipment such as a treadmill

    Science.gov (United States)

    Cox, Daryl F.; Hochanadel, Charles D.; Haynes, Howard D.

    2010-05-18

    The invention is a human and animal performance data acquisition, analysis, and diagnostic system for fitness and therapy devices having an interface box removably disposed on incoming power wiring to a fitness and therapy device, at least one current transducer removably disposed on said interface box for sensing current signals to said fitness and therapy device, and a means for analyzing, displaying, and reporting said current signals to determine human and animal performance on said device using measurable parameters.

  10. 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.

  11. 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

  12. 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...

  13. 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...

  14. 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...

  15. 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

  16. 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

  17. 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

  18. 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...

  19. 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

  20. Effects of Long Term Antibiotic Therapy on Human Oral and Fecal Viromes.

    Science.gov (United States)

    Abeles, Shira R; Ly, Melissa; Santiago-Rodriguez, Tasha M; Pride, David T

    2015-01-01

    Viruses are integral members of the human microbiome. Many of the viruses comprising the human virome have been identified as bacteriophage, and little is known about how they respond to perturbations within the human ecosystem. The intimate association of phage with their cellular hosts suggests their communities may change in response to shifts in bacterial community membership. Alterations to human bacterial biota can result in human disease including a reduction in the host's resilience to pathogens. Here we report the ecology of oral and fecal viral communities and their responses to long-term antibiotic therapy in a cohort of human subjects. We found significant differences between the viral communities of each body site with a more heterogeneous fecal virus community compared with viruses in saliva. We measured the relative diversity of viruses, and found that the oral viromes were significantly more diverse than fecal viromes. There were characteristic changes in the membership of oral and fecal bacterial communities in response to antibiotics, but changes in fecal viral communities were less distinguishing. In the oral cavity, an abundance of papillomaviruses found in subjects on antibiotics suggests an association between antibiotics and papillomavirus production. Despite the abundance of papillomaviruses identified, in neither the oral nor the fecal viromes did antibiotic therapy have any significant impact upon overall viral diversity. There was, however, an apparent expansion of the reservoir of genes putatively involved in resistance to numerous classes of antibiotics in fecal viromes that was not paralleled in oral viromes. The emergence of antibiotic resistance in fecal viromes in response to long-term antibiotic therapy in humans suggests that viruses play an important role in the resilience of human microbial communities to antibiotic disturbances.

  1. Otitis media in Brazilian human immunodeficiency virus infected children undergoing antiretroviral therapy.

    Science.gov (United States)

    Miziara, I D; Weber, R; Araújo Filho, B Cunha; Pinheiro Neto, C Diógenes

    2007-11-01

    To assess changes in the prevalence of otitis media, associated with the use of highly active antiretroviral therapy, in Brazilian human immunodeficiency virus (HIV) infected children. Division of otorhinolaryngology, Hospital das Clínicas, Sao Paulo University Medical School, Brazil. A cohort of 459 HIV-infected children aged below 13 years. The prevalence of otitis media and the serum cluster of differentiation four glycoprotein T lymphocyte count were compared for children receiving highly active antiretroviral therapy (with protease inhibitors) and those receiving standard antiretroviral therapy (without protease inhibitors). Otitis media was present in 33.1 per cent of the children. Children aged from zero years to five years 11 months receiving highly active antiretroviral therapy had a higher prevalence of acute otitis media (p=0.02) and a lower prevalence of chronic otitis media (p=0.02). Children who were receiving highly active antiretroviral therapy had a mean serum cluster of differentiation four glycoprotein T lymphocyte count greater than that of those who were receiving standard antiretroviral therapy (pBrazilian HIV-infected children was associated with a lower prevalence of chronic otitis media.

  2. Towards quantifying dynamic human-human physical interactions for robot assisted stroke therapy.

    Science.gov (United States)

    Mohan, Mayumi; Mendonca, Rochelle; Johnson, Michelle J

    2017-07-01

    Human-Robot Interaction is a prominent field of robotics today. Knowledge of human-human physical interaction can prove vital in creating dynamic physical interactions between human and robots. Most of the current work in studying this interaction has been from a haptic perspective. Through this paper, we present metrics that can be used to identify if a physical interaction occurred between two people using kinematics. We present a simple Activity of Daily Living (ADL) task which involves a simple interaction. We show that we can use these metrics to successfully identify interactions.

  3. 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

  4. The use of human factors methods to identify and mitigate safety issues in radiation therapy

    International Nuclear Information System (INIS)

    Chan, Alvita J.; Islam, Mohammad K.; Rosewall, Tara; Jaffray, David A.; Easty, Anthony C.; Cafazzo, Joseph A.

    2010-01-01

    Background and purpose: New radiation therapy technologies can enhance the quality of treatment and reduce error. However, the treatment process has become more complex, and radiation dose is not always delivered as intended. Using human factors methods, a radiotherapy treatment delivery process was evaluated, and a redesign was undertaken to determine the effect on system safety. Material and methods: An ethnographic field study and workflow analysis was conducted to identify human factors issues of the treatment delivery process. To address specific issues, components of the user interface were redesigned through a user-centered approach. Sixteen radiation therapy students were then used to experimentally evaluate the redesigned system through a usability test to determine the effectiveness in mitigating use errors. Results: According to findings from the usability test, the redesigned system successfully reduced the error rates of two common errors (p < .04 and p < .01). It also improved the mean task completion time by 5.5% (p < .02) and achieved a higher level of user satisfaction. Conclusions: These findings demonstrated the importance and benefits of applying human factors methods in the design of radiation therapy systems. Many other opportunities still exist to improve patient safety in this area using human factors methods.

  5. Study on therapy of 188Re labelled stannic sulfur suspension in nude mice bearing human colon tumor

    International Nuclear Information System (INIS)

    Li Huiyuan; Wu Yuanfang; Dong Mo

    2003-01-01

    The effect of therapy, tissue distribution and stability are studied in nude mice bearing human colon tumor after injections of 188 Re labelled stannic sulfur suspension. The tissues are observed with electric microscope. The results show that 188 Re labelled stannic sulfur suspension is stabilized in the tumor and its inhibitive effects on human colon tumor cells are obvious. 188 Re labelled stannic sulfur suspension is a potential radiopharmaceuticals for therapy of human tumor

  6. 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.

  7. Application of human amniotic mesenchymal cells as an allogeneic transplantation cell source in bone regenerative therapy

    International Nuclear Information System (INIS)

    Tsuno, Hiroaki; Yoshida, Toshiko; Nogami, Makiko; Koike, Chika; Okabe, Motonori; Noto, Zenko; Arai, Naoya; Noguchi, Makoto; Nikaido, Toshio

    2012-01-01

    Autogenous mesenchymal stem cells (MSCs) have therapeutic applications in bone regenerative therapy due to their pluripotency. However, the ability of MSCs to proliferate and differentiate varies between donors. Furthermore, alternative sources of MSCs are required for patients with contraindications to autogenous cell therapy. The aim of this study was to evaluate the potential of mesenchymal cells from the human amniotic membrane (HAM) as a source of cells for allogeneic transplantation in bone regenerative therapy. Cells that retained a proliferative capacity of more than 50 population doubling level were distinguished from other HAM cells as HAMα cells and induced to osteogenic status—their in vivo osteogenesis was subsequently investigated in rats. It was found that HAMα cells were spindle shaped and were positive for MSC markers and negative for hematopoietic stem cell markers. Alkaline phosphatase activity and calcium deposition increased with osteogenic status of HAMα cells. The expression of osteocalcin mRNA was increased in HAMα cells cultured on calcium phosphate scaffolds. Moreover, xenografted HAMα cells remained viable and produced extracellular matrix for several weeks. Thus, this study suggests that human amniotic mesenchymal cells possess osteogenic differentiation potential and could be applied to allogeneic transplantation in bone regenerative therapy. - Highlights: ► Human amniotic mesenchymal cells include cells (HAMα cells) that have the properties of MSCs. ► HAMα cells have excellent osteogenic differentiation potential. ► Osteogenic differentiation ability of HAMα was amplified by calcium phosphate scaffolds. ► HAMα cells can be applicable to allogeneic cell transplantation in bone regenerative therapy.

  8. Application of human amniotic mesenchymal cells as an allogeneic transplantation cell source in bone regenerative therapy

    Energy Technology Data Exchange (ETDEWEB)

    Tsuno, Hiroaki [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Yoshida, Toshiko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Nogami, Makiko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Orthopedic Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Koike, Chika; Okabe, Motonori [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Noto, Zenko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Arai, Naoya; Noguchi, Makoto [Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Nikaido, Toshio, E-mail: tnikaido@med.u-toyama.ac.jp [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan)

    2012-12-01

    Autogenous mesenchymal stem cells (MSCs) have therapeutic applications in bone regenerative therapy due to their pluripotency. However, the ability of MSCs to proliferate and differentiate varies between donors. Furthermore, alternative sources of MSCs are required for patients with contraindications to autogenous cell therapy. The aim of this study was to evaluate the potential of mesenchymal cells from the human amniotic membrane (HAM) as a source of cells for allogeneic transplantation in bone regenerative therapy. Cells that retained a proliferative capacity of more than 50 population doubling level were distinguished from other HAM cells as HAM{alpha} cells and induced to osteogenic status-their in vivo osteogenesis was subsequently investigated in rats. It was found that HAM{alpha} cells were spindle shaped and were positive for MSC markers and negative for hematopoietic stem cell markers. Alkaline phosphatase activity and calcium deposition increased with osteogenic status of HAM{alpha} cells. The expression of osteocalcin mRNA was increased in HAM{alpha} cells cultured on calcium phosphate scaffolds. Moreover, xenografted HAM{alpha} cells remained viable and produced extracellular matrix for several weeks. Thus, this study suggests that human amniotic mesenchymal cells possess osteogenic differentiation potential and could be applied to allogeneic transplantation in bone regenerative therapy. - Highlights: Black-Right-Pointing-Pointer Human amniotic mesenchymal cells include cells (HAM{alpha} cells) that have the properties of MSCs. Black-Right-Pointing-Pointer HAM{alpha} cells have excellent osteogenic differentiation potential. Black-Right-Pointing-Pointer Osteogenic differentiation ability of HAM{alpha} was amplified by calcium phosphate scaffolds. Black-Right-Pointing-Pointer HAM{alpha} cells can be applicable to allogeneic cell transplantation in bone regenerative therapy.

  9. 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).

  10. Human cytomegalovirus antigens in malignant gliomas as targets for adoptive cellular therapy

    Directory of Open Access Journals (Sweden)

    Daniel eLandi

    2014-11-01

    Full Text Available Malignant gliomas are the most common primary brain tumor in adults, with over 12,000 new cases diagnosed in the United States each year. Over the last decade, investigators have reliably identified human cytomegalovirus (HCMV proteins, nucleic acids, and virions in most high-grade gliomas, including glioblastoma (GBM. This discovery is significant because human cytomegalovirus gene products can be targeted by immune-based therapies.In this review, we describe the current level of understanding regarding the presence and role in pathogenesis of HCMV in GBM. We describe our success detecting and expanding HCMV-specific cytotoxic T lymphocytes to kill GBM cells and explain how these cells can be used as a platform for enhanced cellular therapies. We discuss alternative approaches that capitalize on HCMV infection to treat patients with HCMV-positive tumors. Adoptive cellular therapy for HCMV-positive GBM has been tried in a small number of patients with some benefit, but we reason why, to date, these approaches generally fail to generate long-term remission or cure. We conjecture how cellular therapy for GBM can be improved and describe the barriers that must be overcome to cure these patients.

  11. Adjuvant electrochemotherapy in veterinary patients: a model for the planning of future therapies in humans

    Directory of Open Access Journals (Sweden)

    Baldi Alfonso

    2009-08-01

    Full Text Available Abstract The treatment of soft tissue tumors needs the coordinated adoption of surgery with radiation therapy and eventually, chemotherapy. The radiation therapy (delivered with a linear accelerator can be preoperative, intraoperative, or postoperative. In selected patients adjuvant brachytherapy can be adopted. The goal of these associations is to achieve tumor control while maximally preserving the normal tissues from side effects. Unfortunately, the occurrence of local and distant complications is still elevated. Electrochemotherapy is a novel technique that combines the administration of anticancer agents to the application of permeabilizing pulses in order to increase the uptake of antitumor molecules. While its use in humans is still confined to the treatment of cutaneous neoplasms or the palliation of skin tumor metastases, in veterinary oncology this approach is rapidly becoming a primary treatment. This review summarizes the recent progresses in preclinical oncology and their possible transfer to humans.

  12. Human Gongylonema pulchrum Infection: Esophageal Symptoms and Need for Prolonged Albendazole Therapy.

    Science.gov (United States)

    Libertin, Claudia R; Reza, Mohammed; Peterson, Joy H; Lewis, Jason; Hata, D Jane

    2017-04-01

    AbstractWe describe a case of human infection with Gongylonema pulchrum acquired in southeast Georgia. The patient presented with intermittent yet persistent nausea and vomiting for months. This case describes the need for extraction of worms on two occasions each followed by courses of albendazole treatment. Gongylonema pulchrum infections with high worm burden may relapse after extraction of the worm and a 3-day short course of albendazole therapy. Longer courses of albendazole may be indicated in selected circumstances.

  13. Primary Radiation Therapy for Head-and-Neck Cancer in the Setting of Human Immunodeficiency Virus

    International Nuclear Information System (INIS)

    Klein, Emily A.; Guiou, Michael; Farwell, D. Gregory; Luu, Quang; Lau, Derick H.; Stuart, Kerri; Vaughan, Andrew; Vijayakumar, Srinivasan; Chen, Allen M.

    2011-01-01

    Purpose: To analyze outcomes after radiation therapy for head-and-neck cancer among a cohort of patients with human immunodeficiency virus (HIV). Methods and Materials: The medical records of 12 patients with serologic evidence of HIV who subsequently underwent radiation therapy to a median dose of 68 Gy (range, 64-72 Gy) for newly diagnosed squamous cell carcinoma of the head and neck were reviewed. Six patients (50%) received concurrent chemotherapy. Intensity-modulated radiotherapy was used in 6 cases (50%). All patients had a Karnofsky performance status of 80 or 90. Nine patients (75%) were receiving antiretroviral therapies at the time of treatment, and the median CD4 count was 460 (range, 266-800). Toxicity was graded according to the Radiation Therapy Oncology Group / European Organization for the Treatment of Cancer toxicity criteria. Results: The 3-year estimates of overall survival and local-regional control were 78% and 92%, respectively. Acute Grade 3+ toxicity occurred in 7 patients (58%), the most common being confluent mucositis (5 patients) and moist skin desquamation (4 patients). Two patients experienced greater than 10% weight loss, and none experienced more than 15% weight loss from baseline. Five patients (42%) experienced treatment breaks in excess of 10 cumulative days, although none required hospitalization. There were no treatment-related fatalities. Conclusions: Radiation therapy for head-and-neck cancer seems to be relatively well tolerated among appropriately selected patients with HIV. The observed rates of toxicity were comparable to historical controls without HIV.

  14. An examination of human factors in external beam radiation therapy: Findings and implications

    International Nuclear Information System (INIS)

    Henriksen, K.; Kaye, R.D.; Jones, R.E. Jr.; Morisseau, D.S.; Persensky, J.J.

    1994-01-01

    To better understand the contributing factors to human error in external beam radiation therapy, the US Nuclear Regulatory Commission has undertaken a series of human factors evaluations. A team of human factors specialists, assisted by a panel of radiation oncologists, medical physicists, and radiation technologists, conducted visits to 24 radiation oncology departments at community hospitals, university centers, and free-standing clinics. A function and task analysis was initially performed to guide subsequent evaluations in the areas of human-system interfaces, procedures, training and qualifications, and organizational policies and practices. Representative findings and implications for improvement are discussed within the context of a dynamic model which holds that misadministration likely results from the unanticipated interaction of several necessary but singly insufficient conditions

  15. Multidisciplinary team of intensive therapy: humanization and fragmentation of the work process.

    Science.gov (United States)

    Evangelista, Viviane Canhizares; Domingos, Thiago da Silva; Siqueira, Fernanda Paula Cerântola; Braga, Eliana Mara

    2016-01-01

    to understand the meaning of humanized care in intensive care units considering the experience of the multidisciplinary team. descriptive and exploratory qualitative research. For this purpose, we conducted semi-structured interviews with 24 professionals of the heath-care team, and, after transcription, we organized the qualitative data according to content analysis. from two main categories, we were able to understand that humanized care is characterized in the actions of health-care: effective communication, team work, empathy, singularity, and integrality; and mischaracterized in the management processes, specifically in the fragmentation of the work process and health-care, in the precarious work conditions, and in differing conceptual aspects of the political proposal of humanization. care activities in intensive therapy are guided by the humanization of care and corroborate the hospital management as a challenge to be overcome to boost advances in the operationalization of this Brazilian policy.

  16. Hyperbaric oxygen therapy attenuates central sensitization induced by a thermal injury in humans

    DEFF Research Database (Denmark)

    Rasmussen, V M; Borgen, A E; Jansen, E C

    2015-01-01

    BACKGROUND: Hyperbaric oxygen (HBO2 ) treatment has in animal experiments demonstrated antinociceptive effects. It was hypothesized that these effects would attenuate secondary hyperalgesia areas (SHAs), an expression of central sensitization, after a first-degree thermal injury in humans. METHODS...... was demonstrated. However, in the nine volunteers starting with the control session, a statistical significant attenuation of SHAs was demonstrated in the HBO2 session (P = 0.004). CONCLUSIONS: The results indicate that HBO2 therapy in humans attenuates central sensitization induced by a thermal skin injury......, compared with control. These new and original findings in humans corroborate animal experimental data. The thermal injury model may give impetus to future human neurophysiological studies exploring the central effects of hyperbaric oxygen treatment....

  17. 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 ...

  18. 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....

  19. Anti-EGFR therapy radiosensitizes human lung adenocarcinoma xenograft in nude mouse

    International Nuclear Information System (INIS)

    Wang Hui; Li Tianran; Tian Jiahe; Qu Baolin; Zhu Hui

    2008-01-01

    Objective: To investigate the effect of Gefitinib on radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. Methods: Human lung adenocarcinoma cell line A549 was used to establish nude mouse xenograft tumor model. The mice were derided into 4 groups: control, irradiation alone, Gefinitib alone and radiation combined with Genifitib. Radiation schedule was 3 fractions of 5 Gy, once daily. Gefitinib was daily administered by gavage at 100 mg/(kg·day -1 ) for 14 days. In the combination group, radiotherapy was performed 2 hours after Gefitinib administration. Tumor diameter was measured every other day. Percentage of tumor growth inhibition, growth delay time and regrowth delay time were evaluated. Results: For A549 xenografts in radiation alone, gefitinib alone and combination therapy groups, the percentage of tumor growth inhibition was 22.7%, 12.4% and 38.2%, respectively (F=25.75, P=0.000). Tumor growth delay time was 6.0, 7.8 and 21.6 days, respectively (F=70.49, P=0.000). Tumor regrowth delay time in combination therapy and irradiation alone groups was 23.4 and 10.2 days. (F=174.24, P= 0.000). Sensitizing enhancement ratio of combination group was 1.5 in growth and 1.7 in regrowth. Conclusions: Anti-EGFR therapy enhances the radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. (authors)

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. 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.

  3. Gene expression studies on human keratinocytes transduced with human growth hormone gene for a possible utilization in gene therapy

    International Nuclear Information System (INIS)

    Mathor, Monica Beatriz.

    1994-01-01

    Taking advantage of the recent progress in the DNA-recombinant techniques and of the potentiality of normal human keratinocytes primary culture to reconstitute the epidermis, it was decided to genetically transform these keratinocytes to produce human growth hormone under controllable conditions that would be used in gene therapy at this hormone deficient patients. The first step to achieve this goal was to standardize infection of keratinocytes with retrovirus producer cells containing a construct which included the gene of bacterial b-galactosidase. The best result was obtained cultivating the keratinocytes for 3 days in a 2:1 mixture of retrovirus producer cells and 3T3-J2 fibroblasts irradiated with 60 Gy, and splitting these infected keratinocytes on 3T3-J2 fibroblasts feeder layer. Another preliminary experiment was to infect normal human keratinocytes with interleukin-6 gene (hIL-6) that, in pathologic conditions, could be reproduced by keratinocytes and secreted to the blood stream. Thus, we verify that infected keratinocytes secrete an average amount of 500 ng/10 6 cell/day of cytokin during the in vitro life time, that certify the stable character of the injection. These keratinocytes, when grafted in mice, secrete hIL-6 to the blood stream reaching levels of 40 pg/ml of serum. After these preliminary experiments, we construct a retroviral vector with the human growth hormone gene (h GH) driven by human metallothionein promoter (h PMT), designated DChPMTGH. Normal human keratinocytes were infected with DChPMTGH producer cells, following previously standardized protocol, obtaining infected keratinocytes secreting to the culture media 340 ng h GH/10 6 cell/day without promoter activation. This is the highest level of h GH secreted in human keratinocytes primary culture described in literature. The h GH value increases approximately 10 times after activation with 100 μM Zn +2 for 8-12 hours. (author). 158 refs., 42 figs., 6 tabs

  4. Low-level light therapy potentiates NPe6-mediated photodynamic therapy in a human osteosarcoma cell line via increased ATP.

    Science.gov (United States)

    Tsai, Shang-Ru; Yin, Rui; Huang, Ying-Ying; Sheu, Bor-Ching; Lee, Si-Chen; Hamblin, Michael R

    2015-03-01

    Low-level light therapy (LLLT) is used to stimulate healing, reduce pain and inflammation, and preserve tissue from dying. LLLT has been shown to protect cells in culture from dying after various cytotoxic insults, and LLLT is known to increase the cellular ATP content. Previous studies have demonstrated that maintaining a sufficiently high ATP level is necessary for the efficient induction and execution of apoptosis steps after photodynamic therapy (PDT). We asked whether LLLT would protect cells from cytotoxicity due to PDT, or conversely whether LLLT would enhance the efficacy of PDT mediated by mono-l-aspartyl chlorin(e6) (NPe6). Increased ATP could lead to enhanced cell uptake of NPe6 by the energy dependent process of endocytosis, and also to more efficient apoptosis. In this study, human osteosarcoma cell line MG-63 was subjected to 1.5J/cm(2) of 810nm near infrared radiation (NIR) followed by addition of 10μM NPe6 and after 2h incubation by 1.5J/cm(2) of 652nm red light for PDT. PDT combined with LLLT led to higher cell death and increased intracellular reactive oxygen species compared to PDT alone. The uptake of NPe6 was moderately increased by LLLT, and cellular ATP was increased. The mitochondrial respiratory chain inhibitor antimycin A abrogated the LLLT-induced increase in cytotoxicity. Taken together, these results demonstrate that LLLT potentiates NPe6-mediated PDT via increased ATP synthesis and is a potentially promising strategy that could be applied in clinical PDT. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Improving the Therapeutic Potential of Human Granzyme B for Targeted Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Georg Melmer

    2013-01-01

    Full Text Available Conventional cancer treatments lack specificity and often cause severe side effects. Targeted therapeutic approaches are therefore preferred, including the use of immunotoxins (ITs that comprise cell-binding and cell death-inducing components to allow the direct and specific delivery of pro-apoptotic agents into malignant cells. The first generation of ITs consisted of toxins derived from bacteria or plants, making them immunogenic in humans. The recent development of human cytolytic fusion proteins (hCFP consisting of human effector enzymes offers the prospect of highly-effective targeted therapies with minimal side effects. One of the most promising candidates is granzyme B (GrB and this enzyme has already demonstrated its potential for targeted cancer therapy. However, the clinical application of GrB may be limited because it is inactivated by the overexpression in tumors of its specific inhibitor serpin B9 (PI-9. It is also highly charged, which means it can bind non-specifically to the surface of non-target cells. Furthermore, human enzymes generally lack an endogenous translocation domain, thus the endosomal release of GrB following receptor-mediated endocytosis can be inefficient. In this review we provide a detailed overview of these challenges and introduce promising solutions to increase the cytotoxic potency of GrB for clinical applications.

  6. Speech therapy in adolescents with Down syndrome: In pursuit of communication as a fundamental human right.

    Science.gov (United States)

    Rvachew, Susan; Folden, Marla

    2018-02-01

    The achievement of speech intelligibility by persons with Down syndrome facilitates their participation in society. Denial of speech therapy services by virtue of low cognitive skills is a violation of their fundamental human rights as proclaimed in the Universal Declaration of Human Rights in general and in Article 19 in particular. Here, we describe the differential response of an adolescent with Down syndrome to three speech therapy interventions and demonstrate the use of a single subject randomisation design to identify effective treatments for children with complex communication disorders. Over six weeks, 18 speech therapy sessions were provided with treatment conditions randomly assigned to targets and sessions within weeks, specifically comparing auditory-motor integration prepractice and phonological planning prepractice to a control condition that included no prepractice. All treatments involved high intensity practice of nonsense word targets paired with tangible referents. A measure of generalisation from taught words to untaught real words in phrases revealed superior learning in the auditory-motor integration condition. The intervention outcomes may serve to justify the provision of appropriate supports to persons with Down syndrome so that they may achieve their full potential to receive information and express themselves.

  7. 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.

  8. 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.

  9. Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells.

    Directory of Open Access Journals (Sweden)

    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

  10. Radiation therapy patient education using VERT: combination of technology with human care.

    Science.gov (United States)

    Jimenez, Yobelli A; Lewis, Sarah J

    2018-05-13

    The Virtual Environment for Radiotherapy Training (VERT) system is a recently available tool for radiation therapy education. The majority of research regarding VERT-based education is focused on students, with a growing area of research being VERT's role in patient education. Because large differences in educational requirements exist between students and patients, focused resources and subsequent evaluations are necessary to provide solid justification for the unique benefits and challenges posed by VERT in a patient education context. This commentary article examines VERT's role in patient education, with a focus on salient visual features, VERT's ability to address some of the spatial challenges associated with RT patient education and how to combine technology with human care. © 2018 The Authors. Journal of Medical Radiation Sciences published by John Wiley & Sons Australia, Ltd on behalf of Australian Society of Medical Imaging and Radiation Therapy and New Zealand Institute of Medical Radiation Technology.

  11. Iodine 131 labeled GD2 monoclonal antibody in the diagnosis and therapy of human neuroblastoma

    International Nuclear Information System (INIS)

    Cheung, N.K.V.; Miraldi, F.D.

    1988-01-01

    High dose marrow ablative therapy followed by autologous bone marrow transplantation (ABMT) has prolonged survival in patients with neuroblastoma. Total body and focal irradiation play an integral role in the overall treatment of this disease. The biological basis for radiation is the radiosensitivity and the lack of sublethal repair in neuroblastoma cells. However, radiation therapy has not by itself been adequate because of the usual widespread nature of neuroblastoma and the inability to achieve selective tumor versus normal tissue delivery, especially at multiple tumor sites. Monoclonal antibodies are agents selected for their specificity for human tumors. In vivo they have the ability of targeting selectively to occult metastases. This paper discusses how the availability of radioisotopes and the development of conjugation chemistries have greatly expanded the potentials of these antibodies

  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. Function-blocking antibodies to human vascular adhesion protein-1: a potential anti-inflammatory therapy.

    Science.gov (United States)

    Kirton, Christopher M; Laukkanen, Marja-Leena; Nieminen, Antti; Merinen, Marika; Stolen, Craig M; Armour, Kathryn; Smith, David J; Salmi, Marko; Jalkanen, Sirpa; Clark, Michael R

    2005-11-01

    Human vascular adhesion protein-1 (VAP-1) is a homodimeric 170-kDa sialoglycoprotein that is expressed on the surface of endothelial cells and functions as a semicarbazide-sensitive amine oxidase and as an adhesion molecule. Blockade of VAP-1 has been shown to reduce leukocyte adhesion and transmigration in in vivo and in vitro models, suggesting that VAP-1 is a potential target for anti-inflammatory therapy. In this study we have constructed mouse-human chimeric antibodies by genetic engineering in order to circumvent the potential problems involved in using murine antibodies in man. Our chimeric anti-VAP-1 antibodies, which were designed to lack Fc-dependent effector functions, bound specifically to cell surface-expressed recombinant human VAP-1 and recognized VAP-1 in different cell types in tonsil. Furthermore, the chimeric antibodies prevented leukocyte adhesion and transmigration in vitro and in vivo. Hence, these chimeric antibodies have the potential to be used as a new anti-inflammatory therapy.

  16. Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis.

    Directory of Open Access Journals (Sweden)

    Helga Rodrigues

    Full Text Available The treatment of anxiety is on the edge of a new era of combinations of pharmacologic and psychosocial interventions. A new wave of translational research has focused on the use of pharmacological agents as psychotherapy adjuvants using neurobiological insights into the mechanism of the action of certain psychological treatments such as exposure therapy. Recently, d-cycloserine (DCS an antibiotic used to treat tuberculosis has been applied to enhance exposure-based treatment for anxiety and has proved to be a promising, but as yet unproven intervention. The present study aimed to evaluate the efficacy of DCS in the enhancement of exposure therapy in anxiety disorders. A systematic review/meta-analysis was conducted. Electronic searches were conducted in the databases ISI-Web of Science, Pubmed and PsycINFO. We included only randomized, double-blind, placebo-controlled trials with humans, focusing on the role of DCS in enhancing the action of exposure therapy for anxiety disorders. We identified 328 references, 13 studies were included in our final sample: 4 on obsessive-compulsive disorder, 2 on panic disorder, 2 on social anxiety disorder, 2 on posttraumatic stress disorder, one on acrophobia, and 2 on snake phobia. The results of the present meta-analysis show that DCS enhances exposure therapy in the treatment of anxiety disorders (Cohen d =  -0.34; CI: -0.54 to -0.14, facilitating the specific process of extinction of fear. DCS seems to be effective when administered at a time close to the exposure therapy, at low doses and a limited number of times. DCS emerges as a potential new therapeutic approach for patients with refractory anxiety disorders that are unresponsive to the conventional treatments available. When administered correctly, DCS is a promising strategy for augmentation of CBT and could reduce health care costs, drop-out rates and bring faster relief to patients.

  17. 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

  18. Leukemic blast cell colony formation in semisolid culture with erythropoietin: a case report of acute poorly differentiated erythroid leukemia.

    Science.gov (United States)

    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.

  19. Epobis is a Nonerythropoietic and Neuroprotective Agonist of the Erythropoietin Receptor with Anti-Inflammatory and Memory Enhancing Effects

    Directory of Open Access Journals (Sweden)

    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.

  20. Effect of radiation therapy on the mitogenic response of in vitro irradiated human lymphocytes to phytohaemagglutinin

    International Nuclear Information System (INIS)

    Baral, E.; Blomgren, H.; Einhorn, N.; Lax, I.; Juhlin, I.

    1977-01-01

    Irradiation of human peripheral lymphocytes in vitro reduces their capacity to be triggered to DNA-synthesis by PHA in a two-dose shaped fashion suggesting the presence of one relatively radiationsensitive and one relatively resistant cell population. Intracavitary and external radiation therapy for carcinoma of the uterus and vagina, which reduced the lymphocyte counts by approximately 66 per cent, did not significantly change the ratio of these subpopulations, indicating that PHA-reactive cells cannot be grouped into radiation sensitive and resistant subpopulations

  1. Preparation and radiolabeling of human serum albumin (HSA)-coated magnetite nanoparticles for magnetically targeted therapy

    International Nuclear Information System (INIS)

    Zhang Chunfu; Cao Jinquan; Yin Duanzhi; Wang Yongxian; Feng Yanlin; Tan Jiajue

    2004-01-01

    In this paper, we describe the preparation of human serum albumin-coated magnetic particles of about 200 nm in diameter with narrow size distribution radiolabeled with 188 Re for the purpose of magnetically targeted therapy. The optimum radiolabeling conditions are: SnCl 2 ·2H 2 O 8 mg/ml, citric acid 20 mg/ml, vitamin C 8 mg/ml, labeling volume 500 μl and a reaction time of 3 h. The stability of the radiolabeled particles is suitable for in vivo study

  2. Preparation and radiolabeling of human serum albumin (HSA)-coated magnetite nanoparticles for magnetically targeted therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Chunfu E-mail: zchunfu@yahoo.com.cn; Cao Jinquan; Yin Duanzhi; Wang Yongxian; Feng Yanlin; Tan Jiajue

    2004-12-01

    In this paper, we describe the preparation of human serum albumin-coated magnetic particles of about 200 nm in diameter with narrow size distribution radiolabeled with {sup 188}Re for the purpose of magnetically targeted therapy. The optimum radiolabeling conditions are: SnCl{sub 2}{center_dot}2H{sub 2}O 8 mg/ml, citric acid 20 mg/ml, vitamin C 8 mg/ml, labeling volume 500 {mu}l and a reaction time of 3 h. The stability of the radiolabeled particles is suitable for in vivo study.

  3. The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy

    Science.gov (United States)

    Miao, L; Fraefel, C; Sia, K C; Newman, J P; Mohamed-Bashir, S A; Ng, W H; Lam, P Y P

    2014-01-01

    Background: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. Methods: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. Results: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. Conclusion: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers. PMID:24196790

  4. Time to reconsider nonsurgical therapy of benign nontoxic multinodular goitre. Focus on recombinant human TSH (rhTSH) augmented radioiodine therapy

    DEFF Research Database (Denmark)

    Fast, Søren; Nielsen, Viveque; Bonnema, Steen

    2009-01-01

    alternatives are needed. Until recently, levothyroxine therapy was the preferred non-surgical alternative, but due to low efficacy and potential side-effects, it is not recommended for routine use in recent international guidelines. Conventional radioiodine (131I)-therapy has been used for two decades......, which makes 131I-therapy less feasible. Another challenge is the negative correlation between initial goitre size and goitre volume reduction (GVR). With its ability to more than double the thyroid 131I-uptake, recombinant human TSH (rhTSH) increases the absorbed radiation dose and thus enhances the GVR...... efficacy. Thus, although in its infancy, and still experimental, rhTSH-augmented 131I-therapy may profoundly alter the nonsurgical treatment of benign non-toxic MNG....

  5. Human-animal relationships: from daily life to animal-assisted therapies

    Directory of Open Access Journals (Sweden)

    Marine Grandgeorge

    2011-12-01

    Full Text Available Humans have a long history of relationship with domestic animals and nowadays pets often act as "social substitutes" through bonding. There is some evidence that pet presence at home may induce well being in people and the development of social skills in children. Animal assisted therapies aim at developing these skills in patients on the basis of human animal interactions. Experimental data obtained on animal models suggest that this is indeed a promising line. There is however a lack of clear scientific data that would help defines what the most appropriate procedures or species may be. Improvements are observed, but again sound scientific data are mostly missing. Attention must be given to the welfare of the animals being used.

  6. Human-Based Human Milk Fortifier as Rescue Therapy in Very Low Birth Weight Infants Demonstrating Intolerance to Bovine-Based Human Milk Fortifier.

    Science.gov (United States)

    Sandhu, Amanjot; Fast, Sharla; Bonnar, Kari; Baier, Ronald John; Narvey, Michael

    2017-11-01

    To describe the results of utilizing a human milk-based human milk fortifier (HMHMF) as rescue therapy to meet nutritional requirements in very low birth weight and preterm infants demonstrating feeding intolerance to bovine-based human milk fortifier (BHMF) in the Canadian Neonatal Intensive Care Unit (NICU) setting. At two Level III NICUs in Winnipeg, MB, Canada, a rescue protocol was implemented to provide HMHMF for infants demonstrating intolerance to BHMF. To qualify for rescue, infants were required to experience two episodes of significant gastrointestinal (GI) symptoms associated with fortification with BHMF. A case series report was conducted retrospectively examining the success of rescue therapy, growth rates, protein, and calorie intakes before and after initiation of HMHMF in seven infants. Seven infants (birth weight 723 ± 247 g, gestation 25.3 ± 3.4 weeks) were treated with rescue fortification with HMHMF. All infants were transitioned off parenteral nutrition (PN) without relapse of GI symptoms. Growth rate, protein, and calorie intakes improved with the use of HMHMF. Very low birth weight and preterm infants with GI intolerance to BHMF were successfully rescued with use of HMHMF. Improvements in growth were achieved without need for supplementation with PN through achievement of sufficient enteral calorie and protein intakes.

  7. RPGR: Its role in photoreceptor physiology, human disease, and future therapies.

    Science.gov (United States)

    Megaw, Roly D; Soares, Dinesh C; Wright, Alan F

    2015-09-01

    Mammalian photoreceptors contain specialised connecting cilia that connect the inner (IS) to the outer segments (OS). Dysfunction of the connecting cilia due to mutations in ciliary proteins are a common cause of the inherited retinal dystrophy retinitis pigmentosa (RP). Mutations affecting the Retinitis Pigmentosa GTPase Regulator (RPGR) protein is one such cause, affecting 10-20% of all people with RP and the majority of those with X-linked RP. RPGR is located in photoreceptor connecting cilia. It interacts with a wide variety of ciliary proteins, but its exact function is unknown. Recently, there have been important advances both in our understanding of RPGR function and towards the development of a therapy. This review summarises the existing literature on human RPGR function and dysfunction, and suggests that RPGR plays a role in the function of the ciliary gate, which controls access of both membrane and soluble proteins to the photoreceptor outer segment. We discuss key models used to investigate and treat RPGR disease and suggest that gene augmentation therapy offers a realistic therapeutic approach, although important questions still remain to be answered, while cell replacement therapy based on retinal progenitor cells represents a more distant prospect. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Towards precision medicine-based therapies for glioblastoma: interrogating human disease genomics and mouse phenotypes.

    Science.gov (United States)

    Chen, Yang; Gao, Zhen; Wang, Bingcheng; Xu, Rong

    2016-08-22

    Glioblastoma (GBM) is the most common and aggressive brain tumors. It has poor prognosis even with optimal radio- and chemo-therapies. Since GBM is highly heterogeneous, drugs that target on specific molecular profiles of individual tumors may achieve maximized efficacy. Currently, the Cancer Genome Atlas (TCGA) projects have identified hundreds of GBM-associated genes. We develop a drug repositioning approach combining disease genomics and mouse phenotype data towards predicting targeted therapies for GBM. We first identified disease specific mouse phenotypes using the most recently discovered GBM genes. Then we systematically searched all FDA-approved drugs for candidates that share similar mouse phenotype profiles with GBM. We evaluated the ranks for approved and novel GBM drugs, and compared with an existing approach, which also use the mouse phenotype data but not the disease genomics data. We achieved significantly higher ranks for the approved and novel GBM drugs than the earlier approach. For all positive examples of GBM drugs, we achieved a median rank of 9.2 45.6 of the top predictions have been demonstrated effective in inhibiting the growth of human GBM cells. We developed a computational drug repositioning approach based on both genomic and phenotypic data. Our approach prioritized existing GBM drugs and outperformed a recent approach. Overall, our approach shows potential in discovering new targeted therapies for GBM.

  9. Mathematical Modeling and Evaluation of Human Motions in Physical Therapy Using Mixture Density Neural Networks.

    Science.gov (United States)

    Vakanski, A; Ferguson, J M; Lee, S

    2016-12-01

    The objective of the proposed research is to develop a methodology for modeling and evaluation of human motions, which will potentially benefit patients undertaking a physical rehabilitation therapy (e.g., following a stroke or due to other medical conditions). The ultimate aim is to allow patients to perform home-based rehabilitation exercises using a sensory system for capturing the motions, where an algorithm will retrieve the trajectories of a patient's exercises, will perform data analysis by comparing the performed motions to a reference model of prescribed motions, and will send the analysis results to the patient's physician with recommendations for improvement. The modeling approach employs an artificial neural network, consisting of layers of recurrent neuron units and layers of neuron units for estimating a mixture density function over the spatio-temporal dependencies within the human motion sequences. Input data are sequences of motions related to a prescribed exercise by a physiotherapist to a patient, and recorded with a motion capture system. An autoencoder subnet is employed for reducing the dimensionality of captured sequences of human motions, complemented with a mixture density subnet for probabilistic modeling of the motion data using a mixture of Gaussian distributions. The proposed neural network architecture produced a model for sets of human motions represented with a mixture of Gaussian density functions. The mean log-likelihood of observed sequences was employed as a performance metric in evaluating the consistency of a subject's performance relative to the reference dataset of motions. A publically available dataset of human motions captured with Microsoft Kinect was used for validation of the proposed method. The article presents a novel approach for modeling and evaluation of human motions with a potential application in home-based physical therapy and rehabilitation. The described approach employs the recent progress in the field of

  10. 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.

  11. Human Recombinant Peptide Sponge Enables Novel, Less Invasive Cell Therapy for Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Michiyuki Miyamoto

    2018-01-01

    Full Text Available Bone marrow stromal cell (BMSC transplantation has the therapeutic potential for ischemic stroke. However, it is unclear which delivery routes would yield both safety and maximal therapeutic benefits. We assessed whether a novel recombinant peptide (RCP sponge, that resembles human collagen, could act as a less invasive and beneficial scaffold in cell therapy for ischemic stroke. BMSCs from green fluorescent protein-transgenic rats were cultured and Sprague–Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAo. A BMSC-RCP sponge construct was transplanted onto the ipsilateral intact neocortex 7 days after MCAo. A BMSC suspension or vehicle was transplanted into the ipsilateral striatum. Rat motor function was serially evaluated and histological analysis was performed 5 weeks after transplantation. The results showed that BMSCs could proliferate well in the RCP sponge and the BMSC-RCP sponge significantly promoted functional recovery, compared with the vehicle group. Histological analysis revealed that the RCP sponge provoked few inflammatory reactions in the host brain. Moreover, some BMSCs migrated to the peri-infarct area and differentiated into neurons in the BMSC-RCP sponge group. These findings suggest that the RCP sponge may be a promising candidate for animal protein-free scaffolds in cell therapy for ischemic stroke in humans.

  12. Modelling cell population growth with applications to cancer therapy in human tumour cell lines.

    Science.gov (United States)

    Basse, Britta; Baguley, Bruce C; Marshall, Elaine S; Wake, Graeme C; Wall, David J N

    2004-01-01

    In this paper we present an overview of the work undertaken to model a population of cells and the effects of cancer therapy. We began with a theoretical one compartment size structured cell population model and investigated its asymptotic steady size distributions (SSDs) (On a cell growth model for plankton, MMB JIMA 21 (2004) 49). However these size distributions are not similar to the DNA (size) distributions obtained experimentally via the flow cytometric analysis of human tumour cell lines (data obtained from the Auckland Cancer Society Research Centre, New Zealand). In our one compartment model, size was a generic term, but in order to obtain realistic steady size distributions we chose size to be DNA content and devised a multi-compartment mathematical model for the cell division cycle where each compartment corresponds to a distinct phase of the cell cycle (J. Math. Biol. 47 (2003) 295). We then incorporated another compartment describing the possible induction of apoptosis (cell death) from mitosis phase (Modelling cell death in human tumour cell lines exposed to anticancer drug paclitaxel, J. Math. Biol. 2004, in press). This enabled us to compare our model to flow cytometric data of a melanoma cell line where the anticancer drug, paclitaxel, had been added. The model gives a dynamic picture of the effects of paclitaxel on the cell cycle. We hope to use the model to describe the effects of other cancer therapies on a number of different cell lines. Copyright 2004 Elsevier Ltd.

  13. Expression of DMP-1 in the human pulp tissue using low level laser therapy

    International Nuclear Information System (INIS)

    Neto, Natalino Lourenço; Teixeira Marques, Nádia Carolina; Fernandes, Ana Paula; Silva, Thiago Cruvinel; Andrade Moreira Machado, Maria Aparecida; Oliveira, Thais Marchini; Rodini, Camila Oliveira

    2015-01-01

    This study aimed to evaluate the effects of low-level laser therapy (LLLT) on DMP-1 expression in pulp tissue repair of human primary teeth. Twenty mandibular primary molars were randomly assigned into the following groups: Group I—Buckley’s Formocresol (FC); Group II—Calcium Hydroxide (CH); Group III—LLLT + CH and Group IV—LLLT + Zinc oxide/Eugenol. The teeth at the regular exfoliation period were extracted for histological analysis and immunolocalization of DMP-1. Descriptive analysis was performed on the dentin pulp complex. Histopathological assessment showed internal resorption in group FC. Groups CH and LLLT + CH provided better pulpal repair due to the absence of inflammation and the formation of hard tissue barrier. These two groups presented odontoblastic layer expressing DMP-1. According to this study, low level laser therapy preceding the use of calcium hydroxide exhibited satisfactory bio-inductive activity on pulp tissue repair of human primary teeth. However, other histological and cellular studies are needed to confirm the laser tissue action and efficacy. (paper)

  14. Effects of the photodynamic therapy on microbial reduction of diabetic ulcers in humans

    Science.gov (United States)

    Carrinho Aureliano, Patrícia Michelassi; Andreani, Dora Inés. Kozusny; Morete, Vislaine de Aguiar; Iseri Giraldeli, Shizumi; Baptista, Alessandra; Navarro, Ricardo Scarparo; Villaverde, Antonio Balbin

    2018-02-01

    Diabetes Mellitus is a chronic disease that can lead to lower-limb ulceration. The photodynamic therapy (PDT) is based on light interaction with a photosensitizer capable to promote bacterial death and tissue repair acceleration. This study analyzed the effects of PDT in the repair of human diabetic ulcers, by means of microbiological assessment. The clinical study was composed of 12 patients of both sexes with diabetic ulcers in lower limbs that were divided into two groups, control group (n=6) and PDT group (n=6). All patients were treated with collagenase/chloramphenicol during the experimental period, in which 6 of them have received PDT with methylene blue dye (0.01%) associated with laser therapy (660 nm), dose of 6 J/cm2¨ and 30 mW laser power. PDT group received ten treatment sessions. Wounds were evaluated for micro-organisms analysis. It was found a reduction in the occurrence of Staphylococcus aureus in both groups, being that reduction more pronounced in the PDT group. Microbial count was performed on PDT group, showing a statistical difference reduction (p<0.05) when compared before and after the treatment. It is concluded that PDT seems to be effective in microbial reduction of human diabetic wounds, promoting acceleration and improvement of tissue repair quality.ty.

  15. Light ions radiobiological effects on human tumoral cells: measurements modelling and application to hadron-therapy

    International Nuclear Information System (INIS)

    Jalade, P.

    2005-11-01

    In classical radiotherapy, the characteristics of photons interactions undergo limits for the treatment of radioresistant and not well located tumours. Pioneering treatments of patients at the Lawrence Laboratory at Berkeley has demonstrated two advantages of hadrons beams: the Relative Biologic Effect (the RBE) and the ballistic of the beams. Since 1994, the clinical centre at Chiba, has demonstrated successfully the applicability of the method. A physics group, managed by G. Kraft, at Darmstadt in Germany, has underlined the advantages of carbon beams. An European pool, called ENGIGHT (European Network for LIGHt ion Therapy) has been created in which the French ETOILE project appeared. The purpose of the thesis concerns measurements and models of 'in vitro' human cells survival. In the first part, the nowadays situation in particles interactions, tracks and cells structures and radiobiology is presented here. The second is devoted to the models based on the beam tracks and localization of the physical dose. Discussion of sensitivity to various parameters of the model has been realized with the help of numerical simulations. Finally the predictions of the improved model has been compared to experimental irradiations of human cells with argon and carbon beams of the GANIL machine. Conclusion of such study shows the performance and limits of a local model for predicting the radiobiological efficiency of light ions in hadron-therapy. (author)

  16. Smart sensors and virtual physiology human approach as a basis of personalized therapies in diabetes mellitus.

    Science.gov (United States)

    Fernández Peruchena, Carlos M; Prado-Velasco, Manuel

    2010-01-01

    Diabetes mellitus (DM) has a growing incidence and prevalence in modern societies, pushed by the aging and change of life styles. Despite the huge resources dedicated to improve their quality of life, mortality and morbidity rates, these are still very poor. In this work, DM pathology is revised from clinical and metabolic points of view, as well as mathematical models related to DM, with the aim of justifying an evolution of DM therapies towards the correction of the physiological metabolic loops involved. We analyze the reliability of mathematical models, under the perspective of virtual physiological human (VPH) initiatives, for generating and integrating customized knowledge about patients, which is needed for that evolution. Wearable smart sensors play a key role in this frame, as they provide patient's information to the models.A telehealthcare computational architecture based on distributed smart sensors (first processing layer) and personalized physiological mathematical models integrated in Human Physiological Images (HPI) computational components (second processing layer), is presented. This technology was designed for a renal disease telehealthcare in earlier works and promotes crossroads between smart sensors and the VPH initiative. We suggest that it is able to support a truly personalized, preventive, and predictive healthcare model for the delivery of evolved DM therapies.

  17. Mutagenesis in sequence encoding of human factor VII for gene therapy of hemophilia

    Directory of Open Access Journals (Sweden)

    B Kazemi

    2009-12-01

    Full Text Available "nBackground: Current treatment of hemophilia which is one of the most common bleeding disorders, involves replacement therapy using concentrates of FVIII and FIX .However, these concentrates have been associated with viral infections and thromboembolic complications and development of antibodies. "nThe use of recombinant human factor VII (rhFVII is effective  for the treatment of patients with  hemophilia A or B, who develop antibodies ( referred as inhibitors against  replacement therapy , because it induces coagulation independent of FVIII and FIX. However, its short half-life and high cost have limited its use. One potential solution to this problem may be the use of FVIIa gene transfer, which would attain continuing therapeutic levels of expression from a single injection. The aim of this study was to engineer a novel hFVII (human FVII gene containing a cleavage site for the intracellular protease and furin, by PCR mutagenesis "nMethods: The sequence encoding light and heavy chains of hFVII, were amplified by using hFVII/pTZ57R and specific primers, separately. The PCR products were cloned in pTZ57R vector. "nResults and discussion: Cloning was confirmed by restriction analysis or PCR amplification using specific primers and plasmid universal primers. Mutagenesis of sequence encoding light and heavy chain was confirmed by restriction enzyme. "nConclusion: In the present study, it was provided recombinant plasmids based on mutant form of DNA encoding light and heavy chains.  Joining mutant form of DNA encoding light chain with mutant heavy chain led to a new variant of hFVII. This variant can be activated by furin and an increase in the proportion of activated form of FVII. This mutant form of hFVII may be used for gene therapy of hemophilia.

  18. Dystrophin Expressing Chimeric (DEC) Human Cells Provide a Potential Therapy for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Siemionow, Maria; Cwykiel, Joanna; Heydemann, Ahlke; Garcia, Jesus; Marchese, Enza; Siemionow, Krzysztof; Szilagyi, Erzsebet

    2018-06-01

    Duchenne Muscular Dystrophy (DMD) is a progressive and lethal disease caused by mutations of the dystrophin gene. Currently no cure exists. Stem cell therapies targeting DMD are challenged by limited engraftment and rejection despite the use of immunosuppression. There is an urgent need to introduce new stem cell-based therapies that exhibit low allogenic profiles and improved cell engraftment. In this proof-of-concept study, we develop and test a new human stem cell-based approach to increase engraftment, limit rejection, and restore dystrophin expression in the mdx/scid mouse model of DMD. We introduce two Dystrophin Expressing Chimeric (DEC) cell lines created by ex vivo fusion of human myoblasts (MB) derived from two normal donors (MB N1 /MB N2 ), and normal and DMD donors (MB N /MB DMD ). The efficacy of fusion was confirmed by flow cytometry and confocal microscopy based on donor cell fluorescent labeling (PKH26/PKH67). In vitro, DEC displayed phenotype and genotype of donor parent cells, expressed dystrophin, and maintained proliferation and myogenic differentiation. In vivo, local delivery of both DEC lines (0.5 × 10 6 ) restored dystrophin expression (17.27%±8.05-MB N1 /MB N2 and 23.79%±3.82-MB N /MB DMD ) which correlated with significant improvement of muscle force, contraction and tolerance to fatigue at 90 days after DEC transplant to the gastrocnemius muscles (GM) of dystrophin-deficient mdx/scid mice. This study establishes DEC as a potential therapy for DMD and other types of muscular dystrophies.

  19. Passive heat therapy improves endothelial function, arterial stiffness and blood pressure in sedentary humans.

    Science.gov (United States)

    Brunt, Vienna E; Howard, Matthew J; Francisco, Michael A; Ely, Brett R; Minson, Christopher T

    2016-09-15

    A recent 30 year prospective study showed that lifelong sauna use reduces cardiovascular-related and all-cause mortality; however, the specific cardiovascular adaptations that cause this chronic protection are currently unknown. We investigated the effects of 8 weeks of repeated hot water immersion ('heat therapy') on various biomarkers of cardiovascular health in young, sedentary humans. We showed that, relative to a sham group which participated in thermoneutral water immersion, heat therapy increased flow-mediated dilatation, reduced arterial stiffness, reduced mean arterial and diastolic blood pressure, and reduced carotid intima media thickness, with changes all on par or greater than what is typically observed in sedentary subjects with exercise training. Our results show for the first time that heat therapy has widespread and robust effects on vascular function, and as such, could be a viable treatment option for improving cardiovascular health in a variety of patient populations, particularly those with limited exercise tolerance and/or capabilities. The majority of cardiovascular diseases are characterized by disorders of the arteries, predominantly caused by endothelial dysfunction and arterial stiffening. Intermittent hot water immersion ('heat therapy') results in elevations in core temperature and changes in cardiovascular haemodynamics, such as cardiac output and vascular shear stress, that are similar to exercise, and thus may provide an alternative means of improving health which could be utilized by patients with low exercise tolerance and/or capabilities. We sought to comprehensively assess the effects of 8 weeks of heat therapy on biomarkers of vascular function in young, sedentary subjects. Twenty young, sedentary subjects were assigned to participate in 8 weeks (4-5 times per week) of heat therapy (n = 10; immersion in a 40.5°C bath sufficient to maintain rectal temperature ≥ 38.5°C for 60 min per session) or thermoneutral water

  20. Tissue-engineered human bioartificial muscles expressing a foreign recombinant protein for gene therapy

    Science.gov (United States)

    Powell, C.; Shansky, J.; Del Tatto, M.; Forman, D. E.; Hennessey, J.; Sullivan, K.; Zielinski, B. A.; Vandenburgh, H. H.

    1999-01-01

    Murine skeletal muscle cells transduced with foreign genes and tissue engineered in vitro into bioartificial muscles (BAMs) are capable of long-term delivery of soluble growth factors when implanted into syngeneic mice (Vandenburgh et al., 1996b). With the goal of developing a therapeutic cell-based protein delivery system for humans, similar genetic tissue-engineering techniques were designed for human skeletal muscle stem cells. Stem cell myoblasts were isolated, cloned, and expanded in vitro from biopsied healthy adult (mean age, 42 +/- 2 years), and elderly congestive heart failure patient (mean age, 76 +/- 1 years) skeletal muscle. Total cell yield varied widely between biopsies (50 to 672 per 100 mg of tissue, N = 10), but was not significantly different between the two patient groups. Percent myoblasts per biopsy (73 +/- 6%), number of myoblast doublings prior to senescence in vitro (37 +/- 2), and myoblast doubling time (27 +/- 1 hr) were also not significantly different between the two patient groups. Fusion kinetics of the myoblasts were similar for the two groups after 20-22 doublings (74 +/- 2% myoblast fusion) when the biopsy samples had been expanded to 1 to 2 billion muscle cells, a number acceptable for human gene therapy use. The myoblasts from the two groups could be equally transduced ex vivo with replication-deficient retroviral expression vectors to secrete 0.5 to 2 microg of a foreign protein (recombinant human growth hormone, rhGH)/10(6) cells/day, and tissue engineered into human BAMs containing parallel arrays of differentiated, postmitotic myofibers. This work suggests that autologous human skeletal myoblasts from a potential patient population can be isolated, genetically modified to secrete foreign proteins, and tissue engineered into implantable living protein secretory devices for therapeutic use.

  1. Human Papilloma Virus Infection Does Not Predict Response to Interferon Therapy in Ocular Surface Squamous Neoplasia.

    Science.gov (United States)

    Galor, Anat; Garg, Nisha; Nanji, Afshan; Joag, Madhura; Nuovo, Gerard; Palioura, Sotiria; Wang, Gaofeng; Karp, Carol L

    2015-11-01

    To identify the frequency of human papilloma virus (HPV) in ocular surface squamous neoplasia (OSSN) and to evaluate differences in clinical features and treatment response of tumors with positive versus negative HPV results. Retrospective case series. Twenty-seven patients with OSSN. Ocular surface squamous neoplasia specimens were analyzed for the presence of HPV. Clinical features and response to interferon were determined retrospectively and linked to the presence (versus absence) of HPV. Clinical characteristics of OSSN by HPV status. Twenty-one of 27 tumors (78%) demonstrated positive HPV results. The HPV genotypes identified included HPV-16 in 10 tumors (48%), HPV-31 in 5 tumors, HPV-33 in 1 tumor, HPV-35 in 2 tumors, HPV-51 in 2 tumors, and a novel HPV in 3 tumors (total of 23 tumors because 1 tumor had 3 identified genotypes). Tumors found in the superior limbus were more likely to show positive HPV results (48% vs. 0%; P=0.06, Fisher exact test). Tumors with positive HPV-16 results were larger (68 vs. 34 mm2; P=0.08, Mann-Whitney U test) and were more likely to have papillomatous morphologic features (50% vs. 12%; P=0.07, Fisher exact test) compared with tumors showing negative results for HPV-16. Human papilloma virus status was not found to be associated with response to interferon therapy (P=1.0, Fisher exact test). Metrics found to be associated with a nonfavorable response to interferon were male gender and tumors located in the superior conjunctivae. The presence of HPV in OSSN seems to be more common in lesions located in the nonexposed, superior limbus. Human papilloma virus presence does not seem to be required for a favorable response to interferon therapy. Copyright © 2015 American Academy of Ophthalmology. All rights reserved.

  2. Successful blood conservation during craniosynostotic correction with dual therapy using procrit and cell saver.

    Science.gov (United States)

    Krajewski, Kara; Ashley, Rebekah K; Pung, Nina; Wald, Sam; Lazareff, Jorge; Kawamoto, Henry K; Bradley, James P

    2008-01-01

    Craniosynostotic correction typically performed around infant physiologic nadir of hemoglobin (approximately 3-6 months of age) is associated with high transfusion rates of packed red blood cells and other blood products. As a blood conserving strategy, we studied the use of 1) recombinant human erythropoietin or Procrit (to optimize preoperative hematocrit) and 2) Cell Saver (to recycle the slow, constant ooze of blood during the prolonged case). UCLA Patients with craniosynostosis from 2003-2005 were divided into 1) the study group (Procrit and Cell Saver) or 2) the control group (n = 79). The study group 1) received recombinant human erythropoietin at 3 weeks, 2 weeks, and 1 week preoperatively and 2) used Cell Saver intraoperatively. Outcomes were based on morbidities and transfusion rate comparisons. The 2 groups were comparable with regards to age (5.66 and 5.71 months), and operative times (3.11 vs 2.59 hours). In the study group there was a marked increase in preoperative hematocrit (56.2%). The study group had significantly lower transfusions rates (5% vs 100% control group) and lower volumes transfused than in the control group (0.05 pediatric units vs 1.74 pediatric units). Additionally, of the 80% of patients in the study group who received Cell Saver blood at the end of the case, approximately 31% would have needed a transfusion if the recycled blood were unavailable. Our data showed that for elective craniosynostotic correction, successful blood conserving dual therapy with Procrit and Cell Saver might be used to decrease transfusion rates and the need for any blood products.

  3. Combination therapy with sivelestat and recombinant human soluble thrombomodulin for ARDS and DIC patients

    Directory of Open Access Journals (Sweden)

    Miyoshi S

    2014-09-01

    Full Text Available Seigo Miyoshi,1 Ryoji Ito,1 Hitoshi Katayama,1 Kentaro Dote,2 Mayuki Aibiki,3 Hironobu Hamada,1,4 Takafumi Okura,1 Jitsuo Higaki1 1Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, 2Intensive Care Division, Ehime University Hospital, 3Department of Emergency and Critical Care Medicine, School of Medicine, Ehime University, Shitsukawa, Toon, Ehime, 4Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi, Minami-ku, Hiroshima, Japan Background: Neutrophil elastase, alveolar thrombin generation, and fibrin deposition play crucial roles in the development of acute respiratory distress syndrome (ARDS and disseminated intravascular coagulation (DIC. However, the usefulness of combination therapy with a selective neutrophil elastase inhibitor, sivelestat, and recombinant human soluble thrombomodulin (rhTM for patients with ARDS and DIC remains unknown. Methods: We conducted a retrospective data analysis of 142 ARDS patients with DIC to assess the effects of sivelestat combined with rhTM. Patients were divided into four groups: control (no sivelestat or rhTM treatment, sivelestat treatment alone, rhTM treatment alone, and combined treatment with sivelestat and rhTM. A Cox proportional hazard model was used to assess subject mortality rates. The efficacy of these drugs was evaluated based on survival rate, number of ventilator-free days, and change in PaO2/FIO2 (P/F ratios and DIC scores before and at 7 days after a diagnosis of ARDS with DIC. Results: Multivariate analysis showed that patient age, combination therapy, gas exchange, organ failure, cause, associated disease score, and serum C-reactive protein levels were predictors of mortality for patients with ARDS and DIC. As compared with untreated controls, combination therapy significantly improved the 60-day survival rate of patients with ARDS and DIC

  4. [Effect of recombinant human growth hormone therapy on metabolic parameters in patients with craniopharyngioma].

    Science.gov (United States)

    Mao, J F; Wang, X; Xiong, S Y; Zheng, J J; Yu, B Q; Nie, M; Wu, X Y; Qi, S T

    2017-11-14

    Objective: To investigate the effects of recombinant human growth hormone (rhGH) on metabolic parameters in patients with craniopharyngioma surgeries. Methods: Totallys 30 patients with craniopharyngioma were included in this retrospective study. They were divided into growth hormone (GH) group and control group according to whether they received rhGH therapy or not. The following parameters, including body mass index (BMI), weight, waist circumstance, transaminase, fasting blood glucose, lipid profile and high-sensitivity C-reactive protein (hsCRP) were compared after rhGH therapy for 4-6 months. Results: In GH group, patients were 18-46 (30.0±8.8) years old. The duration after craniopharyngioma surgery was (12.9±5.4) years. Before rhGH therapy, they had got sufficient thyroid and glucocorticoid hormone replacement. After rhGH therapy, the body weight decreased from (92.3±20.1) to (87.6 ±14.6) kg ( P =0.190), with a reduction of BMI from (30.1±5.9) to (28.2±3.7) kg/m(2) ( P =0.120). The waist circumference decreased from (104.4±9.4) cm to (98.8±10.6) cm ( P =0.002). Alanine aminotransferase (ALT) decreased from (52±34) to (28±19) U/L ( P =0.029), with a reduction of aspartate transaminase (AST) from (46±21) to (33±18) U/L ( P =0.035) and γ-glutamyl transpeptadase (GGT) from (59±42) to (29±15) U/L ( P =0.02). hsCRP decreased from (5.3±4.9) to (2.3±2.8) mg/L ( P =0.006) and triglyceride (TG) decreased from (1.8±0.7) to (1.5±0.6) mmol/L ( P =0.028). Fasting blood glucose, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and free fat acid (FFA) were not significantly changed(all P >0.05). In the control group, the above mentioned parameters did not changed significantly during 4-6 months of observational period(all P >0.05). Conclusion: rhGH therapy improves metabolic parameters in patients after craniopharyngioma surgery by decreasing body weight, waist circumstance and fat deposit in liver, as well as

  5. Physician Decisions to Defer Antiretroviral Therapy in Key Populations: Implications for Reducing Human Immunodeficiency Virus Incidence and Mortality in Malaysia

    OpenAIRE

    Ferro, Enrico G.; Culbert, Gabriel J.; Wickersham, Jeffrey A.; Marcus, Ruthanne; Steffen, Alana D.; Pauls, Heather A.; Westergaard, Ryan P.; Lee, Christopher K.; Kamarulzaman, Adeeba; Altice, Frederick L.

    2017-01-01

    Abstract Background. Antiretroviral therapy (ART) is recommended for all people living with human immunodeficiency virus (HIV), yet physician attitudes and prescribing behaviors toward members of key risk populations may limit ART access and undermine treatment as prevention strategies. Methods. Physicians in Malaysia (N = 214) who prescribe antiretroviral therapy (ART) responded in an Internet-based survey to hypothetical clinical scenarios of HIV patients, varying by key risk population and...

  6. 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.

  7. Hematopoietic Stem Cell Therapy as a Counter-Measure for Human Exploration of Deep Space

    Science.gov (United States)

    Ohi, S.; Roach, A.-N.; Ramsahai, S.; Kim, B. C.; Fitzgerald, W.; Riley, D. A.; Gonda, S. R.

    2004-01-01

    Human exploration of deep space depends, in part, on our ability to counter severe/invasive disorders that astronauts experience in space environments. The known symptoms include hematological/cardiac abnormalities,bone and muscle losses, immunodeficiency, neurological disorders, and cancer. Exploiting the extraordinary plasticity of hematopoietic stem cells (HSCs), which differentiate not only to all types of blood cells, but also to various tissues, we have advanced a hypothesis that ome of the space-caused disorders maybe amenable to hematopoietis stem cell therapy(HSCT) so as to maintain promote human exploration of deep space. Using mouse models of human anemia beta-thaiassemia) as well as spaceflight (hindlimb unloading system), we have obtained feasibility results of HSCT for space anemia, muscle loss, and immunodeficiency. For example, in the case of HSCT for muscle loss, the beta-galactosidese marked HSCs were detected in the hindlimbs of unloaded mouse following transplantation by -X-gal wholemaunt staining procedure. Histochemicaland physical analyses indicated structural contribution of HSCs to the muscle. HSCT for immunodeficiency was investigated ising beta-galactosidese gene-tagged Escherichia coli as the infectious agent. Results of the X-gal staining procedure indicated the rapeutic role of the HSCT. To facilitate the HSCT in space, growth of HSCs were optimized in the NASA Rotating Wall Vessel (RWV) culture systems, including Hydrodynamic Focusing Bioreactor (HFB).

  8. In vitro efficiency and mechanistic role of indocyanine green as photodynamic therapy agent for human melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Mamoon, A.M.; Miller, L.; Gamal-Eldeen, A. M.; Ruppel, M. E.; Smith, R. J.; Tsang, T.; Miller, L. M.

    2009-05-02

    Photodynamic therapy (PDT) is a promising treatment for superficial cancer. However, poor therapeutic results have been reported for melanoma, due to the high melanin content. Indocyanine green (ICG) has near infrared absorption (700-800 nm) and melanins do not absorb strongly in this area. This study explores the efficiency of ICG as a PDT agent for human melanoma, and its mechanistic role in the cell death pathway. Human skin melanoma cells (Sk-Mel-28) were incubated with ICG and exposed to a low power Ti:Sapphire laser. Synchrotron-assisted Fourier transform infrared microspectroscopy and hierarchical cluster analysis were used to assess the cell damage and changes in lipid, protein, and nucleic acids. The cell death pathway was determined by analysis of cell viability and apoptosis and necrosis markers. In the cell death pathway, {sup 1}O{sub 2} generation evoked rapid multiple consequences that trigger apoptosis after laser exposure for only 15min including the release of cytochrome c, the activation of total caspases, caspase-3, and caspase-9, the inhibition of NF-{Kappa}B P65, and the enhancement of DNA fragmentation, and histone acetylation. ICG/PDT can efficiently and rapidly induce apoptosis in human melanoma cells and it can be considered as a new therapeutic approach for topical treatment of melanoma.

  9. From the Cover: Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells

    Science.gov (United States)

    Sapir, Tamar; Shternhall, Keren; Meivar-Levy, Irit; Blumenfeld, Tamar; Cohen, Hamutal; Skutelsky, Ehud; Eventov-Friedman, Smadar; Barshack, Iris; Goldberg, Iris; Pri-Chen, Sarah; Ben-Dor, Lya; Polak-Charcon, Sylvie; Karasik, Avraham; Shimon, Ilan; Mor, Eytan; Ferber, Sarah

    2005-05-01

    Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of adult human liver cells into functional insulin-producing cells. PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner. When transplanted under the renal capsule of diabetic, immunodeficient mice, the cells ameliorated hyperglycemia for prolonged periods of time. Inducing developmental redirection of adult liver offers the potential of a cell-replacement therapy for diabetics by allowing the patient to be the donor of his own insulin-producing tissue. pancreas | transdifferentiation

  10. 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...

  11. Applicability of sodium alginate in decorporation therapy of strontium radioisotopes in human being

    International Nuclear Information System (INIS)

    Ferreira, Aloisio Cordilha

    1999-10-01

    The increasing release of fission products from nuclear weapon tests in the environment has been rising the levels of radioactive contamination of food chains caused by the fall-out of these elements. In cases of accidental exposure, human subjects could be submitted to an internal contamination, which is likely to include several radionuclides. Special concern must be given, however, to the radioactive isotopes of strontium, cesium and iodine, along with the highly radio toxic transuranium elements like cerium. It was found that sodium alginate, a polyelectrolyte commonly used in food industry and obtained from brown algae (Phaeophyceae), provides the selective suppression of absorption of radioactive strontium presented in the ingested food material with no disturbance of the electrolyte balance nor undesirable side effects, even for a long term treatment. Moreover, these patterns were maintained when alginate was associated to other decontamination additives, specially those related to the other radioisotopes mentioned above, as, in this case, losses in the effectiveness, mutual interference or adverse health effects were not detected. These conclusions ground the discussion about the present trend in the usual choice of EDTA/DTPA complex therapy rather than of alginate therapy for medical assistance of radiocontaminated patients, although they corroborate the efficiency and usefulness of alginate salts in situations related to extensive intakes of strontium radioisotopes alone or associated to other fission products. The purpose of the present work is to make a general review of the alginate therapy as well as to discuss its present and future therapeutic importance from the scientific and institutional points of view. (author)

  12. Improving Gene Therapy Efficiency through the Enrichment of Human Hematopoietic Stem Cells.

    Science.gov (United States)

    Masiuk, Katelyn E; Brown, Devin; Laborada, Jennifer; Hollis, Roger P; Urbinati, Fabrizia; Kohn, Donald B

    2017-09-06

    Lentiviral vector (LV)-based hematopoietic stem cell (HSC) gene therapy is becoming a promising clinical strategy for the treatment of genetic blood diseases. However, the current approach of modifying 1 × 10 8 to 1 × 10 9 CD34 + cells per patient requires large amounts of LV, which is expensive and technically challenging to produce at clinical scale. Modification of bulk CD34 + cells uses LV inefficiently, because the majority of CD34 + cells are short-term progenitors with a limited post-transplant lifespan. Here, we utilized a clinically relevant, immunomagnetic bead (IB)-based method to purify CD34 + CD38 - cells from human bone marrow (BM) and mobilized peripheral blood (mPB). IB purification of CD34 + CD38 - cells enriched severe combined immune deficiency (SCID) repopulating cell (SRC) frequency an additional 12-fold beyond standard CD34 + purification and did not affect gene marking of long-term HSCs. Transplant of purified CD34 + CD38 - cells led to delayed myeloid reconstitution, which could be rescued by the addition of non-transduced CD38 + cells. Importantly, LV modification and transplantation of IB-purified CD34 + CD38 - cells/non-modified CD38 + cells into immune-deficient mice achieved long-term gene-marked engraftment comparable with modification of bulk CD34 + cells, while utilizing ∼7-fold less LV. Thus, we demonstrate a translatable method to improve the clinical and commercial viability of gene therapy for genetic blood cell diseases. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  13. 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

  14. [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.

  15. Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy

    Science.gov (United States)

    Niederer, Heather A.; Bangham, Charles R. M.

    2014-01-01

    Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety. PMID:25365582

  16. Preventive physical therapy and care humanization in the treatment of a bedridden, home care, neurologic patient

    Directory of Open Access Journals (Sweden)

    Lina Faria

    Full Text Available Abstract Introduction: This case study investigated the impact of preventive physical therapy on shoulder problems and the prevention of pressure ulcers (PU in a bedridden, home care, post-neurological surgery patient. Objective: To highlight the importance of physical therapy in the prevention of comorbidities, chronic neurological sequelae, and PU. Materials and Methods: In the immediate post-surgical phase, the patient was treated with preventive measures against PU, according to the Pressure Ulcer Prevention Protocol of the University of São Paulo, the National Pressure Ulcer Advisory Panel, and the Braden Scale. In addition, we used the modified Ashworth scale to assess spasticity. A kinesiotherapy program based on the Bobath's concept was used to prevent subluxation of the plegic arm and help in the recovery of functional movements. Results: The use of preventive measures and delivery of humanized care during a six-month period helped prevent the development of stage 3 and 4 PU and physical, functional, and respiratory complications. By the end of six months, the patient was found to be at low risk of developing PU. Conclusion: Notwithstanding the difficulties experienced during treatment, especially for the positioning of the arm and performance of transferring and positioning techniques, the results of this study are in agreement with aspects considered important for treatment outcomes.

  17. Vitamin D as an adjunctive therapy in asthma. Part 2: A review of human studies.

    Science.gov (United States)

    Kerley, Conor P; Elnazir, Basil; Faul, John; Cormican, Liam

    2015-06-01

    Vitamin D deficiency (VDD) is highly prevalent worldwide, with adverse effects on bone health but also potentially other unfavorable consequences. VDD and asthma-incidence/severity share many common risk factors, including winter season, industrialization, poor diet, obesity, dark skin pigmentation, and high latitude. Multiple anatomical areas relevant to asthma contain both the enzyme responsible for producing activated vitamin D and the vitamin D receptor suggesting that activated vitamin D (1,25-dihydroxyvitamin D) may have important local effects at these sites. Emerging evidence suggests that VDD is associated with increased airway hyperresponsiveness, decreased pulmonary function, worse asthma control, and possibly decreased response to standard anti-asthma therapy. However the effect is inconsistent with preliminary evidence from different studies suggesting vitamin D is both beneficial and detrimental to asthma genesis and severity. Current evidence suggests that supplementation with moderate doses of vitamin D may be appropriate for maintenance of bone health in asthmatics, particularly steroid users. However emerging data from an increasing number of randomized, controlled, intervention studies of vitamin D supplementation in pediatric and adult asthma are becoming available and should help determine the importance, if any of vitamin D for asthma pathogenesis. The purpose of this second of a two-part review is to review the current human literature on vitamin D and asthma, discussing the possible consequences of VDD for asthma and the potential for vitamin D repletion as adjunct therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. MRI Reconstructions of Human Phrenic Nerve Anatomy and Computational Modeling of Cryoballoon Ablative Therapy.

    Science.gov (United States)

    Goff, Ryan P; Spencer, Julianne H; Iaizzo, Paul A

    2016-04-01

    The primary goal of this computational modeling study was to better quantify the relative distance of the phrenic nerves to areas where cryoballoon ablations may be applied within the left atria. Phrenic nerve injury can be a significant complication of applied ablative therapies for treatment of drug refractory atrial fibrillation. To date, published reports suggest that such injuries may occur more frequently in cryoballoon ablations than in radiofrequency therapies. Ten human heart-lung blocs were prepared in an end-diastolic state, scanned with MRI, and analyzed using Mimics software as a means to make anatomical measurements. Next, generated computer models of ArticFront cryoballoons (23, 28 mm) were mated with reconstructed pulmonary vein ostias to determine relative distances between the phrenic nerves and projected balloon placements, simulating pulmonary vein isolation. The effects of deep seating balloons were also investigated. Interestingly, the relative anatomical differences in placement of 23 and 28 mm cryoballoons were quite small, e.g., the determined difference between mid spline distance to the phrenic nerves between the two cryoballoon sizes was only 1.7 ± 1.2 mm. Furthermore, the right phrenic nerves were commonly closer to the pulmonary veins than the left, and surprisingly tips of balloons were further from the nerves, yet balloon size choice did not significantly alter calculated distance to the nerves. Such computational modeling is considered as a useful tool for both clinicians and device designers to better understand these associated anatomies that, in turn, may lead to optimization of therapeutic treatments.

  19. Efficiency of Human Epiphyseal Chondrocytes with Differential Replication Numbers for Cellular Therapy Products

    Directory of Open Access Journals (Sweden)

    Michiyo Nasu

    2016-01-01

    Full Text Available The cell-based therapy for cartilage or bone requires a large number of cells; serial passages of chondrocytes are, therefore, needed. However, fates of expanded chondrocytes from extra fingers remain unclarified. The chondrocytes from human epiphyses morphologically changed from small polygonal cells to bipolar elongated spindle cells and to large polygonal cells with degeneration at early passages. Gene of type II collagen was expressed in the cells only at a primary culture (Passage 0 and Passage 1 (P1 cells. The nodules by implantation of P0 to P8 cells were composed of cartilage and perichondrium. The cartilage consisted of chondrocytes with round nuclei and type II collagen-positive matrix, and the perichondrium consisted of spindle cells with type I collage-positive matrix. The cartilage and perichondrium developed to bone with marrow cavity through enchondral ossification. Chondrogenesis and osteogenesis by epiphyseal chondrocytes depended on replication number in culture. It is noteworthy to take population doubling level in correlation with pharmaceutical efficacy into consideration when we use chondrocytes for cell-based therapies.

  20. Impact of human platelet lysate on the expansion and chondrogenic capacity of cultured human chondrocytes for cartilage cell therapy.

    Science.gov (United States)

    Sykes, J G; Kuiper, J H; Richardson, J B; Roberts, S; Wright, K T; Kuiper, N J

    2018-05-01

    High hopes have been pinned on regenerative medicine strategies in order to prevent the progression of cartilage damage to osteoarthritis, particularly by autologous chondrocyte implantation (ACI). The loss of chondrocyte phenotype during in vitro monolayer expansion, a necessary step to obtain sufficient cell numbers, may be a key limitation in ACI. In this study, it was determined whether a shorter monolayer expansion approach could improve chondrogenic differentiation. The effects of two supplement types, foetal bovine serum (FBS) and Stemulate™ (a commercial source of human platelet lysate), on the expansion and re-differentiation potential of human chondrocytes, isolated from five individuals, were compared. Chondrocytes were expanded with 10 % FBS or 10 % Stemulate™. Pellets were cultured for 28 d in chondrogenic differentiation medium and assessed for the presence of cartilage matrix molecules and genes associated with chondrogenicity. Stemulate™ significantly enhanced the proliferation rate [average population doubling times: FBS, 25.07 ± 6.98 d (standard error of the mean, SEM) vs. Stemulate™, 13.10 ± 2.57 d (SEM)]. Sulphated glycosaminoglycans (sGAG), total collagen and qRT-PCR analyses of cartilage genes showed that FBS-expanded chondrocytes demonstrated significantly better chondrogenic capacity than Stemulate™-expanded chondrocytes. Histologically, FBS-expanded chondrocyte pellets appeared to be more stable, with a more intense staining for toluidine blue, indicating a greater chondrogenic capacity. Although Stemulate™ positively influenced chondrocyte proliferation, it had a negative effect on chondrogenic differentiation potential. This suggested that, in the treatment of cartilage defects, Stemulate™ might not be the ideal supplement for expanding chondrocytes (which maintained a chondrocyte phenotype) and, hence, for cell therapies (including ACI).

  1. Impact of human platelet lysate on the expansion and chondrogenic capacity of cultured human chondrocytes for cartilage cell therapy

    Directory of Open Access Journals (Sweden)

    JG Sykes

    2018-05-01

    Full Text Available High hopes have been pinned on regenerative medicine strategies in order to prevent the progression of cartilage damage to osteoarthritis, particularly by autologous chondrocyte implantation (ACI. The loss of chondrocyte phenotype during in vitro monolayer expansion, a necessary step to obtain sufficient cell numbers, may be a key limitation in ACI. In this study, it was determined whether a shorter monolayer expansion approach could improve chondrogenic differentiation. The effects of two supplement types, foetal bovine serum (FBS and Stemulate™ (a commercial source of human platelet lysate, on the expansion and re-differentiation potential of human chondrocytes, isolated from five individuals, were compared. Chondrocytes were expanded with 10 % FBS or 10 % Stemulate™. Pellets were cultured for 28 d in chondrogenic differentiation medium and assessed for the presence of cartilage matrix molecules and genes associated with chondrogenicity. Stemulate™ significantly enhanced the proliferation rate [average population doubling times: FBS, 25.07 ± 6.98 d (standard error of the mean, SEM vs. Stemulate™, 13.10 ± 2.57 d (SEM]. Sulphated glycosaminoglycans (sGAG, total collagen and qRT-PCR analyses of cartilage genes showed that FBS-expanded chondrocytes demonstrated significantly better chondrogenic capacity than Stemulate™-expanded chondrocytes. Histologically, FBS-expanded chondrocyte pellets appeared to be more stable, with a more intense staining for toluidine blue, indicating a greater chondrogenic capacity. Although Stemulate™ positively influenced chondrocyte proliferation, it had a negative effect on chondrogenic differentiation potential. This suggested that, in the treatment of cartilage defects, Stemulate™ might not be the ideal supplement for expanding chondrocytes (which maintained a chondrocyte phenotype and, hence, for cell therapies (including ACI.

  2. 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

  3. Dog as a model in studies on human hereditary diseases and their gene therapy.

    Science.gov (United States)

    Switonski, Marek

    2014-03-01

    During the last 15 years spectacular progress has been achieved in knowledge on the dog genome organization and the molecular background of hereditary diseases in this species. A majority of canine genetic diseases have their counterparts in humans and thus dogs are considered as a very important large animal model in human biomedicine. Among canine monogenic diseases with known causative gene mutations there are two large groups classified as retinal dystrophies and lysosomal storage diseases. Specific types of these diseases are usually diagnosed in a single or several breeds. A well known disorder, restricted to a single breed, is congenital stationary night blindness described in Briards. This disease is a counterpart of Leber amaurosis in children. On the other hand, one of the most common monogenic human diseases (Duchenne muscular dystrophy), has its canine counterparts in several breeds (e.g., the Golden retriever, Beagle and German short-haired pointer). For some of the canine diseases gene therapy strategy was successfully applied, e.g., for congenital stationary night blindness, rod-cone dystrophy and muccopolysaccharydoses type I, IIIB and VII. Since phenotypic variability between the breeds is exceptionally high, the dog is an interesting model to study the molecular background of congenital malformations (e.g., dwarfism and osteoporosis imperfecta). Also disorders of sexual development (DSD), especially testicular or ovotesticular DSD (78,XX; SRY-negative), which is widely distributed across dozens of breeds, are of particular interest. Studies on the genetic background of canine cancers, a major health problem in this species, are also quite advanced. On the other hand, genetic studies on canine counterparts of major human complex diseases (e.g., obesity, the metabolic syndrome and diabetes mellitus) are still in their infancy. Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish

  4. Human induced pluripotent stem cells labeled with fluorescent magnetic nanoparticles for targeted imaging and hyperthermia therapy for gastric cancer

    International Nuclear Information System (INIS)

    Li, Chao; Ruan, Jing; Yang, Meng; Pan, Fei; Gao, Guo; Qu, Su; Shen, You-Lan; Dang, Yong-Jun; Wang, Kan; Jin, Wei-Lin; Cui, Da-Xiang

    2015-01-01

    Human induced pluripotent stem (iPS) cells exhibit great potential for generating functional human cells for medical therapies. In this paper, we report for use of human iPS cells labeled with fluorescent magnetic nanoparticles (FMNPs) for targeted imaging and synergistic therapy of gastric cancer cells in vivo. Human iPS cells were prepared and cultured for 72 h. The culture medium was collected, and then was co-incubated with MGC803 cells. Cell viability was analyzed by the MTT method. FMNP-labeled human iPS cells were prepared and injected into gastric cancer-bearing nude mice. The mouse model was observed using a small-animal imaging system. The nude mice were irradiated under an external alternating magnetic field and evaluated using an infrared thermal mapping instrument. Tumor sizes were measured weekly. iPS cells and the collected culture medium inhibited the growth of MGC803 cells. FMNP-labeled human iPS cells targeted and imaged gastric cancer cells in vivo, as well as inhibited cancer growth in vivo through the external magnetic field. FMNP-labeled human iPS cells exhibit considerable potential in applications such as targeted dual-mode imaging and synergistic therapy for early gastric cancer

  5. 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.

  6. Creosote bush lignans for human disease treatment and prevention: Perspectives on combination therapy

    Directory of Open Access Journals (Sweden)

    John Gnabre

    2015-07-01

    Full Text Available The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata, are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. The plant is rich in simple bisphenyl lignans and tricyclic lignans known as cyclolignans. These compounds are responsible for many of the pharmacological activities of extracts of the plants. Some of these activities, namely antiherpes, antioxidant, antifungal, and anti-inflammatory, were known a century ago. Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. This review summarizes the recent findings on creosote bush lignans. We introduce the concept of a cocktail of safe well-characterized natural products from the creosote bush that would represent a bridge between oriental herbal medicines and Western drug-based therapies.

  7. [Human plague and pneumonic plague : pathogenicity, epidemiology, clinical presentations and therapy].

    Science.gov (United States)

    Riehm, Julia M; Löscher, Thomas

    2015-07-01

    Yersinia pestis is a highly pathogenic gram-negative bacterium and the causative agent of human plague. In the last 1500 years and during three dreaded pandemics, millions of people became victims of Justinian's plague, the Black Death, or modern plague. Today, Y. pestis is endemic in natural foci of Asian, African and American countries. Due to its broad dissemination in mammal species and fleas, eradication of the pathogen will not be possible in the near future. In fact, plague is currently classified as a "re-emerging disease". Infection may occur after the bite of an infected flea, but also after oral ingestion or inhalation of the pathogen. The clinical presentations comprise the bubonic and pneumonic form, septicemia, rarely pharyngitis, and meningitis. Most human cases can successfully be treated with antibiotics. However, the high transmission rate and lethality of pneumonic plague require international and mandatory case notification and quarantine of patients. Rapid diagnosis, therapy and barrier nursing are not only crucial for the individual patient but also for the prevention of further spread of the pathogen or of epidemics. Therefore, WHO emergency schedules demand the isolation of cases, identification and surveillance of contacts as well as control of zoonotic reservoir animals and vectors. These sanctions and effective antibiotic treatment usually allow a rapid containment of outbreaks. However, multiple antibiotic resistant strains of Y. pestis have been isolated from patients in the past. So far, no outbreaks with such strains have been reported.

  8. HIV, human papillomavirus, and cervical neoplasia and cancer in the era of highly active antiretroviral therapy.

    Science.gov (United States)

    De Vuyst, Hugo; Lillo, Flavia; Broutet, Nathalie; Smith, Jennifer S

    2008-11-01

    The objective of this study was to review the literature on the epidemiological association between human papillomavirus (HPV), HIV, and cervical neoplasia, and the impact of highly active antiretroviral therapy (HAART) on this association. MEDLINE was searched using the terms 'human papillomavirus', 'HPV', 'HIV', 'cervix', 'neoplasm', and 'antiretroviral' to identify articles published before December 2006. HIV-infection was strongly associated with a higher prevalence, incidence, and persistence of HPV infection and correlated with prevalence, incidence, persistence, and progression of squamous intraepithelial lesions. The association between HIV and invasive cervical carcinoma has been more difficult to establish, but is now fully recognized. HAART seems to have little, if any, beneficial effect on the natural history of intraepithelial lesions in HIV-positive women. Despite this fact, HAART, does increase the life expectancy of HIV-positive women. Therefore, it remains important to closely monitor HPV-related disease in women with HIV who are receiving HAART, particularly in regions of the world where cervical screening is not available routinely.

  9. Effects of acute exercise on fear extinction in rats and exposure therapy in humans: Null findings from five experiments.

    Science.gov (United States)

    Jacquart, Jolene; Roquet, Rheall F; Papini, Santiago; Powers, Mark B; Rosenfield, David; Smits, Jasper A J; Monfils, Marie-H

    2017-08-01

    Exposure therapy is an established learning-based intervention for the treatment of anxiety disorders with an average response rate of nearly 50%, leaving room for improvement. Emerging strategies to enhance exposure therapy in humans and fear extinction retention in animal models are primarily pharmacological. These approaches are limited as many patients report preferring non-pharmacological approaches in therapy. With general cognitive enhancement effects, exercise has emerged as a plausible non-pharmacological augmentation strategy. The present study tested the hypothesis that fear extinction and exposure therapy would be enhanced by a pre-training bout of exercise. We conducted four experiments with rats that involved a standardized conditioning and extinction paradigm and a manipulation of exercise. In a fifth experiment, we manipulated vigorous-intensity exercise prior to a standardized virtual reality exposure therapy session among adults with fear of heights. In experiments 1-4, exercise did not facilitate fear extinction, long-term memory, or fear relapse tests. In experiment 5, human participants showed an overall reduction in fear of heights but exercise did not enhance symptom improvement. Although acute exercise prior to fear extinction or exposure therapy, as operationalized in the present 5 studies, did not enhance outcomes, these results must be interpreted within the context of a broader literature that includes positive findings. Taken all together, this suggests that more research is necessary to identify optimal parameters and key individual differences so that exercise can be implemented successfully to treat anxiety disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. 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.

  11. 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.

  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. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. Simultaneous determination of triple therapy for Helicobacter pylori in human plasma by reversed phase chromatography with online wavelength switching

    Science.gov (United States)

    Ahmed, Sameh; Atia, Noha N.

    2015-02-01

    The infection of gastric mucosa by Helicobacter pylori (HP) is an essential cofactor in the aetiology of gastroduodenal ulcer and gastric carcinoma. Because of the bacterial resistance, combination therapy containing omeprazole (OME), tinidazole (TNZ) and clarithromycin (CLA) is commonly used for eradication of HP. However, the simultaneous determination of the triple therapy in human plasma was not reported. A simple, reproducible, and selective HPLC method was developed for the simultaneous determination of the triple therapy mixture used for management of HP infections in human plasma. An HPLC procedure based on a liquid-liquid extraction, enrichment of the analytes and subsequent reversed-phase chromatography with UV detection was used. To enable sensitive and selective detection, the method involved the use of online wavelength switching detection, with two different detection wavelengths; 280 nm for detection of OME and TNZ and 210 nm for detection of CLA. Separations were performed on C18 analytical column with acetonitrile-10 mM phosphate buffer of pH = 3.0 at flow rate of 1.0 mL min-1. The linear ranges in human plasma were 0.05-10 μg mL-1 with correlation coefficients >0.9990. The detection limits in human plasma were 0.02-0.07 μg mL-1. Validation parameters were assessed in compliance with US-FDA guidelines. The method proved to be valuable for the therapeutic drug monitoring after oral administration of triple therapy tablets.

  1. The Reasoned Arguments of a Group of Future Biotechnology Technicians on a Controversial Socio-Scientific Issue: Human Gene Therapy

    Science.gov (United States)

    Simonneaux, Laurence; Chouchane, Habib

    2011-01-01

    We tried to determine the reasoning behind the stances taken by a group of 19-21-year-old students on the controversial issue of the feasibility and acceptability of human gene therapy. The students were in training at a biotechnology institute. We organised classroom debates, punctuated by phases of epistemological "disturbances". We…

  2. 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...

  3. 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,

  4. 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...

  5. Age and duration of testosterone therapy predict time to return of sperm count after human chorionic gonadotropin therapy.

    Science.gov (United States)

    Kohn, Taylor P; Louis, Matthew R; Pickett, Stephen M; Lindgren, Mark C; Kohn, Jaden R; Pastuszak, Alexander W; Lipshultz, Larry I

    2017-02-01

    To determine factors that influence sperm recovery after T-associated infertility. Clinical retrospective study. Academic male-infertility urology clinic. Sixty-six men who presented with infertility after T use. T cessation and combination high-dose hCG and selective estrogen modulator (SERM) therapy. Whether patients successfully achieved or failed to achieve a total motile count (TMC) of greater than 5 million sperm within 12 months of T cessation and initiation of therapy. A TMC of greater than 5 million sperm was achieved by 46 men (70%). Both increased age and duration of T use directly correlated with time to sperm recovery at both 6 and 12 months of hCG/SERM therapy. Age more consistently limited sperm recovery, while duration of T use had less influence at 12 months than at 6 months. Only 64.8% of azoospermic men achieved a TMC greater than 5 million sperm at 12 months, compared with 91.7% of cryptozoospermic men, yet this did not predict a failure of sperm recovery. Increasing age and duration of T use significantly reduce the likelihood of recovery of sperm in the ejaculate, based on a criterion of a TMC of 5 million sperm, at 6 and 12 months. Physicians should be cautious in pursuing long-term T therapy, particularly in men who still desire fertility. Using these findings, physicians can counsel men regarding the likelihood of recovery of sperm at 6 and 12 months. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  6. Outcomes of human immunodeficiency virus-infected children after anti-retroviral therapy in Malaysia.

    Science.gov (United States)

    Moy, Fong Siew; Fahey, Paul; Nik Yusoff, Nik K; Razali, Kamarul A; Nallusamy, Revathy

    2015-02-01

    To describe outcome and examine factors associated with mortality among human immunodeficiency virus (HIV)-infected children in Malaysia after anti-retroviral therapy (ART). Retrospective and prospective data collected through March 2009 from children in four different states in Malaysia enrolled in TREAT Asia's Pediatric HIV Observational Database were analysed. Of 347 children in the cohort, only 278 (80.1%) were commenced on ART. The median CD4 count and median age at baseline prior to ART was 272 cells/μL and 4.2 years (interquartile range (IQR): 1.4, 7.4 years), respectively. The median duration of follow-up was 3.7 years (IQR: 1.8, 6.0) with 32 deaths giving a crude mortality rate of 2.86 per 100 child-years. The mortality rate highest in the first 6 months of ART was 10.62 per 100 child-years and declined to 1.83 per 100 child-years thereafter. On univariate analyses, only baseline median CD4 percentage, weight for age z score, height for age z score and anaemia were significantly associated with mortality. Upon including all four of these predictors into a single multivariate model, only weight for age z score remained statistically significantly predictive of mortality. Children commenced on ART had high mortality in the first 6 months especially in those with low CD4 percentage, wasting and anaemia. Poor nutritional status is an important independent predictor of mortality in this study. Besides initiating ART therapy, nutritional support and intervention must receive the utmost attention. © 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  7. DNA damage and gene therapy of xeroderma pigmentosum, a human DNA repair-deficient disease

    International Nuclear Information System (INIS)

    Dupuy, Aurélie; Sarasin, Alain

    2015-01-01

    Graphical abstract: - Highlights: • Full correction of mutation in the XPC gene by engineered nucleases. • Meganucleases and TALENs are inhibited by 5-MeC for inducing double strand breaks. • Gene therapy of XP cells is possible using homologous recombination for DSB repair. - Abstract: Xeroderma pigmentosum (XP) is a genetic disease characterized by hypersensitivity to ultra-violet and a very high risk of skin cancer induction on exposed body sites. This syndrome is caused by germinal mutations on nucleotide excision repair genes. No cure is available for these patients except a complete protection from all types of UV radiations. We reviewed the various techniques to complement or to correct the genetic defect in XP cells. We, particularly, developed the correction of XP-C skin cells using the fidelity of the homologous recombination pathway during repair of double-strand break (DSB) in the presence of XPC wild type sequences. We used engineered nucleases (meganuclease or TALE nuclease) to induce a DSB located at 90 bp of the mutation to be corrected. Expression of specific TALE nuclease in the presence of a repair matrix containing a long stretch of homologous wild type XPC sequences allowed us a successful gene correction of the original TG deletion found in numerous North African XP patients. Some engineered nucleases are sensitive to epigenetic modifications, such as cytosine methylation. In case of methylated sequences to be corrected, modified nucleases or demethylation of the whole genome should be envisaged. Overall, we showed that specifically-designed TALE-nuclease allowed us to correct a 2 bp deletion in the XPC gene leading to patient's cells proficient for DNA repair and showing normal UV-sensitivity. The corrected gene is still in the same position in the human genome and under the regulation of its physiological promoter. This result is a first step toward gene therapy in XP patients

  8. DNA damage and gene therapy of xeroderma pigmentosum, a human DNA repair-deficient disease

    Energy Technology Data Exchange (ETDEWEB)

    Dupuy, Aurélie [Laboratory of Genetic Instability and Oncogenesis UMR8200CNRS, Institut Gustave Roussy and University Paris-Sud, Villejuif (France); Sarasin, Alain, E-mail: alain.sarasin@gustaveroussy.fr [Laboratory of Genetic Instability and Oncogenesis UMR8200CNRS, Institut Gustave Roussy and University Paris-Sud, Villejuif (France); Service de Génétique, Institut Gustave Roussy (France)

    2015-06-15

    Graphical abstract: - Highlights: • Full correction of mutation in the XPC gene by engineered nucleases. • Meganucleases and TALENs are inhibited by 5-MeC for inducing double strand breaks. • Gene therapy of XP cells is possible using homologous recombination for DSB repair. - Abstract: Xeroderma pigmentosum (XP) is a genetic disease characterized by hypersensitivity to ultra-violet and a very high risk of skin cancer induction on exposed body sites. This syndrome is caused by germinal mutations on nucleotide excision repair genes. No cure is available for these patients except a complete protection from all types of UV radiations. We reviewed the various techniques to complement or to correct the genetic defect in XP cells. We, particularly, developed the correction of XP-C skin cells using the fidelity of the homologous recombination pathway during repair of double-strand break (DSB) in the presence of XPC wild type sequences. We used engineered nucleases (meganuclease or TALE nuclease) to induce a DSB located at 90 bp of the mutation to be corrected. Expression of specific TALE nuclease in the presence of a repair matrix containing a long stretch of homologous wild type XPC sequences allowed us a successful gene correction of the original TG deletion found in numerous North African XP patients. Some engineered nucleases are sensitive to epigenetic modifications, such as cytosine methylation. In case of methylated sequences to be corrected, modified nucleases or demethylation of the whole genome should be envisaged. Overall, we showed that specifically-designed TALE-nuclease allowed us to correct a 2 bp deletion in the XPC gene leading to patient's cells proficient for DNA repair and showing normal UV-sensitivity. The corrected gene is still in the same position in the human genome and under the regulation of its physiological promoter. This result is a first step toward gene therapy in XP patients.

  9. Regulation of interferon receptor expression in human blood lymphocytes in vitro and during interferon therapy

    International Nuclear Information System (INIS)

    Lau, A.S.; Hannigan, G.E.; Freedman, M.H.; Williams, B.R.

    1986-01-01

    Interferons (IFN) elicit antiviral and antineoplastic activities by binding to specific receptors on the cell surface. The binding characteristics of IFN to human lymphocytes were studied using IFN alpha 2 labeled with 125 I to high specific activity. The specific binding curves generated were analyzed by the LIGAND program of Munson and Rodbard to determine receptor numbers. The number of receptors in peripheral blood lymphocytes (PBL) and tonsillar B-lymphocytes (TBL) from normal individuals were 505 +/- 293 (n = 10) and 393 +/- 147 (n = 3) respectively. When these cells were preincubated in vitro with unlabeled IFN alpha 2, the receptor number decreased to 82 +/- 45 and 61 +/- 16 respectively. Receptor binding activities recovered gradually over a period of 72 h when the cells were incubated in IFN-free medium. This recovery of receptors could be blocked by the addition of actinomycin D to the incubation medium. A similar decrease in receptor expression was observed in vivo in PBL from patients being treated daily with 5 X 10(6) units/m2 per d of IFN alpha 2 by subcutaneous injection, for acute lymphoblastic leukemia or papilloma virus infections. Receptor numbers in PBL in vivo were further reduced concurrent with the progression of IFN therapy. Thus, the reduction in IFN receptor expression observed in vitro can be demonstrated in vivo. These studies indicate that monitoring IFN receptor expression in vivo can provide information regarding the availability of IFN receptors at the cell surface for the mediation of IFN actions during the course of IFN therapy

  10. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia.

    Science.gov (United States)

    Cavazzana-Calvo, Marina; Payen, Emmanuel; Negre, Olivier; Wang, Gary; Hehir, Kathleen; Fusil, Floriane; Down, Julian; Denaro, Maria; Brady, Troy; Westerman, Karen; Cavallesco, Resy; Gillet-Legrand, Beatrix; Caccavelli, Laure; Sgarra, Riccardo; Maouche-Chrétien, Leila; Bernaudin, Françoise; Girot, Robert; Dorazio, Ronald; Mulder, Geert-Jan; Polack, Axel; Bank, Arthur; Soulier, Jean; Larghero, Jérôme; Kabbara, Nabil; Dalle, Bruno; Gourmel, Bernard; Socie, Gérard; Chrétien, Stany; Cartier, Nathalie; Aubourg, Patrick; Fischer, Alain; Cornetta, Kenneth; Galacteros, Frédéric; Beuzard, Yves; Gluckman, Eliane; Bushman, Frederick; Hacein-Bey-Abina, Salima; Leboulch, Philippe

    2010-09-16

    The β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound β(E)/β(0)-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas. The β(E)-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated β(E)-globin with partial instability. When this is compounded with a non-functional β(0) allele, a profound decrease in β-globin synthesis results, and approximately half of β(E)/β(0)-thalassaemia patients are transfusion-dependent. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe β(E)/β(0)-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl(-1), of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells.

  11. Enrichment of human hematopoietic stem/progenitor cells facilitates transduction for stem cell gene therapy.

    Science.gov (United States)

    Baldwin, Kismet; Urbinati, Fabrizia; Romero, Zulema; Campo-Fernandez, Beatriz; Kaufman, Michael L; Cooper, Aaron R; Masiuk, Katelyn; Hollis, Roger P; Kohn, Donald B

    2015-05-01

    Autologous hematopoietic stem cell (HSC) gene therapy for sickle cell disease has the potential to treat this illness without the major immunological complications associated with allogeneic transplantation. However, transduction efficiency by β-globin lentiviral vectors using CD34-enriched cell populations is suboptimal and large vector production batches may be needed for clinical trials. Transducing a cell population more enriched for HSC could greatly reduce vector needs and, potentially, increase transduction efficiency. CD34(+) /CD38(-) cells, comprising ∼1%-3% of all CD34(+) cells, were isolated from healthy cord blood CD34(+) cells by fluorescence-activated cell sorting and transduced with a lentiviral vector expressing an antisickling form of beta-globin (CCL-β(AS3) -FB). Isolated CD34(+) /CD38(-) cells were able to generate progeny over an extended period of long-term culture (LTC) compared to the CD34(+) cells and required up to 40-fold less vector for transduction compared to bulk CD34(+) preparations containing an equivalent number of CD34(+) /CD38(-) cells. Transduction of isolated CD34(+) /CD38(-) cells was comparable to CD34(+) cells measured by quantitative PCR at day 14 with reduced vector needs, and average vector copy/cell remained higher over time for LTC initiated from CD34(+) /38(-) cells. Following in vitro erythroid differentiation, HBBAS3 mRNA expression was similar in cultures derived from CD34(+) /CD38(-) cells or unfractionated CD34(+) cells. In vivo studies showed equivalent engraftment of transduced CD34(+) /CD38(-) cells when transplanted in competition with 100-fold more CD34(+) /CD38(+) cells. This work provides initial evidence for the beneficial effects from isolating human CD34(+) /CD38(-) cells to use significantly less vector and potentially improve transduction for HSC gene therapy. © 2015 AlphaMed Press.

  12. Long-term use of first-line highly active antiretroviral therapy is not associated with carotid artery stiffness in human immunodeficiency virus-positive patients

    Directory of Open Access Journals (Sweden)

    Haohui Zhu

    2014-09-01

    Conclusion: The first-line highly active antiretroviral therapy currently used in China is not associated with carotid artery stiffness in human immunodeficiency virus-positive patients with good highly active antiretroviral therapy compliance. Human immunodeficiency virus may play a role in the development of atherosclerosis.

  13. Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy?

    Science.gov (United States)

    Harrison, Louis; Blackwell, Kimberly

    2004-01-01

    Hypoxia is a common feature of solid tumors that occurs across a wide variety of malignancies. Hypoxia and anemia (which contributes to tumor hypoxia) can lead to ionizing radiation and chemotherapy resistance by depriving tumor cells of the oxygen essential for the cytotoxic activities of these agents. Hypoxia may also reduce tumor sensitivity to radiation therapy and chemotherapy through one or more indirect mechanisms that include proteomic and genomic changes. These effects, in turn, can lead to increased invasiveness and metastatic potential, loss of apoptosis, and chaotic angiogenesis, thereby further increasing treatment resistance. Investigations of the prognostic significance of pretreatment tumor oxygenation status have shown that hypoxia (oxygen tension [pO(2)] value effect of hypoxia on standard cancer treatment, a variety of hypoxia- and anemia-targeted therapies have been studied in an effort to improve therapeutic effectiveness and patient outcomes. Early evidence from experimental and clinical studies suggests the administration of recombinant human erythropoietin (rHuEPO) may enhance the effectiveness of radiation therapy and chemotherapy by increasing hemoglobin levels and ameliorating anemia in patients with disease- or treatment-related anemia. However, further research is needed in the area of hypoxia-related treatment resistance and its reversal.

  14. Influence of the chemical composition of human tissues on dose distributions in hadron-therapy

    International Nuclear Information System (INIS)

    Batin, E.

    2008-06-01

    To compute the dose distribution, treatment planning systems require the exact anatomical location of tissues provided by computed tomography (CT) and the exact range of hadron beams in tissues based on the water equivalent ratio (WER). Since CT numbers are determined with x-rays and with an energy different from that used in hadron-therapy, a relation between CT numbers and the WER must to be established. We propose a determination of the WER with a Monte-Carlo simulation (GEANT4). We have determined the WER for 76 human tissues for a 135 MeV proton beam and for a 290 MeV/A carbon beam. The difference between the stoichiometric calibration and the simulated WER is lower than 1%. An additional 2% uncertainty that arises from the uncertainty in the CT numbers measurement should also be considered. The calculated WER were used to convert the deposited energy curve into the human tissue deposited energy curve for a 135 MeV proton beam and for a 290 MeV/A carbon beam. For both beams, the difference between the rescaled Bragg peak location and the one from the simulated curve is lower than 0.5 mm over the whole range of CT numbers. The differences between the maximum deposited energy can reach 3% for the proton beam in bones and vary between 1.5% and 3.5% for all tissues for the carbon beam. The scaling in two dimensions can be improved by using an additional factor that takes the scattering into account. (author)

  15. Photodynamic therapy induces antifibrotic alterations in primary human vocal fold fibroblasts.

    Science.gov (United States)

    Zhang, Chi; Wang, Jiajia; Chou, Adriana; Gong, Ting; Devine, Erin E; Jiang, Jack J

    2018-04-18

    Photodynamic therapy (PDT) is a promising treatment modality for laryngeal dysplasia, early-stage carcinoma, and papilloma, and was reported to have the ability to preserve laryngeal function and voice quality without clinical fibrotic response. We aimed to investigate the mechanism behind the antifibrotic effects of PDT on primary human vocal fold fibroblasts (VFFs) in vitro. In vitro analysis from one human donor. Cell viability of VFFs in response to varying doses of PDT was investigated by the Cell Counting Kit-8 method. Sublethal-dose PDT (SL-PDT) was used for the following experiments. Expression of genes related to vocal fold extracellular matrix formation was analyzed by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting. Effects of PDT on cell migration, collagen contraction, and transforming growth factor β-1 (TGF-β1)-induced myofibroblast differentiation were also analyzed. PDT affects the viability of VFFs in a dose-dependent manner. SL-PDT significantly changed the expression profile of VFFs with antifibrotic effects. It also inhibited cell migration, reduced collagen contraction, and reversed the fibroblast-myofibroblast differentiation induced by TGF-β1. SL-PDT induces antifibrotic alterations in VFFs. This could explain the low incidence of vocal fold scar associated with PDT. Moreover, PDT may be useful in treating existing vocal fold scars. Further studies should focus on the in vivo effect of PDT on vocal fold wound healing and scar remodeling. NA Laryngoscope, 2018. © 2018 The American Laryngological, Rhinological and Otological Society, Inc.

  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. Focal Electrically Administered Therapy (FEAT): Device parameter effects on stimulus perception in humans

    Science.gov (United States)

    Borckardt, Jeffrey J.; Linder, Katie; Ricci, Raffaella; Li, Xingbao; Anderson, Berry; Arana, Ashley; Nahas, Ziad; Amassian, Vahe; Long, James; George, Mark S.; Sackeim, Harold A.

    2010-01-01

    Background Focal Electrically-Administered Therapy (FEAT) is a new method of transcranial electrical stimulation capable of focal modulation of cerebral activity. Other than invasive studies in animals and examination of motor output in humans, there are limited possibilities for establishing basic principles about how variation in stimulus parameters impact on patterns of intracortical stimulation. This study used a simpler paradigm, and evaluated the effects of different stimulation parameters on subjective perception of the quality and location of scalp pain. Methods In two studies, 19 subjects were randomly stimulated over the left forehead, varying the anode-cathode arrangement, the intensity of stimulation, the electrode size and placement, and whether the current flow was unidirectional or bidirectional. Subjects rated the location of the sensation, and its quality. Results The perceived center of stimulation moved toward the cathode, regardless of placement. This shift in subjective sensation was more prominent when the electricity was unidirectional. Additionally, more intense stimulation, as well as stimulation with a smaller electrode, caused greater perceived pain. Unidirectional stimulation was rated more painful when traveling from a large anode to a small cathode and less painful when traveling from a small anode to a large cathode. Finally, participants were more likely to perceive the electrical stimulation as moving towards a specific direction when the intensity was high than when it was low. Conclusions The intensity and location of sensations can be manipulated by varying the intensity, current direction, or geometry of electrodes. PMID:19092677

  18. Usage of Human Mesenchymal Stem Cells in Cell-based Therapy: Advantages and Disadvantages.

    Science.gov (United States)

    Kim, Hee Jung; Park, Jeong-Soo

    2017-03-01

    The use of human mesenchymal stem cells (hMSCs) in cell-based therapy has attracted extensive interest in the field of regenerative medicine, and it shows applications to numerous incurable diseases. hMSCs show several superior properties for therapeutic use compared to other types of stem cells. Different cell types are discussed in terms of their advantages and disadvantages, with focus on the characteristics of hMSCs. hMSCs can proliferate readily and produce differentiated cells that can substitute for the targeted affected tissue. To maximize the therapeutic effects of hMSCs, a substantial number of these cells are essential, requiring extensive ex vivo cell expansion. However, hMSCs have a limited lifespan in an in vitro culture condition. The senescence of hMSCs is a double-edged sword from the viewpoint of clinical applications. Although their limited cell proliferation potency protects them from malignant transformation after transplantation, senescence can alter various cell functions including proliferation, differentiation, and migration, that are essential for their therapeutic efficacy. Numerous trials to overcome the limited lifespan of mesenchymal stem cells are discussed.

  19. Plasticity of the human visual system after retinal gene therapy in patients with Leber’s congenital amaurosis

    Science.gov (United States)

    Ashtari, Manzar; Zhang, Hui; Cook, Philip A.; Cyckowski, Laura L.; Shindler, Kenneth S.; Marshall, Kathleen A.; Aravand, Puya; Vossough, Arastoo; Gee, James C.; Maguire, Albert M.; Baker, Chris I.; Bennett, Jean

    2015-01-01

    Much of our knowledge of the mechanisms underlying plasticity in the visual cortex in response to visual impairment, vision restoration, and environmental interactions comes from animal studies. We evaluated human brain plasticity in a group of patients with Leber’s congenital amaurosis (LCA), who regained vision through gene therapy. Using non-invasive multimodal neuroimaging methods, we demonstrated that reversing blindness with gene therapy promoted long-term structural plasticity in the visual pathways emanating from the treated retina of LCA patients. The data revealed improvements and normalization along the visual fibers corresponding to the site of retinal injection of the gene therapy vector carrying the therapeutic gene in the treated eye compared to the visual pathway for the untreated eye of LCA patients. After gene therapy, the primary visual pathways (for example, geniculostriate fibers) in the treated retina were similar to those of sighted control subjects, whereas the primary visual pathways of the untreated retina continued to deteriorate. Our results suggest that visual experience, enhanced by gene therapy, may be responsible for the reorganization and maturation of synaptic connectivity in the visual pathways of the treated eye in LCA patients. The interactions between the eye and the brain enabled improved and sustained long-term visual function in patients with LCA after gene therapy. PMID:26180100

  20. 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

  1. 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

  2. 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.

  3. 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...

  4. 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...

  5. 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...

  6. [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.

  7. 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....

  8. 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

  9. 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).

  10. Comparative study on radon effects and thermal effects on humans in radon hot spring therapy

    International Nuclear Information System (INIS)

    Yamaoka, K.; Mitsunobu, F.; Hanamoto, K.; Tanizaki, Y.; Sugita, K.; Kohima, S.

    2003-01-01

    Full text: The radon therapy is used radon ( 222 Rn) gas, which mainly emits alpha-rays, and induces a small amount of active oxygen in the body. Because most of the diseases to which the radon therapy as well as the thermal therapy is applied are related to activated oxygen, in this study the effects of the radioactivity of radon and thermal effects were compared under the room or the hot spring condition with the similar chemical component, using as the parameters which are closely involved in the clinical for radon therapy. In the results, the radon and thermal therapy enhanced the antioxidation function, such as the activities of superoxide dismutase (SOD) and catalase, which inhibit lipid peroxidation and total cholesterol produce in the body. Moreover the therapy enhanced concanavalin A (ConA)-induced mitogen response, and increased the level of CD4, which is the marker of helper T cell, and decreased the level of CD8, which is the common marker of killer T cell and supresser T cell, in the white cell differentiation antigen (CD4/CD8) assay. Furthermore, the therapy increased the levels of alpha atrial natriuretic polypeptide (alpha ANP), beta endorphin, adrenocorticotropic hormone (ACTH), insulin and glucose-phosphate dehydrogenase (G-6-PDH), and decreased the vasopression level. The results were on the whole larger in the radon group than in the thermal group. The findings suggest that the radon therapy more contributes to the prevention of life style-related diseases related to peroxidation reactions and immune depression than thermal therapy. Moreover these indicate what may be a part of the mechanism for the alleviation of hypertension, osteoarthritis (pain) and diabetes mellitus brought about more radon therapy than thermal therapy

  11. Timing of Initiation of Antiretroviral Therapy in Human Immunodeficiency Virus (HIV)–Associated Tuberculous Meningitis

    Science.gov (United States)

    Török, M. Estee; Yen, Nguyen Thi Bich; Chau, Tran Thi Hong; Mai, Nguyen Thi Hoang; Phu, Nguyen Hoan; Mai, Pham Phuong; Dung, Nguyen Thi; Van Vinh Chau, Nguyen; Bang, Nguyen Duc; Tien, Nguyen Anh; Minh, N. H.; Hien, Nguyen Quang; Thai, Phan Vuong Khac; Dong, Doan The; Anh, Do Thi Tuong; Thoa, Nguyen Thi Cam; Hai, Nguyen Ngoc; Lan, Nguyen Ngoc; Lan, Nguyen Thi Ngoc; Quy, Hoang Thi; Dung, Nguyen Huy; Hien, Tran Tinh; Chinh, Nguyen Tran; Simmons, Cameron Paul; de Jong, Menno; Wolbers, Marcel; Farrar, Jeremy James

    2015-01-01

    Background The optimal time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)–associated tuberculous meningitis is unknown. Methods We conducted a randomized, double-blind, placebo-controlled trial of immediate versus deferred ART in patients with HIV-associated tuberculous meningitis to determine whether immediate ART reduced the risk of death. Antiretroviral drugs (zidovudine, lamivudine, and efavirenz) were started either at study entry or 2 months after randomization. All patients were treated with standard antituberculosis treatment, adjunctive dexamethasone, and prophylactic co-trimoxazole and were followed up for 12 months. We conducted intention-to-treat, per-protocol, and prespecified subgroup analyses. Results A total of 253 patients were randomized, 127 in the immediate ART group and 126 in the deferred ART group; 76 and 70 patients died within 9 months in the immediate and deferred ART groups, respectively. Immediate ART was not significantly associated with 9-month mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], .81–1.55; P = .50) or the time to new AIDS events or death (HR, 1.16; 95% CI, .87–1.55; P = .31). The percentage of patients with severe (grade 3 or 4) adverse events was high in both arms (90% in the immediate ART group and 89% in the deferred ART group; P = .84), but there were significantly more grade 4 adverse events in the immediate ART arm (102 in the immediate ART group vs 87 in the deferred ART group; P = .04). Conclusions Immediate ART initiation does not improve outcome in patients presenting with HIV-associated tuberculous meningitis. There were significantly more grade 4 adverse events in the immediate ART arm, supporting delayed initiation of ART in HIV-associated tuberculous meningitis. Clinical Trials Registration ISRCTN63659091. PMID:21596680

  12. Safety and Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells Therapy for Retinal Degeneration.

    Directory of Open Access Journals (Sweden)

    S N Leow

    Full Text Available To investigate the safety and efficacy of subretinal injection of human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs on retinal structure and function in Royal College of Surgeons (RCS rats.RCS rats were divided into 2 groups: hWJ-MSCs treated group (n = 8 and placebo control group (n = 8. In the treatment group, hWJ-MSCs from healthy donors were injected into the subretinal space in one eye of each rat at day 21. Control group received saline injection of the same volume. Additional 3 animals were injected with nanogold-labelled stem cells for in vivo tracking of cells localisation using a micro-computed tomography (microCT. Retinal function was assessed by electroretinography (ERG 3 days before the injection and repeated at days 15, 30 and 70 after the injection. Eyes were collected at day 70 for histology, cellular and molecular studies.No retinal tumor formation was detected by histology during the study period. MicroCT scans showed that hWJ-MSCs stayed localised in the eye with no systemic migration. Transmission electron microscopy showed that nanogold-labelled cells were located within the subretinal space. Histology showed preservation of the outer nuclear layer (ONL in the treated group but not in the control group. However, there were no significant differences in the ERG responses between the groups. Confocal microscopy showed evidence of hWJ-MSCs expressing markers for photoreceptor, Müller cells and bipolar cells.Subretinal injection of hWJ-MSCs delay the loss of the ONL in RCS rats. hWJ-MSCs appears to be safe and has potential to differentiate into retinal-like cells. The potential of this cell-based therapy for the treatment of retinal dystrophies warrants further studies.

  13. Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients

    Directory of Open Access Journals (Sweden)

    Wim Adriaensen

    2018-01-01

    Full Text Available Patients with visceral leishmaniasis (VL–human immunodeficiency virus (HIV coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients respond poorly to conventional VL treatment and play an important role in parasite transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic drugs, new interventions that target host immunity may offer an effective alternative. In this review, we first summarize current views on how VL immunopathology is significantly affected by HIV coinfection. We then review current clinical and promising preclinical immunomodulatory interventions in the field of VL and discuss how these may operate in the context of a concurrent HIV infection. Caveats are formulated as these interventions may unpredictably impact the delicate balance between boosting of beneficial VL-specific responses and deleterious immune activation/hyperinflammation, activation of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to prioritize a target molecule and a more detailed account of the immunological status induced by the coinfection as well as surrogate markers of cure and protection are still required. We do, however, argue that virologically suppressed VL patients with a recovered immune system, in whom effective antiretroviral therapy alone is not able to restore protective immunity, can be considered a relevant target group for an immunomodulatory intervention. Finally, we provide perspectives on the translation of novel theories on synergistic immune cell cross-talk into an effective treatment strategy for VL–HIV-coinfected patients.

  14. Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients

    Science.gov (United States)

    Adriaensen, Wim; Dorlo, Thomas P. C.; Vanham, Guido; Kestens, Luc; Kaye, Paul M.; van Griensven, Johan

    2018-01-01

    Patients with visceral leishmaniasis (VL)–human immunodeficiency virus (HIV) coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients respond poorly to conventional VL treatment and play an important role in parasite transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic drugs, new interventions that target host immunity may offer an effective alternative. In this review, we first summarize current views on how VL immunopathology is significantly affected by HIV coinfection. We then review current clinical and promising preclinical immunomodulatory interventions in the field of VL and discuss how these may operate in the context of a concurrent HIV infection. Caveats are formulated as these interventions may unpredictably impact the delicate balance between boosting of beneficial VL-specific responses and deleterious immune activation/hyperinflammation, activation of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to prioritize a target molecule and a more detailed account of the immunological status induced by the coinfection as well as surrogate markers of cure and protection are still required. We do, however, argue that virologically suppressed VL patients with a recovered immune system, in whom effective antiretroviral therapy alone is not able to restore protective immunity, can be considered a relevant target group for an immunomodulatory intervention. Finally, we provide perspectives on the translation of novel theories on synergistic immune cell cross-talk into an effective treatment strategy for VL–HIV-coinfected patients. PMID:29375567

  15. The effect of interferential therapy upon cutaneous blood flow in humans.

    Science.gov (United States)

    Noble, J G; Henderson, G; Cramp, A F; Walsh, D M; Lowe, A S

    2000-01-01

    The aim of the current controlled and blinded study was to investigate the effect of various interferential current frequencies upon cutaneous blood flow in humans using laser Doppler flowmetry, in an attempt to define the physiological mechanisms involved. Following approval from the university's ethical committee, 50 healthy volunteers (25 male, 25 female; age 18-34 years) were randomly allocated into one of five experimental groups: (i) control; neither suction nor interferential current was applied, (ii) placebo; suction only was applied, (iii) IFT 1; 10-100 Hz beat frequency applied, (iv) IFT 2; 80-100 Hz beat frequency applied, and (v) IFT 3; 10-20 Hz beat frequency applied. In the IFT groups, interferential currents were applied through four suction electrodes positioned to target the quadriceps femoris muscle. The following parameters were used in all IFT groups: 125 micros pulse duration, 4 kHz carrier frequency and a 6/6 sweep. In IFT groups 1 and 2 only, the rotating vector system was made active. Ambient and skin temperatures were measured concomitantly. Repeated-measures ANOVA showed a significant difference between groups (P=0.0361) and over time (P=0.0001) for blood flow data; one-factor ANOVA showed a significant increase in blood flow in the IFT 3 group (10-20 Hz) when compared to all experimental groups at 12 min (P=0.0156). In addition, at 21 min, there were significant differences between the IFT 3 group and all other groups except control (P=0.0213). Statistical analysis of skin temperature data demonstrated significant differences over time (P=0.0001) and a significant interactive effect (P=0.0022), with no significant differences observed between groups. These findings provide some evidence of a putative vasodilatory effect caused by interferential current therapy when applied through suction electrodes at a modulated frequency of 10-20 Hz.

  16. Safety and Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells Therapy for Retinal Degeneration.

    Science.gov (United States)

    Leow, S N; Luu, Chi D; Hairul Nizam, M H; Mok, P L; Ruhaslizan, R; Wong, H S; Wan Abdul Halim, Wan Haslina; Ng, M H; Ruszymah, B H I; Chowdhury, S R; Bastion, M L C; Then, K Y

    2015-01-01

    To investigate the safety and efficacy of subretinal injection of human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs) on retinal structure and function in Royal College of Surgeons (RCS) rats. RCS rats were divided into 2 groups: hWJ-MSCs treated group (n = 8) and placebo control group (n = 8). In the treatment group, hWJ-MSCs from healthy donors were injected into the subretinal space in one eye of each rat at day 21. Control group received saline injection of the same volume. Additional 3 animals were injected with nanogold-labelled stem cells for in vivo tracking of cells localisation using a micro-computed tomography (microCT). Retinal function was assessed by electroretinography (ERG) 3 days before the injection and repeated at days 15, 30 and 70 after the injection. Eyes were collected at day 70 for histology, cellular and molecular studies. No retinal tumor formation was detected by histology during the study period. MicroCT scans showed that hWJ-MSCs stayed localised in the eye with no systemic migration. Transmission electron microscopy showed that nanogold-labelled cells were located within the subretinal space. Histology showed preservation of the outer nuclear layer (ONL) in the treated group but not in the control group. However, there were no significant differences in the ERG responses between the groups. Confocal microscopy showed evidence of hWJ-MSCs expressing markers for photoreceptor, Müller cells and bipolar cells. Subretinal injection of hWJ-MSCs delay the loss of the ONL in RCS rats. hWJ-MSCs appears to be safe and has potential to differentiate into retinal-like cells. The potential of this cell-based therapy for the treatment of retinal dystrophies warrants further studies.

  17. DNA damage and gene therapy of xeroderma pigmentosum, a human DNA repair-deficient disease.

    Science.gov (United States)

    Dupuy, Aurélie; Sarasin, Alain

    2015-06-01

    Xeroderma pigmentosum (XP) is a genetic disease characterized by hypersensitivity to ultra-violet and a very high risk of skin cancer induction on exposed body sites. This syndrome is caused by germinal mutations on nucleotide excision repair genes. No cure is available for these patients except a complete protection from all types of UV radiations. We reviewed the various techniques to complement or to correct the genetic defect in XP cells. We, particularly, developed the correction of XP-C skin cells using the fidelity of the homologous recombination pathway during repair of double-strand break (DSB) in the presence of XPC wild type sequences. We used engineered nucleases (meganuclease or TALE nuclease) to induce a DSB located at 90 bp of the mutation to be corrected. Expression of specific TALE nuclease in the presence of a repair matrix containing a long stretch of homologous wild type XPC sequences allowed us a successful gene correction of the original TG deletion found in numerous North African XP patients. Some engineered nucleases are sensitive to epigenetic modifications, such as cytosine methylation. In case of methylated sequences to be corrected, modified nucleases or demethylation of the whole genome should be envisaged. Overall, we showed that specifically-designed TALE-nuclease allowed us to correct a 2 bp deletion in the XPC gene leading to patient's cells proficient for DNA repair and showing normal UV-sensitivity. The corrected gene is still in the same position in the human genome and under the regulation of its physiological promoter. This result is a first step toward gene therapy in XP patients. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. [Pulmonary hypertension in human immunodeficiency virus-infected patients: the role of antiretroviral therapy].

    Science.gov (United States)

    Olalla, Julián; Urdiales, Daniel; Pombo, Marta; del Arco, Alfonso; de la Torre, Javier; Prada, José Luis

    2014-03-20

    Pulmonary arterial hypertension (PAH) is a serious disorder, more prevalent in patients infected with human immunodeficiency virus (HIV). It is not entirely clear what role is played by highly active antiretroviral therapy (HAART) in PAH development or course. Our aim was to describe PAH prevalence in a series of HIV-infected patients and identify possible links with cumulative and current use of different antiretrovirals. Cross-sectional study of a cohort of HIV-infected patients attending a hospital in southern Spain. Demographic data, data on HIV infection status and on cumulative and recent antiretroviral treatment were recorded. Transthoracic echocardiography was performed in all study participants. PAH was defined as pulmonary artery systolic pressure of 36mmHg or more. A total of 400 patients participated in the study; 178 presented with tricuspid regurgitation and 22 of these presented with PAH (5.5%). No differences were encountered in age, sex, CD4 lymphocytes, proportion of naive patients or patients with AIDS. No differences were encountered in cumulative use of antiretrovirals. However, recent use of lamivudine was associated with a greater presence of PAH, whereas recent use of tenofovir and emtricitabine was associated with a lower presence of PAH. Logistic regression analysis was performed including the use of lamivudine, emtricitabine and tenofovir. Only recent use of tenofovir was associated with a lower presence of PAH (odds ratio 0.31; 95% confidence interval: 0.17-0.84). PAH prevalence in our study was similar to others series. Current use of tenofovir may be associated with lower PAH prevalence. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  19. 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 ...

  20. [Effect of M007 mediated photodynamic therapy on proliferation of human osteosarcoma MG63 cells in vitro].

    Science.gov (United States)

    Zhou, Yu-Kai; Wu, Wen-Zhi; Zhang, Lan; Yang, Chun-Hui; Wang, Yan-Ping

    2012-01-01

    To investigate the effect of a new photosensitizer, M007 mediated photodynamic therapy on proliferation of human osteosarcoma MG63 cells in vitro. Human osteosarcoma MG63 cells were prepared as 1 x 10(6) /mL single-cell suspension, and 1 mL cells were transferred into 60 mL culture dish, then treated with 5 different gradient dosages (0, 2, 4, 8, 16 micromol/L) of M007 followed by photodynamic therapy or dark reaction for 10 min. The survival rate of the cells and the mode of cell death were detected by flow cytometry with the stain of Annexin V-FITC/PI. The effect on proliferation of survival cells was observed by MTT assay and colony-forming assay. M007 mediated photodynamic therapy induced the inactivation of MG63 human osteosarcoma cells in the way of late apoptosis/necrosis or becoming naked nucleus predominately. More than 90% MG63 cells in M007-PDT group were dead under the treatment of 2-16 micromol/L M007. The survival rates of 4-16 micromol/L M007-PDT group were steadily less than 1%. The optical densities did not increase with extension of culture time in 2-8 micromol/L M007-PDT group (P > 0.05). There were 16 survival alive cells found occasionally in 2 micromol/L M007-PDT group, but no colonies found in other groups. M007 mediated photodynamic therapy totally inactivated human osteosarcoma MG63 cells in vitro with the dosage more than 4 micromol/L.

  1. Recombinant human thyrotropin-stimulated radioiodine therapy of nodular goiter allows major reduction of the radiation burden with retained efficacy

    DEFF Research Database (Denmark)

    Fast, Søren; Hegedüs, Laszlo; Grupe, Peter

    2010-01-01

    Context and Objective: Stimulation with recombinant human TSH (rhTSH) before radioiodine ((131)I) therapy augments goiter volume reduction (GVR). Observations indicate that rhTSH has a preconditioning effect beyond increasing thyroid (131)I uptake. We test the hypothesis that an equivalent GVR mi....... This approach is attractive in terms of minimizing posttherapeutic restrictions and in reducing the potential risk of radiation-induced malignancy....

  2. In Vitro Efficacy and Mechanistic Role of Indocyanine Green as a Photodynamic Therapy Agent for Human Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Mamoon, A.; Gamal-Eldeen, A; Ruppel, M; Smith, R; Tsang, T; Miller, L

    2009-01-01

    Photodynamic therapy (PDT) is a promising treatment for superficial cancer. However, poor therapeutic results have been reported for melanoma, due to the high melanin content. Indocyanine green (ICG) has near infrared absorption (700-800nm) and melanins do not absorb strongly in this area. This study explores the efficiency of ICG as a PDT agent for human melanoma, and its mechanistic role in the cell death pathway.

  3. Isolation and Characterization of Human Myoblast Culture In Vitro for Technologies of Cell and Gene Therapy of Skeletal Muscle Pathologies.

    Science.gov (United States)

    Tabakov, V Yu; Zinov'eva, O E; Voskresenskaya, O N; Skoblov, M Yu

    2018-03-01

    We analyzed cultures of 5 independent myoblast lines from human skeletal muscles. It was shown that the content of desmin-positive cells in cultures at early passages exceeds 90%. Typical morphofunctional signs of myogenic differentiation disturbances were identified and their dynamics was studied. Signs of alternative adipogenic and chondrogenic differentiation of cells were revealed. Based on these data, limitations for the use of myoblast cultures of certain passages for biomedical research and cell therapy were evaluated.

  4. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer.

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-04-17

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  5. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M.; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-05-01

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  6. Non-formal Therapy and Learning Potentials through Human Gesture Synchronised to Robotic Gesture

    DEFF Research Database (Denmark)

    Petersson, Eva; Brooks, Tony

    2007-01-01

    Children with severe physical disabilities have limited possibilities for joyful experiences and interactive play. Physical training and therapy to improve such opportunities for these children is often enduring, tedious and boring through repetition-and this is often the case for both patient an...... additional opportunities, and motivated non-formal potentials in therapy and learning to supplement the field....

  7. Meta-Analyses of Human Cell-Based Cardiac Regeneration Therapies

    DEFF Research Database (Denmark)

    Gyöngyösi, Mariann; Wojakowski, Wojciech; Navarese, Eliano P

    2016-01-01

    In contrast to multiple publication-based meta-analyses involving clinical cardiac regeneration therapy in patients with recent myocardial infarction, a recently published meta-analysis based on individual patient data reported no effect of cell therapy on left ventricular function or clinical...

  8. Sex-dependent regulation of hypoxic ventilation in mice and humans is mediated by erythropoietin

    DEFF Research Database (Denmark)

    Soliz, Jorge; Thomsen, Jonas Juhl; Soulage, Christophe

    2009-01-01

    increased in women. We conclude that Epo exerts a sex-dependent impact on hypoxic ventilation improving the response in female mice and in women that most probably involves sexual hormones. Our data provides an explanation as to why women are less susceptible to hypoxia-associated syndromes than men....

  9. 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

    exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVA P = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other...... (10% Co2 with 10% O2) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVA P > 0.05). Hypocapnic normoxia, produced...

  10. Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity

    DEFF Research Database (Denmark)

    Thomsen, J J; Rentsch, R L; Robach, P

    2007-01-01

    HuEpo treatment VO2max increased (Ptime-to-exhaustion (80% VO2max) was increased by 54.0 and 54.3% (Ptime point...... week 11), TTE was decreased by 26.8% as compared to pre rHuEpo administration. In conclusion, in healthy non-athlete subjects rHuEpo administration prolongs submaximal exercise performance by about 54% independently of the approximately 12% increase in VO2max....

  11. 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.)

  12. Sequence-engineered mRNA Without Chemical Nucleoside Modifications Enables an Effective Protein Therapy in Large Animals

    Science.gov (United States)

    Thess, Andreas; Grund, Stefanie; Mui, Barbara L; Hope, Michael J; Baumhof, Patrick; Fotin-Mleczek, Mariola; Schlake, Thomas

    2015-01-01

    Being a transient carrier of genetic information, mRNA could be a versatile, flexible, and safe means for protein therapies. While recent findings highlight the enormous therapeutic potential of mRNA, evidence that mRNA-based protein therapies are feasible beyond small animals such as mice is still lacking. Previous studies imply that mRNA therapeutics require chemical nucleoside modifications to obtain sufficient protein expression and avoid activation of the innate immune system. Here we show that chemically unmodified mRNA can achieve those goals as well by applying sequence-engineered molecules. Using erythropoietin (EPO) driven production of red blood cells as the biological model, engineered Epo mRNA elicited meaningful physiological responses from mice to nonhuman primates. Even in pigs of about 20 kg in weight, a single adequate dose of engineered mRNA encapsulated in lipid nanoparticles (LNPs) induced high systemic Epo levels and strong physiological effects. Our results demonstrate that sequence-engineered mRNA has the potential to revolutionize human protein therapies. PMID:26050989

  13. 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...

  14. 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...

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. Volume of the human hippocampus and clinical response following electroconvulsive therapy

    DEFF Research Database (Denmark)

    Oltedal, Leif; Narr, Katherine L.; Abbott, Christopher

    2018-01-01

    Background: Hippocampal enlargements are commonly reported following electroconvulsive therapy (ECT). To clarify mechanisms, we examined if ECT induced hippocampal volume change relates to dose (number of ECT sessions and electrode placement) and acts as a biomarker of clinical outcome. Methods...

  1. Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation.

    Directory of Open Access Journals (Sweden)

    Michael P Hefferan

    Full Text Available Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1 causes an inherited form of Amyotrophic Lateral Sclerosis (ALS. Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs into the lumbar spinal cord of SOD1(G93A rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1(G93A rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A animals.Presymptomatic SOD1(G93A rats (60-65 days old received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1(G93A rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1(G93A rats protected α-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to α-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1(G93A rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50-65% loss of large caliber descending motor axons.These data demonstrate that in order to achieve a more

  2. Synergistic Effect of Combination Topotecan and Chronomodulated Radiation Therapy on Xenografted Human Nasopharyngeal Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, YanLing; Chen, Xin; Ren, PeiRong; Su, Zhou; Cao, HongYing; Zhou, Jie; Zou, XiaoYan; Fu, ShaoZhi; Lin, Sheng; Fan, Juan; Yang, Bo; Sun, XiaoYang [Department of Oncology, Affiliated Hospital of Luzhou Medical College, Luzhou (China); Zhou, Yan; Chen, Yue [Department of Medical Imaging, Luzhou Medical College, Luzhou (China); Yang, LingLin, E-mail: yanglinglin2003@tom.com [Department of Oncology, Affiliated Hospital of Luzhou Medical College, Luzhou (China); Wu, JingBo, E-mail: wjb6147@163.com [Department of Oncology, Affiliated Hospital of Luzhou Medical College, Luzhou (China)

    2013-10-01

    Purpose: To investigate the in vivo chronomodulated radiosensitizing effect of topotecan (TPT) on human nasopharyngeal carcinoma (NPC) and its possible mechanisms. Methods and Materials: Xenografted BALB/c (nu/nu) NPC mice were synchronized with an alternation of 12 hours of light from 0 to 12 hours after light onset (HALO) and 12 hours of darkness to establish a unified biological rhythm. Chronomodulated radiosensitization of TPT was investigated by analysis of tumor regrowth delay (TGD), pimonidazole hydrochloride, histone H2AX phosphorylation, (γ-H2AX) topoisomerase I (Top I), cell cycle, and apoptosis after treatment with (1) TPT (10 mg/kg) alone; (2) radiation therapy alone (RT); and (3) TPT+RT at 3, 9, 15, and 21 HALO. The tumor-loaded mice without any treatment were used as controls. Results: The TPT+RT combination was more effective than TPT or RT as single agents. The TPT+RT combination at 15 HALO was best (TGD = 58.0 ± 3.6 days), and TPT+RT at 3 HALO was worst (TGD = 35.0 ± 1.5 days) among the 4 TPT+RT groups (P<.05). Immunohistochemistry analysis revealed a significantly increased histone H2AX phosphorylation expression and decreased pimonidazole hydrochloride expression in the TPT+RT group at the same time point. The results suggested that the level of tumor hypoxia and DNA damage varied in a time-dependent manner. The expression of Top I in the TPT+RT group was also significantly different from the control tumors at 15 HALO (P<.05). Cell apoptosis index was increased and the proportion of cells in S phase was decreased (P<.05) with the highest value in 15 HALO and the lowest in 3 HALO. Conclusions: This study suggested that TPT combined with chronoradiotherapy could enhance the radiosensitivity of xenografted NPC. The TPT+RT group at 15 HALO had the best therapeutic effect. The chronomodulated radiosensitization mechanisms of TPT might be related to circadian rhythm of tumor hypoxia, cell cycle redistribution, DNA damage, and expression of Top I.

  3. Synergistic Effect of Combination Topotecan and Chronomodulated Radiation Therapy on Xenografted Human Nasopharyngeal Carcinoma

    International Nuclear Information System (INIS)

    Zhang, YanLing; Chen, Xin; Ren, PeiRong; Su, Zhou; Cao, HongYing; Zhou, Jie; Zou, XiaoYan; Fu, ShaoZhi; Lin, Sheng; Fan, Juan; Yang, Bo; Sun, XiaoYang; Zhou, Yan; Chen, Yue; Yang, LingLin; Wu, JingBo

    2013-01-01

    Purpose: To investigate the in vivo chronomodulated radiosensitizing effect of topotecan (TPT) on human nasopharyngeal carcinoma (NPC) and its possible mechanisms. Methods and Materials: Xenografted BALB/c (nu/nu) NPC mice were synchronized with an alternation of 12 hours of light from 0 to 12 hours after light onset (HALO) and 12 hours of darkness to establish a unified biological rhythm. Chronomodulated radiosensitization of TPT was investigated by analysis of tumor regrowth delay (TGD), pimonidazole hydrochloride, histone H2AX phosphorylation, (γ-H2AX) topoisomerase I (Top I), cell cycle, and apoptosis after treatment with (1) TPT (10 mg/kg) alone; (2) radiation therapy alone (RT); and (3) TPT+RT at 3, 9, 15, and 21 HALO. The tumor-loaded mice without any treatment were used as controls. Results: The TPT+RT combination was more effective than TPT or RT as single agents. The TPT+RT combination at 15 HALO was best (TGD = 58.0 ± 3.6 days), and TPT+RT at 3 HALO was worst (TGD = 35.0 ± 1.5 days) among the 4 TPT+RT groups (P<.05). Immunohistochemistry analysis revealed a significantly increased histone H2AX phosphorylation expression and decreased pimonidazole hydrochloride expression in the TPT+RT group at the same time point. The results suggested that the level of tumor hypoxia and DNA damage varied in a time-dependent manner. The expression of Top I in the TPT+RT group was also significantly different from the control tumors at 15 HALO (P<.05). Cell apoptosis index was increased and the proportion of cells in S phase was decreased (P<.05) with the highest value in 15 HALO and the lowest in 3 HALO. Conclusions: This study suggested that TPT combined with chronoradiotherapy could enhance the radiosensitivity of xenografted NPC. The TPT+RT group at 15 HALO had the best therapeutic effect. The chronomodulated radiosensitization mechanisms of TPT might be related to circadian rhythm of tumor hypoxia, cell cycle redistribution, DNA damage, and expression of Top I

  4. A preliminary report on stem cell therapy for neuropathic pain in humans

    Directory of Open Access Journals (Sweden)

    Vickers ER

    2014-05-01

    Full Text Available E Russell Vickers,1 Elisabeth Karsten,2 John Flood,3 Richard Lilischkis21Sydney Oral and Maxillofacial Surgery, NSW, Australia; 2Regeneus Ltd, Gordon, NSW, Australia; 3St Vincents Hospital, Sydney, NSW, AustraliaObjective: Mesenchymal stem cells (MSCs have been shown in animal models to attenuate chronic neuropathic pain. This preliminary study investigated if: i injections of autologous MSCs can reduce human neuropathic pain and ii evaluate the safety of the procedure.Methods: Ten subjects with symptoms of neuropathic trigeminal pain underwent liposuction. The lipoaspirate was digested with collagenase and washed with saline three times. Following centrifugation, the stromal vascular fraction was resuspended in saline, and then transferred to syringes for local injections into the pain fields. Outcome measures at 6 months assessed reduction in: i pain intensity measured by standard numerical rating scale from 0–10 and ii daily dosage requirements of antineuropathic pain medication.Results: Subjects were all female (mean age 55.3 years ± standard deviation [SD] 14.67; range 27–80 years with pain symptoms lasting from 4 months to 6 years and 5 months. Lipoaspirate collection ranged from 102–214 g with total cell numbers injected from 33 million to 162 million cells. Cell viability was 62%–91%. There were no systemic or local tissue side effects from the stem cell therapy (n=41 oral and facial injection sites. Clinical pain outcomes showed that at 6 months, 5/9 subjects had reduced both pain intensity scores and use of antineuropathic medication. The mean pain score pre-treatment was 7.5 (SD 1.58 and at 6 months had decreased to 4.3 (SD 3.28, P=0.018, Wilcoxon signed-rank test. Antineuropathic pain medication use showed 5/9 subjects reduced their need for medication (gabapentin, P=0.053, Student's t-test.Conclusion: This preliminary open-labeled study showed autologous administration of stem cells for neuropathic trigeminal pain

  5. In vivo determination of the absorption and scattering spectra of the human prostate during photodynamic therapy

    Science.gov (United States)

    Finlay, Jarod C.; Zhu, Timothy C.; Dimofte, Andreea; Stripp, Diana C. H.; Malkowicz, S. B.; Whittington, Richard; Miles, Jeremy; Glatstein, Eli; Hahn, Stephen M.

    2004-06-01

    A continuing challenge in photodynamic therapy is the accurate in vivo determination of the optical properties of the tissue being treated. We have developed a method for characterizing the absorption and scattering spectra of prostate tissue undergoing PDT treatment. Our current prostate treatment protocol involves interstitial illumination of the organ via cylindrical diffusing optical fibers (CDFs) inserted into the prostate through clear catheters. We employ one of these catheters to insert an isotropic white light point source into the prostate. An isotropic detection fiber connected to a spectrograph is inserted into a second catheter a known distance away. The detector is moved along the catheter by a computer-controlled step motor, acquiring diffuse light spectra at 2 mm intervals along its path. We model the fluence rate as a function of wavelength and distance along the detector"s path using an infinite medium diffusion theory model whose free parameters are the absorption coefficient μa at each wavelength and two variables A and b which characterize the reduced scattering spectrum of the form μ"s = Aλ-b. We analyze our spectroscopic data using a nonlinear fitting algorithm to determine A, b, and μa at each wavelength independently; no prior knowledge of the absorption spectrum or of the sample"s constituent absorbers is required. We have tested this method in tissue simulating phantoms composed of intralipid and the photosensitizer motexafin lutetium (MLu). The MLu absorption spectrum recovered from the phantoms agrees with that measured in clear solution, and μa at the MLu absorption peak varies linearly with concentration. The ´"s spectrum reported by the fit is in agreement with the known scattering coefficient of intralipid. We have applied this algorithm to spectroscopic data from human patients sensitized with MLu (2 mg kg-1) acquired before and after PDT. Before PDT, the absorption spectra we measure include the characteristic MLu absorption

  6. Adjuvant electrochemotherapy in veterinary patients: a model for the planning of future therapies in humans

    OpenAIRE

    Spugnini, Enrico P; Citro, Gennaro; Baldi, Alfonso

    2009-01-01

    Abstract The treatment of soft tissue tumors needs the coordinated adoption of surgery with radiation therapy and eventually, chemotherapy. The radiation therapy (delivered with a linear accelerator) can be preoperative, intraoperative, or postoperative. In selected patients adjuvant brachytherapy can be adopted. The goal of these associations is to achieve tumor control while maximally preserving the normal tissues from side effects. Unfortunately, the occurrence of local and distant complic...

  7. 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.

  8. Modeling Viral Infectious Diseases and Development of Antiviral Therapies Using Human Induced Pluripotent Stem Cell-Derived Systems.

    Science.gov (United States)

    Trevisan, Marta; Sinigaglia, Alessandro; Desole, Giovanna; Berto, Alessandro; Pacenti, Monia; Palù, Giorgio; Barzon, Luisa

    2015-07-13

    The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs), which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host-pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance.

  9. Modeling Viral Infectious Diseases and Development of Antiviral Therapies Using Human Induced Pluripotent Stem Cell-Derived Systems

    Directory of Open Access Journals (Sweden)

    Marta Trevisan

    2015-07-01

    Full Text Available The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs, which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host–pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance.

  10. 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.

  11. 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

  12. What Therapies are Favored in the Treatment of the Psychological Sequelae of Trauma in Human Trafficking Victims?

    Science.gov (United States)

    Salami, Temilola; Gordon, Mollie; Coverdale, John; Nguyen, Phuong T

    2018-03-01

    Human trafficking is a major public health concern that brings about deleterious psychological consequences and sequelae. Although a number of risk and protective factors for the health consequences of human trafficking victims have been identified, there is a dearth of information in the area of treatment. Specifically, we found no articles comparing the different components of prevailing trauma treatment strategies, and the potential usefulness of these strategies in the treatment of human trafficking victims. To this end, we compared and contrasted the different therapeutic treatments typically implemented with victims of trauma (including domestic violence victims and torture victims), and discussed how the different components of these treatments may or may not be helpful for human trafficking victims. We assessed the impact of these treatments on the psychological consequences of trauma and, in particular on posttraumatic stress disorder. We also assessed the potential usefulness of these treatments with co-occurring problems such as substance use, psychosis, dissociation, and other mood and anxiety disorders. On the basis of the prevailing research, we highlighted cognitive therapies as being preferred in addressing the needs of human trafficking victims. Mental health providers who work with human trafficking victims should become aware of and practiced in the use of cognitive therapeutic approaches in treating this population. Efficacy and effectiveness studies are needed to validate our recommendations.

  13. Efficacy of Prompt Initiation of Antiretroviral Therapy in the Treatment of Hemophagocytic Lymphohistiocytosis Triggered by Uncontrolled Human Immunodeficiency Virus

    Directory of Open Access Journals (Sweden)

    Bryan P. Fitzgerald

    2017-01-01

    Full Text Available Hemophagocytic lymphohistiocytosis (HLH is a life-threatening, rapidly progressive hematologic disorder involving uncontrolled immune system activation. HLH has been associated with viral infections, including human immunodeficiency virus (HIV infections. We report a case of a critically ill 30-year-old female who was hospitalized with HIV-associated HLH, with a CD4 count of 4 cells/mL and HIV viral load of 1,842,730 copies/mL. After ruling out other potential infectious causes of HLH, antiretroviral therapy (ART was initiated with darunavir, ritonavir, tenofovir, and emtricitabine. Within one week of initiation of ART, the patient began to improve clinically and hematologically and was stable enough for discharge from the hospital three weeks after starting therapy. This case suggests that treatment with ART in patients with HIV-associated HLH should be considered even in critically ill patients with low CD4 counts.

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

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    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

  15. Discrepant Results of Experimental Human Mesenchymal Stromal Cell Therapy after Myocardial Infarction: Are Animal Models Robust Enough?

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    Melina C den Haan

    Full Text Available Human mesenchymal stromal cells (MSCs have been reported to preserve cardiac function in myocardial infarction (MI models. Previously, we found a beneficial effect of intramyocardial injection of unstimulated human MSCs (uMSCs on cardiac function after permanent coronary artery ligation. In the present study we aimed to extend this research by investigating the effect of intramyocardial injection of human MSCs pre-stimulated with the pro-inflammatory cytokine interferon-gamma (iMSCs, since pro-inflammatory priming has shown additional salutary effects in multiple experimental disease models.MI was induced in NOD/Scid mice by permanent ligation of the left anterior descending coronary artery. Animals received intramyocardial injection of uMSCs, iMSCs or PBS. Sham-operated animals were used to determine baseline characteristics. Cardiac performance was assessed after 2 and 14 days using 7-Tesla magnetic resonance imaging and pressure-volume loop measurements. Histology and q-PCR were used to confirm MSC engraftment in the heart.Both uMSC and iMSC therapy had no significant beneficial effect on cardiac function or remodelling in contrast to our previous studies.Animal models for cardiac MSC therapy appear less robust than initially envisioned.

  16. Targeting PEPT1: a novel strategy to improve the antitumor efficacy of doxorubicin in human hepatocellular carcinoma therapy.

    Science.gov (United States)

    Gong, Yanxia; Wu, Xiang; Wang, Tao; Zhao, Jia; Liu, Xi; Yao, Zhi; Zhang, Qingyu; Jian, Xu

    2017-06-20

    Proton coupled oligopeptide transporter 1 (PEPT1) is a member of the peptide transporter superfamily and plays important role in the absorption of oligopeptide and peptidomimetic drugs. Our previous research verified that PEPT1 expressed specifically in human Hepatocellular carcinoma (HCC) tissue and cell lines and showed potential transport activity to be a new candidate of the tumor therapeutic target. In this study, we aim to explore the feasibility of a novel tumor target therapeutic strategy: Targeting PEPT1 to improve the antitumor efficacy of Doxorubicin in human HCC therapy. First, Doxorubicin was conjugated with Glycylglycylglycine (Gly-Gly-Gly) - a tripeptide which was known as the substrate of PEPT1 and characterized by HPLC and MS successfully. Doxorubicin-tripeptide conjugate was then observed to clarify the target delivery by PEPT1 and the antitumor effect on human hepatocarcinoma in vivo and in vitro. Furthermore, the improvement of the toxic and side effect of Doxorubicin after conjugation was also evaluated by some biochemical tests. Our results reveal that targeting PEPT1 may contribute to the efficient delivery of Doxorubicin to hepatocarcinoma cells and the reduction of drug toxicity. PEPT1 has the prospect to be a novel target of HCC therapy.

  17. Brief Report: External Beam Radiation Therapy for the Treatment of Human Pluripotent Stem Cell-Derived Teratomas.

    Science.gov (United States)

    Lee, Andrew S; Tang, Chad; Hong, Wan Xing; Park, Sujin; Bazalova-Carter, Magdalena; Nelson, Geoff; Sanchez-Freire, Veronica; Bakerman, Isaac; Zhang, Wendy; Neofytou, Evgenios; Connolly, Andrew J; Chan, Charles K; Graves, Edward E; Weissman, Irving L; Nguyen, Patricia K; Wu, Joseph C

    2017-08-01

    Human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced PSCs (hiPSCs), have great potential as an unlimited donor source for cell-based therapeutics. The risk of teratoma formation from residual undifferentiated cells, however, remains a critical barrier to the clinical application of these cells. Herein, we describe external beam radiation therapy (EBRT) as an attractive option for the treatment of this iatrogenic growth. We present evidence that EBRT is effective in arresting growth of hESC-derived teratomas in vivo at day 28 post-implantation by using a microCT irradiator capable of targeted treatment in small animals. Within several days of irradiation, teratomas derived from injection of undifferentiated hESCs and hiPSCs demonstrated complete growth arrest lasting several months. In addition, EBRT reduced reseeding potential of teratoma cells during serial transplantation experiments, requiring irradiated teratomas to be seeded at 1 × 10 3 higher doses to form new teratomas. We demonstrate that irradiation induces teratoma cell apoptosis, senescence, and growth arrest, similar to established radiobiology mechanisms. Taken together, these results provide proof of concept for the use of EBRT in the treatment of existing teratomas and highlight a strategy to increase the safety of stem cell-based therapies. Stem Cells 2017;35:1994-2000. © 2017 AlphaMed Press.

  18. Goal-directed fluid therapy: stroke volume optimisation and cardiac dimensions in supine healthy humans

    DEFF Research Database (Denmark)

    Jans, O.; Tollund, C.; Bundgaard-Nielsen, M.

    2008-01-01

    BACKGROUND: Based on maximisation of cardiac stroke volume (SV), peri-operative individualised goal-directed fluid therapy improves patient outcome. It remains, however, unknown how fluid therapy by this strategy relates to filling of the heart during supine rest as reference for the anaesthetised...... by thoracic electrical admittance, central venous oxygenation and pressure, and arterial plasma atrial natriuretic peptide. Also, muscle and brain oxygenation were assessed by near infrared spectroscopy (n=7). RESULTS: The HUT reduced the mentioned indices of CBV, the end-diastolic dimensions of the heart...... therapy is that when a maximal SV is established for patients, cardiac pre-load is comparable to that of supine healthy subjects Udgivelsesdato: 2008/4...

  19. 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

  20. Anti-leukemic therapies induce cytogenetic changes of human bone marrow-derived mesenchymal stem cells.

    Science.gov (United States)

    Yeh, Su-Peng; Lo, Wen-Jyi; Lin, Chiao-Lin; Liao, Yu-Min; Lin, Chen-Yuan; Bai, Li-Yuan; Liang, Ji-An; Chiu, Chang-Fang

    2012-02-01

    Both bone marrow hematopoietic cells (BM-HCs) and mesenchymal stem cells (BM-MSCs) may have cytogenetic aberrations in leukemic patients, and anti-leukemic therapy may induce cytogenetic remission of BM-HCs. The impact of anti-leukemic therapy on BM-MSCs remains unknown. Cytogenetic studies of BM-MSCs from 15 leukemic patients with documented cytogenetic abnormalities of BM-HCs were investigated. To see the influence of anti-leukemic therapy on BM-MSCs, cytogenetic studies were carried out in seven of them after the completion of anti-leukemic therapy, including anthracycline/Ara-C-based chemotherapy in two patients, high-dose busulfan/cyclophosphamide-based allogeneic transplantation in two patients, and total body irradiation (TBI)-based allogeneic transplantation in three patients. To simulate the effect of TBI in vitro, three BM-MSCs from one leukemic patient and two normal adults were irradiated using the same dosage and dosing schedule of TBI and cytogenetics were re-examined after irradiation. At the diagnosis of leukemia, two BM-MSCs had cytogenetic aberration, which were completely different to their BM-HCs counterpart. After the completion of anti-leukemic therapy, cytogenetic aberration was no longer detectable in one patient. Unexpectedly, BM-MSCs from three patients receiving TBI-based allogeneic transplantation acquired new, clonal cytogenetic abnormalities after transplantation. Similarly, complex cytogenetic abnormalities were found in all the three BM-MSCs exposed to in vitro irradiation. In conclusion, anti-leukemic treatments induce not only "cytogenetic remission" but also new cytogenetic abnormalities of BM-MSCs. TBI especially exerts detrimental effect on the chromosomal integrity of BM-MSCs and highlights the equal importance of investigating long-term adverse effect of anti-leukemic therapy on BM-MSCs as opposed to beneficial effect on BM-HCs.

  1. Cupping therapy: An analysis of the effects of suction on skin and the possible influence on human health.

    Science.gov (United States)

    Lowe, Duane T

    2017-11-01

    Cupping therapy is a traditional therapy that has been employed worldwide for thousands of years. Despite a lack of quality clinical studies evaluating the efficacy of cupping therapy, its long history and widespread use throughout the world suggests the commonly claimed health benefits should not be completely discounted as without merit. The goal of this paper is to present the research detailing what is known concerning the effects of suction on skin and underlying tissue, and the reaction of the body to that stimulus. Understanding the literature on the physiological effects of this mechanical force may help elaborate an explanation for the advertised local and systemic effects of cupping therapy. Negative pressure causes stretching of the skin and underlying tissue and dilation of the capillaries. This stimulates an increase in tissue blood flow, eventually leading to capillary rupture and ecchymosis. Macrophages phagocytize the erythrocytes in the extravascular space which stimulates the production of Heme Oxygenase-1 (HO-1) to metabolize the heme. Heme catalysis results in the production of carbon monoxide (CO), biliverdin(BV)/bilirubin(BR) and iron. HO-1, BV, BR, and CO has been shown to have antioxidant, anti-inflammatory, antiproliferative, and neuromodulatory effects in animal and human systems. These substances also stimulate a shift of macrophages to the anti-inflammatory M2 phenotype. There is evidence that the effects are both local and systemic. Besides the mechanical effect of cupping increasing the local blood flow and stretching underlying tissue, activation of the HO-1 system could account for many of cupping therapy's claimed local and systemic health benefits. Published by Elsevier Ltd.

  2. Potential role of herbal remedies in stem cell therapy: proliferation and differentiation of human mesenchymal stromal cells.

    Science.gov (United States)

    Udalamaththa, Vindya Lankika; Jayasinghe, Chanika Dilumi; Udagama, Preethi Vidya

    2016-08-11

    Stem cell therapy has revolutionized modern clinical therapy with the potential of stem cells to differentiate into many different cell types which may help to replace different cell lines of an organism. Innumerous trials are carried out to merge new scientific knowledge and techniques with traditional herbal extracts that may result in less toxic, affordable, and highly available natural alternative therapeutics. Currently, mesenchyamal stromal cell (MSC) lines are treated with individual and mixtures of crude herbal extracts, as well as with purified compounds from herbal extracts, to investigate the mechanisms and effects of these on stem cell growth and differentiation. Human MSCs (hMSCs) possess multilineage, i.e., osteogenic, neurogenic, adipogenic, chondrogenic, and myogenic, differentiation abilities. The proliferative and differentiation properties of hMSCs treated with herbal extracts have shown promise in diseases such as osteoporosis, neurodegenerative disorders, and other tissue degenerative disorders. Well characterized herbal extracts that result in increased rates of tissue regeneration may be used in both stem cell therapy and tissue engineering for replacement therapy, where the use of scaffolds and vesicles with enhanced attaching and proliferative properties could be highly advantageous in the latter. Although the clinical application of herbal extracts is still in progress due to the variability and complexity of bioactive constituents, standardized herbal preparations will strengthen their application in the clinical context. We have critically reviewed the proliferative and differentiation effects of individual herbal extracts on hMSCs mainly derived from bone marrow and elaborated on the plausible underlying mechanisms of action. To be fruitfully used in reparative and regenerative therapy, future directions in this area of study should (i) make use of hMSCs derived from different non-traditional sources, including medical waste material

  3. Social Learning Theory and Behavioral Therapy: Considering Human Behaviors within the Social and Cultural Context of Individuals and Families.

    Science.gov (United States)

    McCullough Chavis, Annie

    2011-01-01

    This article examines theoretical thoughts of social learning theory and behavioral therapy and their influences on human behavior within a social and cultural context. The article utilizes two case illustrations with applications for consumers. It points out the abundance of research studies concerning the effectiveness of social learning theory, and the paucity of research studies regarding effectiveness and evidence-based practices with diverse groups. Providing a social and cultural context in working with diverse groups with reference to social learning theory adds to the literature for more cultural considerations in adapting the theory to women, African Americans, and diverse groups.

  4. em>In vivoem> biological response to extracorporeal shockwave therapy in human tendinopathy

    DEFF Research Database (Denmark)

    Waugh, C. M.; Morrissey, D.; Jones, E.

    2015-01-01

    Extracorporeal shock wave therapy (ESWT) is a non-invasive treatment for chronic tendinopathies, however little is known about the in-vivo biological mechanisms of ESWT. Using microdialysis, we examined the real-time biological response of healthy and pathological tendons to ESWT. A single session...

  5. Combination photodynamic therapy of human breast cancer using salicylic acid and methylene blue

    Science.gov (United States)

    Hosseinzadeh, Reza; Khorsandi, Khatereh; Jahanshiri, Maryam

    2017-09-01

    The objective of this study was to evaluate the effects of combination therapy with methylene blue (MB) assisted photodynamic therapy (PDT) and salicylic acid (SA) as chemo-therapy anticancer agent. The binding of salicylic acid to methylene blue was studied using spectrophotometric method. The results show the 1:2 complex formation between SA and MB. The binding constants and related Gibbs free energies o are obtained (Kb1 = 183.74, Kb2 = 38.13 and ∆ Gb1° = 12.92 kJ·mol- 1, ∆ Gb2° =9.02 kJ·mol- 1). The spectrophotometric results show the improvement in solubilization and reduction prevention for SA and MB in the complex form. These results are in agreements with cellular experiments. The dark toxicity measurements represent the improve efficacy of chemotherapy using combination of SA and MB. The photodynamic therapy results (using red LED as light source (630 nm; power density: 30 mW cm- 2)) show that the cancer cell killing efficiency of MB increases in the combination with SA due to reduction prevention and stabilization of monomeric form of MB.

  6. Detection of lipoatrophy in human immunodeficiency virus-1-infected children treated with highly active antiretroviral therapy.

    NARCIS (Netherlands)

    Hartman, K.; Verweel, G.; Groot, R. de; Hartwig, N.G.

    2006-01-01

    BACKGROUND: Highly active antiretroviral therapy has been associated with lipodystrophy in adults. Much is unknown about its characteristics, especially in children. OBJECTIVE: To obtain an objective case definition of the lipodystrophy syndrome. METHODS: This was a cross-sectional study. One

  7. Neuroplasticity Changes on Human Motor Cortex Induced by Acupuncture Therapy: A Preliminary Study

    Directory of Open Access Journals (Sweden)

    Yi Yang

    2017-01-01

    Full Text Available While neuroplasticity changes measured by transcranial magnetic stimulation have been proved to be highly correlated to motor recovery and have been tested in various forms of interventions, it has not been applied to investigate the neurophysiologic mechanism of acupuncture therapy. The aim of this study is to investigate neuroplasticity changes induced by a single session of acupuncture therapy in healthy adults, regarding the excitability change on bilateral primary motor cortex and interhemispheric inhibition. Ten subjects took a 30-minute acupuncture therapy and the same length relaxing phase in separate days. Transcranial magnetic stimulation measures, including resting motor threshold, amplitudes of motor-evoked potential, and interhemispheric inhibition, were assessed before and 10 minutes after intervention. Acupuncture treatment showed significant changes on potential ampl