Skip to main content
SpringerLink
Log in

History and Biology of Erythropoietin in Hematopoietic and Non-Neural Tissues

  • Chapter
Erythropoietin and the Nervous System

  • 617 Accesses

Abstract

Erythropoietin (EPO) is a glycoprotein hormone, which is produced in kidney and liver, and is mainly involved in regulating proliferation and maturation of red blood cells. EPO gene expression is induced by hypoxia through the transcription factor hypoxia inducible factor-1, which has been found to be the main regulator of oxygen homeostasis in the body. Suppression of apoptosis is the principle mechanism of action of EPO in maintaining erythropoiesis. It has been recently recognized that EPO is a member of the cytokine type I superfamily and it has multiple effects in organs and tissues different from the hematopoietic system. Recent evidence of EPO as a protective factor in various injury models in the nervous system and heart has raised the possibility that EPO can exert protective effects in many organs in the body. However, whether the mechanism of protective action involves inhibition of apoptosis remains to be seen.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci USA 1990;87:5978–5982

    Article  PubMed  CAS  Google Scholar 

  • Bachmann S, Le Hir M, Eckardt KU. Co-localization of erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin. J Histochem Cytochem. 1993 Mar;41(3):335–41.

    PubMed  CAS  Google Scholar 

  • Bahlmann FH, de Groot K, Haller H, Fliser D. Erythropoietin: is it more than correcting anaemia? Nephrol Dial Transplant. 2004 Jan;19(1):20–2.

    Article  PubMed  CAS  Google Scholar 

  • Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, Sharp FR. Role of hypoxiainducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol. 2000 Sep;48(3):285–96.

    Article  PubMed  CAS  Google Scholar 

  • Bert P. La pression baromètrique. Recherches de physiologie expérimentale. Paris: Masson. 1878

    Google Scholar 

  • Bert P. Sur la richesse en hèmoglobine du sang des animaux vivant sur le hauts lieux. C R Acad Sci Paris. 1882; 94: 805–807

    Google Scholar 

  • Beru N, McDonald J, Lacombe C, Goldwasser E. Expression of the erythropoietin gene. Mol Cell Biol. 1986 Jul;6(7):2571–5.

    PubMed  CAS  Google Scholar 

  • Bonsdorff E and Jalavisto E. A humoral mechanism in anoxic erythrocytosis. Acta Physiol Scand. 1948; 16: 150–170

    Article  CAS  Google Scholar 

  • Broudy VC, Lin N, Brice M, Nakamoto B, Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells. Blood. 1991 Jun 15;77(12):2583–90.

    PubMed  CAS  Google Scholar 

  • Buemi M, Vaccaro M, Sturiale A, Galeano MR, Sansotta C, Cavallari V, Floccari F, D’Amico D, Torre V, Calapai G, Frisina N, Guarneri F, Vermiglio G. Recombinant human erythropoietin influences revascularization and healing in a rat model of random ischaemic flaps. Acta Derm Venereol. 2002;82(6):411–7.

    Article  PubMed  CAS  Google Scholar 

  • Cai Z, Manalo DJ, Wei G, Rodriguez ER, Fox-Talbot K, Lu H, Zweier JL, Semenza GL. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation. 2003 Jul 8;108(1):79–85.

    Article  PubMed  CAS  Google Scholar 

  • Carlini RG, Alonzo EJ, Dominguez J, Blanca I, Weisinger JR, Rothstein M, Bellorin-Font E. Effect of recombinant human erythropoietin on endothelial cell apoptosis. Kidney Int 1999;55:546–553

    Article  PubMed  CAS  Google Scholar 

  • Carlini RG, Reyes AA, Rothstein M. Recombinant human erythropoietin stimulates angiogenesis in vitro Kidney Int 1995; 47:740–745

    CAS  Google Scholar 

  • Carnot P and Deflandre C. Sur l’activité hémopoiétique du serum au cours de la régénération du sang. C R Acad Sci Paris 1906; 143: 384–386

    CAS  Google Scholar 

  • Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11715–20.

    Article  PubMed  CAS  Google Scholar 

  • Dame C, Sola MC, Lim KC, Leach KM, Fandrey J, Ma Y, Knopfle G, Engel JD, Bungert J. Hepatic erythropoietin gene regulation by GATA-4. J Biol Chem. 2004 Jan 23;279(4):2955–61.

    Article  PubMed  CAS  Google Scholar 

  • Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001 Oct 5;107(1):43–54.

    Article  PubMed  CAS  Google Scholar 

  • Erslev AJ. Humoral regulation of red cell production. Blood 1953; 8: 349–357

    PubMed  CAS  Google Scholar 

  • Erslev AJ. In vitro production of erythropoietin by kidneys perfused with a serum-free solution. Blood. 1974 Jul;44(1):77–85

    PubMed  CAS  Google Scholar 

  • Fandrey J, Bunn HF. In vivo and in vitro regulation of erythropoietin mRNA: measurement by competitive polymerase chain reaction. Blood. 1993 Feb 1;81(3):617–23.

    PubMed  CAS  Google Scholar 

  • Fandrey J, Huwiler A, Frede S, Pfeilschifter J, Jelkmann W. Distinct signaling pathways mediate phorbol-ester-induced and cytokine-induced inhibition of erythropoietin gene expression. Eur J Biochem. 1994 Dec 1;226(2):335–40.

    Article  PubMed  CAS  Google Scholar 

  • Fandrey J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am J Physiol Regul Integr Comp Physiol. 2004 Jun;286(6):R977–88.

    PubMed  CAS  Google Scholar 

  • Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood. 1992 Apr 15;79(8):1987–94.

    PubMed  CAS  Google Scholar 

  • Fisher JW, Birdwell BJ. The production of an erythropoietic factor by the in situ perfused kidney. Acta Haematol. 1961;26:224–32.

    Article  PubMed  CAS  Google Scholar 

  • Fried W. The liver as a source of extrarenal erythropoietin production. Blood. 1972 Nov;40(5):671–7

    PubMed  CAS  Google Scholar 

  • Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ. 2004 Jul;11Suppl 1:S37–44.

    Article  PubMed  CAS  Google Scholar 

  • Gordon AS, Cooper GW, Zanjani ED. The kidney and erythropoiesis. Semin Hematol. 1967 Oct;4(4):337–58.

    PubMed  CAS  Google Scholar 

  • Gurney CW, Goldwasser E, Pan C. Studies on erythropoiesis. VI. Erythropoietin in human plasma. J Lab Clin Med. 1957 Oct;50(4):534–42.

    PubMed  CAS  Google Scholar 

  • Heeschen C, Aicher A, Lehmann R, Fichtlscherer S, Vasa M, Urbich C, Mildner-Rihm C, Martin H, Zeiher AM, Dimmeler S. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003 Aug 15;102(4):1340–6.

    Article  PubMed  CAS  Google Scholar 

  • Hellwig-Burgel T, Rutkowski K, Metzen E, Fandrey J, Jelkmann W. Interleukin-lbeta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. Blood. 1999 Sep 1;94(5):1561–7.

    PubMed  CAS  Google Scholar 

  • Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003 Feb 13;348(7):593–600.

    Article  PubMed  Google Scholar 

  • Imagawa S, Yamamoto M, Ueda M, Miura Y. Erythropoietin gene expression by hydrogen peroxide. Int J Hematol. 1996 Oct;64(3—4):189–95.

    Article  PubMed  CAS  Google Scholar 

  • Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIF alpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001 Apr 20;292(5516):464–8.

    PubMed  CAS  Google Scholar 

  • Jacobs K, Shoemaker C, Rudersdorf R, Neill SD, Kaufman RJ, Mufson A, Seehra J, Jones SS, Hewick R, Fritsch EF, Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature. 1985 Feb 28–Mar 6;313(6005):806–10.

    Article  PubMed  CAS  Google Scholar 

  • Jacobson LO, Goldwasser E, Fried W and Plazk L. Role of the kidney in erythropoiesis. Nature 1957; 179: 633–34

    Article  PubMed  CAS  Google Scholar 

  • Jelkmann W and Hellwig-Burge. Biology of erythropoietin. Adv Exp Med Biol. 2001;502:169–87

    PubMed  CAS  Google Scholar 

  • Jelkmann W, Bauer C. Demonstration of high levels of erythropoietin in rat kidneys following hypoxic hypoxia. Pflugers Arch. 1981 Nov;392(1):34–9.

    Article  PubMed  CAS  Google Scholar 

  • Jelkmann W. Erythropoietin. J Endocrinol Invest. 2003 Sep;26(9):832–7.

    PubMed  CAS  Google Scholar 

  • Jelkmann W. Erythropoietin: structure, control of production and function. Physiol Rev. 1992 Apr;72(2):449–89.

    PubMed  CAS  Google Scholar 

  • Juul SE, Yachnis AT, Christensen RD. Tissue distribution of erythropoietin and erythropoietin receptor in the developing human fetus. Early Hum Dev. 1998 Oct;52(3):235–49.

    Article  PubMed  CAS  Google Scholar 

  • Kashii Y, Uchida M, Kirito K, Tanaka M, Nishijima K, Toshima M, Ando T, Koizumi K, Endoh T, Sawada K, Momoi M, Miura Y, Ozawa K, Komatsu N. A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of phosphatidylinositol 3-kinase-Akt activation pathway in erythropoietin signal transduction. Blood. 2000 Aug 1;96(3):941–9.

    PubMed  CAS  Google Scholar 

  • Kawakami M, Sekiguchi M, Sato K, Kozaki S, Takahashi M. Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia. J Biol Chem. 2001 Oct 19;276(42):39469–75.

    Article  PubMed  CAS  Google Scholar 

  • Kieran MW, Perkins AC, Orkin SH, Zon LI. Thrombopoietin rescues in vitro erythroid formation from mouse embryos lacking the erythropoietin receptor. Proc Natl Acad Sci US A 1996; 93:9126–31

    Article  CAS  Google Scholar 

  • Kobayashi T, Yanase H, Iwanaga T, Sasaki R, Nagao M. Epididymis is a novel site of erythropoietin production in mouse reproductive organs. Biochem Biophys Res Commun. 2002 Aug 9;296(1):145–51.

    Article  PubMed  CAS  Google Scholar 

  • Koury ST, Koury MJ, Bondurant MC, Caro J, Graber SE. Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration. Blood. 1989 Aug 1;74(2):645–51.

    PubMed  CAS  Google Scholar 

  • Kuratowska Z, Lewartowski B, Michalak E. Studies on the production of erythropoietin by isolated perfused organs. Blood. 1961 Nov;18:527–34.

    Google Scholar 

  • Leverrier Y, Thomas J, Mathieu AL, Low W, Blanquier B, Marvel J. Role of PI3-kinase in Bcl-X induction and apoptosis inhibition mediated by IL-3 or IGF-1 in Baf-3 cells. Cell Death Differ. 1999 Mar;6(3):290–6.

    Article  PubMed  CAS  Google Scholar 

  • Lin CH, Lim SK, D’Agati VG, Costantini F Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev. 1996 10:154–64

    PubMed  CAS  Google Scholar 

  • Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7580–4.

    Article  PubMed  CAS  Google Scholar 

  • Marti HH, Wenger RH, Rivas LA, Straumann U, Digicaylioglu M, Henn V, Yonekawa Y, Bauer C, Gassmann M. Erythropoietin gene expression in human, monkey and murine brain. Eur JNeurosci. 1996 Apr;8(4):666–76.

    Article  CAS  Google Scholar 

  • Masuda S, Kobayashi T, Chikuma M, Nagao M, Sasaki R. The oviduct produces erythropoietin in an estrogen-and oxygen-dependent manner. Am J Physiol Endocrinol Metab. 2000 Jun;278(6):E1038–44.

    PubMed  CAS  Google Scholar 

  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999 May 20;399(6733):271–5.

    Article  PubMed  CAS  Google Scholar 

  • Miescher F. Über die beziehungen zwischen meereshöhe und beschaffenheit des blutes. Corresp. Bl. Schweiz Aerzte 1893; 23: 809–830

    Google Scholar 

  • Miller CP, Liu ZY, Noguchi CT, Wojchowski DM. A minimal cytoplasmic subdomain of the erythropoietin receptor mediates erythroid and megakaryocytic cell development. Blood. 1999 Nov l5;94(10):3381–7.

    PubMed  CAS  Google Scholar 

  • Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. J Biol Chem. 1977 Aug 10;252(15):5558–64

    PubMed  CAS  Google Scholar 

  • Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience. 1997 Jan;76(1):105–16.

    Article  PubMed  CAS  Google Scholar 

  • Reissmann KR. Studies on the mechanism of erythropoietic stimulation in parabiotic rats during hypoxia. Blood 1950; 5: 372–380

    PubMed  CAS  Google Scholar 

  • Ribatti D, Presta M, Vacca A, Ria R, Giuliani R, Dell’Era P, Nico B, Roncali L, Dammacco F. Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 1999;93:2627–2636

    PubMed  CAS  Google Scholar 

  • Salceda S, Caro J. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem. 1997 Sep 5;272(36):22642–7.

    Article  PubMed  CAS  Google Scholar 

  • Saray A, Ozakpinar R, Koc C, Serel S, Sen Z, Can Z. Effect of chronic and short-term erythropoietin treatment on random flap survival in rats: an experimental study. Laryngoscope. 2003 Jan;113(1):85–9.

    Article  PubMed  CAS  Google Scholar 

  • Schuster SJ, Wilson JH, Erslev AJ, Caro J. Physiologic regulation and tissue localization of renal erythropoietin messenger RNA. Blood. 1987 Jul;70(1):316–8.

    PubMed  CAS  Google Scholar 

  • Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishida A, Fujita Y, Kothari S, Mohle R, Sauvage LR, Moore MA, Storb RF, Hammond WP. Evidence for circulating bone marrow-derived endothelial cells. Blood. 1998 Jul 15;92(2):362–7.

    PubMed  CAS  Google Scholar 

  • Sieff CA, Ekern SC, Nathan DG, Anderson JW. Combinations of recombinant colony-stimulating factors are required for optimal hematopoietic differentiation in serum-deprived culture. Blood. 1989 Feb 15;73(3):688–93.

    PubMed  CAS  Google Scholar 

  • Sieff CA, Emerson SG, Mufson A, Gesner TG, Nathan DG. Dependence of highly enriched human bone marrow progenitors on hemopoietic growth factors and their response to recombinant erythropoietin. J Clin Invest. 1986 Jan;77(1):74–81.

    Article  PubMed  CAS  Google Scholar 

  • Silva M, Benito A, Sanz C, Prosper F, Ekhterae D, Nunez G, Fernandez-Luna JL. Erythropoietin can induce the expression of bcl-x(L) through Stat5 in erythropoietin-dependent progenitor cell lines. J Biol Chem. 1999 Aug 6;274(32):22165–9.

    Article  PubMed  CAS  Google Scholar 

  • Siren AL, Knerlich F, Poser W, Gleiter CH, Bruck W, Ehrenreich H. Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol (Berl). 2001 Mar;101(3):271–6.

    PubMed  CAS  Google Scholar 

  • Socolovsky M, Fallon AE, Wang S, Bragnara C, Lodish HF. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/-mice: a direct role for Stat5 in Bcl-X(L) induction. Cell. 1999 Jul 23;98(2):181–91.

    Article  PubMed  CAS  Google Scholar 

  • Spivak JL, Hogans BB. The in vivo metabolism of recombinant human erythropoietin in the rat. Blood 1989; 73:90–9

    PubMed  CAS  Google Scholar 

  • Spivak JL, Pham T, Isaacs M, Hankins WD. Erythropoietin is both a mitogen and a survival factor. Blood. 1991 Mar 15;77(6):1228–33.

    PubMed  CAS  Google Scholar 

  • Suda T, Suda J, Ogawa M. Disparate differentiation in mouse hemopoietic colonies derived from paired progenitors. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2520–4.

    Article  PubMed  CAS  Google Scholar 

  • Tramontano AF, Muniyappa R, Black AD, Blendea MC, Cohen I, Deng L, Sowers JR, Cutaia MV, El-Sherif N. Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun. 2003 Sep 5;308(4):990–4.

    Article  PubMed  CAS  Google Scholar 

  • Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001 Jul 6;89(1):El–7.

    Google Scholar 

  • Viault F. Sur l’augmentation considerable du nombre des globules rouge dans le sang chez les inhabitants des hauts plateaux de l’Amerique du Sud. C R Acad Sci Paris 1890; 111:917–918

    Google Scholar 

  • Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995 Jun6;92(12):5510–4.

    Article  PubMed  CAS  Google Scholar 

  • Wojchowski DM, Gregory RC, Miller CP, Pandit AK, Pircher TJ. Signal transduction in the erythropoietin receptor system. Exp Cell Res. 1999 Nov 25;253(1): 143–56.

    Article  PubMed  CAS  Google Scholar 

  • Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML. Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development. 1999 Aug; 126(16):3597–605.

    PubMed  CAS  Google Scholar 

  • Yokomizo R, Matsuzaki S, Uehara S, Murakami T, Yaegashi N, Okamura K. Erythropoietin and erythropoietin receptor expression in human endometrium throughout the menstrual cycle. Mol Hum Reprod. 2002 May;8(5):441–6.

    Article  PubMed  CAS  Google Scholar 

  • Zanjani ED, Peterson EN, Gordon AS, Wasserman LR. Erythropoietin production in the fetus: role of the kidney and maternal anemia. J Lab Clin Med. 1974 Feb;83(2):281–7

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Giorgia Melli, Sanjay C. Keswani & Ahmet Höke

Authors
  1. Giorgia Melli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanjay C. Keswani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmet Höke
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. School of Medicine, Johns Hopkins University, USA

    Ahmet Höke M.D., Ph.D. (Associate Professor of Neurology and Neuroscience) (Associate Professor of Neurology and Neuroscience)

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer Science+Business Media, Inc.

About this chapter

Cite this chapter

Melli, G., Keswani, S.C., Höke, A. (2006). History and Biology of Erythropoietin in Hematopoietic and Non-Neural Tissues. In: Höke, A. (eds) Erythropoietin and the Nervous System. Springer, Boston, MA . https://doi.org/10.1007/978-0-387-30011-5_1

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-30011-5_1

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-30010-8

  • Online ISBN: 978-0-387-30011-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation