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Maternal diet modulates placental nutrient transporter gene expression in a mouse model of diabetic pregnancy


Autoři: Claudia Kappen aff001;  Claudia Kruger aff001;  Sydney Jones aff002;  Nils J. Herion aff001;  J. Michael Salbaum aff002
Působiště autorů: Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America aff001;  Baton Rouge, Louisiana, United States of America Regulation of Gene Expression Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224754

Souhrn

Diabetes in the mother during pregnancy is a risk factor for birth defects and perinatal complications and can affect long-term health of the offspring through developmental programming of susceptibility to metabolic disease. We previously showed that Streptozotocin-induced maternal diabetes in mice is associated with altered cell differentiation and with smaller size of the placenta. Placental size and fetal size were affected by maternal diet in this model, and maternal diet also modulated the risk for neural tube defects. In the present study, we sought to determine the extent to which these effects might be mediated through altered expression of nutrient transporters, specifically glucose and fatty acid transporters in the placenta. Our results demonstrate that expression of several transporters is modulated by both maternal diet and maternal diabetes. Diet was revealed as the more prominent determinant of nutrient transporter expression levels, even in pregnancies with uncontrolled diabetes, consistent with the role of diet in placental and fetal growth. Notably, the largest changes in nutrient transporter expression levels were detected around midgestation time points when the placenta is being formed. These findings place the critical time period for susceptibility to diet exposures earlier than previously appreciated, implying that mechanisms underlying developmental programming can act on placenta formation.

Klíčová slova:

Diet – Fatty acids – Gene expression – Mouse models – Nutrients – placenta – Pregnancy


Zdroje

1. Rijpert M, Evers IM, de Vroede MA, de Valk HW, Heijnen CJ, Visser GH. Risk factors for childhood overweight in offspring of type 1 diabetic women with adequate glycemic control during pregnancy: Nationwide follow-up study in the Netherlands. Diabetes Care. 2009;32: 2099–2104. doi: 10.2337/dc09-0652 19651922

2. Vlachova Z, Bytoft B, Knorr S, Clausen TD, Jensen RB, Mathiesen ER, et al. Increased metabolic risk in adolescent offspring of mothers with type 1 diabetes: the EPICOM study. Diabetologia. 2015;58: 1454–1463. doi: 10.1007/s00125-015-3589-5 25924986

3. Catalano PM, Hauguel-De Mouzon S. Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? Am J Obstet Gynecol. 2011;204: 479–487. doi: 10.1016/j.ajog.2010.11.039 21288502

4. Plagemann A, Harder T, Kohlhoff R, Rohde W, Dorner G. Overweight and obesity in infants of mothers with long-term insulin-dependent diabetes or gestational diabetes. Int J Obes Relat Metab Disord. 1997;21: 451–456. doi: 10.1038/sj.ijo.0800429 9192228

5. Bozkurt L, Gobl CS, Rami-Merhar B, Winhofer Y, Baumgartner-Parzer S, Schober E, et al. The cross-link between adipokines, insulin resistance and obesity in offspring of piabetic Pregnancies. Horm Res Paediatr. 2016;86: 300–308. doi: 10.1159/000448076 27657553

6. Dimasuay KG, Boeuf P, Powell TL, Jansson T. Placental responses to mhanges in the maternal environment determine fetal growth. Front Physiol. 2016;7: 12. doi: 10.3389/fphys.2016.00012 26858656

7. Burton GJ, Fowden AL, Thornburg KL. Placental origins of chronic disease. Physiol Rev. 2016;96: 1509–1565. doi: 10.1152/physrev.00029.2015 27604528

8. Jansson T. Placenta plays a critical role in maternal-fetal resource allocation. Proc Natl Acad Sci USA. 2016;113: 11066–11068. doi: 10.1073/pnas.1613437113 27660237

9. Kappen C, Kruger C, MacGowan J, Salbaum JM. Maternal diet modulates placenta growth and gene expression in a mouse model of diabetic pregnancy. PLoS One. 2012;7: e38445. doi: 10.1371/journal.pone.0038445 22701643

10. Kappen C, Kruger C, MacGowan J, Salbaum JM. Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancy. Reprod Toxicol. 2011;31: 41–49. doi: 10.1016/j.reprotox.2010.09.002 20868740

11. Salbaum JM, Kruger C, Zhang X, Delahaye NA, Pavlinkova G, Burk DH, Kappen C. Altered gene expression and spongiotrophoblast differentiation in placenta from a mouse model of diabetes in pregnancy. Diabetologia. 2011;54: 1909–1920. doi: 10.1007/s00125-011-2132-6 21491160

12. Konno T, Rempel LA, Rumi MA, Graham AR, Asanoma K, Renaud SJ, et al. Chromosome-substituted rat strains provide insights into the genetics of placentation. Physiol Genomics. 2011;43: 930–941. doi: 10.1152/physiolgenomics.00069.2011 21652768

13. Dauber A, Munoz-Calvo MT, Barrios V, Domene HM, Kloverpris S, Serra-Juhe C, et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med. 2016;8: 363–374. doi: 10.15252/emmm.201506106 26902202

14. Conover CA, Boldt HB, Bale LK, Clifton KB, Grell JA, Mader JR, et al. Pregnancy-associated plasma protein-A2 (PAPP-A2): tissue expression and biological consequences of gene knockout in mice. Endocrinology. 2011;152: 2837–2844. doi: 10.1210/en.2011-0036 21586553

15. Christians JK, de Zwaan DR, Fung SH. Pregnancy associated plasma protein A2 (PAPP-A2) affects bone size and shape and contributes to natural variation in postnatal growth in mice. PLoS One. 2013;8: e56260. doi: 10.1371/journal.pone.0056260 23457539

16. Vaughan OR, Rosario FJ, Powell TL, Jansson T. Regulation of placental amino acid transport and fetal growth. Prog Mol Biol Transl Sci. 2017;145: 217–251. doi: 10.1016/bs.pmbts.2016.12.008 28110752

17. Ericsson A, Saljo K, Sjostrand E, Jansson N, Prasad PD, Powell TL, et al. Brief hyperglycaemia in the early pregnant rat increases fetal weight at term by stimulating placental growth and affecting placental nutrient transport. J Physiol. 2007;581: 1323–1332. doi: 10.1113/jphysiol.2007.131185 17430988

18. Jansson T, Ekstrand Y, Bjorn C, Wennergren M, Powell TL. Alterations in the activity of placental amino acid transporters in pregnancies complicated by diabetes. Diabetes. 2002;51: 2214–2219. doi: 10.2337/diabetes.51.7.2214 12086952

19. Kuruvilla AG, D'Souza SW, Glazier JD, Mahendran D, Maresh MJ, Sibley CP. Altered activity of the system A amino acid transporter in microvillous membrane vesicles from placentas of macrosomic babies born to diabetic women. J Clin Invest. 1994;94:689–695. doi: 10.1172/JCI117386 8040323

20. Pavlinkova G, Salbaum JM, Kappen C. Maternal diabetes alters transcriptional programs in the developing embryo. BMC Genomics. 2009;10: 274. doi: 10.1186/1471-2164-10-274 19538749

21. Kruger C, Kappen C. Expression of cartilage developmental genes in Hoxc8- and Hoxd4-transgenic mice. PLoS One. 2010;5: e8978. doi: 10.1371/journal.pone.0008978 20126390

22. Boileau P, Mrejen C, Girard J, Hauguel-de Mouzon S. Overexpression of GLUT3 placental glucose transporter in diabetic rats. J Clin Invest. 1995;96: 309–317. doi: 10.1172/JCI118036 7615800

23. Das UG, Sadiq HF, Soares MJ, Hay WW Jr., Devaskar SU. Time-dependent physiological regulation of rodent and ovine placental glucose transporter (GLUT-1) protein. Am J Physiol. 1998;274: R339–347. doi: 10.1152/ajpregu.1998.274.2.R339 9486290

24. Korgun ET, Acar N, Sati L, Kipmen-Korgun D, Ozen A, Unek G, et al. Expression of glucocorticoid receptor and glucose transporter-1 during placental development in the diabetic rat. Folia Histochem Cytobiol. 2011;49: 325–334. doi: 10.5603/fhc.2011.0045 21744335

25. Ogura K, Sakata M, Yamaguchi M, Kurachi H, Murata Y. High concentration of glucose decreases glucose transporter-1 expression in mouse placenta in vitro and in vivo. J Endocrinol. 1999;160: 443–452. doi: 10.1677/joe.0.1600443 10076190

26. Devaskar SU, Devaskar UP, Schroeder RE, deMello D, Fiedorek FT Jr., Mueckler M. Expression of genes involved in placental glucose uptake and transport in the nonobese diabetic mouse pregnancy. Am J Obstet Gynecol. 1994;171: 1316–1323. doi: 10.1016/0002-9378(94)90154-6 7977540

27. Stanirowski PJ, Szukiewicz D, Pyzlak M, Abdalla N, Sawicki W, Cendrowski K. Impact of pre-gestational and gestational diabetes mellitus on the expression of glucose transporters GLUT-1, GLUT-4 and GLUT-9 in human term placenta. Endocrine. 2017;55: 799–808. doi: 10.1007/s12020-016-1202-4 27981520

28. Jansson T, Wennergren M, Powell TL. Placental glucose transport and GLUT 1 expression in insulin-dependent diabetes. Am J Obstet Gynecol. 1999;180: 163–168. doi: 10.1016/s0002-9378(99)70169-9 9914598

29. Gaither K, Quraishi AN, Illsley NP. Diabetes alters the expression and activity of the human placental GLUT1 glucose transporter. J Clin Endocrinol Metab. 1999;84: 695–701. doi: 10.1210/jcem.84.2.5438 10022440

30. Sakata M, Kurachi H, Imai T, Tadokoro C, Yamaguchi M, Yoshimoto Y, et al. Increase in human placental glucose transporter-1 during pregnancy. Eur J Endocrinol. 1995;132: 206–212. doi: 10.1530/eje.0.1320206 7858740

31. Currie MJ, Bassett NS, Gluckman PD. Ovine glucose transporter-1 and -3: cDNA partial sequences and developmental gene expression in the placenta. Placenta. 1997;18: 393–401. doi: 10.1016/s0143-4004(97)80039-2 9250701

32. Ehrhardt RA, Bell AW. Developmental increases in glucose transporter concentration in the sheep placenta. Am J Physiol. 1997;273: R1132–1141. doi: 10.1152/ajpregu.1997.273.3.R1132 9321896

33. Yamaguchi M, Sakata M, Ogura K, Miyake A. Gestational changes of glucose transporter gene expression in the mouse placenta and decidua. J Endocrinol Invest. 1996;19: 567–569. doi: 10.1007/BF03349018 8905482

34. Ishida M, Ohashi S, Kizaki Y, Naito J, Horiguchi K, Harigaya T. Expression profiling of mouse placental lactogen II and its correlative genes using a cDNA microarray analysis in the developmental mouse placenta. J Reprod Dev. 2007;53: 69–76. doi: 10.1262/jrd.18002 17062983

35. Sciullo E, Cardellini G, Baroni MG, Torresi P, Buongiorno A, Pozzilli P, et al. Glucose transporter (Glut1, Glut3) mRNA in human placenta of diabetic and non-diabetic pregnancies. Early Pregnancy. 1997;3: 172–182. 10086067

36. Ganguly A, Touma M, Thamotharan S, De Vivo DC, Devaskar SU. Maternal calorie restriction causing uteroplacental insufficiency differentially affects mammalian placental glucose and leucine transport molecular mechanisms. Endocrinology. 2016;157: 4041–4054. doi: 10.1210/en.2016-1259 27494059

37. Lesage J, Hahn D, Leonhardt M, Blondeau B, Breant B, Dupouy JP. Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels. J Endocrinol. 2002;174: 37–43. doi: 10.1677/joe.0.1740037 12098661

38. Ganguly A, McKnight RA, Raychaudhuri S, Shin BC, Ma Z, Moley K, et al. Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction. Am J Physiol Endocrinol Metab. 2007;292: E1241–1255. doi: 10.1152/ajpendo.00344.2006 17213475

39. Schmidt S, Hommel A, Gawlik V, Augustin R, Junicke N, Florian S, et al. Essential role of glucose transporter GLUT3 for post-implantation embryonic development. J Endocrinol. 2009;200: 23–33. doi: 10.1677/JOE-08-0262 18948350

40. Zohn IE, Sarkar AA. The visceral yolk sac endoderm provides for absorption of nutrients to the embryo during neurulation. Birth Defects Res A Clin Mol Teratol. 2010;88: 593–600. doi: 10.1002/bdra.20705 20672346

41. Constancia M, Angiolini E, Sandovici I, Smith P, Smith R, Kelsey G, et al. Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems. Proc Natl Acad Sci USA. 2005;102: 19219–19224. doi: 10.1073/pnas.0504468103 16365304

42. Hahn T, Desoye G. Ontogeny of glucose transport systems in the placenta and its progenitor tissues. Early Pregnancy. 1996;2: 168–182. 9363214

43. Xing AY, Challier JC, Lepercq J, Cauzac M, Charron MJ, Girard J, et al. Unexpected expression of glucose transporter 4 in villous stromal cells of human placenta. J Clin Endocrinol Metab. 1998;83: 4097–4101. doi: 10.1210/jcem.83.11.5290 9814498

44. Ericsson A, Hamark B, Powell TL, Jansson T. Glucose transporter isoform 4 is expressed in the syncytiotrophoblast of first trimester human placenta. Hum Reprod. 2005;20: 521–530. doi: 10.1093/humrep/deh596 15528266

45. Kevorkova O, Ethier-Chiasson M, Lafond J. Differential expression of glucose transporters in rabbit placenta: effect of hypercholesterolemia in dams. Biol Reprod. 2007;76:487–495. doi: 10.1095/biolreprod.106.055285 17135483

46. Lucy MC, Green JC, Meyer JP, Williams AM, Newsom EM, Keisler DH. Short communication: glucose and fructose concentrations and expression of glucose transporters in 4- to 6-week pregnancies collected from Holstein cows that were either lactating or not lactating. J Dairy Sci. 2012;95: 5095–5101. doi: 10.3168/jds.2012-5456 22916914

47. Wali JA, de Boo HA, Derraik JG, Phua HH, Oliver MH, Bloomfield FH, et al. Weekly intra-amniotic IGF-1 treatment increases growth of growth-restricted ovine fetuses and up-regulates placental amino acid transporters. PLoS One. 2012;7: e37899. doi: 10.1371/journal.pone.0037899 22629469

48. Mairesse J, Lesage J, Breton C, Breant B, Hahn T, Darnaudery M, et al. Maternal stress alters endocrine function of the feto-placental unit in rats. Am J Physiol Endocrinol Metab. 2007;292: E1526–1533. doi: 10.1152/ajpendo.00574.2006 17264224

49. Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ. Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature. 1995;377: 151–155. doi: 10.1038/377151a0 7675081

50. Korgun ET, Demir R, Hammer A, Dohr G, Desoye G, Skofitsch G, et al. Glucose transporter expression in rat embryo and uterus during decidualization, implantation, and early postimplantation. Biol Reprod. 2001;65: 1364–1370. doi: 10.1095/biolreprod65.5.1364 11673251

51. Barone S, Fussell SL, Singh AK, Lucas F, Xu J, Kim C, et al. Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension. J Biol Chem. 2009;284: 5056–5066. doi: 10.1074/jbc.M808128200 19091748

52. Limesand SW, Regnault TR, Hay WW Jr. Characterization of glucose transporter 8 (GLUT8) in the ovine placenta of normal and growth restricted fetuses. Placenta. 2004;25: 70–77. doi: 10.1016/j.placenta.2003.08.012 15013641

53. Vaughan OR, Davies KL, Ward JW, de Blasio MJ, Fowden AL. A physiological increase in maternal cortisol alters uteroplacental metabolism in the pregnant ewe. J Physiol. 2016;594: 6407–6418. doi: 10.1113/JP272301 27292274

54. Janzen C, Lei MYY, Jeong ISD, Ganguly A, Sullivan P, Paharkova V, et al. Humanin (HN) and glucose transporter 8 (GLUT8) in pregnancies complicated by intrauterine growth restriction. PLoS One. 2018;13: e0193583. doi: 10.1371/journal.pone.0193583 29590129

55. Adastra KL, Frolova AI, Chi MM, Cusumano D, Bade M, Carayannopoulos MO, et al. Slc2a8 deficiency in mice results in reproductive and growth impairments. Biol Reprod. 2012;87: 49. doi: 10.1095/biolreprod.111.097675 22649075

56. Membrez M, Hummler E, Beermann F, Haefliger JA, Savioz R, Pedrazzini T, et al. GLUT8 is dispensable for embryonic development but influences hippocampal neurogenesis and heart function. Mol Cell Biol. 2006;26: 4268–4276. doi: 10.1128/MCB.00081-06 16705176

57. Gawlik V, Schmidt S, Scheepers A, Wennemuth G, Augustin R, Aumuller G, et al. Targeted disruption of Slc2a8 (GLUT8) reduces motility and mitochondrial potential of spermatozoa. Mol Membr Biol. 2008;25: 224–235. doi: 10.1080/09687680701855405 18428038

58. DeBosch BJ, Chi M, Moley KH. Glucose transporter 8 (GLUT8) regulates enterocyte fructose transport and global mammalian fructose utilization. Endocrinology. 2012;153: 4181–4191. doi: 10.1210/en.2012-1541 22822162

59. Acosta O, Ramirez VI, Lager S, Gaccioli F, Dudley DJ, Powell TL, et al. Increased glucose and placental GLUT-1 in large infants of obese nondiabetic mothers. Am J Obstet Gynecol. 2015;212: 227 e1–7.

60. Augustin R, Carayannopoulos MO, Dowd LO, Phay JE, Moley JF, Moley KH. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking. J Biol Chem. 2004;279:16229–16236. doi: 10.1074/jbc.M312226200 14739288

61. Keembiyehetty C, Augustin R, Carayannopoulos MO, Steer S, Manolescu A, Cheeseman CI, et al. Mouse glucose transporter 9 splice variants are expressed in adult liver and kidney and are up-regulated in diabetes. Mol Endocrinol. 2006;20: 686–697. doi: 10.1210/me.2005-0010 16293642

62. Preitner F, Bonny O, Laverriere A, Rotman S, Firsov D, Da Costa A, et al. Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy. Proc Natl Acad Sci USA. 2009;106: 15501–15516. doi: 10.1073/pnas.0904411106 19706426

63. Dawson PA, Mychaleckyj JC, Fossey SC, Mihic SJ, Craddock AL, Bowden DW. Sequence and functional analysis of GLUT10: a glucose transporter in the Type 2 diabetes-linked region of chromosome 20q12-13.1. Mol Genet Metab. 2001;74: 186–199. doi: 10.1006/mgme.2001.3212 11592815

64. Novakovic B, Gordon L, Robinson WP, Desoye G, Saffery R. Glucose as a fetal nutrient: dynamic regulation of several glucose transporter genes by DNA methylation in the human placenta across gestation. J Nutr Biochem. 2013;24: 282–288. doi: 10.1016/j.jnutbio.2012.06.006 22901689

65. Kuhnel E, Kleff V, Stojanovska V, Kaiser S, Waldschutz R, Herse F, et al. Placental-specific overexpression of sFlt-1 alters trophoblast differentiation and nutrient transporter expression in an IUGR mouse model. J Cell Biochem. 2017;118: 1316–1329. doi: 10.1002/jcb.25789 27859593

66. Qiao L, Guo Z, Bosco C, Guidotti S, Wang Y, Wang M, et al. Maternal high-fat feeding increases placental lipoprotein lipase activity by reducing SIRT1 expression in mice. Diabetes. 2015;64: 3111–3120. Epub 2015/05/08. doi: 10.2337/db14-1627 25948680

67. Diaz P, Harris J, Rosario FJ, Powell TL, Jansson T. Increased placental fatty acid transporter 6 and binding protein 3 expression and fetal liver lipid accumulation in a mouse model of obesity in pregnancy. Am J Physiol Regul Integr Comp Physiol. 2015;309: R1569–1577. doi: 10.1152/ajpregu.00385.2015 26491104

68. Chassen SS, Ferchaud-Roucher V, Gupta MB, Jansson T, Powell TL. Alterations in placental long chain polyunsaturated fatty acid metabolism in human intrauterine growth restriction. Clin Sci. 2018;132: 595–607. doi: 10.1042/CS20171340 29463583

69. Segura MT, Demmelmair H, Krauss-Etschmann S, Nathan P, Dehmel S, Padilla MC, et al. Maternal BMI and gestational diabetes alter placental lipid transporters and fatty acid composition. Placenta. 2017;57: 144–151. doi: 10.1016/j.placenta.2017.07.001 28864004

70. Dube E, Gravel A, Martin C, Desparois G, Moussa I, Ethier-Chiasson M, et al. Modulation of fatty acid transport and metabolism by maternal obesity in the human full-term placenta. Biol Reprod. 2012;87: 14, 1–1. doi: 10.1095/biolreprod.111.098095 22553224

71. Ma Y, Zhu MJ, Uthlaut AB, Nijland MJ, Nathanielsz PW, Hess BW, et al. Upregulation of growth signaling and nutrient transporters in cotyledons of early to mid-gestational nutrient restricted ewes. Placenta. 2011;32: 255–263. doi: 10.1016/j.placenta.2011.01.007 21292322

72. Zhu MJ, Ma Y, Long NM, Du M, Ford SP. Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe. Am J Physiol Regul Integr Comp Physiol. 2010;299: R1224–1231. doi: 10.1152/ajpregu.00309.2010 20844260

73. Ye K, Li L, Zhang D, Li Y, Wang HQ, Lai HL, et al. Effect of maternal obesity on fetal growth and expression of placental fatty acid transporters. J Clin Res Pediatr Endocrinol. 2017;9: 300–307. doi: 10.4274/jcrpe.4510 28588000

74. Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. 2006;142C: 77–85. doi: 10.1002/ajmg.c.30087 16602102

75. Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med. 2004;25: 495–520. doi: 10.1016/j.mam.2004.06.004 15363638

76. Oey NA, den Boer ME, Ruiter JP, Wanders RJ, Duran M, Waterham HR, et al. High activity of fatty acid oxidation enzymes in human placenta: implications for fetal-maternal disease. J Inherit Metab Dis. 2003;26: 385–392. doi: 10.1023/a:1025163204165 12971426

77. Sferruzzi-Perri AN, Camm EJ. The programming power of the placenta. Front Physiol. 2016;7: 33. doi: 10.3389/fphys.2016.00033 27014074

78. Gaccioli F, Lager S, Powell TL, Jansson T. Placental transport in response to altered maternal nutrition. J Dev Orig Health Dis. 2013;4: 101–115. doi: 10.1017/S2040174412000529 25054676


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