#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

The Role of Intestinal Microbiota in the Development and Severity of Chemotherapy-Induced Mucositis


Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis.


Vyšlo v časopise: The Role of Intestinal Microbiota in the Development and Severity of Chemotherapy-Induced Mucositis. PLoS Pathog 6(5): e32767. doi:10.1371/journal.ppat.1000879
Kategorie: Review
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000879

Souhrn

Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis.


Zdroje

1. BellmLA

EpsteinJB

Rose-PedA

MartinP

FuchsHJ

2000 Patient reports of complications of bone marrow transplantation. Support Care Cancer 8 33 39

2. BlijlevensNM

DonnellyJP

De PauwBE

2000 Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplant 25 1269 1278

3. SonisST

2004 The pathobiology of mucositis. Nat Rev Cancer 4 277 284

4. SonisST

OsterG

FuchsH

BellmL

BradfordWZ

2001 Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 19 2201 2205

5. BlijlevensNM

DonnellyJP

DePauwBE

2005 Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients. Bone Marrow Transplant 36 703 707

6. LutgensLC

BlijlevensNM

DeutzNE

DonnellyJP

LambinP

2005 Monitoring myeloablative therapy-induced small bowel toxicity by serum citrulline concentration: a comparison with sugar permeability tests. Cancer 103 191 199

7. CaniPD

BibiloniR

KnaufC

WagetA

NeyrinckAM

2008 Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57 1470 1481

8. FrankDN

St AmandAL

FeldmanRA

BoedekerEC

HarpazN

2007 Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104 13780 13785

9. GosselinkMP

SchoutenWR

van LieshoutLM

HopWC

LamanJD

2004 Eradication of pathogenic bacteria and restoration of normal pouch flora: comparison of metronidazole and ciprofloxacin in the treatment of pouchitis. Dis Colon Rectum 47 1519 1525

10. ManichanhC

VarelaE

MartinezC

AntolinM

LlopisM

2008 The gut microbiota predispose to the pathophysiology of acute postradiotherapy diarrhea. Am J Gastroenterol 103 1754 1761

11. TurnbaughPJ

LeyRE

MahowaldMA

MagriniV

MardisER

2006 An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444 1027 1031

12. EdlundC

NordCE

2000 Effect on the human normal microflora of oral antibiotics for treatment of urinary tract infections. J Antimicrob Chemother 46 Suppl 1 41 48

13. StringerAM

GibsonRJ

BowenJM

LoganRM

AshtonK

2009 Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. Int J Exp Pathol 90 489 499

14. van VlietMJ

TissingWJ

DunCA

MeessenNE

KampsWA

2009 Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut. Clin Infect Dis 49 262 270

15. PowellDW

1981 Barrier function of epithelia. Am J Physiol 241 G275 G288

16. CarioE

2005 Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut 54 1182 1193

17. MedzhitovR

2007 Recognition of microorganisms and activation of the immune response. Nature 449 819 826

18. SartorRB

2008 Microbial influences in inflammatory bowel diseases. Gastroenterology 134 577 594

19. AtumaC

StrugalaV

AllenA

HolmL

2001 The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am J Physiol Gastrointest Liver Physiol 280 G922 G929

20. JohanssonME

PhillipsonM

PeterssonJ

VelcichA

HolmL

2008 The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A 105 15064 15069

21. SwidsinskiA

Loening-BauckeV

TheissigF

EngelhardtH

BengmarkS

2007 Comparative study of the intestinal mucus barrier in normal and inflamed colon. Gut 56 343 350

22. ConstansA

2005 Giving a nod2 the right target. The scientist 19 24 25

23. DoyleSL

O'NeillLA

2006 Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol 72 1102 1113

24. FranchiL

WarnerN

VianiK

NunezG

2009 Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev 227 106 128

25. Rakoff-NahoumS

PaglinoJ

Eslami-VarzanehF

EdbergS

MedzhitovR

2004 Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118 229 241

26. CarioE

GerkenG

PodolskyDK

2004 Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 127 224 238

27. CarioE

2008 Therapeutic impact of toll-like receptors on inflammatory bowel diseases: a multiple-edged sword. Inflamm Bowel Dis 14 411 421

28. ChenJ

RaoJN

ZouT

LiuL

MarasaBS

2007 Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity. Am J Physiol Gastrointest Liver Physiol 293 G568 G576

29. FukataM

MichelsenKS

EriR

ThomasLS

HuB

2005 Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol 288 G1055 G1065

30. RachmilewitzD

KatakuraK

KarmeliF

HayashiT

ReinusC

2004 Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126 520 528

31. Vicente-SuarezI

TakahashiY

ChengF

HornaP

WangHW

2007 Identification of a novel negative role of flagellin in regulating IL-10 production. Eur J Immunol 37 3164 3175

32. Vijay-KumarM

WuH

AitkenJ

KolachalaVL

NeishAS

2007 Activation of toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm Bowel Dis 13 856 864

33. KobayashiKS

ChamaillardM

OguraY

HenegariuO

InoharaN

2005 Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307 731 734

34. WatanabeT

KitaniA

MurrayPJ

WakatsukiY

FussIJ

2006 Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. Immunity 25 473 485

35. HampeJ

CuthbertA

CroucherPJ

MirzaMM

MascherettiS

2001 Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357 1925 1928

36. HugotJP

ChamaillardM

ZoualiH

LesageS

CezardJP

2001 Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411 599 603

37. OguraY

BonenDK

InoharaN

NicolaeDL

ChenFF

2001 A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411 603 606

38. BjorckP

BeilhackA

HermanEI

NegrinRS

EnglemanEG

2008 Plasmacytoid dendritic cells take up opsonized antigen leading to CD4+ and CD8+ T cell activation in vivo. J Immunol 181 3811 3817

39. HapfelmeierS

MullerAJ

StecherB

KaiserP

BarthelM

2008 Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in DeltainvG S. Typhimurium colitis. J Exp Med 205 437 450

40. NiessJH

ReineckerHC

2006 Dendritic cells in the recognition of intestinal microbiota. Cell Microbiol 8 558 564

41. BorodyTJ

WarrenEF

LeisS

SuraceR

AshmanO

2003 Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 37 42 47

42. FrickJS

SchenkK

QuitadamoM

KahlF

KoberleM

2007 Lactobacillus fermentum attenuates the proinflammatory effect of Yersinia enterocolitica on human epithelial cells. Inflamm Bowel Dis 13 83 90

43. KellyD

CampbellJI

KingTP

GrantG

JanssonEA

2004 Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol 5 104 112

44. KhanMA

MaC

KnodlerLA

ValdezY

RosenbergerCM

2006 Toll-like receptor 4 contributes to colitis development but not to host defense during Citrobacter rodentium infection in mice. Infect Immun 74 2522 2536

45. O'HaraAM

O'ReganP

FanningA

O'MahonyC

MacsharryJ

2006 Functional modulation of human intestinal epithelial cell responses by Bifidobacterium infantis and Lactobacillus salivarius. Immunology 118 202 215

46. SokolH

PigneurB

WatterlotL

LakhdariO

Bermudez-HumaranLG

2008 Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105 16731 16736

47. BegAA

2004 ComPPARtmentalizing NF-kappaB in the gut. Nat Immunol 5 14 16

48. MatsumotoM

BennoY

2007 The relationship between microbiota and polyamine concentration in the human intestine: a pilot study. Microbiol Immunol 51 25 35

49. EwaschukJB

DiazH

MeddingsL

DiederichsB

DmytrashA

2008 Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol 295 G1025 G1034

50. BarcenillaA

PrydeSE

MartinJC

DuncanSH

StewartCS

2000 Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl Environ Microbiol 66 1654 1661

51. DuncanSH

HoldGL

HarmsenHJ

StewartCS

FlintHJ

2002 Growth requirements and fermentation products of Fusobacterium prausnitzii, and a proposal to reclassify it as Faecalibacterium prausnitzii gen. nov., comb. nov. Int J Syst Evol Microbiol 52 2141 2146

52. HamerHM

JonkersD

VenemaK

VanhoutvinS

TroostFJ

2008 Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 27 104 119

53. HamerHM

JonkersDM

BastA

VanhoutvinSA

FischerMA

2008 Butyrate modulates oxidative stress in the colonic mucosa of healthy humans. Clin Nutr

54. NanceyS

BienvenuJ

CoffinB

AndreF

DescosL

2002 Butyrate strongly inhibits in vitro stimulated release of cytokines in blood. Dig Dis Sci 47 921 928

55. Di SabatinoA

MoreraR

CiccocioppoR

CazzolaP

GottiS

2005 Oral butyrate for mildly to moderately active Crohn's disease. Aliment Pharmacol Ther 22 789 794

56. HarigJM

SoergelKH

KomorowskiRA

WoodCM

1989 Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 320 23 28

57. RamosMG

BambirraEA

CaraDC

VieiraEC

Alvarez-LeiteJI

1997 Oral administration of short-chain fatty acids reduces the intestinal mucositis caused by treatment with Ara-C in mice fed commercial or elemental diets. Nutr Cancer 28 212 217

58. VenkatramanA

RamakrishnaBS

ShajiRV

KumarNS

PulimoodA

2003 Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF-kappaB. Am J Physiol Gastrointest Liver Physiol 285 G177 G184

59. WangQ

WangXD

JeppssonB

AnderssonR

KarlssonB

1996 Influence of colostomy on in vivo and in vitro permeability of the rat colon. Dis Colon Rectum 39 663 670

60. SamonteVA

GotoM

RavindranathTM

FazalN

HollowayVM

2004 Exacerbation of intestinal permeability in rats after a two-hit injury: burn and Enterococcus faecalis infection. Crit Care Med 32 2267 2273

61. EutameneH

LamineF

ChaboC

TheodorouV

RochatF

2007 Synergy between Lactobacillus paracasei and its bacterial products to counteract stress-induced gut permeability and sensitivity increase in rats. J Nutr 137 1901 1907

62. HeymanM

TerpendK

MenardS

2005 Effects of specific lactic acid bacteria on the intestinal permeability to macromolecules and the inflammatory condition. Acta Paediatr Suppl 94 34 36

63. QinHL

ZhengJJ

TongDN

ChenWX

FanXB

2008 Effect of Lactobacillus plantarum enteral feeding on the gut permeability and septic complications in the patients with acute pancreatitis. Eur J Clin Nutr 62 923 930

64. StratikiZ

CostalosC

SevastiadouS

KastanidouO

SkouroliakouM

2007 The effect of a bifidobacter supplemented bovine milk on intestinal permeability of preterm infants. Early Hum Dev 83 575 579

65. ZengJ

LiYQ

ZuoXL

ZhenYB

YangJ

2008 Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 28 994 1002

66. LiuQ

NobaekS

AdawiD

MaoY

WangM

2001 Administration of Lactobacillus plantarum 299v reduces side-effects of external radiation on colon anastomotic healing in an experimental model. Colorectal Dis 3 245 252

67. QinHL

ShenTY

GaoZG

FanXB

HangXM

2005 Effect of lactobacillus on the gut microflora and barrier function of the rats with abdominal infection. World J Gastroenterol 11 2591 2596

68. MoorthyG

MuraliMR

DevarajSN

2008 Lactobacilli facilitate maintenance of intestinal membrane integrity during Shigella dysenteriae 1 infection in rats. Nutrition

69. AijazS

Sanchez-HerasE

BaldaMS

MatterK

2007 Regulation of tight junction assembly and epithelial morphogenesis by the heat shock protein Apg-2. BMC Cell Biol 8 49

70. ArvansDL

VavrickaSR

RenH

MuschMW

KangL

2005 Luminal bacterial flora determines physiological expression of intestinal epithelial cytoprotective heat shock proteins 25 and 72. Am J Physiol Gastrointest Liver Physiol 288 G696 G704

71. MatsuoK

ZhangX

OnoY

NagatomiR

2009 Acute stress-induced colonic tissue HSP70 expression requires commensal bacterial components and intrinsic glucocorticoid. Brain Behav Immun 23 108 115

72. VenkatramanA

RamakrishnaBS

PulimoodAB

1999 Butyrate hastens restoration of barrier function after thermal and detergent injury to rat distal colon in vitro. Scand J Gastroenterol 34 1087 1092

73. MoncadaDM

KammanadimintiSJ

ChadeeK

2003 Mucin and Toll-like receptors in host defense against intestinal parasites. Trends Parasitol 19 305 311

74. Van der SluisM

De KoningBA

De BruijnAC

VelcichA

MeijerinkJP

2006 Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131 117 129

75. KandoriH

HirayamaK

TakedaM

DoiK

1996 Histochemical, lectin-histochemical and morphometrical characteristics of intestinal goblet cells of germfree and conventional mice. Exp Anim 45 155 160

76. Caballero-FrancoC

KellerK

De SimoneC

ChadeeK

2007 The VSL#3 probiotic formula induces mucin gene expression and secretion in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 292 G315 G322

77. KimY

KimSH

WhangKY

KimYJ

OhS

2008 Inhibition of Escherichia coli O157:H7 attachment by interactions between lactic acid bacteria and intestinal epithelial cells. J Microbiol Biotechnol 18 1278 1285

78. MattarAF

TeitelbaumDH

DrongowskiRA

YongyiF

HarmonCM

2002 Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture model. Pediatr Surg Int 18 586 590

79. BarceloA

ClaustreJ

MoroF

ChayvialleJA

CuberJC

2000 Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut 46 218 224

80. MackDR

AhrneS

HydeL

WeiS

HollingsworthMA

2003 Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro. Gut 52 827 833

81. BourliouxP

KoletzkoB

GuarnerF

BraescoV

2003 The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium “The Intelligent Intestine,” held in Paris, June 14, 2002. Am J Clin Nutr 78 675 683

82. HooperLV

GordonJI

2001 Commensal host-bacterial relationships in the gut. Science 292 1115 1118

83. RollsBA

TurveyA

CoatesME

1978 The influence of the gut microflora and of dietary fibre on epithelial cell migration in the chick intestine. Br J Nutr 39 91 98

84. WebbP

ChananaAD

CronkiteEP

LaissueJA

JoelDD

1980 Comparison of DNA renewal in germ-free and conventional mice using [125I]iododeoxyuridine and [3H]thymidine. Cell Tissue Kinet 13 227 237

85. SavageDC

SiegelJE

SnellenJE

WhittDD

1981 Transit time of epithelial cells in the small intestines of germfree mice and ex-germfree mice associated with indigenous microorganisms. Appl Environ Microbiol 42 996 1001

86. KarraschT

SteinbrecherKA

AllardB

BaldwinAS

JobinC

2006 Wound-induced p38MAPK-dependent histone H3 phosphorylation correlates with increased COX-2 expression in enterocytes. J Cell Physiol 207 809 815

87. YanF

CaoH

CoverTL

WhiteheadR

WashingtonMK

2007 Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132 562 575

88. AyabeT

SatchellDP

WilsonCL

ParksWC

SelstedME

2000 Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 1 113 118

89. CashHL

WhithamCV

BehrendtCL

HooperLV

2006 Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313 1126 1130

90. StroberW

2006 Immunology. Unraveling gut inflammation. Science 313 1052 1054

91. Di GiacintoC

MarinaroM

SanchezM

StroberW

BoirivantM

2005 Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J Immunol 174 3237 3246

92. WangZ

XiaoG

YaoY

GuoS

LuK

2006 The role of bifidobacteria in gut barrier function after thermal injury in rats. J Trauma 61 650 657

93. MullerCA

AutenriethIB

PeschelA

2005 Innate defenses of the intestinal epithelial barrier. Cell Mol Life Sci 62 1297 1307

94. StringerAM

GibsonRJ

LoganRM

BowenJM

YeohAS

2009 Gastrointestinal microflora and mucins may play a critical role in the development of 5-Fluorouracil-induced gastrointestinal mucositis. Exp Biol Med (Maywood) 234 430 441

95. BesselinkMG

van SantvoortHC

BuskensE

BoermeesterMA

van GoorH

2008 Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 371 651 659

96. CannonJP

LeeTA

BolanosJT

DanzigerLH

2005 Pathogenic relevance of Lactobacillus: a retrospective review of over 200 cases. Eur J Clin Microbiol Infect Dis 24 31 40

97. LedouxD

LabombardiVJ

KarterD

2006 Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin's disease. Int J STD AIDS 17 280 282

98. LiongMT

2008 Safety of probiotics: translocation and infection. Nutr Rev 66 192 202

99. KatakuraK

LeeJ

RachmilewitzD

LiG

EckmannL

2005 Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J Clin Invest 115 695 702

100. RachmilewitzD

KarmeliF

TakabayashiK

HayashiT

Leider-TrejoL

2002 Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 122 1428 1441

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2010 Číslo 5
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#