nach oben

Diabetologia

Erschienen in:

14.12.2018 | Review

Use of human islets to understand islet biology and diabetes: progress, challenges and suggestions

verfasst von: Nathaniel J. Hart, Alvin C. Powers

Erschienen in: Diabetologia | Ausgabe 2/2019

Einloggen, um Zugang zu erhalten

Abstract

Over the last two decades, improved access to human islets and the development of human islet distribution networks have enabled the use of millions of human islets in hundreds of scientific research projects, leading to a dramatic increase in our understanding of human islet biology. Here we discuss recent scientific advances as well as methodological and experimental challenges that impact human islet quality, experimental outcomes and the reporting of human islets used in scientific publications. In a survey of over 200 scientific publications with human islet experimentation, we found that the reporting of critical information was quite variable, sometimes obscure, and often failed to adequately outline the experiments and results using human islets. As the complexity of human islet research grows, we propose that members of the human islet research ecosystem work together to develop procedures and approaches for accessible and transparent collecting and reporting of crucial human islet characteristics and, through this, enhance collaboration, reproducibility and rigour, leading to further advances in our understanding of human islet biology.

Nur mit Berechtigung zugänglich

Kaddis JS, Olack BJ, Sowinski J et al (2009) Human pancreatic islets and diabetes research. JAMA 301(15):1580–1587. https://doi.org/10.1001/jama.2009.482 CrossRefPubMedPubMedCentral

Niland JC, Stiller T, Cravens J et al (2010) Effectiveness of a web-based automated cell distribution system. Cell Transplant 19(9):1133–1142. https://doi.org/10.3727/096368910X505486 CrossRefPubMedPubMedCentral

Kulkarni RN, Stewart AF (2014) Summary of the Keystone islet workshop (April 2014): the increasing demand for human islet availability in diabetes research. Diabetes 63(12):3979–3981. https://doi.org/10.2337/db14-1303 CrossRefPubMedPubMedCentral

Kaddis JS, Danobeitia JS, Niland JC et al (2010) Multicenter analysis of novel and established variables associated with successful human islet isolation outcomes. Am J Transplant 10(3):646–656. https://doi.org/10.1111/j.1600-6143.2009.02962.x CrossRefPubMedPubMedCentral

Kaddis JS, Hanson MS, Cravens J et al (2013) Standardized transportation of human islets: an islet cell resource center study of more than 2,000 shipments. Cell Transplant 22(7):1101–1111. https://doi.org/10.3727/096368912X653219 CrossRefPubMed

Balamurugan AN, Naziruddin B, Lockridge A et al (2014) Islet product characteristics and factors related to successful human islet transplantation from the Collaborative Islet Transplant Registry (CITR) 1999-2010. Am J Transplant 14(11):2595–2606. https://doi.org/10.1111/ajt.12872 CrossRefPubMedPubMedCentral

Hilling DE, Bouwman E, Terpstra OT, Marang-Van De Mheen PJ (2014) Effects of donor-, pancreas-, and isolation-related variables on human islet isolation outcome: a systematic review. Cell Transplant 23(8):921–928. https://doi.org/10.3727/096368913X666412 CrossRefPubMed

Nano R, Clissi B, Melzi R et al (2005) Islet isolation for allotransplantation: variables associated with successful islet yield and graft function. Diabetologia 48(5):906–912. https://doi.org/10.1007/s00125-005-1725-3 CrossRefPubMed

Lyon J, Manning Fox JE, Spigelman AF et al (2016) Research-focused isolation of human islets from donors with and without diabetes at the Alberta Diabetes Institute IsletCore. Endocrinology 157(2):560–569. https://doi.org/10.1210/en.2015-1562 CrossRefPubMed

10.

Shapiro AMJ, Pokrywczynska M, Ricordi C (2016) Clinical pancreatic islet transplantation. Nat Rev Immunol 13:268–277

11.

Ponte GM, Pileggi A, Messinger S et al (2007) Toward maximizing the success rates of human islet isolation: influence of donor and isolation factors. Cell Transplant 16(6):595–607. https://doi.org/10.3727/000000007783465082 CrossRefPubMed

12.

Ricordi C, Goldstein JS, Balamurugan AN et al (2016) National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: manufacture of a complex cellular product at eight processing facilities. Diabetes 65(11):3418–3428. https://doi.org/10.2337/db16-0234 CrossRefPubMedPubMedCentral

13.

Henquin JC (2018) Influence of organ donor attributes and preparation characteristics on the dynamics of insulin secretion in isolated human islets. Physiol Rep 6(5):e13646. https://doi.org/10.14814/phy2.13646 CrossRefPubMedCentral

14.

Kayton NS, Poffenberger G, Henske J et al (2015) Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles. Am J Physiol Endocrinol Metab 308(7):E592–E602. https://doi.org/10.1152/ajpendo.00437.2014 CrossRefPubMedPubMedCentral

15.

Westacott MJ, Farnsworth NL, St Clair JR et al (2017) Age-dependent decline in the coordinated [Ca²⁺] and insulin secretory dynamics in human pancreatic islets. Diabetes 66(9):2436–2445. https://doi.org/10.2337/db17-0137 CrossRefPubMedPubMedCentral

16.

Brissova M, Haliyur R, Saunders D et al (2018) α Cell function and gene expression are compromised in type 1 diabetes. Cell Rep 22(10):2667–2676. https://doi.org/10.1016/j.celrep.2018.02.032 CrossRefPubMed

17.

Hart NJ, Aramandla R, Poffenberger G et al (2018) Cystic fibrosis-related diabetes is caused by islet loss and inflammation. JCI Insight 3(8):e98240. https://doi.org/10.1172/jci.insight.98240 CrossRefPubMedCentral

18.

Babon JAB, DeNicola ME, Blodgett DM et al (2016) Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nat Med 22(12):1482–1487. https://doi.org/10.1038/nm.4203 CrossRefPubMedPubMedCentral

19.

Wang YJ, Golson ML, Schug J et al (2016) Single-cell mass cytometry analysis of the human endocrine pancreas. Cell Metab 24(4):616–626. https://doi.org/10.1016/j.cmet.2016.09.007 CrossRefPubMedPubMedCentral

20.

Wang YJ, Schug J, Won K-J et al (2016) Single-cell transcriptomics of the human endocrine pancreas. Diabetes 65(10):3028–3038. https://doi.org/10.2337/db16-0405 CrossRefPubMedPubMedCentral

21.

Segerstolpe Å, Palasantza A, Eliasson P et al (2016) Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab 24(4):593–607. https://doi.org/10.1016/j.cmet.2016.08.020 CrossRefPubMedPubMedCentral

22.

Michels AW, Landry LG, McDaniel KA et al (2017) Islet-derived CD4 T cells targeting proinsulin in human autoimmune diabetes. Diabetes 66(3):722–734. https://doi.org/10.2337/db16-1025 CrossRefPubMed

23.

Ediger BN, Lim H-W, Juliana C et al (2017) LIM domain-binding 1 maintains the terminally differentiated state of pancreatic β cells. J Clin Invest 127(1):215–229. https://doi.org/10.1172/JCI88016 CrossRefPubMed

24.

Raum JC, Soleimanpour SA, Groff DN et al (2015) Tshz1 regulates pancreatic β-cell maturation. Diabetes 64(8):2905–2914. https://doi.org/10.2337/db14-1443 CrossRefPubMedPubMedCentral

25.

Delong T, Wiles TA, Baker RL et al (2016) Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351(6274):711–714. https://doi.org/10.1126/science.aad2791 CrossRefPubMedPubMedCentral

26.

Sanyoura M, Jacobsen L, Carmody D et al (2018) Pancreatic histopathology of human monogenic diabetes due to causal variants in KCNJ11, HNF1A, GATA6, and LMNA. J Clin Endocrinol Metab 103(1):35–45. https://doi.org/10.1210/jc.2017-01159 CrossRefPubMed

27.

Woodmansey C, McGovern AP, McCullough KA et al (2017) Incidence, demographics, and clinical characteristics of diabetes of the exocrine pancreas (type 3c): a retrospective cohort study. Diabetes Care 40(11):1486–1493. https://doi.org/10.2337/dc17-0542 CrossRefPubMed

28.

Oram RA, Patel K, Hill A et al (2016) A type 1 diabetes genetic risk score can aid discrimination between type 1 and type 2 diabetes in young adults. Diabetes Care 39(3):337–344. https://doi.org/10.2337/dc15-1111 CrossRefPubMed

29.

Farmer A, Fox R (2011) Diagnosis, classification, and treatment of diabetes. BMJ 342:d3319. https://doi.org/10.1136/bmj.d3319 CrossRefPubMed

30.

Haliyur R, Tong X, Sanyoura M et al (2018) Human islets expressing HNF1A variant have defective beta‐cell transcriptional regulatory networks. J Clin Invest. https://doi.org/10.1172/JCI121994

31.

Shepherd M, Shields B, Hammersley S et al (2016) Systematic population screening, using biomarkers and genetic testing, identifies 2.5% of the U.K. pediatric diabetes population with monogenic diabetes. Diabetes Care 39(11):1879–1888. https://doi.org/10.2337/dc16-0645 CrossRefPubMedPubMedCentral

32.

Hope SV, Wienand-Barnett S, Shepherd M et al (2016) Practical Classification Guidelines for Diabetes in patients treated with insulin: a cross-sectional study of the accuracy of diabetes diagnosis. Br J Gen Pract 66(646):e315–e322. https://doi.org/10.3399/bjgp16X684961 CrossRefPubMedPubMedCentral

33.

Brissova M, Fowler MJ, Nicholson WE et al (2005) Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem 53(9):1087–1097. https://doi.org/10.1369/jhc.5C6684.2005 CrossRefPubMed

34.

Cabrera O, Berman DM, Kenyon NS et al (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A 103(7):2334–2339. https://doi.org/10.1073/pnas.0510790103 CrossRefPubMedPubMedCentral

35.

Pan FC, Wright C (2011) Pancreas organogenesis: from bud to plexus to gland. Dev Dyn 240(3):530–565. https://doi.org/10.1002/dvdy.22584 CrossRefPubMed

36.

Gregg BE, Moore PC, Demozay D et al (2012) Formation of a human β-cell population within pancreatic islets is set early in life. J Clin Endocrinol Metab 97(9):3197–3206. https://doi.org/10.1210/jc.2012-1206 CrossRefPubMedPubMedCentral

37.

Steiner DJ, Kim A, Miller K, Hara M (2014) Pancreatic islet plasticity: interspecies comparison of islet architecture and composition. Islets 2:135–145. https://doi.org/10.4161/isl.2.3.11815 CrossRef

38.

Nair G, Hebrok M (2015) Islet formation in mice and men: lessons for the generation of functional insulin-producing β-cells from human pluripotent stem cells. Curr Opin Genet Dev 32:171–180. https://doi.org/10.1016/j.gde.2015.03.004 CrossRefPubMedPubMedCentral

39.

Brissova M, Shostak A, Fligner CL et al (2015) Human islets have fewer blood vessels than mouse islets and the density of islet vascular structures is increased in type 2 diabetes. J Hitsochem Cytochem 63(8):637–645. https://doi.org/10.1369/0022155415573324 CrossRef

40.

Rodriguez-Diaz R, Abdulreda MH, Formoso AL et al (2011) Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab 14(1):45–54. https://doi.org/10.1016/j.cmet.2011.05.008 CrossRefPubMedPubMedCentral

41.

Otonkoski T, Banerjee M, Korsgren O et al (2008) Unique basement membrane structure of human pancreatic islets: implications for beta-cell growth and differentiation. Diabetes Obes Metab 10 Suppl 4:119–127. https://doi.org/10.1111/j.1463-1326.2008.00955.x CrossRefPubMed

42.

Virtanen I, Banerjee M, Palgi J et al (2008) Blood vessels of human islets of Langerhans are surrounded by a double basement membrane. Diabetologia 51(7):1181–1191. https://doi.org/10.1007/s00125-008-0997-9 CrossRefPubMed

43.

Benner C, van der Meulen T, Cacéres E et al (2014) The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15(1):620. https://doi.org/10.1186/1471-2164-15-620 CrossRefPubMedPubMedCentral

44.

Dai C, Brissova M, Hang Y et al (2012) Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets. Diabetologia 55(3):707–718. https://doi.org/10.1007/s00125-011-2369-0 CrossRefPubMed

45.

Arda HE, Li L, Tsai J et al (2016) Age-dependent pancreatic gene regulation reveals mechanisms governing human β cell function. Cell Metab 23(5):909–920. https://doi.org/10.1016/j.cmet.2016.04.002 CrossRefPubMedPubMedCentral

46.

Rorsman P, Braun M (2013) Regulation of insulin secretion in human pancreatic islets. Annu Rev Physiol 75(1):155–179. https://doi.org/10.1146/annurev-physiol-030212-183754 CrossRefPubMed

47.

Henquin JC, Dufrane D, Nenquin M (2006) Nutrient control of insulin secretion in isolated normal human islets. Diabetes 55(12):3470–3477. https://doi.org/10.2337/db06-0868 CrossRefPubMed

48.

Rodriguez-Diaz R, Molano RD, Weitz JR et al (2018) Paracrine interactions within the pancreatic islet determine the glycemic set point. Cell Metab 27(3):549–558.e4. https://doi.org/10.1016/j.cmet.2018.01.015 CrossRefPubMed

49.

Hodson DJ, Mitchell RK, Bellomo EA et al (2013) Lipotoxicity disrupts incretin-regulated human β cell connectivity. J Clin Invest 123(10):4182–4194. https://doi.org/10.1172/JCI68459 CrossRefPubMedPubMedCentral

50.

Johnston NR, Mitchell RK, Haythorne E et al (2016) Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab 24(3):389–401. https://doi.org/10.1016/j.cmet.2016.06.020 CrossRefPubMedPubMedCentral

51.

Bader E, Migliorini A, Gegg M et al (2016) Identification of proliferative and mature β-cells in the islets of Langerhans. Nature 535(7612):430–434. https://doi.org/10.1038/nature18624 CrossRefPubMed

52.

Dorrell C, Schug J, Canaday PS et al (2016) Human islets contain four distinct subtypes of β cells. Nat Commun 7:11756. https://doi.org/10.1038/ncomms11756 CrossRefPubMedPubMedCentral

53.

Gutierrez GD, Gromada J, Sussel L (2017) Heterogeneity of the pancreatic beta cell. Front Genet 8:22. https://doi.org/10.3389/fgene.2017.00022 CrossRefPubMedPubMedCentral

54.

Avrahami D, Wang YJ, Klochendler A et al (2017) β-Cells are not uniform after all - novel insights into molecular heterogeneity of insulin-secreting cells. Diabetes Obes Metab 19(Suppl 1):147–152. https://doi.org/10.1111/dom.13019 CrossRefPubMedPubMedCentral

55.

Eizirik DL, Pipeleers DG, Ling Z et al (1994) Major species differences between humans and rodents in the susceptibility to pancreatic beta-cell injury. Proc Natl Acad Sci U S A 91(20):9253–9256. https://doi.org/10.1073/pnas.91.20.9253 CrossRefPubMedPubMedCentral

56.

Eizirik DL (1996) Beta-cell defence and repair mechanisms in human pancreatic islets. Horm Metab Res 28(06):302–305. https://doi.org/10.1055/s-2007-979799 CrossRefPubMed

57.

Welsh N, Margulis B, Borg LA et al (1995) Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus. Mol Med 1(7):806–820. https://doi.org/10.1007/BF03401895 CrossRefPubMedPubMedCentral

58.

Kawahara DJ, Kenney JS (1991) Species differences in human and rat islet sensitivity to human cytokines. Monoclonal anti-interleukin-1 (IL-1) influences on direct and indirect IL-1-mediated islet effects. Cytokine 3(2):117–124. https://doi.org/10.1016/1043-4666(91)90031-8 CrossRefPubMed

59.

Eizirik DL, Sandler S, Welsh N et al (1994) Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. J Clin Invest 93(5):1968–1974. https://doi.org/10.1172/JCI117188 CrossRefPubMedPubMedCentral

60.

Eizirik DL, Korbutt GS, Hellerström C (1992) Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the beta-cell function. J Clin Invest 90(4):1263–1268. https://doi.org/10.1172/JCI115989 CrossRefPubMedPubMedCentral

61.

Dai C, Kayton NS, Shostak A et al (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest 126(5):1857–1870. https://doi.org/10.1172/JCI83657 CrossRefPubMedPubMedCentral

62.

Westermark P, Andersson A, Westermark GT (2011) Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev 91(3):795–826. https://doi.org/10.1152/physrev.00042.2009 CrossRefPubMed

63.

Thorel F, Népote V, Avril I et al (2010) Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464(7292):1149–1154. https://doi.org/10.1038/nature08894 CrossRefPubMedPubMedCentral

64.

Talchai C, Xuan S, Lin HV et al (2012) Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150(6):1223–1234. https://doi.org/10.1016/j.cell.2012.07.029 CrossRefPubMedPubMedCentral

65.

Spijker HS, Ravelli RBG, Mommaas-Kienhuis AM et al (2013) Conversion of mature human β-cells into glucagon-producing α-cells. Diabetes 62(7):2471–2480. https://doi.org/10.2337/db12-1001 CrossRefPubMedPubMedCentral

66.

Chera S, Baronnier D, Ghila L et al (2014) Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Nature 514(7523):503–507. https://doi.org/10.1038/nature13633 CrossRefPubMedPubMedCentral

67.

Cinti F, Bouchi R, Kim-Muller JY et al (2016) Evidence of β-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab 101(3):1044–1054. https://doi.org/10.1210/jc.2015-2860 CrossRefPubMed

68.

Wang Z, York NW, Nichols CG, Remedi MS (2014) Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab 19(5):872–882. https://doi.org/10.1016/j.cmet.2014.03.010 CrossRefPubMedPubMedCentral

69.

Kulkarni RN, Mizrachi E-B, Ocana AG, Stewart AF (2012) Human β-cell proliferation and intracellular signaling: driving in the dark without a road map. Diabetes 61(9):2205–2213. https://doi.org/10.2337/db12-0018 CrossRefPubMedPubMedCentral

70.

Bernal-Mizrachi E, Kulkarni RN, Scott DK et al (2014) Human β-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map. Diabetes 63(3):819–831. https://doi.org/10.2337/db13-1146 CrossRefPubMedPubMedCentral

71.

Stewart AF (2014) Betatrophin versus bitter-trophin and the elephant in the room: time for a new normal in β-cell regeneration research. Diabetes 63(4):1198–1199. https://doi.org/10.2337/db14-0009 CrossRefPubMedPubMedCentral

72.

Stewart AF, Hussain MA, García-Ocaña A et al (2015) Human β-cell proliferation and intracellular signaling: part 3. Diabetes 64(6):1872–1885. https://doi.org/10.2337/db14-1843 CrossRefPubMedPubMedCentral

73.

Dai C, Hang Y, Shostak A et al (2017) Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. J Clin Invest 127(10):3835–3844. https://doi.org/10.1172/JCI91761 CrossRefPubMedPubMedCentral

74.

Solloway MJ, Madjidi A, Gu C et al (2015) Glucagon couples hepatic amino acid catabolism to mTOR-dependent regulation of α-cell mass. Cell Rep 12(3):495–510. https://doi.org/10.1016/j.celrep.2015.06.034 CrossRefPubMed

75.

Dean ED, Li M, Prasad N et al (2017) Interrupted glucagon signaling reveals hepatic α cell axis and role for l-glutamine in α cell proliferation. Cell Metab 25(6):1362–1373.e5. https://doi.org/10.1016/j.cmet.2017.05.011 CrossRefPubMedPubMedCentral

76.

Dean ED, Unger RH, Holland WL (2017) Glucagon antagonism in islet cell proliferation. Proc Natl Acad Sci U S A 114(12):3006–3008. https://doi.org/10.1073/pnas.1700468114 CrossRefPubMedPubMedCentral

77.

Kim J, Okamoto H, Huang Z et al (2017) Amino acid transporter Slc38a5 controls glucagon receptor inhibition-induced pancreatic α cell hyperplasia in mice. Cell Metab 25(6):1348–1361. https://doi.org/10.1016/j.cmet.2017.05.006 CrossRefPubMed

78.

Poitout V, Satin LS, Kahn SE et al (2018) A call for improved reporting of human islet characteristics in research articles. Diabetologia. https://doi.org/10.1007/00125-018-4784-y

Titel: Use of human islets to understand islet biology and diabetes: progress, challenges and suggestions
verfasst von: Nathaniel J. Hart
Alvin C. Powers
Publikationsdatum: 14.12.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 2/2019
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-018-4772-2

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

19.04.2024 | Vorhofflimmern | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Use of human islets to understand islet biology and diabetes: progress, challenges and suggestions

Abstract

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Update Innere Medizin

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2019

Increased NEFA levels reduce blood Mg2+ in hypertriacylglycerolaemic states via direct binding of NEFA to Mg2+

A call for improved reporting of human islet characteristics in research articles

Non-alcoholic fatty liver disease in the first trimester and subsequent development of gestational diabetes mellitus

Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

Afternoon exercise is more efficacious than morning exercise at improving blood glucose levels in individuals with type 2 diabetes: a randomised crossover trial

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Update Innere Medizin